Journal articles: 'B 20.5 UL 2011'

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Alvarado, Yesid, Michael J. Keating, Susan O'Brien, Hagop M. Kantarjian, William G. Wierda, Troy Sneed, Nitin Jain, and Guillermo Garcia-Manero. "Azacytidine and Vorinostat in Patients with Chronic Lymphocytic Leukemia (CLL) Diagnosed with Therapy-Related Myelodysplastic Syndromes/Acute Myeloid Leukemia (t-MDS/AML)." Blood 124, no. 21 (December 6, 2014): 5627. http://dx.doi.org/10.1182/blood.v124.21.5627.5627.

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Abstract Background: There is evidence of a leukemogenic effect of purine analogues, mainly when combined with DNA-damaging agents. Various series report an approximately 5% rate of t-MDS/AML in patients treated with a fludarabine-based regimen. Patients are generally old, and old age is associated with worse outcomes. To date, there is no established standard therapy recommendation for this group of patients, and results of prospective treatment evaluations are scarce. Aim: To determine the characteristics and treatment outcomes of patients with CLL and t-MDS/AML. Methods: We analyzed a group of 6 patients with newly diagnosed t-MDS/AML who were treated in our institution from September 2011 to July 2014. Patients were enrolled in a phase II trial of azacitidine (75 mg/m2 IV daily x 5 days) in combination with vorinostat (200 mg orally three times daily x 5 days) (Arm A) or azacitidine alone (Arm B), with courses repeated every 3-8 weeks. This trial was designed to uniformly treat patients not eligible for other leukemia protocols due to comorbidities. Results: At baseline, all patients had an underlying diagnosis of CLL that was in remission or minimally active. The median percentage of CLL bone marrow involvement was 10% (range 0-60%), and ALC was 0.9 K/uL (range 0.2-9.79). The median number of prior CLL treatments was 2 (range 0-3). All patients had previously received fludarabine-based regimens. The median time from chemotherapy to t-MDS/AML diagnosis was 10 years (range 4-10). All patients were male, and the median age was 72 years (range 52-72). All patients had 3-line cytopenia, with median WBC 2.3 K/uL (range 0.8-8.9), ANC 0.55 K/uL (range 0-1.22), hemoglobin 9.6 G/DL (range 8.3-10.4), platelets 39 K/uL (range 6-80), and bone marrow blast percentage of 5% (range 1-18%). The karyotype was complex in all patients. Molecular studies showed that 3 patients had TP53 gene mutations. Five patients received treatment in Arm A, and only 1 patient was randomized to Arm B. Patients received a median of 4 cycles (range 2-7) and remained in the study for a median time of 216 days (range 86-329) before progression. None of the patients achieved remission, but stable disease was observed in 5 out of 6 patients. At the time of this analysis, 4 patients are dead and 2 are still alive: one discontinued treatment because of prolonged myelosuppression and is receiving best supportive care, and the other is recovering from cycle number 4 of treatment. The median survival in the group from the time of treatment initiation was 10.1 months and from the time of study discontinuation was 3.1 months. Further therapy was attempted in 3 patients without response. Conclusion: This is a group of patients with poor prognostic features. Azacytidine and vorinostat have been previously reported to be a safe combination (Garcia-Manero et al. ASH 2010, abstract 604) and may constitute a reasonable treatment alternative. Further prospective studies involving larger numbers of patients are required. Abstract 5627. Table 1: Baseline Patient Characteristics. Patient Age WBC K/uL Hb G/DL Plt K/uL BM Blast % CLL BM % Cytogenetic Molecular Prior CLL Treatments Treatment Arm Best Response 1 52 11 9.6 6 18 60 -3,-4,-5q,-6,-7, -7p,-12, +16 TP53 mutation 1.FCR x 62. Rituximab + Lenalidomide A NR 2 74 1 10 41 3 10 -3p,-5q,-7,-15,-17,-19 TP53 mutation 1. FCR x 42. FCR x 53. BR x 2 A SD 3 68 2.2 9.4 27 6 30 +7,-7p,t(7,21) Negative 1. FCR x 62. FCR x 4 B SD 4 73 2.3 9.7 39 6 0 +2,-5q,+8,-17,-18,+19,+20,-Y Negative 1. FCR x 6 A SD 5 71 0.8 8.3 39 4 0 +2,+4,t(5;17),+6,-7,-9, +13, +15,-16,-17,+18,+19,-20,+21 Negative 1. FR x 12. BR x43. MEDI-551 A SD 6 74 2.4 10.4 80 1 10 t(1;3),inv3,-5q,-18 TP53 mutation 1. R-CHOP x 62. BR x 13. FCR x 4 A SD WBC: White blood cells, Hb: hemoglobin, Plt: Platelets, BM: Bone Marrow, CLL: Chronic Lymphocytic Leukemia, F: Fludarabine, C: Cyclophosphamide, R: Rituximab, B: Bendamustine, MEDI-551: anti-CD19 antibody, NR: no response, SD: stable disease. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

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Storek, Jan, Rob Woolson, Paul K. Wallace, Gregory Sempowski, Peter A. McSweeney, Maureen Mayes, Leslie Crofford, Sharon LeClercq, Richard A. Nash, and Keith M. Sullivan. "Low Blood Counts of Memory/Effector CD8 T Cells, Gamma/Delta T Cells, Memory B Cells and Plasmacytoid Dendritic Cells and High Counts of Th2 Cells in Systemic Sclerosis." Blood 118, no. 21 (November 18, 2011): 4917. http://dx.doi.org/10.1182/blood.v118.21.4917.4917.

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Abstract Abstract 4917 Introduction: Systemic sclerosis (SSc) is presumed to result from aberrant activation of autoreactive T cells. However, the exact pathogenesis of SSc is not known. Patients and Methods: To contribute to the understanding of the immunopathology of systemic sclerosis (SSc), we compared blood counts of multiple lymphocyte subsets between 20 adult SSc patients not treated with immunomodulatory drugs and healthy controls. The patients had to fit entry criteria for SCOT trial (Scleroderma – Cyclophosphamide or Transplantation?, www.sclerodermatrial.org), i.e, 1. symptoms for no longer than 5 years (except for Raynaud's phenomenon), 2. diffuse scleroderma, and 3. either moderate lung involvement (forced vital capacity (FVC) or diffusion of carbon monoxide (DLCO) between 45 and 70% predicted) or moderate kidney involvement (history of hypertensive renal crisis, but normal renal function at study entry). Multiparameter flow cytometry was used for the determination of the lymphocyte subset counts. Results: Counts of the following subsets were significantly lower in the patients compared to the controls: total T cells (median 1316 vs 2088/ul, p=0.015), total CD8 T cells (273 vs 580/ul, p<0.001), central memory CD8 T cells (23 vs 87/ul, p<0.001), effector memory CD8 T cells (17 vs 39/ul, p=0.015), effector CD8 T cells (28 vs 68/ul, p=0.001), gamma/delta T cells (31 vs 77/ul, p<0.001), switched (IgM/DàIgG/A isotype switched) memory B cells (6 vs 26/ul, p<0.001), non-switched memory B cells (7 vs 17/ul, p=0.004), and plasmacytoid dendritic cells (2 vs 6/ul, p=0.002). Counts of Th2-biased (producing interleukin-4 upon polyclonal stimulation) CD4 as well as CD8 T cells were significantly higher in the patients compared to the controls (248 vs 139/ul for CD4, p=0.002, and 259 vs 164/ul for CD8, p<0.001). Conclusion: Immunopathology of SSc is complex. Low blood counts of memory/effector CD8 T cells, gamma/delta T cells, memory B cells and plasmacytoid dendritic cells and Th2-biased T cells may play a role in the pathogenesis of SSc. However, cause and effect relations need to be established. Given previous reports of increased numbers of CD8 and gamma/delta T cells in the affected tissues of patients with systemic sclerosis and increased numbers of plasmacytoid dendritic cells in the affected tissues of patients with autoimmune diseases (compared to healthy individuals) (Prescott RJ et al: J Pathol 166 (1992) 255–63, Atamas SP et al: Arthritis Rheum 42 (1999) 1168–78, Giacomelli R et al: Arthritis Rheum 41 (1998) 327–34, Yurovski VV et al: J Immunol 153 (1994) 881–91, Nestle FO et al: J Exp Med 202 (2005) 35–43, Farkas L et al: Am J Pathol 159 (2001) 237–43), it is possible that the low blood counts of CD8 T cells, gamma/delta T cells and plasmacytoid dendritic cells result from redistribution of these cells from blood to affected tissues. Disclosures: No relevant conflicts of interest to declare.

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Roesch, Erin Elizabeth, and Catherine Broome. "Complement Blockade with C1 Esterase Inhibitor in Refractory Immune Thrombocytopenia." Blood 126, no. 23 (December 3, 2015): 2253. http://dx.doi.org/10.1182/blood.v126.23.2253.2253.

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Immune thrombocytopenia (ITP) is an acquired thrombocytopenia due to autoantibody-mediated destruction of platelets. Multiple therapies targeting antibody production, the reticuloendothelial system and platelet production are used to treat ITP, including glucocorticoids, intravenous immune globulin (IVIG), Rituximab, splenectomy and thrombopoietin-receptor agonists. The response to therapy is heterogeneous, supporting the concept that multiple mechanisms are ultimately responsible for thrombocytopenia. In vitro complement fixation assays have shown that serum obtained from 50% of patients with ITP is able to fix complement to the platelet surface. Autoantibodies to platelet surface antigens GPIIb/IIIa and/or GPIb/IX have also been shown to activate complement via the classical pathway. We suspect that complement fixation/activation plays an important role in platelet destruction in ITP. Proposed mechanisms include C3b deposition on the platelet surface leading to opsonization, direct damage to platelets by C5b-9, and a role for complement in the imbalance in T-cell regulator/effector activity. T-cell activity has been proposed to stimulate B-cell production of autoantibodies against platelet surface antigens. C1 esterase inhibitor (C1INH) is a member of the serine protease inhibitor family and interacts with C1 esterase to block activation of the classical pathway of complement activation. Case reports have demonstrated that C1INH can prevent C3-mediated lysis of PNH erythrocytes (DeZern 2014) and attenuate hemolysis in a patient with DAT C3d positive autoimmune hemolytic anemia (Wouters 2013). Based on these data, we hypothesized 1) complement activation/deposition may play an important role in persistent thrombocytopenia in refractory ITP, and 2) blockade of the classical pathway with C1INH may lead to prolonged platelet survival. Two female patients with a history of autoimmune disease (systemic lupus erythematosus (SLE) and Sjogren's) and primary refractory ITP [steroids, IVIG, Rituximab, and Romiplostim (23-38 days)] were treated with C1INH, Berinert 20 units/kg. Within 8 hours of first C1INH dose, platelet count improved significantly in both patients. Given the rapid increase in platelet count, each patient received two additional doses of C1INH. Both patients demonstrated a continued increase in platelet count with no further C1NH therapy. In patient 1, platelet count normalized on day 63 and remains normal without additional therapy 194 days post C1INH treatment. In patient 2, platelet count has risen to 568K 14 days after C1INH administration. These cases clinically illustrate a thought provoking relationship between antigen/antibody complexes, complement activation, and platelet destruction in ITP. We suspect a potential biphasic response to C1INH therapy. We hypothesize immediate inhibition of the classical pathway and subsequent decrease of C3b deposition on platelet surface may be responsible for the acute rise in platelet count, while a reset of T-cell regulatory/effector function via complement blockade may be accountable for the longevity of platelet count increase and normalization seen in our patients. Refractory ITP may involve antibody-mediated complement activation via the classical pathway. The destruction of platelets may be driven by C3b-mediated phagocytosis and/or by C5b-9-mediated membrane damage, as well as by modulation of the immune system and T regulator cell function. In our patients, the commercially available C1INH, Berinert, was well-tolerated and platelet count improvement was noted almost immediately after administration and has appeared to be sustained. Future studies evaluating treatments that target inhibition of the complement pathway may be an effective alternative or adjunctive therapy for refractory immune thrombocytopenia. Table 1. Platelet Counts Baseline Diagnosis Prior to 1st C1NH dose 8 hours post 1st C1NH dose Prior to 2nd C1NH dose 8 hours post 2nd C1NH dose Prior to 3rd C1NH dose Post 3rd C1NH dose 7 days post 1st C1NH dose 10 days post 1st C1NH dose 14 days post 1st C1INH dose Patient 162yo F H/O SLE 160 K/UL 0 K/UL 2 K/UL 12 K/UL 5 K/UL 9 K/UL 15 K/UL 30 K/UL 38 K/UL 105/UL 139K/UL Patient 247yo F H/O Sjogren's Unknown 1 K/UL 4K/UL 8K/UL 9 K/UL 18 K/UL 18 K/UL 25 K/UL 122 K/UL 469 K/UL 568 K/UL Disclosures Off Label Use: Berinert and its use in ITP.. Broome:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.

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Ramadas, Poornima, Jennifer Leibovitch, and Teresa Gentile. "Hemophagocytic Lymphohistiocytosis: A Single Institution Experience." Blood 134, Supplement_1 (November 13, 2019): 4877. http://dx.doi.org/10.1182/blood-2019-127517.

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Background: Hemophagocytic lymphohistiocytosis [HLH], is a rare life-threatening syndrome of excessive immune activation. It can be primary due to genetic predisposition or secondary due to infections, immune disorders or malignancies. With nonspecific clinical presentation, a high index of suspicion is required to make the diagnosis. Prompt treatment of underlying etiology and HLH specific therapy is warranted to prevent adverse clinical outcome. Methods: After IRB approval, we conducted a retrospective chart review of adult patients (pts) ≥ 18 years diagnosed with HLH between January 1st, 2010 and June 30th, 2019. We recorded age at diagnosis, gender, cause of HLH, symptoms, laboratory testing, bone marrow pathology, imaging, treatment and outcome. Results: We found a total of 15 patients in the time interval. Pt age ranged from 22 to 64 years with a median of 46 years. 60% were females and 40% were males. 14 pts had secondary HLH and one pt tested positive for HLH gene mutations. Etiology of HLH was malignancy in 6 (40%), infection in 5 (33%), rheumatological disease in 3 (20%) and cause was unclear in one pt but suspected to be an infection. One pt had prior allogenic stem cell transplant and one pt developed HLH even after completion of treatment for lymphoma. On presentation, 14 (93%) had fever, 6 (40%) had respiratory symptoms, 6 (40%) had neurological symptoms, 2 (13%) had a skin rash, 2 (13%) had bleeding manifestations and 3 (20%) required pressor support. Hemoglobin ranged from 5.5 to 13.3 g/dL on presentation, with median of 10.1 g/dL and 14 (93%) had Hb <9 g/dL. Absolute neutrophil count ranged from 0.3 to 16.94 x 103/uL with median of 2.87x103/uL and decreased to < 1000x103/uL in 11 (73%) and < 500x103/uL in 7 (46%). Platelet counts on presentation ranged from 18 to 244x103/uL with median of 82x103/uL and decreased to <100x103/uL in 14 (93%) and <20x103/uL in 8 (53%). 14 (93%) had bicytopenia. Initial ferritin levels ranged from 1,552 to 2,62,080 ng/ml with median of 5,515 ng/ml and increased to >10,000 ng/ml in 10 (66%) and highest level was 4,57,970 ng/ml. All 15 pts had some degree of hepatic dysfunction and one pt had acute kidney injury. Triglyceride levels were >265 mg/dL in 6 (40%). 10 (66%) had laboratory evidence of disseminated intravascular coagulation (DIC), one pt had clinical DIC. Blood cultures were negative in everyone, except 2 pts who developed infection during the hospital course, one with Candida krusei and the other with methicillin sensitive staphylococcus aureus. Bone marrow biopsy was performed in 14 (93%) and all of them demonstrated hemophagocytosis. 3 (20%) underwent lumbar puncture and 2 had elevated CSF protein. 11 (73%) had immunological testing and all of them had elevated soluble IL-2 receptor alpha (sCD25 or sIL-2R). Of the 3 pts who had HLH genetic testing, one had HLH associated mutations. Organomegaly was noted in 11 (73.3%) (4 had hepatosplenomegaly, 6 had splenomegaly, one had hepatomegaly). 6 (40%) had lung infiltrates. MRI brain was done in 5 (33%) and 2 had patchy hyperintensities. 11 (73.3%) were treated with HLH-94 protocol with etoposide and dexamethasone. One pt had matched unrelated donor Allogenic stem cell transplant. 13 (86.6%) had initial recovery. At the time of data cut off, 10 (66%) were alive. Of the 3 pts who initially recovered, one pt died of relapsed lymphoma, one died of HLH relapse and one developed Clostridium difficile infection with bowel perforation. [Refer to Table 1]. Conclusion: Even though literature suggests that malignancy associated HLH has a worse prognosis, our small series did not suggest that. We also noted that HLH associated with rheumatological diseases leads to a superior outcome if the underlying disease is adequately treated. The most significant finding in our series was a patient with diffuse large B cell lymphoma who was diagnosed to have primary HLH with HLH associated mutations. Typically, primary HLH presents in the first few years of life. This patient case points to the fact that patients with primary HLH can have a late presentation and can also be associated with immunological disorders with a predisposition to malignancy. This finding suggests that all patients diagnosed with HLH should have genetic testing done for HLH associated mutations, as this will impact treatment decisions and these patients will benefit from more intense treatment which may include an allogenic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

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Qiao, Junjing, Dandan Zhao, Le Xuan Truong Nguyen, Herman Wu, Gang Liu, Shanshan Suo, Huafeng Wang, et al. "Spred1 Insufficiency in the Hematopoietic and/or Vascular Compartments of the Bone Marrow (BM) Niche Promotes Aggressive Leukemogenesis in Chronic Myelogenous Leukemia (CML)." Blood 134, Supplement_1 (November 13, 2019): 3791. http://dx.doi.org/10.1182/blood-2019-127616.

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Spred1, a member of the Sprouty family of proteins and a negative regulator of RAS-MAPK signaling, is highly expressed in normal hematopoietic stem cells (HSCs) where it negatively regulates self-renewal activity. Lack of Spred1 function has been associated with aberrant hematopoiesis (Tadokoro, 2018). Spred1 knocked-out (KO) mice fed with high-fat diet develop a myeloproliferative phenotype (Tadokoro, 2018), and lower SPRED1 expression in acute myeloid leukemia associates with a poor outcome (Li, 2015; Olsson, 2014; Pasmant, 2015), suggesting a potential role of this gene as a tumor suppressor in myeloid malignancies. In CML, however, the role of Spred1 has not been fully dissected. Thus, we generated Spred1 KO CML (i.e., Spred1-/-SCLtTA/BCR-ABL) mice by crossing Spred1 KO (a gift from Dr. Yoshimura, Japan) with inducible SCLtTA/BCR-ABL CML mice. Spred1 KO mice showed increased cell cycling of BM long-term HSCs (LTHSCs; Lin-Sca-1+c-kit+Flt3-CD150+CD48-; G0: 62% vs 76%), and increased white blood cell (WBC) counts [14 vs 5.9 k/ul at 12 weeks (w) old, n=15 per group, p<0.0001], as compared to wt mice. Upon B/A induction by tetracycline withdrawal, Spred1-/-SCLtTA/BCR-ABL mice had higher WBC (102.5 vs 12 k/ul at 4 w, n=15 per group, p<0.0001), more pronounced splenomegaly (spleen weight: 0.28g vs 0.19g, n=4 per group, p=0.06) and a significantly shorter survival (median: 39 vs 83 days, n=23 per group, p<0.0001) than Spred1 wt CML mice. In Spred1-/-SCLtTA/BCR-ABL mice, we observed a more rapid expansion of circulating mature myeloid cells (CD11b+Gr-1+ cells: 63% vs 25%, n=8 per group, p<0.01) and a deeper decrease of BM LTHSCs (1,385 vs 2,164 per femur, n=5 per group, p<0.01) and increase of spleen LTHSCs (27330 vs 18546, n=5 per group, p<0.01) at 4 w after B/A induction compared with Spred1 wt CML mice. Further, we found a higher fraction of Spred-/-SCLtTA/BCR-ABL mice (33% vs 10%) developed lymph node enlargement, with infiltration with pro-B lymphoblastic cells (B220+CD43+CD19+IgM−) compared with Spred1 wt CML mice. Altogether these features suggested that Spred1 insufficiency accelerates CML development and evolution to more aggressive phases of the disease. Since upregulation of Spred1 reportedly disrupts vascular integrity (Fish, 2008; Wang 2008), a finding that we have also confirmed in the BM niche, in order to evaluate separately the leukemogenic effect of Spred1 expression on different compartments of the BM niche, we generated the following conditional Spred1 KO strains: Spred1flox(f)/fMxl-cre+ (Spred1 KO in HSCs, hereafter called Spred1HSCΔ/Δ), Spred1f/fTie2-cre+ [Spred1 KO in endothelial cells (ECs), hereafter called Spred1ECΔ/Δ], Spred1HSCΔ/ΔSCLtTA/BCR-ABL and Spred1ECΔ/ΔSCLtTA/BCR-ABL by crossing SCLtTA/BCR-ABL with the above Spred1 KO mice. LTHSCs from Spred1HSCΔ/ΔSCLtTA/BCR-ABL mice showed an increase in cell cycling, RAS/MAPK/ERK activity and Bcl-2 levels, and higher engraftment in recipient mice (blood: 9.7% vs 26.5% at 6w, 14.8% vs 42% at 8w, 14.7% vs 48% at 12w, n=10 per group, p<0.01), compared to Spred1 wt CML LTHSCs. Spred1HSCΔ/ΔSCLtTA/BCR-ABL mice (n=15) showed enhanced leukemia progression (WBC: 19 vs 12 k/ul, p=0.004; CD11b+Gr-1+ in blood: 36% vs 25%, p=0.04 at 4 w after B/A induction) and a significantly shorter survival (median: 49.5 vs 83 days, p=0.01) compared to Spred1 wt CML mice (n=20). However, the disease in these mice appeared to be overall less aggressive than global Spred1 KO CML (i.e., Spred1-/-SCLtTA/BCR-ABL) mice (WBC: 19 vs 102 k/ul; CD11b+Gr-1+ in blood: 36 vs 63%; Survival: 49.5 vs 39 days), suggesting that Spred1 depletion in other non-hematopoietic cell compartments may also be important for leukemogenesis. In fact, Spred1ECΔ/ΔSCLtTA/BCR-ABL mice (n=8) showed enhanced leukemia progression (WBC: 26 vs 9.8 k/ul at 4 w after B/A induction, p=0.02), a trend for a reduced survival (median: 56 vs 83 days, p=0.09), and increased arteriolar vascularization, compared to Spred1 wt CML mice (n=20). Mechanistic studies on how endothelial Spred1 insufficiency co-participates in leukemogenesis are ongoing. Altogether our results support a role of Spred1 insufficiency in distinct BM niche compartments to produce a more aggressive CML phenotype, likely through different, but complementary mechanisms. Spred1 may therefore emerge as a novel target for advanced CML. Disclosures No relevant conflicts of interest to declare.

