Academic literature on the topic 'D 3.5 UL 2011 C388'

AbstractObjectiveTo simulate impact of Ca supplementation on estimated total Ca intakes among women in a population with low dietary Ca intakes, using WHO recommendations: 1·5–2·0 g elemental Ca/d during pregnancy to prevent pre-eclampsia.DesignSingle cross-sectional 24 h dietary recall data were adjusted using IMAPP software to simulate proportions of women who would meet or exceed the Estimated Average Requirement (EAR) and Tolerable Upper Intake Level (UL) assuming full or partial adherence to WHO guidelines.SettingNationally and regionally representative data, Ethiopia’s ‘lean’ season 2011.SubjectsWomen 15–45 years (n 7908, of whom 492 pregnant).ResultsNational mean usual Ca intake was 501 (sd 244) mg/d. Approximately 89, 91 and 96 % of all women, pregnant women and 15–18 years, respectively, had dietary Ca intakes below the EAR. Simulating 100 % adherence to 1·0, 1·5 and 2·0 g/d estimated nearly all women (>99 %) would meet the EAR, regardless of dosage. Nationally, supplementation with 1·5 and 2·0 g/d would result in intake exceeding the UL in 3·7 and 43·2 % of women, respectively, while at 1·0 g/d those exceeding the UL would be <1 % (0·74 %) except in one region (4·95 %).ConclusionsMost Ethiopian women consume insufficient Ca, increasing risk of pre-eclampsia. Providing Ca supplements of 1·5–2·0 g/d could result in high proportions of women exceeding the UL, while universal consumption of 1·0 g/d would meet requirements with minimal risk of excess. Appropriately tested screening tools could identify and reduce risk to high Ca consumers. Research on minimum effective Ca supplementation to prevent pre-eclampsia is also needed to determine whether lower doses could be recommended.

Abstract Background: SCD is characterized by chronic vaso-occlusive crises and multiorgan failure resulting in poor quality of life and early mortality (Bhatia/Cairo et al, BMT 2014). There is presently no curative therapy for patients with high risk SCD other than HLA-identical sibling AlloSCT. (Freed/