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Beltran, Brady E., Erick Cotacallapa, and Jorge J. Castillo. "Survival and Clinicopathological Characteristics of EBV-Positive Diffuse Large B-Cell Lymphoma." Blood 120, no. 21 (November 16, 2012): 1588. http://dx.doi.org/10.1182/blood.v120.21.1588.1588.

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Abstract Abstract 1588 Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients are <50 years and a specific cut-off for the percentage of EBV expression has not been defined. The goal of this retrospective study is to evaluate clinical and pathological characteristics of EBV+ DLBCL from Peruvian patients. Methods: Between January 2002 and January 2012, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases re positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immuno-histochemistry. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4 using a tissue microarray (TMA) technique. The overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 43 EBV+ DLBCL patients are included in this study. The median age was 73 years (range 25–95 years). Four patients (9% ) were <50 years. The male:female ratio was 2.2:1. B symptoms occurred in 59%, ECOG >21 in 60%, advanced stage (III/IV) in 58%, elevated LDH levels in 44%, and lymphocyte count <1000/uL in 35%. The International Prognostic Index (IPI) score was 0–2 in 39% and 3–5 in 61% of the patients. Extranodal disease occurred in 20 patients (46%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), breast (n=1) and peritoneum (n=1). Three patients had central nervous system involvement (7%), one at presentation and two at relapse. Based on the Hans classification, 76% had non-germinal center profile. Ki67 expression was >80% in 53% of the patients. Eleven evaluated patients had a c-myc-negative status. Chemotherapy was received in 75% of the cases due to poor performance status. The overall response rate with conventional chemotherapy was 46%, with complete response in 39%, partial response in 7%, and no response in 54%. The median survival was 7.5 months. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with median OS of 41, 11 and 1.5 months respectively (p=0.07). A lymphocyte count <1000/uL was a prognostic factor for OS (p=0.001). Conclusions: Based on our study, which is the largest cohort in Latin-America, EBV+ DLBCL is an aggressive entity with frequent extranodal disease and poor response to conventional chemotherapy. The overall survival remains poor. Lymphopenia, as defined as lymphocyte count <1000/uL, appears as a prognostic factor for OS. Disclosures: No relevant conflicts of interest to declare.

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Kline, Justin, Aaron P. Rapoport, Adam M. Petrich, Kenneth S. Cohen, Sachdev P. Thomas, Sreenivasa Nattam, Krishna Rao, et al. "Phase II Study of Temsirolimus and Lenalidomide in Patients with Relapsed and Refractory Lymphomas: Final Analysis of NCI 8309." Blood 128, no. 22 (December 2, 2016): 4147. http://dx.doi.org/10.1182/blood.v128.22.4147.4147.

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Abstract Background: mTOR inhibitors, including temsirolimus (TEM), have demonstrated activity in patients (pts) with relapsed/refractory (rel/ref) lymphomas (J Clin Oncol 2010;28(31):4740). Lenalidomide (LEN) is an immunomodulatory agent with activity in a number of lymphoma subtypes with potential additive or synergistic effects. We previously reported phase I results of TEM/LEN in patients with relapsed/refractory lymphomas and showed good tolerability and evidence of clinical activity (J Clin Oncol 2012;30 suppl; abstract 8075). Recommended phase II doses of TEM 25 mg weekly and LEN 20 mg daily (D1-21, q28D) were tested in 3 histology-based cohorts with final results presented here. Methods: Pts with rel/ref lymphomas having received > 1 cytotoxic regimen were eligible. Other criteria included ANC > 1000/uL, platelets > 75,000/uL, and normal renal and hepatic function. Pts were enrolled into 3 cohorts: DLBCL (cohort A), FL (cohort B), and other lymphomas (cohort C). CLL/SLL was excluded due to poor single-agent TEM activity. TEM was administered at 25 mg IV weekly, and LEN at 20 mg PO daily (D1-21, q28D). Pts received therapy for up to 1 year, or until disease progression or development of toxicities requiring treatment cessation. All pts received ASA prophylaxis. Response assessments were performed after cycle 2, and every 3 months thereafter. Results: 93 pts (31 female, 62 male), mean age 57 years (range, 23-78 years) were enrolled onto cohort A (n=39 DLBCL), cohort B (n=15 FL), or cohort C (n=39; 20 HL, 9 T-NHL, 5 MCL, 4 MZL, 1 WM). The median number of prior treatments was 4 (range, 1-14). 28 pts had relapsed following autologous stem cell transplantation (ASCT). The median number of cycles delivered was 4 (range, 1-12). Grade 3 or higher non-hematologic adverse events (AE) were uncommon with only fatigue and hypokalemia occurring in >10% of pts; ≥ grade 3 hematologic toxicity included anemia (n=27), lymphopenia (n=40), neutropenia (n=44) and thrombocytopenia (n=42). Three grade 5 AEs were observed (colonic perforation, myocardial infarction and sepsis). The overall response rates (ORR) were 25.6% (5 CR; 5 PR), 46.6% (5 CR; 2 PR), and 64.1% (7 CR; 18 PR) for pts in cohorts A, B, and C, respectively. Of note, cohort B (FL) was closed prematurely due to poor accrual. Median progression-free survival (PFS) for pts in cohorts A and C was 6.0 months (95% CI 3.1 - 8.0 months), and 7.3 months (4.2 - 10.8 months), and median duration of response (DOR) was 11.3 months (2.6 months - not reached) and 5.5 months (2.3 months - not reached), respectively. Median overall survival (OS) for pts in cohorts A and C was 10.2 months (5.9 - 20.6 months), 25.5 months (10.1 - not reached), respectively. Among 20 heavily-treated HL pts in cohort C (median prior treatments 6, range 3-14), all of whom progressed on brentuximab vedotin (BV), and 13 of whom had received a prior ASCT, the ORR was 80% (7 CR; 9 PR), and the median PFS, DOR and OS was 9.2 months, 8.1 months, and 25.5 months, respectively. Conclusions: The combination of TEM/LEN therapy was well-tolerated and showed encouraging activity in pts with rel/ref lymphomas. The most significant activity was observed in rel/ref HL, with an 80% response rate, including in pts with prior BV exposure and in those relapsed after ASCT. For DLBCL, the addition of LEN did not improve ORR compared to historical experience with single-agent TEM, but we note a provocative prolongation of both PFS and DOR for this otherwise aggressive disease. Further evaluation of mTOR pathway inhibition and immunomodulatory agents in relapsed HL patients is warranted based on these results. This study was conducted through the University of Chicago Phase II Consortium, supported by NCI contract N01-CM-2011-00071C Disclosures Kline: Vasculox: Research Funding; Merck: Honoraria, Research Funding. Petrich:AbbVie: Employment. Rao:Novocure: Consultancy. Smith:TGTX: Consultancy; Juno: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Genentech: Consultancy, Other: on a DSMB for two trials ; Pharmacyclics: Consultancy; Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy.

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delMoral-Diez, Juan J., Elena Juventina Tuna-Aguilar, Alvaro Aguayo, Antonio Olivas-Martinez, and Gladys P. Agreda-Vasquez. "Prognosis in Patients with Human Immunodeficiency Virus Infection and Advanced Clinical Stage Classic Hodgkin's Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5281. http://dx.doi.org/10.1182/blood-2019-123792.

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Classic Hodgkin's lymphoma (cHL) represents 95% of all Hodgkin lymphomas, and is responsible of 0.5% of all cancer types (Siegel, Miller & Jemal, 2016). In HIV positive patients, the incidence of cHL is high (5-20 fold). The use of combination antiretroviral therapy (CART) and CD4 count >200 cells/uL appears to increase the risk; nonetheless, the risk for developing cHL in HIV infected patients remains high, regardless of CD4 count. The median patients' age of HIV-associated classic Hodgkin's lymphoma (HIV-cHL) ranges from 40 to 49 years old, slightly higher than the age observed in general population. It is more common in men, and tends to manifest with extranodal disease (67% vs 32%), B-symptoms (77% vs 43%), and stage III or IV disease (82% vs 42%) (Shiels et al, 2014). Recent recommendations state that HIV-cHL should receive first-line ABVD chemotherapy treatment while continuing CART (Blanca et al, 2007)(Montoto et al, 2012). To determine the prognosis of de novo advanced stage HIV-cHL and compare it with non-HIV-cHL, we designed an observational, descriptive study, including all HIV-cHL (WHO 2016 criteria) from August 2004 to December 2018, paired with a non-HIV-cHL group by clinical stage and gender. Clinical features between positive and negative HIV groups were compared by standard statistical methods. Overall survival (OS) and relapse-free survival (RFS) were calculated by Kaplan-Meier methodology. Analysis for mortality predictors was performed with a univariate Cox regression model. Data was collected from 21 patients with HIV-cHL, all male and with advanced clinical stage, and compared with 58 non-HIV-cHL patients with the same characteristics. The mean age observed was 42.9 (± 10.88) years in HIV-cHL, and 45.1 (± 17.56) years in non-HIV-cHL (p = 0.50). Among the clinical characteristics, the presence of B symptoms was documented in 85.7% of HIV-cHL, and in 91.4% of non-HIV-cHL (p = 0.43). Among biochemical characteristics in both groups, we observed a significantly lower leucocyte count in HIV-cHL (4.6x103 cells/uL) compared with non-HIV-cHL (6.7x103 cells/uL) (p = 0.02). In the monocyte line, we found that HIV-cHL had lower absolute counts (340 cells/uL) than non-HIV-cHL (708 cells/uL) (p = 0.01). A high IPS was reported in 66.7% of HIV-cHL, and in 67.2% of non-HIV-cHL (p = 1.00). The most common reported histologic subtype was mixed cellularity for both groups, with a prevalence of 38.1% and 38.9%, respectively (p = 0.25). The positivity for Epstein-Barr virus was tested in the biopsies of 18 HIV-cHL, and was 100%. Regarding HIV status in infected patients, a 40-month period was the median time between HIV and cHL diagnosis. The median CD4 cell count was 109 cells/uL. 90.5% of patients were treated with CART at time of cHL diagnosis. Other clinical, biochemical and prognostic characteristics are in Table 1. The median follow-up time for all patients was 31 months; the median follow-up time for HIV-cHL was 10 months, shorter than the median follow-up time for non-HIV-cHL (45 months) (p = 0.01). 85.7% of HIV-cHL and 96.6% of non-HIV-cHL received chemotherapy, with a median of 6 cycles (p = 0.11). Complete response (CR) was documented in 61.1% of HIV-cHL, and in 66.1% of non-HIV-cHL (p = 0.77). RFS was 36.5 months for all patients, being less for HIV-cHL (24 months) compared with non-HIV-cHL (51 months) (p = 0.03). The OS median at the time of last follow-up had not yet been reached in all patients (Figure 1). The univariate analysis showed that age ≥45 years old and stage IV cHL are adverse prognostic factors (p = 0.02, p = 0.03, respectively). IPS ≥4 was an adverse outcome factor for mortality, with statistical significance (p = 0.01) (Figure 2). At last follow-up, 22 (27.8%) patients had died, 6 (28.6%) HIV-cHL and 16 (27.6%) non-HIV-cHL (p = 1.00). Clinical, biochemical and prognostic variables, as well as treatment outcomes were similar between HIV-cHL and non-HIV-cHL. Although follow-up time in the HIV-cHL group is shorter, prognosis in terms of OS is similar. RFS is statistically different between both groups and is shorter in HIV-cHL, but as the OS in both groups remains similar, it is possible that rescue chemotherapy is effective in relapsed patients. There was no difference observed in the likelihood of achieving CR in both groups. IPS ≥4 and CR were independent prognostic factors for OS. IPS as an adverse factor and CR as a favorable one. Prognosis of advanced stage HIV-cHL is similar to non-HIV-cHL patients. Disclosures No relevant conflicts of interest to declare.

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Yang, Yanqin, Yubo Zhang, Jun Zhu, Catherine E. Lai, Jingrong Tang, Lisa J. McReynolds, Amy P. Hsu, et al. "Development of Somatic NRAS Mutation Associated with Rapid Transition from Germline GATA2 Mutation Associated Myelodysplastic Syndrome to Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3616. http://dx.doi.org/10.1182/blood.v126.23.3616.3616.

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Abstract There is increasing recognition of the role of inherited germline predisposition for myeloid disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The additional somatic genetic events required for development of a malignant phenotype are however poorly understood. A 25 year old woman was referred to the NHLBI hematology branch in March 2014 for a seven year history of pancytopenia. Her medical history included recurrent pneumonias, oral ulcers, severe varicella infection and arthralgias. Prior bone marrow examinations at ages 21 and 23 at outside institutions reported normocellular marrow, tri-lineage hematopoiesis and mild dyspoiesis. Cytogenetics were remarkable for trisomy 8 in 80% (aged 21) or 90% (aged 23) of metaphases. Previously unrecognized lymphedema was noted on examination. Peripheral blood counts showed WBC 2.28 K/ul [normal range: 3.98-10.04], HGB 9.9 g/dL [11.2-15.7], PLT: 67 K/ul [173-369], ALC: 0.36 K/ul [1.18-3.74] and AMC: 0.06 [0.24-0.86]. Peripheral blood flow cytometry demonstrated decreased CD3+ CD4+ (T) cells, CD19+ (B) cells and NK cells. HLA-DR15 negative. Bone marrow examination showed trilineage hematopoiesis, 50-60% cellularity, mild erythroid predominance and mildly increased, mildly atypical megakaryocytes. Blasts less than 5%. Bone marrow flow cytometry revealed severely decreased B-cells and monocytes, absent B-cell precursors, absent dendritic cells, inverted CD4:CD8 ratio, and atypical myeloid maturation pattern. Cytogenetics demonstrated stable trisomy 8 in 90% of metaphases. On the basis of this assessment the diagnosis of MDS was confirmed. Sanger sequencing revealed a GATA2 L375S mutation in the second zinc finger of known pathogenic significance. Four months later she developed increased fatigue and easy bruising with worsening thrombocytopenia (PLT: 10K/ul). Bone marrow was dramatically changed; now markedly hypercellular (90-100%) with diffuse sheets of immature cells consistent with blasts having fine chromatin, distinct or prominent nucleoli, and visible cytoplasm. Blasts were positive for CD33, CD56, CD64, CD123, and CD163; and were negative for CD34, CD14, and myeloperoxidase. Cytogenetics showed a new trisomy 20 in 65% of metaphases, in addition to previously seen trisomy 8 in 100%. A diagnosis of acute monoblastic leukemia (M5a subtype) was made. At both clinic visits bone marrow aspirate was collected on an IRB approved research sample acquisition protocol. Whole exome sequencing of 1ug DNA was performed using Agilent SureSelect v5 Exome enrichment Kits on an Illumina HiSeq 2000 with 100-bp paired-end reads (Macrogen, Rockville, MD). Data was mapped to hg19 (BWA) and processed using an in-house pipeline (Samtools/Picard/GATK/VarScan/Annovar). Mean read depth of target regions was 157 and 149. There was high correlation between both samples with the exception of a NRAS:NM_002524:exon3:c.C181A:p.Q61K mutation (57 of 180 reads) seen only in the later sample. Confirmatory ultra-deep sequencing for NRAS was performed using Illumina TruSight Myeloid Sequencing Panel on an Illumina MiSeq. No evidence of the NRAS Q61K mutation was found in the earlier March MDS bone marrow sample even when sequenced to a depth greater than 1750 reads (see figure). The mutation was confirmed in the August AML sample at a variant allele frequency of 35%. If heterozygous this would reflect a clone size of 70%, consistent with data from both cytogenetics (new trisomy 20 in 65% of metaphases) and the 76% blasts documented by bone marrow aspirate smear differential. We report here the rapid progression to AML in a patient with germline GATA2 MDS associated with development of a new trisomy 20 karyotype and a NRAS Q61K mutation. The NRAS mutation was not detectable after the patient achieved a complete remission following induction chemotherapy further supporting this association. This NRAS mutation has been implicated in the pathogenesis of multiple cancers by constitutive activation of proliferative signaling. GATA2 associated MDS is a high-risk pre-leukemic condition with the potential for rapid evolution to AML. This is the first report of acquired somatic mutations in the RAS/RTK signaling pathway in the context of germline GATA2 insufficiency associated with acute leukemic transformation. Figure 1. Figure 1. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding.

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Badar, Talha, Hagop M. Kantarjian, Susan O'Brien, Guillermo Garcia-Manero, Elias Jabbour, Rebecca Garris, Naveen Pemmaraju, et al. "Clinical Outcome of De Novo Adult Acute Lymphoblastic Leukemia (ALL) with 11q23/Mixed Lineage Leukemia (MLL) Gene Rearrangements." Blood 124, no. 21 (December 6, 2014): 5342. http://dx.doi.org/10.1182/blood.v124.21.5342.5342.

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Abstract Introduction: The MLL gene on located on 11q23 plays an essential role in positive regulation of gene expression in early embryonic development and hematopoiesis. Fusion genes, such as MLL-AF4 resulting from t(4:11)(q21;q23), alter normal cellular proliferation and differentiation, favoring leukemogenesis. The DOT1L histone methyltransferase associated with MLL appears to be required for maintenance of ALL. MLL-AF4 is detected in about 10% of de novo B-lymphoblastic leukemia or 30=40% of pro-B ALL subtypes. The 11q23/MLL subtype of ALL has been associated with extremely poor outcomes. We conducted a retrospective analysis of de novo adult ALL with 11q23/MLL gene rearrangements. Methods: Overall the database included 74 pts with 11q23/MLL gene rearrangements referred to our institution between 1980 and 2014. Of these, 20 (27%) pts were relapsed/refractory, 4 (5%) were minimally pretreated, 5 (7%) were inevaluable for response, 3 (4%) had concomitant Philadelphia chromosome, 2 (3%) were T-lineage, 2 (3%) were mature B-ALL. The remaining 38 cases comprised the study cohort evaluated with respect to pretreatment characteristics and outcome measures such as response to therapy, remission duration (CRD), and survival (OS). Results: Baseline characteristics of the cohort included median age 44 yrs (range, 20-75); 26% were older than 60 yrs. Ten (26%) pts had a prior malignancy and were designated secondary ALL. Five (13%) pts had CNS disease at presentation. Median WBC count was 69.8 K/uL (range, 0.5-612); 24 (63%) pts had WBC > 30 K/uL. Nineteen (50%) pts had serum LDH > 1400 U/L. Co-expression of myeloid markers (CD13, CD33 +/- CD117) was noted in 6 (16%) pts. Distribution of the 11q23/MLL gene aberrancies were: t(4;11) (q21; q23) in 25 (66%) pts, 11q23 without translocation partner in 10 (26%) pts, and t(11;19)(q23;p13.1) in 3 (8%) pts. Thirty two (84%) pts were treated per the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate and cytarabine) regimen (3 [10%] received concurrent rituximab) and 6 (16%) pts were treated per the augmented BFM regimen. Overall response rate was 95%; complete remission (CR) in 92% and CR without platelet recovery (CRp) in 3%. Overall median CRD was 26.3 mos (range 0.2-93+ mos); median OS was 24.2 mos. Overall, the 5-yr CRD and OS rates were 19% and 26%, respectively, with a median follow-up of 60 mos (range, 4.8-173+ mos). Median OS in pts with 11q23 without chromosomal translocation was 48.5 mos, compared with 24 mos for t(11; 19) and 13.3 mos for t(4; 11) (p= 0.07) (Fig. 1). There were no differences in outcomes by older age or designation as secondary ALL. Conclusion: The 11q23/MLL positive B-lymphoblastic subsets are associated with differentially inferior outcomes, although MLL-AF4 remains the ALL subset associated with highest risk of disease recurrence particularly in the absence of allogeneic stem cell transplantation; the relatively rarity of these subsets poses challenges in establishing the optimal treatment strategies. Therapeutic approaches incorporating hypomethylating agents, histone deacetylase inhibitors, and CAR-T cells could improve these dismal outcomes; targeted agents such as DOT1L inhibitors are under investigation in clinical trials. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Itchaki, Gilad, Toni Dubeau, Andrew Keezer, Kirsten Meid, Lian Xu, Guang Yang, Zachary R. Hunter, Steven P. Treon, and Jorge J. Castillo. "Non-IgM Secreting Lymphoplasmacytic Lymphoma - Experience of a Reference Center for Waldenstrom Macroglobulinemia." Blood 132, Supplement 1 (November 29, 2018): 2886. http://dx.doi.org/10.1182/blood-2018-99-114254.

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Abstract Background: Lymphoplasmacytic lymphoma (LPL) secreting immunoglobulins other than IgM is rare. Therefore, there are very few case series on non-IgM LPL and little is known about the clinical features and outcomes of patients with this disease. Aim: To describe disease characteristics and clinical outcomes of patients with non-IgM LPL. Methods: We identified cases of non-IgM LPL in the records of the Waldenström Macroglobulinemia (WM) clinic at our institute, between the years of 2000-2018. All patients were part of the clinic's registry. We extracted data from their electronic records and included only cases with centrally-confirmed diagnosis. Response assessment was based on 6th IWWM criteria. Time to events was estimated using the Kaplan-Meier method. Results: We found 31 patients with non-IgM LPL. Median age at diagnosis was 63 years (range, 37-83 years), 45% were over the age of 65, and 65% were women. The paraprotein secreted by these tumors was IgG in 20 cases (65%); IgA in 5 (16%), light-chain (LC) in 2 (6%) and was non-secretory (NS) in 4 (13%). Median level of IgG and IgA at diagnosis was 3,967 mg/dl (range, 804-8,006 mh/dl) and 1,980 mg/dl (range, 1,020-6,210 mg/dl), respectively. We included 5 cases with concurrent IgM paraproteinemia, when it was clearly secreted to a lesser extent than dominant immunoglobulin and had similar LC restriction. Five patients had MGUS preceding diagnosis of LPL. Presenting symptoms were anemia-related (n=13), asymptomatic (n=7), neuropathy, autoimmune phenomena, elevated creatinine, bleeding diathesis and recurrent infections (n=3, each). Only 1 patient had B-symptoms. One patient with IgA LPL and serum IgA level of 4,000 mg/dl presented with retinal vein occlusion due to hyperviscosity. Non-bulky (<5 cm) lymphadenopathy was found in 11 patients (35%), and mild splenomegaly in 5 (16%). Anemia was prevalent (53%) with hemoglobin <10 g/dl in 23%. No patient had neutropenia (ANC <1 K/uL) or thrombocytopenia (platelets <100 K/uL) at presentation. Five patients (16%) presented with mild lymphocytosis (median, 7.1 K/uL; range, 3.3-20.6 K/uL). Βeta-2-microglobulin level was >3 mg/L in 48% of available patients (n=12/24). All bone marrow biopsies showed that malignant cells were positive for CD20 and CD19 by flow cytometry; 14% were CD5 positive (subset/dim); 29% CD23 partially-positive; and all were CD10 negative. Five of 19 cases (26%) had cytogenetic abnormalities, but apart from del6q (n=1), none were of commonly known aberrations in hematological malignancies. Only 1 patient with kidney disease underwent renal biopsy that revealed light-chain deposition disease. Amyloidosis was detected in 2 patients, one with neuropathy and the other patient was asymptomatic. The MYD88 L265P mutation was detected in 10 of 14 patients (71%) tested, and CXCR4 mutations in 2 of 8 patients (25%) tested. Both patients with a CXCR4 mutation needed treatment immediately at diagnosis and subsequently had 4 or more lines of therapy. With a median follow up of 4.6 years (95% CI 2.5-7.6 years), 68% of the patients had been treated (n=21), 90% of whom within the first year from diagnosis. As such, the median time to first treatment was 2.3 months. However, time to next therapy was significantly longer, with a median of 4.7 years. Patients had a median of 3 lines of therapy (range, 1-8), including purine analogues in 33% of patients, alkylating agents in 48%, bendamustine in 38%, anti-CD20 monoclonal antibodies in 90%, proteasome inhibitor in 24%, and immunomodulating drugs in 14%. Two patients received ibrutinib: one achieved VGPR with over 3 years remission duration, after prior 7 lines of therapy; and the other, who had only a brief response, was found to carry the CXCR4 mutation. There were 4 (13%) deaths: 1 patient developed Bing-Neel syndrome at first relapse that ultimately lead to his demise; 1 died from treatment complications; and 2 of unknown cause. The 5-year and 10- year OS are 90% (95% CI 64-98%) and 81% (95% CI 49-94%), respectively (Figure 1). Conclusion: To our knowledge, this is the largest reported series of non-IgM LPL and the first to demonstrate excellent long-term outcomes in these patients. Figure 1. Figure 1. Disclosures Hunter: Pharmacyclics: Consultancy. Treon:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Johnson & Johnson: Consultancy; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Millennium: Research Funding.

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Blum, William, Kate Donohue, Guido Marcucci, Daniel J. DeAngelo, Geoffrey L. Uy, Bayard L. Powell, Wendy Stock, et al. "Challenges for Conducting Clinical Trials Evaluating Maintenance Chemotherapy In Acute Myeloid Leukemia (AML): a Cancer and Leukemia Group B (CALGB) Study." Blood 116, no. 21 (November 19, 2010): 2176. http://dx.doi.org/10.1182/blood.v116.21.2176.2176.

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Abstract Abstract 2176 Recent advances in frontline therapy for newly diagnosed AML include increased dose of anthracycline during induction, multi-agent regimens, high dose cytarabine (HiDAC) as consolidation for core binding factor (CBF) patients (pts), and allogeneic transplantation (alloHCT) during 1st remission for poor risk pts. Prolonged low-dose cytotoxic maintenance therapy does not appear to improve clinical outcomes, but investigation of novel maintenance strategies remains appealing, affording pts an opportunity to receive new therapies without increasing the considerable toxicities of induction/ consolidation. The CALGB performed a phase II study of induction and risk-adapted consolidation, followed by one year of maintenance therapy with decitabine, for newly diagnosed AML pts <60 years of age (CALGB 10503). Induction was daunorubicin 90 mg/m2 for 3 days, etoposide 100 mg/m2 for 3 days, and cytarabine 100 mg/m2 for 7 days (3+3+7). Reinduction (2+2+5) was given for residual disease on day 14. CBF pts in CR received 3 cycles of HiDAC; all other pts received autologous transplantation (autoHCT) if eligible, or HiDAC if not. Poor risk pts in 1st CR received alloHCT off study, when appropriate. Maintenance decitabine (20mg/m2 intravenously for 4–5 days, every 6 weeks for 8 cycles) began within 60–90 days after consolidation for pts with neutrophil ≥1000/uL and platelets ≥75,000/uL. Clinical results for the efficacy of decitabine maintenance for one year are not yet mature; the study closed to accrual July 30, 2010. In a previous study for a slightly more favorable patient cohort that was treated with identical induction and consolidation (CALGB 19808), 29% of all enrolled pts (214/732) and 39% of CR pts were registered to a randomized investigational maintenance therapy. To examine the feasibility of conducting a subsequent randomized trial of maintenance therapy, we analyzed reasons for study discontinuation for all pts enrolled on CALGB 10503; 473 pts had “response” or “off study” data forms submitted, to date. Complete remission* (CR) was achieved in 349 (74%). Reasons for induction failure were primary refractory AML (15%), induction death (5%), and other (6%, including those withdrawn from protocol for alternative therapy presumably due to persistent disease). The most common reason for not receiving maintenance therapy was the presence of AML, either primary refractory as noted or early relapse (7% of CR pts). In pts who achieved CR, the most common reason for not receiving maintenance was removal from the protocol for alloHCT (71/349, 20%). 9% refused further protocol therapy after consolidation, perhaps from “treatment fatigue.” Correlative investigations for CALGB 10503 are ongoing, including identification of novel prognostic markers, targets for treatment, and markers of minimal residual disease. Clearly, clinical investigation of maintenance therapy as part of a comprehensive treatment approach for frontline therapy of AML (inclusive of homogeneous induction and consolidation therapy) requires considerable up-front enrollment in order to reach maintenance accrual goals. Randomized maintenance studies will likely need intergroup participation for timely completion. However, we conclude that the benefits of up-front enrollment (relative to a post-consolidation enrollment strategy) outweigh the accrual burdens. Benefits include uniform pre-maintenance therapy and the potential for novel discovery from correlative studies. Study designs for future maintenance trials for AML in 1st CR must balance expediency with the more comprehensive approach employed in CALGB 10503. Disclosures: Blum: Celgene: Research Funding. Off Label Use: decitabine in AML. DeAngelo: Deminimus: Consultancy.

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Eckrich, Michael J., Stacy Epstein, Carrie Barnhart, Javier Oesterheld, Darci Grochowski, Mark Cannon, and Andrew L. Gilman. "Post-Transplant Donor Lymphocyte Infusion with Methotrexate Prophylaxis Is Associated with Low Incidence of Relapse after CD34-Selected, T Cell-Depleted Haploidentical Donor Stem Cell Transplantation Regardless of NK Alloreactivity." Blood 126, no. 23 (December 3, 2015): 3166. http://dx.doi.org/10.1182/blood.v126.23.3166.3166.

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Abstract Background: NK alloreactivity based on KIR (Killer Immunoglobulin-like Receptor) expression by natural killer cells has been reported to decrease the risk of leukemia relapse after HLA-haploidentical stem cell transplantation (SCT). The use of donors with high KIR B-content score has been correlated with a decreased risk of relapse. Objective: We examined the outcome of leukemia relapse following CD34-positive selected T-cell depleted haploidentical donor peripheral blood SCT followed by donor lymphocyte infusion with methotrexate prophylaxis. Methods: Between 2009-2015, twenty patients underwent haploidentical donor CD34-selected, T cell-depleted peripheral blood SCT on an IRB-approved protocol. Nine patients had acute lymphoblastic leukemia (ALL), and eleven had myeloid leukemia (10 AML, 1 JMML). Among ALL patients, remission status was CR1 in 5, with either induction failure or MRD+ after consolidation, 3 were in CR2 and 1 was CR3. Four patients had T-cell disease. Among AML patients, 5 were in CR1, one had refractory disease and 5 were CR2 or beyond. Ligand-ligand NK alloreactivity based on HLA typing was available for all patients. Receptor-ligand NK alloreactivity based on immunophenotyping of KIR was available in 16 patients and KIR B-content score was available in twelve patients. Patients were considered to have receptor-ligand NK alloreactivity if immunophenotyping of the donor had >5 (cells/uL) expressing KIR2DL1 (recognizes C2 group) or KIR2DL1/2DL13 (recognizes C1 group). Patients with alloreactive KIR only recognizing BW4 were not considered alloreactive due to predicted weak alloreactivity. All patients received a uniform conditioning regimen including TBI 1200cGy, thiotepa 10mg/kg, fludarabine 200mg/m2, and rabbit-anti-thymocyte globulin (rATG) 6mg/kg, with no post-transplant immunosuppression. All patients received a planned donor lymphocyte infusion (DLI) 3-5 x 104 CD3+ cells/kg between days 30- 42 after transplant and received weekly IV methotrexate prophylaxis following DLI. The incidence of relapse and GVHD was evaluated. Results: Based on a ligand-ligand model of NK alloreactivity, only 4/20 patients had NK alloreactivity predicted. Seven patients expressed all 3 ligands and blocked all possible NK alloreactivity. Median follow-up was 306 days (range 45 days-5 years). Four of 20 patients relapsed (1/4 with predicted NK alloreactivity and 3/16 without). Median time to relapse was 110 days (range 124-455 days). NK alloreactivity based on receptor-ligand as defined above was present in 5/16 patients and relapse occurred in 2/5 with and 1/11 without. Donor KIR B-content was >=2 in 4 patients and 0-1 in 8 patients. Relapse occurred in 1/4 with 2 and 2/8 with 0-1. No donors had KIR B-content score of 3-4. The incidence of grade II-IV acute graft-versus-host disease after prophylactic DLI was 25%, with 2 grade II, 3 grade III and no grade IV GVHD. Three patients developed cGVHD, two mild and one severe by NIH consensus criteria. Conclusion: An approach using a DLI followed by methotrexate prophylaxis after a CD34-selected, T-cell depleted SCT for pediatric leukemia diminishes the effect of NK alloreactivity and KIR B-content. Disclosures No relevant conflicts of interest to declare.

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Mocikova, Heidi, Magdalena Klanova, Martin Spacek, Robert Pytlik, Tomas Kozak, Marek Trneny, and Vit Pospisil. "Defining Criteria for Diagnosis of Occult Lymphomatous Involvement in Cerebrospinal Fluid." Blood 124, no. 21 (December 6, 2014): 5412. http://dx.doi.org/10.1182/blood.v124.21.5412.5412.

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Abstract Introduction: Currently, there is no consensus regarding diagnosis and treatment of occult lymphomatous menigeal involvement of cerebrospinal fluid (CSF) in patients with systemic non-Hodgkin lymphomas (NHL), especially in patients with minimal number of clonal cells detected by flow cytometry (FCM) or by cytology. Aim of the study: To describe a cohort of patients with occult lymphomatous involvement in cerebrospinal fluid including the diagnostic methods as well as management. Patients and methods: CSF at diagnosis of B-NHL was examined by FCM, cytology, biochemistry and microRNA analysis in a cohort of 62 patients (systemic DLBCL N=45, MCL N=15, Burkitt lymphoma N=2) between 2010 and 2013. Occult meningeal involvement was defined by: a/ FCM: absolute positive number of clonal cells <20 and concomitant negative finding by cytology; b/ FCM negative for clonal cells and concomitant positive finding by cytology; c/ by abundance of increased levels (≥ 200% of the threshold levels) of oncogenic microRNAs (members of miR-17-92 cluster and miR-21, evaulated by Taq-Man RT PCR) in cerebrospinal fluid in patients either passing a/ or b/. The threshold of individual microRNA abundance was defined by statistical analysis of patients with or without CNS involvement. The patients qualified for occult meningeal involvement were considered to be at high risk of CNS relaps. As a control group, the patients with elevated oncogenic microRNAs and negative FCM or cytology of CSF (N=10), were used. All patients received some form of CNS prophylaxis as a part of standard first line treatment. Results and conclusions: According to described criteria we identified 8 patients with occult meningeal involvement at diagnosis (systemic DLBCL N=4, MCL N=3, Burkitt lymphoma N=1) out of 62 patients: 3 with negative FCM and positive cytology (2-14 cells/ul); and 5 with positive FCM <20 clonal cells and negative cytology, 3 out of them with positive microRNAs. None of these patients with occult meningeal involvement relapsed/progressed into CNS within 12 months. In contrast three out of ten control patients (characterized by elevated oncogenic microRNAs in CSF, but negative for FCM and cytology) relapsed to CNS within 6 months after diagnosis. None of ”triple” negative (FCM, cytology, microRNA) patients (N=44) developed clinically manifest CNS involvement. These results suggest that examination of oncogenic microRNA in CSF at diagnosis is more sensitive method than FCM and cytology of CSF to detect the patients with occult CNS involvement and higher risk of CNS involvement and this should be reflected in treatment strategy in further clinical trials. Grants: GACR305 13-12449P, UNCE204021, PRVOUK: P24/LF1/3, P27/LF1/1, P 27/2012 LF3 Disclosures Spacek: Roche: Consultancy, Travel grants Other.

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Advani, Anjali S., Anna Moseley, Michaela Liedtke, Margaret R. O'Donnell, Ibrahim Aldoss, Martha P. Mims, Kristen Marie O'Dwyer, Megan Othus, and Harry P. Erba. "SWOG 1312 Final Results: A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia." Blood 134, Supplement_1 (November 13, 2019): 227. http://dx.doi.org/10.1182/blood-2019-125340.

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The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (IO) has demonstrated promising results in phase 2 and 3 trials. Pre-clinical studies have demonstrated superior anti-tumor activity when IO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). We assessed the safety of IO in combination with CVP and determined the maximum tolerated dose (MTD) of IO in this regimen for pts with relapsed or refractory (R/R) CD22+ acute leukemia. An expansion cohort was treated at the MTD and efficacy results are presented. Methods: Pts were treated at SWOG institutions from 2014-19. IO was supplied by Pfizer. Eligibility: age > 18 yrs, > 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received C (750 mg/m2) intravenous (IV) Day (D) 1, V (1.4 mg/m2) (max 2 mg) IV D1, P (100 mg) orally D 1-5 and IO (dose escalated as in Table 1) up to a maximum of 6 cycles. Each cycle was 28 d. Dose escalation utilized a standard 3+3 design with the plan to treat 12 additional pts at the MTD. Dose limiting toxicities (DLTs) were considered: (1) > Grade (Gr) 4 non-hematologic toxicities (NHTs) with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count < 500/ uL or platelet count < 25,000/uL] in a bone marrow with < 5% blasts and no evidence of leukemia that lasts > 35 d beyond the last dose of IO; (3) any Gr 3 NHT (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to < Gr 2 by 7 d beyond the last dose of IO; (4) any > Gr 3 elevation in SGOT/ SGPT or bilirubin lasting > 7 d; (5) any IO-related toxicity resulting in permanent discontinuation of IO. Results: 50 pts were enrolled; 2 were ineligible. The median age was 43 yrs (range 20-79), 56% were male, and the median WBC at registration was 2.7 K/uL (range 0.3-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 515 d. Twenty-one pts were in 1st relapse, 12 in 2nd relapse, 4 in 3rd relapse, 1 in 4th relapse, and 10 pts were refractory to their last treatment. Eighteen pts (38%) had received prior blinatumomab; 9 had prior allogeneic hematopoietic stem cell transplant (AHSCT); 30% had poor risk cytogenetics (Ph+, -7, +8, complex, MLL abnormalities, or hypodiploid); 13 pts were tested for the Ph-like signature with 5 pts identified as Ph-like. One death occurred during treatment and was attributed to pneumonia in the setting of active ALL. Gr 3-4 hematologic toxicity related to treatment was common: neutropenia (73%), thrombocytopenia (63%), and anemia (50%). Gr 3-4 NHTs were mainly febrile neutropenia. One DLT occurred at DL 3: prolonged myelosuppression and 1 DLT at DL 5: Gr 3 ascites. Gr 3-4 transaminases or bilirubin occurred in 1 pt (2%) during treatment and in 10 pts (23%) during follow-up. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment but 3 (7%) occurred during follow up (post-transplant). The MTD was DL 5. Thirteen pts (30%) proceeded to AHSCT after study treatment. The complete remission (CR)/ CR with incomplete count recovery rate was 61% (95% CI 39%-80%) in the 23 evaluable pts treated at the MTD, and 60% (3/ 5) in pts with the Ph-like signature. There was no statistically significant difference in response rates or hepatic toxicities between the various DLs. However, all 3 VOD cases occurred either after 2nd transplant (n=2) and/ or at DL 5 (n=2). The rates of CR/CRi were 60% and 50% respectively in DLs 1 and 2. The median overall survival was 7.7 months for all pts, and 10.9 months for pts treated at the MTD. Notably, 1 pt remains in a remission 3.5 yrs out from registration without having a transplant. Conclusion: CVP/IO is relatively well tolerated with high response rates and low toxicity despite a heavily pre-treated group of pts. Minimal residual disease data and additional Ph-like signature data are being compiled. Randomized studies will be needed to determine differences in toxicities and response rates with the various doses. However, there is a suggestion that VOD may increase with higher doses of IO and in the setting of 2 transplants. This regimen may represent a promising strategy in the treatment of elderly pts in the newly diagnosed setting. Disclosures Advani: Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau; Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding.

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Panch, Sandhya R., Yu Ying Yau, Courtney Fitzhugh, Matthew M. Hsieh, John F. Tisdale, Charles D. Bolan, and Susan F. Leitman. "Hematopoietic Progenitor Cell Mobilization In Response To G-CSF Is More Robust In Healthy African American Compared To Caucasian Donors." Blood 122, no. 21 (November 15, 2013): 696. http://dx.doi.org/10.1182/blood.v122.21.696.696.

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Abstract Hematopoietic progenitor cells (HPCs) collected by apheresis of G-CSF-stimulated donors have surpassed bone marrow as the predominant graft source for hematopoietic stem cell transplantation in adults. Among healthy allogeneic donors, demographic characteristics (age, sex, and BMI) and baseline hematologic parameters have been shown to affect HPC mobilization, leading to significant variability in peak levels of CD34 cell egress into the blood and in quantity of CD34 cells harvested by apheresis. Racial differences in G-CSF-mediated HPC mobilization are less well characterized. Benign physiologic neutropenia is common among healthy African Americans (AAs), and may be due to decreased stem cell reserve, fewer G-CSF receptors, or Duffy (null) blood group antigen-mediated decrease in leukocyte trafficking into the circulation. However, preliminary studies have shown relatively robust CD34+ cell mobilization among non-Caucasians given G-CSF (Vasu et al., Blood 2006). We retrospectively analyzed 1,096 consecutive healthy allogeneic related and unrelated first-time donors who self-characterized their race as AA or Caucasian. They underwent G-CSF (filgrastim, Neupogen, Amgen) stimulated HPC collection by leukapheresis from April 1999 to May 2013. G-CSF dose ranged from 10-16 mcg/kg, given daily for 5 days. An unstimulated leukapheresis procedure for lymphocyte collection was performed in the 7 days preceding G-CSF in 336 subjects. Apheresis procedures were performed on the CS-3000 Plus or COBE Spectra device. Baseline lab data included CBC, serologic blood group antigen typing, and Hb electrophoresis in AA donors. CD34+ cell counts were performed on peripheral blood immediately pre-apheresis (2 hours after the 5th dose of G-CSF) and on the apheresis product. Values are given as mean ± SD. All AA (n=215) and Caucasian donors (n=881) with complete data sets were included. Sex ratio was similar among the groups (45 vs 52% male; p=0.09). AAs were younger (39 vs 43 yrs, p=0.001) and had greater weight (86 vs 81 kg, p=0.001) and BMI (30 vs 27; p<0.0001) than Caucasians. G-CSF dose/kg was similar in the 2 groups, but total daily dose of G-CSF was greater in AAs than Caucasians (920 vs 850 mcg, p<0.0001). After adjusting for age, sex, height, weight, and total daily G-CSF dose, peak CD34+ cell mobilization immediately pre-apheresis was higher among AAs than Caucasians (123 ± 87 vs 75 ± 47 cells/uL; p<0.0001) (Figure). When laboratory parameters such as baseline WBC, MNC, and platelet counts were included in the stepwise regression model, AA race remained a significant predictor of higher peak CD34 cell counts. At higher G-CSF doses (16 mcg/kg/d), the difference in mobilization responses between the 2 groups was less apparent (peak CD34 counts 123 vs 93 cells/uL, AA (n=33) vs Caucasian (n=73), p=0.07) than at lower doses (10 mcg/kg/d), where peak CD34 counts were 123 vs 74 cells/uL, AA (n=182) vs Caucasian (n=808), p<0.0001. AAs had lower baseline ANC (3.4 vs 4.0 x 103 cells/uL, p<0.001) than Caucasians, but demonstrated significantly higher peak WBC and MNC counts after G-CSF. In AA donors with known HbS status, presence of sickle cell trait had no effect on CD34 mobilization (peak CD34 counts 123 ± 91 vs 107 ± 72 cells/uL, HbAS (n=41) vs HbAA (n=84), p=0.34). Similarly, in AA donors with known Duffy phenotype, Duffy expression did not affect CD34 mobilization (peak CD34 counts 114 ± 81 vs 134 ± 85 cells/uL, Fya-b- (n=49) vs Fya+ &/Fyb+ (n=20), p=0.4). Lymph-apheresis prior to starting G-CSF was associated with significantly improved CD34+ cell mobilization; however the effect did not differ by race. CD34 apheresis yield was also greater in AAs than Caucasians (51 ± 35 vs 32 ± 21 x 106 cells per liter processed, p <0.0001), consistent with higher pre-apheresis counts. African Americans demonstrated significantly more robust CD34 mobilization responses to G-CSF than Caucasians. The effect was independent of age, BMI, HbS and other variables, and occurred despite physiologically lower neutrophil counts among AAs. A ceiling effect in response to increased doses of G-CSF (>10 mcg/kg) was seen in AAs but not in Caucasians, suggesting that dose titration based on race might be used to optimize HPC yields. Further evaluation of race-associated genetic polymorphisms in relation to G-CSF pharmacokinetics may help improve G-CSF dosing strategies. Disclosures: No relevant conflicts of interest to declare.

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Advani, Anjali S., Anna Moseley, Michaela Liedtke, Margaret O'Donnell, Megan Othus, Martha P. Mims, Kristen O'Dwyer, and Harry P. Erba. "A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia (SWOG 1312)." Blood 128, no. 22 (December 2, 2016): 1634. http://dx.doi.org/10.1182/blood.v128.22.1634.1634.

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Abstract The prognosis of patients (pts) with relapsed/ refractory acute lymphoblastic leukemia (ALL) remains poor and novel therapies are needed. The anti-CD22 immunoconjugate inotuzumab ozogamicin (INO) has demonstrated promising results in both phase 2 and 3 trials (Kantarjian et al. Lancet Oncology 2012; 13(4): 403-11). Pre-clinical studies have demonstrated superior anti-tumor activity when INO is co-administered with cyclophosphamide (C), vincristine (V), and prednisone (P). In this study, SWOG 1312, we assess the safety of INO in combination with CVP and determine the maximum tolerated dose (MTD) of INO in this regimen for patients with relapsed or refractory (R/R) CD22+ acute leukemia (B-ALL, mixed phenotype, and Burkitts). Here, we present our toxicity results. Methods: Pts were treated at limited SWOG institutions from Apr 2014 to present. INO was supplied by Pfizer and an IND was approved by the FDA. The protocol was reviewed and approved by each institutional review board. Eligibility criteria included: age > 18 years (yrs), > 20% blasts expressing CD22, R/R CD22+ acute leukemia (B-ALL, mixed phenotype, or Burkitts), and adequate organ function. All pts received treatment with C (750 mg/m2) intravenous (IV) Day 1, V (1.4 mg/m2) (max 2 mg) IV Day 1, P (100 mg) orally Days 1-5 and IO (dose escalated as in Table 1) IV Days 1, 8, and 15. Each cycle was 28 days, and a maximum of 6 cycles could be administered. Dose escalation was performed using a standard 3x3 design; with the plan to treat 12 pts once the MTD was defined. Dose limiting toxicities (DLTs) were considered: (1) > Grade 4 non-hematologic toxicities with the exception of nausea, vomiting and toxicities secondary to neutropenia and sepsis; (2) prolonged myelosuppression [absolute neutrophil count (ANC) < 500/ uL or platelet count < 25,000/uL] in a bone marrow with < 5% blasts and no evidence of leukemia that lasts > 35 days beyond the most recent dose of IO; (3) any grade 3 non-hematologic toxicity (excluding peripheral neuropathy, hyperglycemia, and toxicities secondary to neutropenia, thrombocytopenia, and sepsis) that does not resolve to Grade 2 or better by 7 days beyond the most recent dose of IO; (4) any > Grade 3 elevation in SGOT/ SGPT or bilirubin lasting ≥ 7 days; (5) any IO-related toxicity resulting in permanent discontinuation of IO. Results: As of 7/14/2016, 24 pts have been enrolled: 2 pts were ineligible and 3 pts are currently receiving treatment and are not evaluable for toxicity. Of the 19 evaluable pts, the median age was 49 yrs (range 21-75), 10 (53%) were male, and the median WBC at registration was 9.4 K/uL (range 0.9-59.6). All pts had B-ALL. The median time from initial diagnosis to registration was 774 days. Five pts were in 1st relapse, 8 in 2nd relapse, 3 in 3rd relapse, 1 in 4th relapse, and 2 pts were primary refractory. Five pts had received prior allogeneic hematopoietic stem cell transplant (AHSCT); 7 pts had poor risk cytogenetics (Ph+, -7, +8, complex, or hypodiploid). One death occurred during treatment and was attributed to pneumonia. Grade 3-4 hematologic toxicity related to treatment was common: neutropenia (11 pts), thrombocytopenia (7 pts), and anemia (6 pts). Grade 3-4 non-hematologic toxicities were almost exclusively febrile neutropenia. One DLT occurred at Dose Level 3: prolonged myelosuppression. No cases of hepatic veno-occlusive disease (VOD) occurred during treatment, and 1 pt experienced Grade 3 alkaline phosphatase at Dose Level 1. Three pts proceeded to AHSCT after study treatment; 1 pt developed VOD post AHSCT however, this fully resolved. Currently, 3 pts have been enrolled to Dose Level 4. Conclusion: The combination of CVP/IO is well tolerated and only 1 significant hepatic event (which subsequently resolved) was observed despite a heavily pre-treated group of patients. Further toxicity results and dose escalation will be presented at the meeting. Response data will also be presented if enrollment is complete. Disclosures Advani: Pfizer: Consultancy, Research Funding. Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Erba:Pfizer: Consultancy; Juno: Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Agios: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy; Celator: Research Funding; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Ariad: Consultancy; Astellas: Research Funding; Astellas: Research Funding; Celator: Research Funding; Agios: Research Funding; Agios: Research Funding; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy.

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Sidharthan, Neeraj, Rema Ganapathy, P. Gangadharan, Sumi Soman, Keechilet Pavithran, Raghuveer Prabhu, Haripriya V. Raju, et al. "Strict Treatment Regimen and Febrile Neutropenia Guidelines Allow Favorable Outcomes for Pediatric ALL in Southern India." Blood 126, no. 23 (December 3, 2015): 4510. http://dx.doi.org/10.1182/blood.v126.23.4510.4510.

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Abstract Background: Children with Acute Lymphoblastic Leukemia (ALL) in resource-poor countries face major challenges including treatment abandonment and poor overall survival (OS) and event-free survival (EFS). To address these issues, in 2002 a non-profit pediatric hematology-oncology center was established in a tertiary medical institution in Kerala, India to provide high-quality treatment and supportive care at low cost. A standardized approach to pediatric leukemia care began in 2010. We present evidence that outcomes on par with that seen in resource-rich nations can be achieved with a rigorous treatment and supportive care approach. Methods: Following IRB approval, we reviewed clinical information and outcomes of all patients above 1 year and less than 14 years of age treated for newly diagnosed B- or T-ALL between January 1, 2010 and January 31, 2015. Seventy-six children were consecutively treated and all are included in this analysis. B-ALL patient treatment was stratified according to BFM relapse risk criteria with standard risk (SR) defined by age 1-6 yrs, peripheral WBC < 20 X 106/ul, good prednisolone response, absence of t(9:22) and t(4:11), and a day 33 marrow in remission by morphology. At any age, poor prednisolone response, t(9:22) or t(4:11), or day 33 marrow not in remission defined high risk (HR), and patients not meeting SR or HR criteria were intermediate risk (IR). Minimal residual disease assessment (MRD) was not utilized in risk stratification or treatment decisions. All patients were treated as per BFM 2002 with modifications. All patients received 4-drug (Vincristine/ Daunorubicin/ L Asparaginase/ Prednisolone) induction and Phase 2 induction of cyclophosphamide, cytosine arabinoside, and daily 6-mercaptopurine (6-MP), followed by consolidation with oral 6-MP and IV methotrexate (MTX), 2 gm/m2 x 4 for SR and IR B-ALL and 5 gm/m2 x 4 for HR B-ALL, T-ALL, and CNS disease. Phase 1 reinduction utilized adriamycin and dexamethasone. The Phase 2 reinduction regimen closely mirrored Phase 2 induction. HR B-ALL and T-ALL patients received 12 Gy prophylactic cranial irradiation, and those with CNS disease 18 Gy. Maintenance therapy consisted of daily oral 6-MP, weekly oral MTX, and monthly IV Vincristine and oral Dexamethasone for 104 weeks. Prophylactic intrathecal MTX was given 11 times through reinduction and every 3 months in maintenance. Febrile neutropenia protocols were enforced to ensure less than 30 minutes elapsed from presentation with fever > 38o C to initiation of broad spectrum antibiotics. To minimize sepsis risk, prophylactic GCSF was given between cycles to target ANC > 0.5 x 106/uL. OS and EFS were assessed by Kaplan-Meier method. Patients were censored at last follow-up. Abandonment was treated as an event in calculating EFS. Kuppuswami Socioeconomic Scale (KES) was applied using phone interviews of guardians. Results: Median follow-up time was 30.3 months (range, 1.9-61 months). One patient (1.3%) died during induction, 1 was censored at loss to follow-up upon transfer of treatment to another center, none abandoned treatment, and 6 (7.9%) relapsed, with 1 (1.3%) relapse within 90 days of diagnosis. At median follow-up, the OS was 93.4% and EFS 90.8% (95% CI, 81.1%-99.1%). SR accounted for 28 (36.8%), IR for 36 (47.4%), and HR for 11 (14.5%) patients. OS by risk stratification is shown in Figure 1. KES analysis on the 65 contactable families revealed a median family income between Indian Rs. 14,000-37,000 (US $218-577)/month, and 14 (21.5%) having income less than Rs. 9,300 (US $145)/month. Thirty (46.1%) stratified as lower-middle class or lower. The primary wage earner had less than a high school education in 21 (32.3%), and was at a clerical or lower work level in 46 (70.8%) of families. Conclusion: Our data demonstrate that, for pediatric ALL, results similar to resource-rich countries can be provided in resource-poor areas through a tertiary care center maintaining adherence to globally accepted guidelines for treatment and management of treatment-associated complications. We plan to report minimum 5-year follow-up for all patients in future. Future prospective studies will examine the role of MRD-based stratification and allogeneic transplant options for high-risk patients, as well as seek to extend the low rates of toxic death and abandonment to neighboring centers by implementation of best practices throughout the region. Figure 1. OS by Risk Stratification Figure 1. OS by Risk Stratification Disclosures No relevant conflicts of interest to declare.

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Chang, Julie E., Vaishalee P. Kenkre, Christopher D. Fletcher, Aric C. Hall, Natalie Scott Callander, Kyungmann Kim, Grace Yi Chen, and Kaitlin Chambers. "Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5470. http://dx.doi.org/10.1182/blood-2019-124489.

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Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

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Roddie, Claire, Maeve A. O'Reilly, Maria A. V. Marzolini, Leigh Wood, Juliana Dias Alves Pinto, Mahnaz Abbasian, Ketki Vispute, et al. "AUTO1, a Novel Fast Off CD19CAR Delivers Durable Remissions and Prolonged CAR T Cell Persistence with Low CRS or Neurotoxicity in Adult ALL." Blood 134, Supplement_1 (November 13, 2019): 226. http://dx.doi.org/10.1182/blood-2019-131086.

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Introduction: In adults, prognosis for B-ALL is poor, patients are more vulnerable to CD19 CAR immunotoxicity and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. We have developed a novel second generation CD19CAR (CAT-41BBz CAR), with a faster off-rate but equivalent on rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 9s vs 4.2 hours) designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary paediatric clinical data of this novel CD19 CAR (AUTO1) supports this assertion. We here describe preliminary data from ALLCAR19 (NCT02935257), a multi-centre, Phase I clinical study of AUTO1 as therapy for r/r adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a semi-automated closed process. Study design: ALLCAR19 is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T cell infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T cells ; if <20% BM blasts, infuse 100 x 106 CAR T cells. Day +9: if no Grade 3-5 CRS/CRES, infuse Dose 2, to a total dose of 410 x 106 CAR T cells). Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months Results: As of 24 July 2019, 16 patients have been leukaphresed, 14 products manufactured (one failed leukaphresis and one currently in manufacture) and 13 patients have received at least 1 dose of AUTO1. Of the 16 patients, median age was 35.5 (range 18-63), 10/16 (63%) had prior blinatumomab or inotuzumab ozogamicin and 12/16 (75%) had prior HSCT. At the time of pre-conditioning, 9/13 (69%) patients were in morphological relapse with >5% leukemic blasts of which 6/13 (46%) had ≥50% blast. 9/13 patients (69%) received the total target split dose of 410 x 106 CAR T cells while 1/13 patients (8%) received a reduced split total dose of 51.3 x 106 CAR T cells due to manufacturing constraints. 3/13 patients (23%) received only a first dose of 10 x 106 CAR T cells. The dose was administered safely to date: No patients experienced ≥Grade 3 CRS (using Lee criteria) and only 1/13 (8%) experienced Grade 3 neurotoxicity (dysphasia) that resolved swiftly with steroids. All patients had robust CAR expansion (median peak expansion 172 CAR/uL blood). Of the 13 patients dosed (1/13 pending 28 day follow up), 10/12 (83%) achieved MRD negative CR at 1 month and all patients had ongoing CAR T cell persistence at last follow up. Two patients experienced CD19 negative relapse (one at M3, one at M6), 1 patient died on D17 before first response evaluation, 1 died in molecular CR from sepsis, and 1 died from persistent disease. Currently, 7/12 remain on study and continue in flow/molecular MRD negative remission with a median follow up of 9.0 months (range 1.2-14.8). Conclusions: AUTO1 delivers excellent early remission rates with initial data showing 83% MRD negative CR and robust CAR expansion and persistence. Despite high tumour burden, the safety profile compares favourably to other CD19 CARs, with no cases of severe CRS and only one case of Gr3 neurotoxicity. This is consistent with experience in the paediatric cohort. Updated results will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

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Saygin, Caner, Nikolaos Papadantonakis, Ryan D. Cassaday, Michaela Liedtke, Katrina Fischer, Tamara J. Dunn, Bhumika Patel, et al. "Prognostic Parameters in Adults with Acute Lymphoblastic Leukemia at Second Complete Response." Blood 128, no. 22 (December 2, 2016): 1603. http://dx.doi.org/10.1182/blood.v128.22.1603.1603.

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Abstract Background: Acute lymphoblastic leukemia (ALL) represents 20% of adult leukemias. With the optimization of doses and schedules of chemotherapy regimens, and incorporation of targeted agents into adult therapy, over 80% of adults with ALL attain a complete remission. However, the majority will ultimately relapse and the utility of prognostic criteria in predicting long-term survival at the time of 1st relapse has not been fully elucidated. We investigated the prognostic significance of neutrophil and platelet count recovery after salvage therapy in predicting long-term survival after second complete response [complete remission (CR), CR with incomplete platelet count recovery (CRp), or CR with incomplete neutrophil count recovery (CRi)] in adult patients (pts) with ALL. Methods: ALL pts at Cleveland Clinic, University of Washington, and Stanford treated during the yrs 1997-2015 were included. A total of 87 adult pts with ALL who achieved CR1 after induction treatment but subsequently relapsed and achieved second complete response with salvage therapy were analyzed. Pts refractory to salvage treatment and cases with isolated extramedullary relapse were excluded. Response to salvage treatment was assessed. CR was defined as <5% blasts with an absolute neutrophil count (ANC) of ≥1000/uL and platelets ≥100,000/uL; CRi: same as CR but ANC <1000/uL; CRp: same as CR but platelets <100,000/uL. Cases with both incomplete ANC and platelet recovery were categorized as CRi. Minimal residual disease (MRD) was assessed by ten-color flow cytometry and any abnormal blast population was considered MRD positive. Cytogenetic (CG) risk was ascribed by CALGB criteria. Results: Of 87 pts included, the median age was 37 yrs (range, 18-76) at diagnosis and 38 yrs (range, 20-73) at relapse. Fifty-five percent were males, 69% were Caucasian, 84% had B-ALL, and 23% had extramedullary involvement in addition to bone marrow involvement. Age, sex, race, immunophenotype and extramedullary involvement had no impact on overall survival (OS) or relapse-free survival (RFS) after first relapse. Sixty-eight percent of pts had available CG data at relapse, and of these, 39% had normal CG, while 37% were poor risk and 24% were grouped in "others". Of the poor risk pts, 68% were Ph+. CG risk at relapse had no impact on OS or RFS after first relapse. Relapse therapies included hyper-CVAD: 26%, high dose cytarabine: 17%; BFM-based regimens: 17%; inotuzumab: 13%; nelarabine: 8%; blinatumomab: 5%; and 14% of pts received other regimens. In addition, 70% of Ph+ pts received tyrosine kinase inhibitors in combination with salvage chemotherapy. Best response achieved was CR in 72%, CRp in 19%, and CRi in 9% of pts. Among 55 pts with MRD assessment following response to relapse therapy, 27% were MRD positive. The frequency of MRD positivity was significantly higher in pts with CRi (100%) as compared to CR (26%) and CRp (11%) (p=0.009). Pts with CRp or CRi after salvage treatment had worse OS compared to those with CR (p=0.006) (Figure 1A). Moreover, pts with CRi had worse RFS than those who attained CR or CRp (p=0.008) (Figure 1B). MRD positivity at the time of relapse response did not impact OS (p=0.48), but MRD negative pts had significantly better RFS than pts with MRD positivity (p<0.001) (Figure 1C). Sixty percent of pts received hematopoietic stem cell transplant (HCT) after salvage therapy in CR2, and 14% had HCT before relapse in CR1. Pts receiving HCT after salvage therapy had significantly longer OS (p<0.001) (Figure 1D) and RFS (p<0.001) (Figure 1E) than pts without HCT. Multivariable cox proportional hazard analysis included relapse treatment response (CR vs CRi vs CRp), MRD status at the time of relapse response, and HCT status, and demonstrated that MRD status at relapse response (p=0.002) and HCT (p<0.001) were independent predictors of RFS after first relapse. Type of salvage therapy response (CR vs CRi vs CRp) did not impact OS (p=0.17) or RFS (p=0.16) in multivariable analysis. Only HCT status was an independent predictor of better OS in multivariable analysis (p=0.006). Conclusion: In adult ALL pts who achieved CR2, CG risk at the time of relapse does not affect long-term survival. MRD positivity at the time of relapse response is an independent predictor of worse RFS, and it is associated with CRi. Ability to get to a successful HCT is the only independent predictor of longer RFS and OS at the time of CR2. Figure 1 Figure 1. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer Inc.: Consultancy, Research Funding; Blinatumomab: Research Funding.

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Castillo, Jorge J., James N. Butera, Eric S. Winer, Frederick Lansigan, Kayla Rosati, and Howard Safran. "Combination Of Ofatumumab and Bortezomib In Patients With Indolent B-Cell Lymphomas Who Relapsed >6 Months After Rituximab-Containing Regimen: A Brown University Oncology Research Group Phase II Study." Blood 122, no. 21 (November 15, 2013): 5121. http://dx.doi.org/10.1182/blood.v122.21.5121.5121.

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Abstract Introduction Based on the activity of ofatumumab in patients with indolent B-cell non-Hodgkin lymphoma (NHL) and the potential synergistic effect of bortezomib in combination with anti-CD20 antibody therapy, a phase II study to investigate the effect of the combination of ofatumumab and bortezomib in patients with relapsed indolent B-cell NHL who relapsed >6 months after receiving a rituximab-containing regimen was initiated. Methods Patients 18 years or older with a pathologically confirmed low-grade B-cell NHL who relapsed >6 months after a rituximab-containing regimen were included in our study. Other inclusion criteria were ECOG performance status <2, and adequate organ function (creatinine <2 mg/dl, total bilirubin <1.5x ULN, and liver transaminases <2.5x ULN) and bone marrow reserve (neutrophils >0.75, and platelets >50,000/uL). Exclusion criteria included HBV+, HIV+, transformed lymphoma, primary cutaneous lymphoma, central nervous system involvement, <6 months expected survival, and active infection. Treatment consisted of ofatumumab 1,000 mg IV and bortezomib 1.6 mg/m2 IV given weekly for 4 weeks (induction), then every 2 months (maintenance) to complete 12 months of therapy. Valacyclovir or acyclovir was given for herpes zoster prophylaxis while on bortezomib. Acetaminophen, diphenhydramine and glucocorticoids were administered prior to ofatumumab infusions. Response was assessed based on the Cheson criteria (2007). A sample size of 44 patients was planned, and an interim analysis after enrollment of 10 patients was undertaken to evaluate safety and early efficacy. Results We present data on 10 patients enrolled between October 2010 and April 2013. Median age was 66 years (range 55-93 years); eight patients (80%) were 60 years or older. There were 7 (70%) men and 3 (30%) women. LDH was elevated in 8 patients (80%). ECOG performance status was 0 in 9 (90%) and 1 in 1 patient (10%). Six patients (60%) had a histological diagnosis of follicular lymphoma, 1 (10%) mantle cell lymphoma, 1 (10%) small lymphocytic lymphoma, 1 (10%) marginal zone lymphoma, and 1 (10%) low-grade B-cell lymphoma, not otherwise specified. Stage III/IV was seen in 5 patients (50%). Eight patients (80%) had a high-risk FLIPI score. Median time from initial diagnosis to current therapy was 65 months (range 20-204 months). Median time from last rituximab-containing regimen was 24 months (range 11-48 months). Median number of previous therapies was 2 (range 1-4). Three patients (30%) had previously received radiotherapy. One patient (10%) had previously undergone autologous stem cell transplantation. Response rates after induction therapy were: 1 (10%) complete response (CR), 3 (30%) partial response (PR), 3 (30%) stable disease, 1 (10%) progressive disease, and 2 (20%) not evaluable for response. With exception of 1 patient who continues on therapy, the patients who achieved a response or had stable disease after induction therapy showed progression of disease during maintenance. Median duration of response in patients who responded was 4 months (range 1-9 months). At the time of this report, 7 patients (70%) are alive with disease, 2 (20%) are alive without evidence of disease, and 1 (10%) has expired. Five grade 3 or 4 adverse events (AEs) occurred; grade 4: diarrhea (n=1) and hyperglycemia (n=1); grade 3: infusion reaction (n=1), nausea (n=1) and rash (n=1). No grade 3 or 4 peripheral neuropathy or hematological AEs were observed. The most common grade 1 or 2 AEs were: infusion reactions (n=6), anemia (n=5), thrombocytopenia (n=5), fatigue (n=4), diarrhea (n=4), hyperglycemia (n=4) and lymphopenia (n=4). No deaths have occurred while on therapy. Conclusions The combination of ofatumumab and bortezomib given weekly for 4 weeks induced a response in 40% and stable disease in 30% of the patients. However, most of the patients experienced progression of disease during the maintenance phase of the study. Furthermore, there were five grade 3 or 4 AEs associated with therapy. Based on this interim analysis, it was decided to stop enrollment. The combination of ofatumumab and bortezomib, however, appears potentially active and deserves further study. Different schemas of therapy with longer induction or different maintenance schedule could prove to be safer and more effective. Disclosures: No relevant conflicts of interest to declare.

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Labrosse, Roxane, Julia Chu, Myriam Armant, Jet van der Spek, Alexandra Miggelbrink, Johnson Fong, John K. Everett, et al. "Outcome of Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome." Blood 134, Supplement_1 (November 13, 2019): 4629. http://dx.doi.org/10.1182/blood-2019-126161.

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Background Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, infections, autoimmunity and lymphoma. Gene therapy (GT) using autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplant for patients who lack well matched donors, avoiding graft-versus-host-disease. An initial experience with gene therapy using a γ-retroviral vector showed correction of hematological defects in 9/10 patients, but was aggravated by development of leukemia in 7 of them. We report the outcomes of a phase I/II clinical trial in which 5 WAS patients underwent GT using a self-inactivating lentiviral (SIN-LV) vector expressing the human WAS cDNA under the control of a 1.6kB fragment of the human WAS promoter. Subjects and Methods Five patients with severe WAS (clinical score 3-5) were enrolled at a median age of 1.8 years (1.4 - 8 years) at a single pediatric tertiary care center. WAS protein (WASP) was absent or markedly decreased in 2 and 3 subjects, respectively. Purified CD34+ cells from mobilized peripheral blood (n = 4) or both mobilized peripheral blood and bone marrow (n = 1) were transduced ex-vivo with the SIN-LV vector and re-infused after conditioning with busulfan (target AUC of 70-80 mg*h/L) and fludarabine (120mg/m2). The median dose of CD34+ cells infused was 9.8 x 106 cells/kg (6.3 - 24.9 x 106 cells/kg) with a mean vector copy number (VCN) of 1.7 copies/cell in CD34+ cells (0.54 - 3.37). In addition to eczema, thrombocytopenia and WAS-related infections in all patients, two subjects also had autoimmunity pre-GT, manifested as skin vasculitis and autoimmune cytopenias. Results All 5 subjects were alive and well at median follow-up of 4.8 years (2.5 - 5.9 years). Multi-lineage vector gene marking was sustained over time. All subjects had improvement or resolution of eczema and none have had any intercurrent severe infectious events. WASP expression measured by flow cytometry in T cells was increased over baseline in all patients, but remained below normal levels and correlated with VCN and cell dose received. Proliferation of T cells in response to anti-CD3, which was initially defective in 4/5 patients, improved post-GT. Humoral immune deficiency was also ameliorated, as evidenced by independence from Ig replacement and vaccine responses in those tested. All subjects remained platelet transfusion-free and none have had severe bleeding events. Platelet levels increased to >50 x 103 cells/uL in two patients with a VCN ≥2 in transduced stem cells and myeloid VCN ~1 copy/cell in neutrophils; the other 3 subjects sustained platelet counts <50 x 103 cells/uL. Cytoskeleton function was highly abnormal in myeloid cells pre-GT, as shown by the near absence of podosome formation in monocyte-derived dendritic cells. At 12 months post-GT, the % of podosome-forming cells was improved in all subjects, and reached the level of healthy controls in the 2 patients with highest VCN in myeloid cells. Both subjects with pre-existing autoimmunity had post-GT autoimmunity: patient 4 had a flare of autoimmune cytopenias at 18 months post-GT, and patient 5 developed refractory autoimmune hepatitis and hemolytic anemia at 8 months post-GT. While all subjects had WASP expression in lymphocytes, those with autoimmunity had poor recovery of T cells, Tregs, and transitional B cells at the time of clinical symptoms. IL-10 producing regulatory B cells were deficient pre-GT and recovered to varying degrees in all subjects. No severe GT-related adverse events have occurred to date. Replication-competent lentivirus was not detected. Analysis of integration site distributions in five subjects showed reconstitution to be highly polyclonal, with no clones expanded to >20% of the transgene-marked cell population. To date, there have been no malignancies reported, either related to GT or WAS itself. Conclusion In summary, our data confirm and extend the safety and efficacy of GT in correcting disease manifestations associated with WAS, as seen in other studies using SIN-LV. Higher VCN in the drug product and in transduced stem cells correlated with better reconstitution of platelets and myeloid function. In contrast to other groups, we found in our study that patients with poor lymphocyte reconstitution post-GT may be at risk of ongoing autoimmunity despite high-level gene marking. Disclosures London: ArQule, Inc: Consultancy; United Therapeutics: Consultancy. Despotovic:Novartis: Research Funding; Amgen: Research Funding; Dova: Honoraria. Forbes:Takeda: Consultancy. Galy:Genethon: Employment. Williams:Novartis: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Other: License of certain IP relevant to hemoglobinopathies. Potential for future royalty/milestone income. Received payment in past through BCH institutional licensing agreement., Research Funding; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder, potential for future royalty/milestone income, Research Funding; Alerion Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. OffLabel Disclosure: CliniMACS technology for CD34+ cell selection

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Advani, Anjali S., Holly Gundacker, Nolyn Nyatanga, Paul Elson, Peter J. Rosen, Jennifer Bates, Mikkael A. Sekeres, et al. "Response to High Dose Cytarabine (HIDAC) As First Salvage for Relapsed Acute Lymphocytic Leukemia in Patients Receiving HIDAC As Initial Therapy." Blood 118, no. 21 (November 18, 2011): 2594. http://dx.doi.org/10.1182/blood.v118.21.2594.2594.

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Abstract Abstract 2594 The treatment of adult acute lymphocytic leukemia (ALL) is challenging. Traditional induction regimens have incorporated vincristine, anthracycline, asparaginase, and steroids that result in high rates of complete remission (CR). However, less than half of pts in CR will be cured. To improve results, high dose cytarabine (HIDAC) has been increasingly incorporated into post-remission therapy. Since HIDAC is often used to treat relapsed ALL, we hypothesized that the prior use of HIDAC would reduce the CR rate when it is applied to pts at the time of their first relapse. Methods: Consecutive pts with ALL in first relapse treated with HIDAC-containing regimens either at the Cleveland Clinic (CC) between the years 1993–2010 or at any institution participating in SWOG trial S9030 (HIDAC 3000 mg/m2 Days 1–5, mitoxantrone 80 mg/m2 Day 1) (1992–1993) were included. HIDAC was defined as a cycle of at least 3000 mg/m2 × 5 days. Remission was defined according to standard criteria. The outcome analysis [CR and overall survival (OS)] was adjusted for the following factors: age, WBC at diagnosis, cytogenetic (CG) risk, immunophenotype, transplant, and prior HIDAC exposure. Results: Sixty-six pts were included (39 treated at CC, and 27 as part of SWOG protocol S9030). All pts received a vincristine/prednisone/anthracycline/steroid-based induction regimen (S8417, CALGB 19802, CALGB 8811) except for 1 pt who was treated with hyperCVAD. Seventeen pts treated at CC had HIDAC incorporated into their initial treatment (1: hyperCVAD; 16: CALGB 19802), but none of the SWOG pts did. The median age was 35 yrs (range 17 to 73). The median WBC at the time of diagnosis for CC pts was 21.4 K/uL (range 0.5–260.0) and median WBC at the time of study registration for SWOG patients was 17.6 K/uL (range 0.4–198.4). Three pts (5%) had a mixed (B/T) lineage leukemia. Three patients had lymphoblastic lymphoma (1 B-cell; 2 T-cell) at the time of initial diagnosis, and had ALL at the time of relapse. For the 39 CC pts, the median time from diagnosis to relapse was 12 mos (range 1–55 mos). CG risk was ascribed by CALGB criteria. Of the 50 pts with evaluable pre-study CG, 20 pts (40%) had normal CG, 18 (36%) miscellaneous, and 12 (24%) poor risk CG. Twenty pts (30%) received HIDAC alone, and 46 (70%) received HIDAC in combination with other drugs for relapsed ALL. The CR rate for all relapsed pts was 32% (CC 36% and SWOG 26%) and was not affected by the addition of other drugs to HIDAC. Twenty-nine patients (44%) were able to proceed to HSCT; and the median OS was 5.4 mos (95% CI: 4.8–6.0 mos). After adjusting for all baseline and demographic factors, the CR rate and OS between pts receiving or not receiving HIDAC during initial treatment was not significantly different. Five of 17 (29%: 95% CI 10%-56%) pts with prior exposure to HIDAC achieved CR while 16 of 49 (33%: 95% CI 20%-48%) pts without prior HIDAC exposure achieved a CR (p=0.80). The 1 year OS (from salvage) for pts treated with HIDAC for relapse who also were treated with prior HIDAC was 12% (95% CI: 0%-27%) and for pts not treated with prior HIDAC was 33% (95% CI: 20%-46%)(p=0.17). Since additional information was available on the CC pts, additional analyses were performed on this subgroup of pts. With the exception of lymphoblastic lymphoma at the time of diagnosis, no other factors correlated with achievement of CR. Achievement of CR was the only factor associated with proceeding to HSCT (79% vs. 36%, p=0.01). Variables associated with improved OS included: lymphoblastic lymphoma at the time of diagnosis (p=0.04; 2 of the 3 pts are still being followed at 80+ and 96+ mos), achievement of CR (p=0.0001), longer remission (> 30 mos, p=0.005), and transplantation (p=0.0001). Conclusion: The outcome of relapsed ALL with HIDAC salvage therapy is dismal, regardless of prior HIDAC exposure; and novel treatments are needed. There was a suggestion that the OS of pts with prior HIDAC exposure may be lower, but further study of 1 year OS with larger pt numbers will be needed to evaluate this. An interesting finding in this study was the favorable outcome of pts with lymphoblastic lymphoma at diagnosis, who subsequently relapsed in the leukemic phase and were treated with HIDAC. However, few pts carried this diagnosis and a larger number of pts are required before drawing firm conclusions. Disclosures: No relevant conflicts of interest to declare.

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Manotas, Karen, Jenny Jin, Cheryl Vinograd, Julia Gabor, Megan Wissert, Richard L. Berkowitz, Janice G. McFarland, and James B. Bussel. "Enhancing Therapy To Avoid Fetal Blood Sampling (FBS) In Antenatal Management Of Alloimmune Thrombocytopenia (AIT)." Blood 122, no. 21 (November 15, 2013): 1072. http://dx.doi.org/10.1182/blood.v122.21.1072.1072.

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Abstract Introduction Neonatal AIT (NAIT) is a potentially life-threatening, often severe thrombocytopenia caused by a parental human platelet antigen (HPA) incompatibility resulting in maternal alloantibodies attacking fetal platelets. NAIT affects approximately 1 in 1000 live births and may be accompanied by intracranial hemorrhage (ICH) in 10-20% of cases. Since there is no routine screening for NAIT, it is usually diagnosed after birth of the first affected thrombocytopenic fetus. Mothers of NAIT babies can be treated during subsequent affected pregnancies with IVIG and corticosteroids to increase fetal platelet counts and avoid fetal/neonatal ICH, using fetal blood sampling (FBS) to monitor treatment. Using this approach in previous studies IVIG 1g/kg alone (no steroids) was shown to not be effective in severely thrombocytopenic fetuses with AIT. While FBS allows enhancing therapy (salvage) in poor responders, it is a high-risk procedure associated with adverse fetal outcomes (eg premature delivery and fatal umbilical cord hemorrhage). This study assessed the efficacy, benefits and pitfalls of: a) 2 different regimens in treatment of fetal AIT, both of which are “more” than IVIG 1g/kg alone, and b) an alternative approach, omitting FBS in affected women without a history of ICH in a prior affected sibling and enhancing treatment empirically at 32 weeks, ie treating mothers as if they had undergone FBS and had a low fetal platelet count (FPC). Methods Antenatal treatment in this study compared IVIG 2g/kg/wk (arm A) to IVIG 1g/kg/wk + prednisone (arm B) starting at 20-30 weeks of gestation until delivery, with FBS at 32 weeks. In the alternative treatment arm which was added at the end of the study, all women were treated with IVIG 2g/kg/wk + prednisone 0.5mg/kg (Salvage) after 32 weeks. This prospective multicenter study included 99 mothers and 102 fetuses enrolled from May 2001 to November 2012. All mothers had documented NAIT and those with ICH in a previous child were excluded. FPC, birth platelet count (BPC) and ICH were compared among the 3 treatment regimens outlined above: 1) arm A, 2) arm B, and 3) either Arm A or Arm B followed by empiric salvage without FBS. Results There was no difference in efficacy of treatment between arm A versus arm B; both increased BPC to greater than or equal to 50k in the fetus/neonate in 85% or so of cases (table 1). In 30 pregnancies in which Salvage was used, there were 16 fetuses who did not undergo FBS and 14 who did. Only 2 of the 30 receiving Salvage had BPC < 50,000/uL (50k); whereas, 9 of 72 neonates not receiving salvage therapy had a BPC < 50k. When only fetuses with an FPC < 50k were included, 13/14 receiving Salvage had a BPC > 50k whereas only 1 of 5 not on Salvage did (table 2; p=0.006). Overall, of 102 fetuses, 11 had a BPC ≤ 50 (poor responders). Among these 11 poor responders, 0 resulted in ICH, 9 did not receive Salvage treatment (5 in arm A; 4 in Arm B), and 1 of 2 receiving Salvage was only on it for 1.5 weeks. Common adverse effects related to IVIG include headaches, skin rashes, flushing and nausea; these were self-reported by treated mothers and obtained by chart review including nursing records. Also increased hemolysis in mothers with blood type A occurred and was presumed to be caused by anti-A present in IVIG (see separate abstract at this meeting). Conclusions Arms A and B were approximately equally effective; however, both resulted in approximately 15% of low FPC at 32 weeks. These findings support the hypothesis that empiric addition of salvage treatment at approximately 32 weeks of gestation is needed in treating affected cases of NAIT to avoid fetal blood sampling and its substantial attendant complications. The addition of Salvage is highly effective in treating fetal AIT and eliminates risks associated with FBS and greatly reduces the chance of a BPC < 50k. However, adverse events have been seen from the increased dosage of IVIG and prolonged prednisone and require careful monitoring. Disclosures: Bussel: Sysmex: Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.

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Grosso, Dolores, Onder Alpdogan, Matthew Carabasi, Joanne Filicko-O'Hara, Sameh Gaballa, Margaret Kasner, Thomas R. Klumpp, et al. "2 Step Myeloablative Haploidentical Transplant (HI MA HSCT) in Intermediate and High-Risk Patients-Changing the Timing of the 2 Step Approach." Blood 132, Supplement 1 (November 29, 2018): 4661. http://dx.doi.org/10.1182/blood-2018-99-110815.

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Abstract Mortality from relapsed disease remains a significant barrier to long term survival (OS) after HI HSCT despite presumed heightened alloreactivity from the mismatched graft. The Jefferson group uses a 2 step approach to HI HSCT where patients are typically conditioned with 12 Gy total body irradiation (TBI) in 8 fractions of 1.5 Gy over 4 days, immediately followed by an infusion of 2 x 108/kg donor CD3+ cells (DLI). After 2 rest days, cyclophosphamide (CY) 60 mg/kg daily x 2 is given for bidirectional tolerization, followed a day later by a CD34 selected stem cell infusion. In an attempt to maximize graft versus tumor (GVT) effects, we changed the timing of the TBI in the 2 step approach. In this updated regimen, TBI was given in 6 fractions of 2.0 Gy over 3 days, resulting in a 24 hour delay between conditioning and DLI. Theoretically, the extra time reduced residual disease burden prior to the introduction of the DLI, in turn reducing the number of donor T cells activated by tumor, thus avoiding their elimination by CY. Major HSCT endpoints of OS (Kaplan Meier), relapse and non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) [cumulative incidence (CI)-EZR Software v 1.37] were assessed using this updated 2 step HI HSCT approach. Forty patients, median age 51 (range 19-65) years with AML (13), MDS (7), B ALL (7), PH+ ALL (4), T cell ALL (2), Burkitt (2), and other heme malignancy (5) with revised disease risk assessment scores of intermediate (21), high (17), and very high (2) were treated from 2013 to 2017. Median follow-up is 36 (range 15 to 56) months. At 24 months, probability of OS was 59%, CI NRM and relapse were 34% and 15% respectively. CI aGVHD (grades 2-4), (grades 3-4), and cGVHD were 38%, 5%, and 20%. Median d+28 T cell chimerism of 36 patients engrafted and alive was 100% (range 97% to 100%). Median CD3/4 and CD3/8 counts at d +28 were 49 (range 9-417) and 54 (8-1329) cells/ul. Of the 4 remaining patients, two without donor specific antibodies rejected their graft, one with a large burden of CMML at the time of HSCT. An additional patient relapsed prior to the attainment of sustained donor T cell chimerism and one patient died of sinusoidal obstructive syndrome prior to d+28. Causes of death were infection (7), regimen toxicity (4), GVHD (2), and disease (3). This updated 2 step regimen was associated with a highly acceptable 2 year OS rate and low rates of disease recurrence. Of the patients that died, cause of death was primarily due to NRM and not relapsed disease suggesting that the added extra day may have enhanced GVT effects. In the absence of donor specific antibodies, the 2 early and 1 late graft rejections are atypical for a 2 step MA HI HSCT approach and were potentially caused by a rebound recipient hematopoiesis allowed by the delay in the DLI in a minority of patients. While formal comparison to prior patient cohorts is not feasible, this relapse rate compares favorably to the 2 year 27% relapse rate in similar patients treated on our initial trial.(Grosso, et al., Blood, 2011, 118:47320). The concept of allowing time for malignancy burden to decline in high risk patients prior to introduction of DLI warrants further evaluation going forward in efforts to reduce relapse after HSCT. Table. Table. Disclosures Porcu: Innate Pharma: Consultancy.

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Baltathakis, Ioannis, Fotios Panitsas, Anna Komitopoulou, Ifigeneia Tzannou, Stavros Gigantes, Spyridoula Vasileiou, Zoi Poulopoulou, et al. "Double Umbilical Cord Blood Transplantation Offers Stable Donor Engraftment and The Prospect Of Cure In Adult Patients With High-Risk Hematologic Malignancies." Blood 122, no. 21 (November 15, 2013): 5516. http://dx.doi.org/10.1182/blood.v122.21.5516.5516.

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Abstract Allogeneic stem cell transplantation (allo-SCT) remains the main therapeutic option for patients with high-risk hematologic malignancies, albeit with the requirement of a properly matched and timely available donor. Dual-unit umbilical cord blood transplantation (dUCBT) has become an alternative modality, which offers immediate access to allo-SCT for most adult patients who lack an appropriate volunteer donor. We retrospectively analyzed the outcomes of consecutive dUCBT procedures that were undertaken by our center over a seven-year period, with focus on factors affecting engraftment and survival. Between 2006 and 2013, 40 patients underwent dUCBT at a median age of 37 years (range, 16-60) for various hematologic malignancies (acute myeloid leukemia: 22, myelodysplastic syndrome: 5, chronic myelogenous leukemia: 2, acute lymphoblastic leukemia: 6, mixed-phenotype acute leukemia: 2, plasmacytoid dendritic cell neoplasm: 1, hepatosplenic T cell lymphoma: 1, chronic lymphocytic leukemia: 1). The majority of patients (73.7%) had advanced or intermediate-phase disease at the time of transplantation, with a median time from diagnosis to transplant of 17.7 months (range:3.1-92.3). Recipient body weight ranged from 48 to 110 kg (median, 73). The conditioning regimen was myeloablative in 33 (82.5%) patients (busulfan-based in 22, and total body irradiation-based in 11 cases). Antithymocyte globulin was not administered during conditioning, with the exception of one case. Most units (55/80, 68.75%) were 4/6 antigen matched to recipient at HLA-A, -B, and -DRB1 loci, and the remaining were 5/6 matched. By retrospective high-resolution typing for class I HLA alleles, histocompatibility was demoted in 62.3% of units. By additional allele-level typing at HLA-C and -DQB1 loci, the degree of compatibility varied from 8/10 to 3/10, with 80.5% of the units being ≤6/10 matched to the patient. The median dose of cryopreserved total nucleated cells (TNC) per unit was 2.53 x 107/kg (range, 1.09-5.66). At infusion, patients received in total a median of 4.55 x 107 TNC/kg (range, 2.65-9.3) and 1.7 x 105 CD34+ cells/kg (range, 0.54-5.14) from both units. The cumulative incidence (CI) of neutrophil engraftment was 92.5% (37/40 patients), with achievement of an absolute neutrophil count (ANC) greater than 500/uL at a median of 20 days (range, 12-52) (Figure 1). Platelet recovery (>50x109/L) occurred at a CI of 63.2%, and a median time of 84 days (range, 32-363). No influence of cell dose (TNC or CD34+) or of the degree of HLA match on the incidence and kinetics of engraftment could be detected. Acute graft-versus-host disease (aGVHD) of grades II-IV and III-IV developed in 85% and 12.65% of patients, respectively. The CI of chronic GVHD was 31% (extensive in 54.5% of cases). There was a statistical trend for increased incidence of cGVHD with <6/10 HLA match at the allele level (p=0.068; HR, 3.35; 95% confidence interval [ci], 0.92-12.24). Non-relapse mortality (NRM) reached 43.1% (95% ci, 27.0-58.2) at 10.3 months, but no case of NRM was noted thereafter (Figure 2). Major causes of NRM were infection/sepsis (n=11), GVHD (n=3), and engraftment failure (n=3). The CI of relapse was 22.7% (95% ci, 10.7-37.5). Relapse was the cause of death of 6 patients. With a median follow-up of 30 months (range, 2-84), overall (OS) and disease-free survival (DFS) rates at 2 years were 36.5% (95% ci, 21-52) and 34.2% (95% ci, 19.3-49.6), respectively (Figure 3). Sixteen of 40 patients are alive and disease-free for a median time of 30 months from transplant. Age ≤37 years, recipient CMV seronegativity, and early disease phase at transplant were associated with improved OS in univariate analysis. Age remained as the only independent risk factor for OS in multivariate analysis of OS (p=0.022). Age ≤37 years was also found to be associated with reduced NRM (p=0.055), and favorable DFS (p=0.04).Figure 1Cumulative Incidence curve of neutrophil (ANC>500/uL) engraftment.Figure 1. Cumulative Incidence curve of neutrophil (ANC>500/uL) engraftment.Figure 2Cumulative Incidence curve of non-relapse mortality.Figure 2. Cumulative Incidence curve of non-relapse mortality.Figure 3Overall Survival (Kaplan-Meier curve).Figure 3. Overall Survival (Kaplan-Meier curve). In conclusion, dUCBT can lead to stable donor engraftment even across multiple HLA disparities and can overcome the barrier of cell dose. Despite considerable early mortality, dUCBT offers the possibility of long-term survival in about one third of adult patients with poor-prognosis hematologic malignancies, for whom allo-SCT would not be otherwise feasible. Disclosures: No relevant conflicts of interest to declare.

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Melani, Christopher, Mark Roschewski, Stefania Pittaluga, Jeffrey Cohen, Andrea Nicole Lucas, Seth M. Steinberg, Elaine S. Jaffe, and Wyndham H. Wilson. "Phase II Study of Interferon-Alpha and DA-EPOCH+/-R in Lymphomatoid Granulomatosis." Blood 132, Supplement 1 (November 29, 2018): 785. http://dx.doi.org/10.1182/blood-2018-99-116707.

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Abstract Background: Lymphomatoid granulomatosis (LYG) is a rare EBV-driven B-cell lymphoproliferative disorder characterized by a reactive T-cell infiltrate that is angioinvasive and angiodestructive. Dysregulated immune surveillance of EBV is thought to contribute to the pathogenesis of LYG and grading of disease is based on the density and number of EBV+ large atypical B-cells. Grade I-II (low-grade) disease is typically polyclonal/oligoclonal and immune-dependent whereas grade III (high-grade) disease is typically monoclonal and immune-independent. Herein, we report additional and extended results from an on-going prospective study at the National Cancer Institute on the treatment of patients with low and high-grade LYG using Interferon-α (INF-α) and/or DA-EPOCH+/-R, respectively. Methods: Pts with histologically confirmed LYG by the Laboratory of Pathology, NCI, were eligible. LYG of any grade or stage was included as were pts with untreated or previously treated disease. Baseline tests included laboratory studies, body CT and FDG-PET, CT or MRI brain, echocardiogram, LP with flow cytometry/cytopathology, and bone marrow aspiration/biopsy. Grade 1-2 LYG pts received primary therapy with INF-α initially at 7.5 MIU TIW which was dose-escalated every 1-2 wks. as tolerated until best response and then continued for 1 yr. Pts with grade 3 LYG received combination chemotherapy with DA-EPOCH+/-R for up to 6 cycles. Pts with progression after primary INF-α therapy and those who progressed after or failed to achieve CR after DA-EPOCH+/-R could cross over to the other treatment. Restaging CT was performed every 4 wks. until stable dose of INF-α and then every 3 mos. and after cycles 4 and 6 of DA-EPOCH+/-R. Surveillance CT was performed every 3, 4, 6 and 12 mos. for post-treatment yrs. 1, 2, 3, and 4-5, respectively, and then as clinically indicated. Results: 70 LYG pts were enrolled between Jan. 1991 and Feb. 2018. Characteristics included; male sex in 45 (64%) pts, median (range) age of 46.2 yrs. (14.9-67) and histologic grade I in 19 (27%), II in 24 (34%), and III in 27 (39%) pts. Twenty-three (33%) pts were untreated, and 32 (46%) and 21 (30%), respectively, had received steroids and/or chemotherapy+/-R. The most common disease sites included lung (100%), CNS (37%), skin (33%), kidney (17%), and liver (17%). Peripheral blood at baseline showed median (range) CD4, CD8 and NK-cell counts of 510 (80-1864; Normal: 359-1565), 138 (8-1245; Normal: 178-853), and 96 (25-1567; Normal: 126-729) cells/uL, respectively, and a median (range) EBV viral load of 100 (1-13,950) copies/mL and 3.48 (0-4.48) Log 10 IU/mL. With a median potential follow-up of 12.9 yrs., 5-yr. PFS and OS for all 67 treated pts was 41% and 70.8%, respectively (Fig.1). There was no significant difference in PFS or OS associated with baseline histologic grade (p=0.47 and p=0.23, respectively) or CNS involvement (p=0.67 and p=0.98, respectively). Of 49 INF-α treated pts, 47 were evaluable for response with an ORR of 60% (CR 55%) and a median (range) TTR of 6.7 mo. (1.4-40) and 5-yr. DOR of 66.6% (95% CI: 45.4-81.1%). ORR was similar [60% (CR 55%)] in the 20 INF-α treated pts with baseline CNS involvement. Overall, in 49 INF-α treated pts, 5-yr. PFS and OS were 46.2% and 72.5%, respectively (Fig.1). Median (range) dose and duration of INF-α was 20 MIU (7.5-40) and 7.9 mo. (0.5-48.6), respectively. Nineteen pts received secondary therapy with DA-EPOCH+/-R for progression during/after INF-α with an ORR of 72% (CR/CRu 56%) in 18 evaluable pts. In 13 evaluable pts refractory to INF-α, ORR was 92% (CR/CRu 69%) with DA-EPOCH+/-R. Of 18 DA-EPOCH+/-R treated pts, 17 were evaluable for response with an ORR of 76% (CR/CRu 41%) and a median (range) TTR of 4.1 mo. (2.6-7.4) and median DOR of 1.5 yrs. (95% CI: 0.3-9.2). Overall, in 18 DA-EPOCH+/-R treated pts, 5-yr. PFS and OS were 27.8% and 66.2%, respectively (Fig.1). Eight pts received secondary INF-α therapy for progression during/after or failure to achieve CR after DA-EPOCH+/-R with an ORR of 75% (CR/CRu 63%). Conclusion: INF-α and DA-EPOCH+/-R result in prolonged remissions in a significant subset of pts with low and high-grade LYG, respectively. Progression to high-grade disease and relapse with low-grade disease following INF-α and DA-EPOCH+/-R treatment, respectively, occurs frequently due to the continued immune dysregulation of EBV and can be successfully treated through cross over to the alternative treatment modality. Disclosures No relevant conflicts of interest to declare.

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Farooqui, Mohammed, Jay Nelson Lozier, Janet Valdez, Nakhle Saba, Ajunae Wells, Susan Soto, Delong Liu, Georg Aue, and Adrian Wiestner. "Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Patients and Has Minimal Effects On Platelet Aggregation." Blood 120, no. 21 (November 16, 2012): 1789. http://dx.doi.org/10.1182/blood.v120.21.1789.1789.

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Abstract Abstract 1789 INTRODUCTION: Ibrutinib (PCI 32765) is an orally administered covalent inhibitor of Bruton's Tyrosine Kinase (BTK). Ibrutinib has significant activity in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is typically well tolerated (Byrd ASCO 2011, O'Brien ASH 2011). Rarely serious bleeding in patients concurrently on oral anticoagulation has been reported but was not related to thrombocytopenia (O'Brien ASH 2011). However, grade 1 or 2 ecchymosis/contusion is a frequent adverse event in patients on ibrutinib. In addition to being essential for B cell receptor signaling BTK is also involved in the signaling of the glycoprotein (GP)VI and GPIV von Willebrand (vW) receptors (Liu, Blood 2006). Thus, it is possible that ibrutinib could increase the bleeding risk by interfering with thrombus formation. In addition, lymphoproliferative disorders and some drugs have been associated with acquired vW-disease (AvWD). METHODS AND PATIENTS: In an ongoing single center, open label phase II trial we treat CLL/SLL patients with ibrutinib 420 mg daily on 28 day cycles (NCT01500733). We measured platelet (PLT) function on the PFA-100 instrument, vW-factor (vWF) antigen levels and activity (vWF-Ag/vWF-Act), and factor VIII (FVIII) on baseline, days 2 and 28. Here we report on effects of ibrutinib on platelet counts and function in 25 patients who completed >2 cycles. RESULTS: PLT counts prior to treatment ranged from 36 k/μl to 256 k/μl with a median of 102 k/μl. Twelve (48%) patients had a pre-treatment PLT count <100 k/μl. Median PLT counts for days 14, 28, and 56 increased to 140, 137, and 135 k/μl, respectively (P<.01). 76% of patients showed an increase after only 2 weeks on drug (median increase 25 k/μl (range 4–183 k/μl) that was sustained at subsequent timepoints. On day 14, 6 patients (24%) had a decrease in PLT count by a median of 13 k/μl from baseline; of these, 3 had a pre-treatment PLT count of <100 k/ul and 1 developed grade III thrombocytopenia (42 k/μl) that resolved to >100 k/μl by day 56. 20% (5 of 25) of patients reported grade 1 spontaneous ecchymosis with no correlation to platelet count, PFA testing, or vWF measurements. Of note we performed lymph node core biopsies in 35 patients taking ibrutinib with minimal bruising. Only 2 patients had more extensive local bruising/ecchymosis at the biopsy site. In 19 patients PFA-100 measurements of epinephrine (EPI) and adenosine diphosphate (ADP) stimulated platelet aggregation times were available (test requires PLT count >100 k/μl). Median changes in closure times with EPI and ADP on treatment were not significantly different from baseline (See table). Four (21%) patients started with abnormally prolonged EPI closure times (one on aspirin, one on ibuprofen; discontinued with the start of ibrutinib) which resolved by day 28 in 3 and decreased in 1. Three (16%) patients had a prolongation of EPI closure times on day 2 that resolved by day 28 in 2 and decreased in 1. All closure times on ADP were low or normal. No patients with abnormal PFA testing demonstrated spontaneous ecchymosis. From baseline to day 28 vWF-Act, vWF-Ag and FVIII decreased (P<0.05; n=24). All 3 values were high normal to elevated prior to treatment and decreased to normal on treatment. CONCLUSION: This preliminary report does not identify any significant ibrutinib effect on platelet function. PLT counts improved rapidly in the majority of patients and when seen transient decreases have been minimal. Three patients (16%) developed an abnormal reading in PLT function tests on treatment but none developed spontaneous echymosis or bleeding. The observed normalization of mildly elevated baseline levels of vWF and FVIII seems most consistent with a reduction in acute phase reactants and there was no evidence for AvWD on ibrutinib. The apparent functional tolerance of BTK inhibition in platelets is likely attributable to redundancy in the affected signaling pathways. This work was supported by the Intramural Research Program of NHLBI, NIH. We thank our patients for participating in these research studies. Disclosures: No relevant conflicts of interest to declare.

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Chari, Ajai, Hearn Jay Cho, Samir Parekh, Kenneth Lau, Gillian Morgan, Donna Catamero, Melissa Cortes, et al. "A Phase II Study of Pomalidomide, Daily Low Dose Oral Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 4520. http://dx.doi.org/10.1182/blood.v128.22.4520.4520.

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Abstract Background A treatment option for patients with relapsed/refractory multiple myeloma (RRMM) is pomalidomide(pom) and dexamethasone (dex), with an overall response rate (ORR) of 33% and median progression free survival (PFS) of 4.2 months. Adding the alkylatingagent cyclophosphamide(Cy) to pom and steroids improves ORR and PFS. Baz et al (Blood, 26 May 2016) combined daily pom with weekly dosing ofCy anddex (PCD), with an ORR of 64.7% and a median PFS of 9.5 months, although grade 3/4 neutropenia increased from 31% to 52%. In our experience, compared to weekly Cy, low dose daily oral Cy is better tolerated with less myelosuppression. Palumbo et al (Blood, 17 Oct 2013) in fact combined pom with alternate day dosing ofCy and prednisone, with an ORR of 51% and a median PFS of 10.4 months and a grade 3/4 neutropenia rate of 42%. However, importantly, granulocyte stimulating factor (G-CSF) and platelet transfusion support wereprohibited, resulting in a lower maximum tolerated dose of pom of 2.5 mg (vs 4 mg in the Baz) and therefore, the rates of neutropenia cannot be compared between the two studies. In the present study, we explored PCD at the doses/schedule shown in table 1 with hematologic support even in patients with baselinecytopenias. This type of metronomic therapy has demonstrated efficacy in refractory B cell malignancies, possibly because the anti-angiogenic effects of metronomic therapy may be synergetic with conventional anti-neoplastic agents. Methods This was an open label, single arm, and single center phase 2study. The primary objective was to evaluate the best ORR. Secondary objectives were to evaluate safety, clinical benefit response (CBR), PFS, and overall survival (OS). Inclusion criteria included lenalidomide refractory, pom naïve RRMM patients with at least 2 prior lines of therapy. Patients were required to have measurable disease, adequate performance status, Cr <3 mg/dL, normal hepatic function, and ANC > 1000/uL and platelets > 50,000/uL if bone marrow plasma cells were < 50%, otherwise >30,000/uL. G-CSF and platelet support were permitted during screening and study treatment if needed. Each drug was administered at the doses and schedule shown in Table 1. Results Overall, 28 evaluable patients with progressive disease (PD) at screening have been enrolled. The median age is 66 (57% > 65 yr) with a median of 3 lines of prior therapy over 5 years since diagnosis. 3 (11%) had ANC<1.5 and 2 (7%) hadplts<50,000/µL at study entry.High-risk molecular findings were present in 13 patients (46%), including 3 with del p53 and 6 with gain of 1q21 by FISH (2 with concurrentt(4;14) and 2 with concurrent del p53). With 8 patients still on study therapy, responses include 3 complete responses (CR), 7 very good partial responses (VGPR), 9 partial responses (PR), 3 minor responses (MR), 5 stable disease (SD), and 1 PD, for an ORR of 67%, CBR (i.e. MR or better) of 78% and a median PFS of approximately 14.5 months. The median OS has not been reached. The most common grade 3/4 toxicity (regardless of drug attribution) was neutropenia with 20 (71%) of subjects experienced grade 3/4 neutropenia. Importantly, there was only 1 episode of febrile neutropenia during study therapy. Grade 3/4 thrombocytopenia was seen in 25% of subjects, and 3/4 anemia seen in 18%. The most common grade 3/4 non-hematologic toxicity was pulmonary disease with Grade 3 lung infections occurring in 21% of subjects (3 viral, 2 bacterial, 1 unknown) and 1 additional grade 3 URI. Of note, all of these admissions occurred at local hospitals and none of these occurred in the setting of neutropenia. One additional pt hadpneumonitisattributed to pom requiring study discontinuation. Grade 3rashwas also observed in 14% of subjects leading to pom dose reductions. Correlative data from peripheral blood and bone marrow aspirates taken at baseline, Cycle 3 Day 15, and at disease progression from all patients will be updated at the time of conference. These include PCD-associated changesin gene expression, clonal evolution and immune microenvironment during therapy and on progression. Conclusions With toxicities similar to those in other studies, the ORR of 67% and PFS of 14 months in our study of PCD compares very favorably to pomdexas well as other triplet regimens containingCy. Disclosures Chari: Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Catamero:Celgene: Honoraria, Speakers Bureau. Verina:Celgene: Speakers Bureau. Jagannath:Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Sun, Weili, Jemily Malvar, Richard Sposto, Anupam Verma, Jennifer J. Wilkes, Robyn M. Dennis, Kenneth Matthew Heym, et al. "Re-Induction Outcome for Pediatric Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of the Therapeutic Advances in Childhood Leukemia Consortium." Blood 126, no. 23 (December 3, 2015): 3760. http://dx.doi.org/10.1182/blood.v126.23.3760.3760.

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Abstract Introduction Remission induction rates after a second or greater relapse is a critical endpoint in phase II trials of childhood acute lymphoblastic leukemia (ALL). A robust benchmark is crucial for identification of novel multi-agent regimens worthy of further study. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium previously reported the response rates of children with multiply relapsed and refractory (R/R) ALL treated between 1995 and 2004, which provided a benchmark for clinical trials. To define more recent treatment patterns and test the robustness of this benchmark, we performed a retrospective cohort review of children with R/R ALL who experienced second or greater treatment failure at TACL consortium sites between 2005 and 2013. Patients and Methods Eligible patients were identified at participating TACL institutions. This cohort was comprised of patients with medullary R/R B-cell precursor ALL who experienced at least 2 treatment failures or relapsed after hematopoietic stem cell transplant. Patient demographic data and details of the initial and R/R disease characteristics were abstracted from medical records and entered into a central database. This study was approved by the IRB of each participating institution. Treatment failure was defined by the presence or re-emergence of circulating blasts, M2/M3 BM, or extramedullary (EM) disease despite therapy. Complete remission (CR) was defined as M1 marrow, no EM disease and evidence of peripheral count recovery. For the purpose of statistical analysis, patients who met these criteria without platelet recovery (CRp) or normal blood count recovery (CRi) were included as CR. Univariate and multivariate logistic regression were utilized to evaluate the risk of re-induction failure. Predictors included in this preliminary analysis were NCI risk criteria at diagnosis, duration of the prior remission, the treatment attempt number, and the EM and BM status at the start of each therapy attempt. Results This report includes 214 patients. Fifty-six percent were male. At initial diagnosis, 32% were at least 10 years old, 26% had initial white blood cell (WBC) counts over 50,000/µL, and 39% were classified as high risk by the NCI risk criteria (Table 1). Therapy involved various combinations of agents and ranged between 2 and 10 attempts. The CR rate was 42% for third treatment attempt and 24% for fourth and subsequent treatment attempts (Table 2). Treatment failures were significantly associated with increased number of treatment attempts (p < 0.001), shorter duration of previous CR (p < 0.001) and NCI risk category at diagnosis (p = 0.018). Conclusion This preliminary analysis found similar CR rates in patients with third treatment failure compared to the 1st TACL retrospective study of the prior decade (42% vs. 44%, Ko et al, 2010) and an Austrian report with a small cohort of patients (Reismüller et al, 2013). Further analysis will be performed in comparison to the initial TACL retrospective study cohort once enrollment to this study has been completed (approximately 400 patients). A robust, contemporary historical control may serve as an alternative to a randomized control when outcome with past therapies in unacceptably poor. Table 1. Patient Characteristics at Initial Diagnosis of Patients with ALL who received at least two treatment attempt (n = 214 patients) Characteristic No of patients % Age, years < 1 (infants) 18 8 1-9 126 59 10 and over 70 33 WBC count/uL < 50K 128 60 50K and over 56 26 Unknown 30 14 NCI risk criteria at diagnosis Non-infants, standard risk 82 38 Non-infants, high risk 84 39 Non-infants, unknown 30 14 Infants 18 8 Sex Female 94 44 Male 120 56 CNS disease Yes 42 20 No 148 69 Unknown 24 11 Karyotype1 Normal 68 30 11q23 (MLL gene) rearranged 19 8 Hypodiploidy 7 3 Hyperdiploidy 26 12 iAMP21 2 1 t(12;21) 6 3 t(1;19) 7 3 t(9;22) 15 7 Other 46 21 Unknown 28 12 1 Karyotype is available for 214 unique patients; 2 entries were reported for 7 patients, and 4 entries were reported for 1 patient. Table 2. Achievement of CR/CRp/CRi After Treatment of R/R ALL by Preceding Remission Duration and Treatment Attempt Third treatment attempt Fourth through tenth treatment attempt Duration of preceding CR Response Total % Response Total % Not achieved (refractory) 24 63 38 20 86 23 < 18 months duration 28 78 36 11 49 22 18 to 36 months duration 9 15 60 3 5 60 ≥ 36 months duration 8 8 100 0 1 0 All patients combined 69 164 42 34 141 24 Disclosures Sun: Gateway for Cancer Researchy: Research Funding; Amgen: Research Funding. Wilkes:Healthcare Research and Quality: Research Funding; Alex's Lemonade Stand Foundation: Research Funding. Gaynon:Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Sigma Tau: Speakers Bureau; JAZZ: Speakers Bureau. Wayne:Medimmune: Honoraria, Other: travel support, Research Funding; NIH: Patents & Royalties; Kite Pharma: Honoraria, Other: travel support; Pfizer: Honoraria; Spectrum Pharmaceuticals: Honoraria, Other: travel support, Research Funding. Whitlock:Amgen: Honoraria.

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Yang, F. Q., H. K. Wang, H. Chen, J. D. Chen, and Z. N. Xia. "Fractionation of Volatile Constituents fromCurcumaRhizome by Preparative Gas Chromatography." Journal of Automated Methods and Management in Chemistry 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/942467.

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A preparative gas chromatography (pGC) method was developed for the separation of volatile components from the methanol extract ofCurcumarhizome. The compounds were separated on a stainless steel column packed with 10% OV-101 (3 m × 6 mm, i.d.), and then, the effluent was split into two gas flows. One percent of the effluent passed to the flame ionization detector (FID) for detection and the remaining 99% were directed to the fraction collector. Five volatile compounds were collected from the methanol extract ofCurcumarhizome (5 g/mL) after 83 single injections (20 uL) with the yield of 5.1–46.2 mg. Furthermore, the structures of the obtained compounds were identified asβ-elemene, curzerene, curzerenone, curcumenol, and curcumenone by MS and NMR spectra, respectively.

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Gaziev, Javid, Antonella Isgro, Katia Paciaroni, Marco Marziali, Gioia De Angelis, Michela Ribersani, Cecilia Alfieri, and Marco Andreani. "Outcomes of Unrelated Bone Marrow Transplantation in Patients with Thalassemia." Blood 132, Supplement 1 (November 29, 2018): 5777. http://dx.doi.org/10.1182/blood-2018-99-109764.

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Abstract Introduction. Bone marrow transplantation from an HLA-matched related or unrelated donor remains the only curative treatment for patients with thalassemia. Although one third of patients with thalassemia can find a matched unrelated donor (MUD) few patients were treated by MUD transplantation. Early experience with the use of MUD transplant in class 3 patients with thalassemia resulted in high rates of graft rejection and transplant-related mortality with thalassemia-free (TFS) survival of 53% (La Nasa G et al. Blood 2002). Significant improvements in MUD transplantation in recent years have prompted us to consider it also for high risk patients with thalassemia. Methods . All patient-donor pairs were typed at high resolution for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and DPB1. Fourteen consecutive patients with a median age of 5 years (range, 2-17.2) received unrelated bone marrow transplantation for thalassemia. Four patients were in class 1, 2 were in class 2 and 8 were in class 3 of risk. All patients were treated with the conditioning regimen consisting of weight-based IV Bu, thiotepa (10 mg/kg/d), CY (200 mg/kg) and thymoglobulin (10 mg/kg) preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −45, and fludarabine (30 mg/m2/d) from D −16 through D −12. Patients received CSA, methylprednisolone and a short course of MTX as GVHD prophylaxis. Results. Between May 2009 and December 2017 un unrelated donor search was performed for 47 patients at our Institute. Forty one patients were Caucasian and 6 patients black African origin. Among Caucasians 16/41 (39%) found a 10/10 and 5/41 (12%) a 9/10 HLA allele-matched unrelated donor, while 1 of 6 black African patients (16.6%) found a 10/10 HLA-matched donor. Among 22 patients with a suitable donor (10/10 or 9/10 HLA allele-matched) 14 received transplantation, 2 patients withdrew consent, 1 patient's donor refused donation, and the remaining 5 patients are awaiting transplant. Twelve patients received 10/10 and 2 patients 9/10 HLA allele-matched grafts. Eight patients had permissive DPB1 mismatches while 2 patients had non-permissive mismatches in the HvG direction and 4 patients in the GvH direction. Median TNC/kg and CD34+/kg infused were 7.2x108 (range, 3.95-12.5) and 7.75x106 (range, 3.47-16.4), respectively. Sustained engraftment occurred in all patients. The median time to neutrophil and platelet recovery was 20 days (range, 15-27) and 19 days (range, 15-28), respectively. All but one patient showed 100% donor chimerism. The patient with stable mixed chimerism (48% donor DNA) has remained transfusion independent for over 3 years with hemoglobin levels >13.5-14 g/dL. Grade 2 and 3-4 acute GVHD occurred in 3 (21%) and 2 (14%) patients, respectively. Two patients developed mild (skin) or severe (skin, gut and liver) chronic GVHD. There was no association between non permissive DPB1 mismatches in the GvH direction and GVHD. All but one patient are alive and are off immunosuppressive therapy. One patient died due to chronic GVHD-related complications. The median follow-up among surviving patients was 2.8 years (range, 0.8-8.6). The 5-year OS and TFS probabilities were 90% (95% CI 47 to 99%) (Figure 1). Patients showed suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ at 6 months was 223±48. At 12 and 24 months recovery of CD4+, CD8+, CD19+ and CD56+ were 597±122, 1077±228, 331±75, 229±64 and 812±284, 1067±405, 218±82, 112±22, respectively. One patient developed mild to moderate hepatic sinusoidal obstruction syndrome which resolved with supportive care. CMV reactivation occurred in 9 patients and none developed CMV disease. One patient developed adenovirus gastroenteritis. EBV reactivation occurred in 4 patients; one developed posttransplant lymphoproliferative disorder that was successfully treated with Rituximab. Bacterial infections were common: 5 (38%) patients developed gram negative or gram positive sepsis and 4 (29%) patients pneumonia. Probable invasive fungal infections occurred in 2 (14%) patients. Conclusions. This study showed that unrelated donor BMT can successfully cure a proportion of patients with thalassemia. Remarkably, despite 57% of patients were in class 3 of risk the 5-year OS and TFS rates were 90%. We conclude that class 3 patients with thalassemia who have a suitably matched unrelated donor should not be denied the option of transplantation. Disclosures No relevant conflicts of interest to declare.

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Batty, Nicolas, Elham Ghonimi, Lei Feng, Luis Fayad, Anas Younes, Maria Alma Rodriguez, Jorge Enrique Romaguera, et al. "Comparison of the international prognostic factors index (IPI) with the absolute monocyte and lymphocyte prognostic index (AMLPI) for patients (Pts) with diffuse large b-cell lymphoma (DLBCL) receiving R-CHOP." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8067. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8067.

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8067 Background: We studied the value of a proposed prognostic index (PI) generated by baseline absolute monocyte (AMC) and lymphocyte (ALC) counts for pts with DLBCL, using values as previously reported (Leukemia 25:1502-9, 2011). Methods: From 03/07 to 01/09, 245 consecutive pts with untreated DLBCL receiving standard R-CHOP from the MDACC database were evaluated. Baseline AMC and ALC were retrospectively recorded. High AMC (≥610/uL) and a low ALC (≤1000/uL) were examined as dichotomized variables for progression-free (PFS) and overall survival (OS). An AMLPI was generated, stratifying pts into 3 risk groups (RGs): low-(AMC <610/uL and ALC >1000/uL), intermediate-(AMC ≥610/uL or ALC ≤1000/uL), and high-risk(AMC ≥610/uL and ALC ≤1000/uL). The prognostic effect of the AMLPI and the IPI were examined by multivariate analysis (MVA). Results: Ninety (37%) had high AMC and 71 (29%) had low ALC. By univariate analysis, a high AMC was associated with inferior PFS (p=0.01) and OS (p=0.03). The frequencies of AMLPI RGs were: low-105 pts (43%), intermediate-119 (48%), and high risk-21 (9%). With a median follow-up of 22 months (range <1-42), 3-year PFS and OS rates for these RGs were 80%, 61%, and 46% (p=0.007) and 92%, 76%, and 60% (p=0.006), respectively. Three-year PFS rates for IPI 0-2 and 3-5 RGs were 73% and 58%, respectively (p=0.0004); comparable OS rates were 88% and 68%(p<0.0001). For pts with IPI 0-2, 1-year PFS rates for AMLPI low, intermediate, and high RGs were 92%, 89% and 80% (p=0.022); comparable 1-year OS rates were 96%, 95% and 80% (p=0.049). By MVA, AMLPI effect (low vs. high RGs) on PFS was significant (p=0.046) as was IPI effect (0-2 vs 3-5, p=0.005); similar results were observed for OS (p=0.052 and p=0.003, respectively). Conclusions: Baseline AMC and AMLPI are significant variables for PFS and OS for pts with DLBCL receiving R-CHOP. AMLPI can identify pts with low, intermediate, and high-risk disease for PFS and OS, particularly for those with IPI 0-2. AMLPI may also add prognostic value beyond that of the IPI.

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Kuhlman, Justin J., Muhamad Alhaj Moustafa, Karan Seegobin, Madiha Iqbal, Ernesto Ayala, Stephen M. Ansell, Allison Claire Rosenthal, et al. "Diffuse large B-cell lymphoma with leukemic involvement." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e19552-e19552. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19552.

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e19552 Background: Leukemic involvement (LI) in diffuse large B cell lymphoma (L-DLBCL) is very rare and has been sparsely reported. We report our experience with this entity in a large academic multi-center setting. Methods: Medical records of patients with DLBCL who received care at Mayo Clinic between 1/2003 and 6/2020 were reviewed. DLBCL patients with LI were identified. LI was defined as increased white blood cell counts and the presence of clonal B cells on peripheral blood flow-cytometry. Kaplan-Meier method was used for survival analysis. Results: Twenty patients with L-DLBCL were identified with a median follow-up of 32.5 months (CI95%, 32.5-NR). Median age at initial diagnosis was 62 (45-80) years. 60% (12/20) were male; 90% (18/20) were Caucasian. Pathologically, 90% (18/20) had DLBCL and 10% (2/20) had high-grade B cell lymphoma (HGBCL) with intermediate features between DLBCL and Burkitt lymphoma. By Hans criteria, 58% (11/19) had germinal center B-cell DLBCL (GCB-DLBCL) and 42% (8/19) had non-germinal center B-cell DLBCL (non-GCB-DLBCL). 40% (8/20) had transformed DLBCL (t-DLBCL); 36% (5/14) had double-hit lymphoma (DHL) by FISH analysis. LI was present in 55% (11/20) at initial diagnosis and 45% (9/20) at relapse. Median WBC was 39.5/ul (range, 4.3-121) with median absolute lymphocyte count of 25 k/ul (range, 0.7-117). Immunophenotypically, the leukemic lymphoma cells expressed CD19, CD20, and CD79a. Bone marrow involvement and pancytopenia were documented in all patients with a median bone marrow cellularity of 80%. Other extranodal sites of involvement with LI included spleen (65%;13/20), liver (20%;4/20), breast and soft tissue (20%;4/20), bladder or kidneys (10%;2/20), skeleton (10%;2/20), and myocardium (5%;1/20). 65% (13/20) had B-symptoms. All patients had LDH elevation (UNL 222 U/L) with a median of 2125 U/L (range, 308-10,760). 45% (5/11) of patients with LI at initial diagnosis had CNS involvement on relapse/progression. All patients with LI at initial diagnosis received anthracycline-based chemoimmunotherapy with or without CNS prophylaxis. Patients with LI at relapse had had a median of 2 prior treatments (range, 1-5) before LI. Median overall survival (OS) for the whole group was 9 months (CI 95%; 5.8-11.8). There were no long-term survivors. Median progression free survival after LI was 4.7 months (CI95%; 0.8-7.6) in the newly diagnosed group and 3 months (CI95%; 0.9-20) in the relapsed group. 90% (18/20) died due to their progressive disease. Cell of origin, DHL status, or newly diagnosed vs. relapsed status did not have a significant impact on OS in patients with L-DLBCL. Conclusions: Leukemic involvement at any time during the course of DLBCL is associated with poor prognosis. It also appears to be a major risk factor for CNS relapse. It is most frequently associated with DHL and t-DLBCL. Novel therapeutic approaches at the time of initial therapy need to be developed for L-DLBCL.

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Kohla, Samah, Sarah Elkourashy, Feryal Abbas, Susanna Jane Akiki, and Mohamed A. Yassin. "Chronic Myelomonocytic Leukemia in Qatar, Single Institute Experience." Blood 136, Supplement 1 (November 5, 2020): 38. http://dx.doi.org/10.1182/blood-2020-134871.

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Background Chronic myelomonocytic leukemia (CMML) is a rare de novo clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The diagnosis is challenging and carrying risk for leukemic transformation. The median age at CMML diagnosis is ~71-73 years, with a male preponderance. According to the 2016 World Health Organization (WHO) classification of myeloid neoplasms, CMML is characterized by the presence of sustained (>3 months) peripheral blood (PB) monocytosis (≥1 × 109/L; monocytes ≥10% of white blood cell count) along with dysplastic features in the bone marrow (BM). < 20% blasts/blasts equivalent in the PB and BM. It has recommended categorization of CMML into "proliferative" (MPN-CMML) and "dysplastic" (MDS-CMML) sub-types; based on a total leukocytic count (TLC) (of ≥13 × 109/L for MPN-CMML). Also, based on PB and BM blast %, CMML can be sub-classified into three categories; (a) CMML-0 (<2% PB blasts including promonocytes and <5% BM blasts), (b) CMML-1 (2-4% PB blasts including promonocytes and 5%-9% BM blasts), and (c) CMML-2 (>5% PB blasts including promonocytes and 10%-19% BM blasts and/or when any Auer rods are present. Objective: To retrospectively analyze the cases of CMML diagnosed in the Hematology Department, National Center for Cancer Care and Research (NCCCR), Doha, Qatar from January 2013 to July 2020 with the assessment of risk and prognosis. Materials and methods: The results from flow cytometry, cytology, PB, and BM morphology, cytogenetics and molecular genetics were re-estimated. The CMML-specific prognostic scoring system (CPSS) was used for the risk stratification. Results:12 patients diagnosed as CMML were detected and included in the study, 10 males and 2 females, with a median age of 64 years. 3 Arabs and 9 non-Arabs. 10 patients were transfusion dependent. 6 patients had splenomegaly and 2 of them had massive splenomegaly (>20 cm in craniocaudal length). According to the TLC, 8 were myeloproliferative (CMML/MP) and 4 were myelodysplastic CMML. 4 of our patients were below 40 years (classified as young adults as per WHO) and all were of the proliferative type. The flow cytometry of PB and/or BM was done to 11 patients. The monocytic cells were characterized by co-expressing CD14 and CD64 and showed aberrant expression of CD56 on 5 patients. According to the morphology of the BM, one case was described as MDS/MPN or MPN, and the rest of the cases were diagnosed as MDS/MPN. According to WHO 2016 diagnostic criteria of CMML: one case was diagnosed as CMML0, one case was diagnosed as CMML1, 9 cases were diagnosed as CMML2 and one case was diagnosed as MPN/MDS -CMML2 or as MPN. The cytogenetic risk was high in 4 patients, intermediate in one patient, and low in 7 patients. According to CPSS, one patient was an intermediate risk I, 4 was intermediate-risk II, and 7 were high risk. Molecular analysis and NGS were done for 4 patients that were most recently diagnosed. One case showed NRAS in 30%, one case showed KRAS in 57%, one case showed DNMT3A and NPM1 each 42% and one case showed WT1 (36%), FLT3 (33%) and NPM1 (15%). Regarding management and supportive care, 10 out of 12 patients required transfusion support. 4 patients (3 Proliferative and one Dysplastic) were not eligible for active management and received only symptomatic treatment. 5 patients of the proliferative type were started on hydroxyurea. The other 3 patients were of dysplastic subtype who received hypomethylating agent +/- allogenic bone marrow transplant. 6 patients traveled back to their home country and lost follow up, 5 expired, and one patient still alive. Conclusion: CMML is a unique and rare hematopoietic neoplasm with complex biology and pathology. It is an aggressive rare disease that carries a dismal prognosis, with poor survival and a high risk of transformation. The therapeutic options are limited. In our clinic, for the 7 years period, CMML was confirmed only in 12 patients. The great majority of them were old males of the non-Arab nationality, transfusion-dependent, presented with TLC (> 13x10^3/ul Proliferative) of CMML2 subtype and high CPSS risk score. 33% of our patients were young adults (less than 40 years old) and were of the proliferative type. The combination of clinical, morphological, immunophenotyping, cytogenetic and molecular information is required to improve the accuracy of CMML prognostication. Disclosures No relevant conflicts of interest to declare.

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ملكاوي, أسماء حسين. "عروض مختصرة." الفكر الإسلامي المعاصر (إسلامية المعرفة سابقا) 17, no. 65 (July 1, 2011): 215–07. http://dx.doi.org/10.35632/citj.v17i65.2621.

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نظرية الأهلية: دراسة تحليلية مقارنة بين الفقه وعلم النفس، هدى محمد حسن هلال، هيرندن: المعهد العالمي للفكر الإسلامي، 2011م، 340 صفحة. علم النفس والعولمة؛ رؤى مستقبلية في التربية والتنمية، مصطفى حجازي، القاهرة: المركز الثقافي العربي، 2010م، 335 صفحة. أزمة علماء النفس المسلمين، مالك بدري، عمان: مركز ديبونو لتعليم التفكير، 2010م، 84 صفحة. إسلامنا والتراث "نحو تقويم الخطاب الديني"، أحمد عبده ماهر، وأحمد عبد الرحيم السايح،خاص: أحمد عبده ماهر، 2010م، 280 صفحة. المعرفة والسلطة في التجربة الإسلامية "قراءة في نشأة علم الأصول ومقاصد الشريعة"، عبد المجيد الصغير، القاهرة: رؤية للنشر والتوزيع، 2010م، 616 صفحة. التبادل الاقتصادي وضبطه بمقاصد الشريعة: دراسة مقارنة، ثناء محمد إحسان الحافظ، بيروت: دار الفكر المعاصر، 2010م، 480 صفحة. الدليل المبسط في مقاصد الشريعة، محمد هاشم كمالي، هيرندن: المعهد العالمي للفكر الإسلامي، 2011م، 48 صفحة. مقاصد الشريعة: دليل للمبتدئ، جاسر عودة، هيرندن: المعهد العالمي للفكر الإسلامي، 2011م، 76 صفحة. Religion and Spirituality in Psychotherapy: An Individual Psychology Perspective, Thor Johansen, New York: Springer Publishing Company; 5 edition (December 7, 2009), 240 pages. Conceptions of Islamic Education: Pedagogical Framings (Global Studies in Education), Yusef Waghid, Switzerland: Peter Lang Publishing, First printing edition (May 25, 2011), 160 pages. Nature and Technology in the World Religions (A Discourse of the World Religions), P. Koslowski, Dordrecht, Netherlands: Kluwer Academic Publishers, (July 29, 2011), 166 pages. Imam Bukhari and the Love of the Prophet- pbuh, (Al-Hidayah Series), Muhammad Tahir-ul-Qadri, London: Minhaj-ul-Quran International (MQI), July 30, 2009, 148 pages. Hadith: Muhammad's Legacy in the Medieval and Modern World. Jonathan Brown, London: Oneworld (June 1, 2009), 304 pages. Light From the East: How the Science of Medieval Islam Helped to Shape the Western World, John Freely, London: B. Tauris (April 12, 2011), 256 pages. للحصول على كامل المقالة مجانا يرجى النّقر على ملف ال PDF في اعلى يمين الصفحة.

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Fiaschetti, Valeria, Chiara Adriana Pistolese, Tommaso Perretta, Elsa Cossu, Chiara Arganini, Claudia Salimbeni, Angela Lia Scarano, Silvia Arduini, and Giovanni Simonetti. "3–5 BI-RADs Microcalcifications: Correlation between MRI and Histological Findings." ISRN Oncology 2011 (August 25, 2011): 1–7. http://dx.doi.org/10.5402/2011/643890.

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Purpose. To evaluate the correlation between MRI and histopathological findings in patients with mammographically detected 3–5 BI-RAD (Breast Imaging Reporting And Data Systems) microcalcifications and to allow a better surgical planning. Materials and Method. 62 female Patients (age ) with screening detected 3–5 BI-RAD microcalcifications underwent dynamic 3 T contrast-enhanced breast MRI. After 30-day (range 24–36 days) period, 55 Patients underwent biopsy using stereotactic vacuum-assisted biopsy (VAB), 5 Patients underwent stereotactic mammographically guided biopsy, and 2 Patients underwent MRI-guided VAB. Results. Microhistology examination demonstrated 36 malignant lesions and 26 benign lesions. The analysis of MRI findings identified 8 cases of MRI BI-RADS 5, 23 cases of MRI BI-RADS 4, 11 cases of MRI BI-RADS 3, 4 cases type A and 7 cases type B, and 20 cases of MRI BI-RADS 1-2. MRI sensitivity, specificity, positive predictive value, and negative predictive value were 88.8%, 76.9%, 84.2%, and 83.3%, respectively.

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Lemieux, Christopher, Imran Ahmad, Nadia M. Bambace, Lea Bernard, Sandra Cohen, Jean-Sebastien Delisle, Thomas Kiss, Jean Roy, and Silvy Lachance. "Safety and Efficacy of Autologous Hematopoietic Cell Transplantation for Elderly Patients with Lymphoma: Chemosensitive Disease Rather Than Age or Co-Morbidity Index Predicts Outcome." Blood 126, no. 23 (December 3, 2015): 3171. http://dx.doi.org/10.1182/blood.v126.23.3171.3171.

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Introduction: High dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (AHCT) are considered standard of care as first line therapy in mantle cell lymphoma (Dreyling et al., 2005; Geisler et al., 2012) and in first line refractory and chemosensitive relapse Non-Hodgkin Lymphoma (NHL) (Philip et al., 1995) . The development of hematopoietic cell transplant comorbidity index (HCT-CI) (Sorror et al., 2009) for recipient selection and transplant risk evaluation have impacted on patient selection. Over the last decade, most transplant program have seen an increase in the median age of AHCT recipients(McCarthy et al., 2013). Limited data are available to optimise elderly patients selection for transplantation while minimising the risk of treatment related toxicity and mortality (TRM). The goal of this study was to identify factors impacting the safety and efficacy of AHCT in the elderly NHL patients in order to better select those who will benefit from this intervention. Method: This is a single center, retrospective study examining outcomes of AHCT in elderly patients (≥60 years old) with NHL. Between January 1st, 2008 and January 1st, 2015, 90 patients met the inclusion criteria and were included in the study. Patients signed an informed consent and the ethics committee of our institution approved the study. Progression-free-survival (PFS) and overall survival (OS) were analyzed according to age at time of transplantation, HCT-CI, lymphoma histology and disease status at time of transplant. Toxicities were analyzed according to age and HCT-CI. Results: Median age at time of NHL diagnostic was 60 years (range 42 to 68) and 63 years at time of transplant (range 60 to 69). One third (33%) of our cohort was ≥65 years old. Histologic sub-type was mainly composed of follicular (36%), mantle cell (20%) and large B-cell lymphoma (38%). 50% of patients had high-risk disease and 31% had low risk disease. HCT-CI was low-risk in 34%, intermediate risk in 40% and high-risk disease in 26%. BEAM/BEAC conditioning regimen was used in 94%. The median graft CD34+/kg cell dose infused was 4.87. The median time to neutrophil engraftment was 10 days (range 8 to 14 days) and platelet recovery was 16 days (range 11 to 43 days). The incidence of febrile neutropenia was 92% with 2% admission to the intensive care unit (ICU) with no difference between patients younger or ≥65 years old. Our cohort received a median of 8 days of antibiotics (range 0 to 41 days). Absolute lymphocyte count < 0,3 X 103 cells/uL at 14 days after transplant was associated with higher incidence of septic choc (p=0,024) and ICU admission (p=0,034). Age ≥65 year was not associated with an increase TRM and was surprisingly associated with less total parenteral nutrition (p=0,046) and narcotics uses (P=0,011). The median length of stay was 26 days. The median follow-up was 27 months (range, 1 to 87), median PFS of 46 months (Confidence Interval (CI); 95%, 24,4-67,6) (graph 1) and OS not reached (graph 2). The estimated 5 years OS is 62% and PFS is 40%. Transplant related mortality (TRM) was only 1% at 100 days and 2% at 1year after transplant. The only 2 patients who died from TRM died from cardiac arrest (1 month) and from an unknown cause (3 months). The 1-year progression rate was 30% (graph 3) and mortality rate only 12%. Progressive disease status following first line therapy was associated with a worse PFS compared to the achievement of a complete remission (Hazard Ratio (HR) 2,77; CI 95%, 1,18; 6,49). Progressive disease status at time of transplant was also associated with a lower PFS (HR 9,30: CI 95% 2,55 to 33,92) and OS (HR 13,44: CI 95% 2,68 to 67,48). HCT-CI score did not correlate with OS. International Prognostic Index (IPI), age and treatment type did not influence PFS or OS. Surprisingly, HCT-CI score did not correlate with toxicities, morbidity or mortality. Conclusion: In this single center retrospective study of elderly patients with NHL, AHCT was proven to be safe and effective. Progressive disease at the time of transplant was associated with worse PFS and OS. HCT-CI did not allow the categorization of patients in different prognostics group. Lymphocyte count at day 14 could identify patients at significant risk of complications. Our data suggest that age alone should not exclude patients from transplantation. However, HDT and AHCT should be reserved to chemosensitive patients and avoided in the elderly patient with progressive disease. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

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Karp, Judith E., John M. Pagel, B. Douglas Smith, Jacqueline M. Greer, D. Michelle Drye, Kelly M. Smith, Kathleen Dorcy, et al. "Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)." Blood 116, no. 21 (November 19, 2010): 186. http://dx.doi.org/10.1182/blood.v116.21.186.186.

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Abstract Abstract 186 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below. Age # < 50 Secondary AML Adverse Genetics MDS/MPD t-AML Single Complex Flt3 ARM A (n = 36) 59ü(24–78) 3 19 5 6 13 3 Total 24/36 = 67% Total 22/36 = 61% ARM B (n = 34) 58ü(20–73) 5 16 9 8 10 5 Total 25/34 = 74% Total 23/34 = 68% Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures: No relevant conflicts of interest to declare.

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Joshi, Krishna Prasad, Dinesh Atwal, Eric R. Siegel, Anusha Jillella, Manojna Konda, Richa Parikh, Aneesha Ananthula, et al. "Absolute lymphocyte count (ALC) as predictor of Pneumocystis Jiroveci Pneumonia (PCP) infection in patients on immune checkpoint inhibitors (ICPi)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14255-e14255. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14255.

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e14255 Background: Checkpoint inhibitor pneumonitis (CIP) is an uncommon but serious immune related adverse event needing treatment with prolonged steroids. PCP prophylaxis is recommended for patients on daily prednisone equivalents of 20 mg or greater for at least 1 month. Known risk factors for PCP infection in general population are glucocorticoid use and defects in cell-mediated immunity. We conducted a retrospective study to evaluate the association between ALC and development PCP infection in the patients with CIP treated with steroids. Methods: A retrospective analysis of subjects who received ICPi for any type of cancer from 2011 to 2018 at a single institution was conducted. PCP was diagnosed by PCR of bronchioalveolar lavage. In patients with CIP, ALC at the beginning of steroid treatment, dose and duration of steroids and development of PCP infection was recorded. The median ALC was compared between the patients with PCP infection and without PCP infection via Welch’s t- test at 5% alpha. Results: Out of 515 patients who received ICPi, there were 429 (83.3%) Caucasians, 79(15.3%) African Americans, 7(1.3%) others. CIP developed in 23 (4.38 %) patients. There were 15(65%) males, 8 females (35%), 20(86.9%) Caucasians and 2(8.6%) African Americans. Median age was 67 Yrs. (range 29-80). Six out of 23 (26%) patients with CIP developed PCP infection. Median ALC in the patients with PCP infection was 0.75 K/uL (range 0.2-0.83) compared to 1.14 K/uL (range 0.18 - 1.76) in those without PCP infection (p = 0.0182). Conclusions: In patients with CIP, low ALC and prolonged steroid therapy are more likely to result in PCP infection as opposed to steroid therapy alone. Low ALC and prolonged steroid therapy may select patients who require PCP prophylaxis. [Table: see text]

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Mamadalieva, Nilufar Z., Mahmoud Z. El-Readi, Abdulaziz A. Janibekov, Ahmad Tahrani, and Michael Wink. "Phytoecdysteroids of Silene guntensis and their in vitro Cytotoxic and Antioxidant Activity." Zeitschrift für Naturforschung C 66, no. 5-6 (June 1, 2011): 215–24. http://dx.doi.org/10.1515/znc-2011-5-604.

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Phytoecdysteroids from aerial parts of Silene guntensis B. Fedtsch were investigated and three phytoecdysteroids were isolated: 2,3-diacetate-22-benzoate-20-hydroxyecdysone (1), 2-deoxy-20-hydroxyecdysone (2), and 20-hydroxyecdysone (3). Their chemical structures were elucidated by DEPT, COSY, 1H and 13C NMR spectroscopy. The isolated compounds 1 - 3 and crude extracts were evaluated for their antiproliferative and antioxidant activities. They exhibited substantial inhibition of cell growth against human cervix adenocarcinoma (HeLa), hepatocellular carcinoma (HepG-2), and breast adenocarcinoma (MCF-7) cells. The chloroform extract showed potent cytotoxic effects [IC50 values (26.58 ± 1.88) μg/mL, (20.99 ± 1.64) μg/mL, and (18.89 ± 2.36) μg/mL, respectively]. The new compound 1 was mildly cytotoxic compared to extracts [(127.97 ± 11.34), (106.76 ± 7.81), and (203.10 ± 19.56) μg/mL, respectively]. Water and n-butanol extracts exhibited good antioxidant activities [IC50 values of (68.90 ± 6.45) μg/mL and (69.12 ± 5.85) μg/mL, respectively].

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Slager, Susan L., Mark C. Lanasa, Sallie D. Allgood, Sara J. Achenbach, Aaron Norman, Celine M. Vachon, Lynn Goldin, et al. "Prevalence of MBL Increases Over Time In Relatives of CLL Families,." Blood 118, no. 21 (November 18, 2011): 3881. http://dx.doi.org/10.1182/blood.v118.21.3881.3881.

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Abstract Abstract 3881 Background: Chronic lymphocytic leukemia (CLL) is largely incurable neoplasm of the blood and has one of the highest familial risks of disease among cancers. Monoclonal B-cell lymphocytosis (MBL) with a CLL immunophenotypic profile (i.e., CLL-like MBL) is a precursor state to CLL. In the general adult population, the prevalence rate of MBL is 5–9% and increases with age. This is in contrast to the 13–18% rate of MBL in first-degree relatives of CLL patients from high-risk families (defined here as families with at least two confirmed living cases of CLL). Few longitudinal studies of MBL incidence exists. One study evaluated MBL status over time in a cohort of individuals with MBL from a rural valley in Northern Italy. Our work herein will be the first to evaluate the status of MBL over time in relatives of CLL patients from high-risk families. Methods: Using a cohort of 41 high-risk CLL families, we evaluated the MBL status and clonal blood B-cell counts in 94 relatives of CLL patients at two time points at least 1 year a part. High sensitivity, multi-color flow cytometry was performed on fresh or previously frozen blood samples in three laboratories: Duke University, the US Food and Drug Administration, and Mayo Clinic. The number of cell events collected for flow cytometry evaluation varied from 1 to 5 x105 cells. To assure concordance across flow cytometry laboratories, 15 samples were evaluated at multiple labs. The concordance of MBL calling was a 100%. We defined three monotypic B-cell subsets as CLL-like MBL (CD5+ CD20dim), atypical MBL (CD5+ CD20+), and non-CLL like MBL (CD5−CD20+). Results: Of the 94 relatives, the median age at consent was 57 years (range 42–93) and 39% were male. At the initial MBL screening, 70 (74%) relatives had normal immunophenotype (NIPT) and 24 (26%) had MBL (1 atypical MBL, 3 non-CLL like MBL, and 20 CLL-like MBL). Seven of the 24 individuals with MBL had monoclonal B-cell counts available at baseline screening; median = 147.4 cells/uL (range 22.7–1663). The 94 relatives underwent repeat evaluation with a median follow up time of 1.8 years (range 1–6). At the second evaluation, we found an increase in the prevalence of MBL, with 11 of the 70 (12%) initially NIPT relatives developing a new MBL clone (10 CLL-like, 1 non-CLL like). These 11 incident MBL cases were from 9 families with 2 families each having 2 relatives changing MBL status. The median number of monoclonal B-cells in these 11 incident MBL cases was 0.58 cells/uL (range 0.38–60.3). The 23 out of the 24 relatives with baseline MBL (20 CLL-like MBL and 3 non-CLL like MBL) had a persistent MBL clone. Only 6 of these 23 individuals had monoclonal B-cell counts available at both time points, and among these 6, the clonal B-cell counts decreased at follow-up screening; median difference −64.1 cells/uL (range −1204.3– 10.5). The second evaluation of the initial atypical MBL relative had too few clonal cells for flow assessment. Conclusion: We found that our CLL-like MBL clones persisted over the period of observation in relatives from high-risk CLL families; this finding is similar to that previously reported using a population-based study conducted in Northern Italy. Notably, 12% of relatives from high-risk CLL families developed incident MBL during just 2 years of follow up. Although these MBL clones are all low count (< 1500 cells/uL), these data provide further evidence that MBL is a marker of inherited predisposition to CLL. It will be important to see how our rate of change of MBL status compares to that of the general population as we continue to follow our cohort of CLL families. Disclosures: No relevant conflicts of interest to declare.

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Vera, L., R. Reategui, B. Beltran, D. Morales, A. Capellino, C. Desposorio, and J. Castillo. "The clinicopathological spectrum of HIV-associated lymphoma: Eleven-year-experience in a general hospital in Peru." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e19561-e19561. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19561.

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e19561 Background: The clinicopathological spectrum of HIV-associated lymphomas in developing countries has not been clearly defined. Thus, this study is aimed to describe these features in cases from a Peruvian population. Methods: This is a retrospective review of the clinical records of patients with diagnosis of HIV in our institution from March 1997 to March 2008. We reviewed 2502 clinical records. The statistical method was descriptive and survival was calculated using the Kaplan-Meier method. Results: Forty-eight patients with HIV-associated lymphoma were identified. Male:female ratio was 15:1. Median age was 42 years (range 27 to 70). 32 patients (67%) had clinical stage III-IV, B symptoms 35 (73%), the International Prognostic Index was low-risk 20 patients (42%), low-intermediate risk 15 patients (31%), high-intermediate risk 10 patients (21%) and high-risk 3 patients (6%). CD4 count lower than 100 cells/uL was 11 patients (23%). The CD4 count median was 184 cells/uL. The nodal localization in 27 patients (56%) was lightly higher. Forty-four cases (92%) were diagnosed with non-Hodgkin lymphoma (NHL) and 4 cases (8%) with Hodgkin lymphoma (HL). From the 44 NHL cases, 40 cases (91%) were of B-cell origin; 23 cases (57.5%) had diffuse large B-cell, 9 cases (22.5%) had Burkitt, 3 cases (7.5%) had plasmablastic, 2 cases (5%) had primary CNS, 2 cases (5%) had MALT and 1 case (2.5%) had primary effusion lymphoma. The remaining 4 cases (9%) were of T-cell origin; 3 cases (75%) had peripheral T-cell lymphoma NOS and 1 case (25%) was ALK-negative anaplastic large cell lymphoma. Only 16 patients (33%) were receiving HAART previously the diagnosis of NHL and 33 patients (68%) received any oncology treatment. Conclusions: This entity is aggressive and frequently has extranodal involvement. Also a high proportion of T-cells lymphomas are found. These findings are in concordance with one prior report of another general hospital from Peru. No significant financial relationships to disclose.

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Reckeweg, Olaf, Armin Schulz, and Francis J. DiSalvo. "Orthoborate Halides with the Formula (M+II)5(BO3)3X: Syntheses, Crystal Structures and Raman Spectra of Eu5(BO3)3Cl and Ba5(BO3)3X (X = Cl, Br)." Zeitschrift für Naturforschung B 66, no. 4 (April 1, 2011): 359–65. http://dx.doi.org/10.1515/znb-2011-0404.

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Single crystals of Eu5(BO3)3Cl were obtained by serendipity by reacting Eu2O3 and Mg with B2O3 at 1300 K in the presence of an NaCl melt for 13 h in silica-jacketed Nb ampoules. Ba5(BO3)3X (X = Cl, Br) crystals were formed by direct synthesis from appropriate amounts of Ba(OH)2, H3BO3 and the respective barium halide (hydrate) in alumina crucibles kept in the open atmosphere at 1300 K for 13 h. The crystal structures of the title compounds were determined with single-crystal X-ray diffraction. All compounds crystallize isotypically to Sr5(BO3)3Cl in the orthorhombic space group C2221 (no. 20, Z = 4) with the lattice parameters a = 1000.34(7), b = 1419.00(9), c = 739.48(5) pm for Eu5(BO3)3Cl, a = 1045.49(5), b = 1487.89(8), c = 787.01(4) pm for Ba5(BO3)3Cl, and a = 1048.76(7), b = 1481.13(9) and c = 801.22(5) pm for Ba5(BO3)3Br. The Raman spectra of all compounds were acquired and are presented and compared to literature data. The incremental volume of the orthoborate (BO3)3− anion has been determined and is compared to the Biltz volume

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Fard, Behnam Khosravani, Mahmood Ghasemi, Hossein Rastgariyan, Seyed Hadi Sajjadi, Houshang Emami, Masoomeh Amani, and Mohammad Hosein Kalantar Motamedi. "Effectiveness of Mouth Washes on Streptococci in Plaque around Orthodontic Appliances." ISRN Dentistry 2011 (September 21, 2011): 1–4. http://dx.doi.org/10.5402/2011/954053.

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Background and Purpose. Fixed orthodontics may be associated with accumulation of Mutans Streptococci (MS), enamel demineralization, and an increased number of carious lesions, predominantly in sites adjacent to brackets. This study was undertaken to assess the effectiveness of Listerine, Oral-B, and Ortho-kin on the accumulation of MS in plaque around orthodontic brackets. Materials and Methods A double-blind randomized cross-over clinical trial on 25 orthodontic patients, classified into 6 groups was done to assess MS in plaque and saliva with the side specific modified Strip-Mutans technique and the plaque (PI) was measured before and after rinsing using 3 types of commercial mouth-rinses. A washout period (3 weeks) was awaited between using each mouth-rinse and the data was analyzed via Wilcoxon and Kruskal Wallis statistical tests. Results. This study of 25 patients, 5 men and 20 women, with an average age of assessed the effectiveness of mouth-rinses on MS. Our results showed that Ortho-kin had a better effect than Oral-B and Listerine (). Ortho-kin also had better effects than Oral-B and Listerine on plaque accumulation (). Conclusion. Ortho-kin showed better effects on decreasing MS and PI because it contained chlorhexidine.

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Li, Mingjia, Aziz Nazha, Paul Elson, Sean Hobson, Mikkael A. Sekeres, Matt E. Kalaycio, Ronald M. Sobecks, et al. "A Prognostic Scoring System for Newly Diagnosed Adult Acute Lymphocytic Leukemia Patients." Blood 124, no. 21 (December 6, 2014): 5252. http://dx.doi.org/10.1182/blood.v124.21.5252.5252.

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Abstract Introduction: Traditional prognostic factors for adult acute lymphocytic leukemia (ALL) include age, white blood count at diagnosis, and cytogenetic (CG) risk. We sought to identify a more detailed prognostic risk score for newly diagnosed adult patients (pts) based on these and other pre-treatment characteristics. Methods: 82 newly diagnosed ALL pts given induction chemotherapy (IC) at our institution between the years 2003-2011 were included, and data were obtained by chart review. Institutional review board approval was obtained. Variables examined included: gender, age, immunophenotype, CG risk, pre-IC body mass index (BMI), pre-IC and day 28 serum albumin, absolute lymphocyte (ALC) and neutrophil (ANC) counts, positive culture (blood or other) during IC, positive imaging suggestive of infection (during IC), and allogeneic hematopoietic cell transplant (AHCT). CG risk was ascribed by CALGB criteria (Blood 1999; 93: 3983). BMI was defined by: underweight (≤ 18.5), normal (> 18.5-25.0), overweight (> 25.0-30.0), moderately obese (> 30.0-35.0), severely obese (> 35.0-40.0), and very severely obese (> 40.0). The primary endpoint was overall survival (OS) which was measured from IC to death or last follow-up. Proportional hazards models were used for univariable and multivariable analyses. In the multivariable analysis stepwise variable selection was used to identify independent predictors. Results were internally validated using a bootstrap algorithm. For convenience measured factors were discretized using a recursive partitioning algorithm. Prognostic groups were formed by assigning “points” to each factor that were based on the magnitude of the estimated regression coefficients of the final model, and then summing the total number of points present. Results: Median age at diagnosis was 43 yrs (range 18-78); 58% male. 71% of pts (58/82) had a B-cell immunophenotype. CG risk included: normal: 15 pts (18%), high: 41 pts (50%), miscellaneous: 9 pts (11%), and unknown: 17 pts (21%). Twenty-four pts (29%) were Ph+. The majority of pts (70%: 57/82) received the CALGB 19802 regimen (Cancer 2013; 119: 90) for IC +/- a tyrosine kinase inhibitor (if they were Ph+). 27% of pts (22/ 82) received AHCT in CR1. Estimated median OS is 41.5 months (95% CI: 15.5-N/A). In univariable analysis age, pre-induction BMI, Day 28 ALC, pre- and Day 28 albumin, Day 28 ANC, Day 28 platelet count, evidence of infection, and CG risk were all seen to impact outcome. In multivariable analysis pre-IC BMI and albumin, age, and Day 28 ALC were identified as independent predictors. Assigning 1 “points” each for age >50, albumin prior to IC ≤ 3.2 g/dL, or Day 28 ALC ≤ 50 /uL and 2 points for BMI ≥ 35, 3 prognostic groups were defined: favorable (0 points) 32% of pts (26/80): estimated 5-yr OS of 68% +/-11%; intermediate (1 points) (29% of pts, 23/80): estimated 5 yr OS of 39% +/-11%, and unfavorable (≥ 2 points) (39% of pts, 31/80) with estimated 5 yr OS of 17% +/- 7% (Figure 1). Conclusion: We have constructed a simple prognostic model for newly diagnosed adults with ALL. This model will need to be validated in a larger group of uniformly treated patients. Table 1 Prognostic Factors for OS in Univariable and Multivariable Analysis Factor Univariable (HR (95% C.I.)) Multivariable (HR (95% C.I.)) Age at dx (≤50 vs. >50) 3.29 (1.80-5.99), p=.0001 2.83 (1.45-5.53), p=.002 Pre-IC BMI (<35 vs. >35) 2.95 (1.57-5.52), p=0.0008 3.88 (1.84-8.17), p=.0004 Pre-IC albumin (≥ 3.2 vs. < 3.2 g/dl) 2.61 (1.43-4.77), p=0.002 2.66 (1.33-5.30), p=.0006 Day 28 ALC (> 50/uL vs. ≤50/uL) 3.57 (1.61-7.91), p=0.002 3.11 (1.33-7.28), p=.009 CG risk 2.03 (0.98-4.22); p=0.06 ------ Day 28 albumin (>2.3 vs. ≤2.3 g/dl) 3.37 (1.66-6.83), p=0.0008 ------ Day 28 ANC (>200/uL vs. ≤200/uL) 4.51 (1.94-10.51), p=.0005 ------ Day 28 platelets (>75K/uL vs. ≤75K/uL) 2.44 (1.26-4.72), p=.008 ------ Any positive culture (no vs. yes) 2.19 (1.19-4.04), p=0.01 ------ Blood culture positive for bacteria (no vs. yes) 2.34 (1.28-4.30), p=0.006 ------ Positive imaging suggestive of infection (no vs. yes) 2.44 (1.34-4.46), p=0.004 ------ Positive blood culture and image (no vs. yes) 1.96 (1.07-3.57), p=0.03 ------ Figure 1 Prognostic Groups Figure 1. Prognostic Groups Disclosures No relevant conflicts of interest to declare.

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Gangatharan, Shane A., John Kuruvilla, Vishal Kukreti, Armand Keating, Manjula Maganti, Melania Pintilie, and Michael Crump. "Stem Cell Dose and Time To Engraftment Does Not Predict Outcome After Autologous Stem Cell Transplantation For Relapsed Aggressive NHL." Blood 122, no. 21 (November 15, 2013): 5542. http://dx.doi.org/10.1182/blood.v122.21.5542.5542.

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Abstract Introduction Autologous stem cell transplantation (ASCT) is the standard of care for relapsed aggressive lymphomas. Time to neutrophil and platelet engraftment is strongly correlated with CD34+ cell number infused but data are conflicting as to whether patients who receive greater numbers of CD34+ stem cells have improved outcomes. We sought to determine whether short term engraftment predicts progression-free survival (PFS) independent of other disease-specific prognostic factors. Methods From the Princess Margaret Cancer Centre transplant database, we identified patients undergoing ASCT for relapsed aggressive lymphoma between 2007-2011. Data were extracted on prognostic features at relapse/progression, stem cell collection, engraftment, and time to progression and death. All patients received platinum-based salvage chemotherapy and those with chemosensitivity were mobilised with cyclophosphamide, etoposide and filgrastim (minimum threshold 2x106 CD34 cells/kg) and proceeded to ASCT. Patients who failed initial mobilisation were remobilised using plerixafor. High-dose therapy consisted of etoposide 60mg/kg Day -4 and melphalan 180mg/m2 Day -3 with stem cells infused on Day 0. Filgrastim 300µg daily was started from Day +7 until neutrophil recovery to >1.0 x106/uL. Platelet engraftment was defined as an unsupported platelet count >20 x 109/L. Results 97 patients with DLBCL (n=66), transformed (n=24) and T-cell lymphoma (n=7) were reviewed. Median age was 54 (range 20-67), 61% were male and median IPI score on relapse was 2. Fifty one percent relapsed within 12 months of last therapy, and of the patients with B-cell lymphoma, 81% received rituximab prior to salvage chemotherapy. Median stem cell dose was 5.7x106 CD34+ cells/kg (range 1.69-17.82) with a median number of apheresis sessions to achieve this of 2 (range 1-4). Median time to neutrophils >0.5x106/uL was 11 days (range 9-14) and platelets >20x106/uL was 14 days (range 10-23). The Spearman correlation test confirmed a higher stem cell dose was significantly associated with shorter time to neutrophil (p=0.0014) and platelet engraftment (p=0.0003). From date of ASCT, median follow-up was 3.1 years in progression-free patients. For the entire cohort, PFS was 50% and overall survival (OS) was 74% at 3 years. On univariable analysis, patients with B-cell lymphoma with IPI score of 0-2 had a 3-year PFS of 59%, v 28% for those with IPI of 3-4 (p=0.03) (n=90). Patients with early relapse within 12 months of last therapy had inferior 3-year PFS, 42% v 59% for those with initial PFS > 1 year (p=0.08). Patients with B-cell lymphoma who received rituximab with primary chemotherapy had worse 3-year PFS: 47% v 69% (p=0.11). There were no associations of PFS with lymphoma subtype, dose of stem cells infused, number of apheresis sessions and neutrophil or platelet engraftment. Similarly, on univariable analysis of OS for the entire cohort, only secondary IPI (0-2 v 3-4) was significant, with 3-year OS 82% v 48%, respectively (p=0.01). Multivariable Cox regression analysis of outcomes for patients with B-cell lymphoma in a model including IPI score, time to relapse, prior rituximab, CD34+ cell dose and neutrophil and platelet engraftment times confirmed IPI was the only significant variable predicting PFS (HR 1.99, p=0.03) and OS (HR 3.2, p=0.006). Conclusions In this cohort of patients with aggressive lymphomas, CD34+ cell dose was correlated with time to neutrophil and platelet engraftment but was not predictive of PFS or OS. Secondary IPI score, relapse within 12 months, and for B-cell lymphomas previous use of rituximab were predictive of outcomes post ASCT. Disclosures: Kuruvilla: Roche: Honoraria. Kukreti:Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Keating:Roche: Honoraria. Crump:Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria.

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Khatun, Hazera, Manzur Morshed, and Sadia Anam. "Induction in Adult Acute Lymphoblastic Leukaemia: A Study of 22 Cases." Journal of Bangladesh College of Physicians and Surgeons 33, no. 1 (June 5, 2016): 18–22. http://dx.doi.org/10.3329/jbcps.v33i1.27995.

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Treatment of acute lymphoblastic leukaemia yields high complete remission (CR) rate with disappointingly low overall survival. We describe the results of induction in 22 cases of adult acute lymphoblastic leukaemia treated between January 2011 and January 2013. Median age at presentation was 28 years (range 13-70). Fatigue (n=15, 68%) was the most frequent presenting complaint followed by fever (n=14, 63.7%). 36.3% patients presented with splenomegaly while 31.8% had lymphadenopathy. The average presenting white cell count was 61 k/ul. B-ALL was more common than TALL (59% and 27% respectively). 8 cases were deemed high risk and 14 cases were standard risk. One patient died early in induction before specific treatment. 20 patients were treated with intensive chemotherapy (CALGB8811=12, MCP 841=4, CCG-BFM=2 and BFM-90=1, others 1). Overall CR was 85% while CR in CALGB8811 was 83.3%.The average time to NADIR was 10 days (range 6 -17 days). The most common complication in induction was neutropenic sepsis (n=19, 86.4%) contributing alone to induction mortality of 15% (n=3). Causative organism was identified in only 31.8% cases (n=7), the commonest being pseudomonas and coagulase negative staphylococcus. Facilities for extended immunophenotyping and cytogenetic tests (in addition to BCR-ABL by PCR) are required for administration of standard of treatment.J Bangladesh Coll Phys Surg 2015; 33(1): 18-22

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Small, Trudy N., Nancy A. Kernan, Ann Jakubowski, James W. Young, Susan Prockop, Miguel-Angel Perales, Richard J. O’Reilly, and Esperanza B. Papadopoulos. "Pilot Trial of Rituximab for the Prevention of Epstein Barr Virus B Cell Lymphoproliferative Disorder (EBV-LPD) Following T Cell Depleted (TCD) Unrelated or HLA-Mismatched Related Hematopoietic Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 2922. http://dx.doi.org/10.1182/blood.v108.11.2922.2922.

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Abstract The risk of developing an EBV-LPD is highest in recipients of an unrelated or HLA-mismatched related TCD HCT, with a reported incidence of 10–23%. Although treatment with anti-B cell monoclonal antibodies and/or adoptive immunotherapy can be curative, these therapies are not always effective and can cause fatal tumor lysis syndrome. We have previously shown that the risk of developing an EBV-LPD after a TCD HCT is greatest within the first 2 to 6 months post HCT, and in patients whose circulating CD4 cell counts are less than 200/ul. We therefore developed a phase I pilot trial to investigate the feasibility of 6 monthly doses of rituximab for the prevention of EBV-LPD. Eligibility included hepatitis B surface antigen negative recipients of a TCD HCT from an unrelated or HLA mismatched related donor, EBV seropositive donor and/or host, ANC of >1500 cells/ul, documentation of remission, negative EBV viremia at baseline, and lack of ongoing infection at the time of enrollment. Patients received a maximum of 6 consecutive monthly doses of rituximab (375 mg/m2/dose) starting approximately 1 month post HCT. Less than six monthly doses were given if the patient developed a circulating CD4 cell count > 200/ul sooner than 7 months post transplant. To date, 22 patients (4–68 years of age, median 19.5 years) have been enrolled on this IRB approved trial, 20 of whom have completed therapy. Rituximab was well tolerated. The main side effect potentially related to rituximab was reversible neutropenia (n=5), which resulted in cessation of treatment as per protocol after the 2nd (n=1), 3rd (n=1), or 4th (n=1) dose. To date, none of the 22 patients on trial have developed an EBV-LPD compared to 10.1% of patients who received an unrelated or HLA MM-related TCD HCT during the same time interval but did not receive prophylactic rituximab. Although 2 patients had prolonged shedding of parainfluenza virus (n=1) or RSV (n=1) from the upper respiratory tract, there was no significant increase in viral or bacterial infections in patients who received rituximab prophylaxis. No patient on trial developed a fatal infection. Eighteen of 22 patients enrolled on trial are alive at a median of 14.5 months post HCT. One patient died of GVHD and 3 high risk patients succumbed to relapse. In evaluable patients, recovery of normal numbers of circulating B cells occurred between 5 and 12 months after the last dose of rituximab. This trial suggests that monthly rituximab can be safely given during the first 6 months after a TCD HCT, resulting in a decreased incidence of EBV-LPD. Larger trials investigating the optimum number and timing of Rituximab doses required to prevent this complication are needed as are studies evaluating recovery of specific B cell function in recipients of rituximab after allogeneic HCT.

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Journal articles on the topic 'B 20.5 UL 2011'

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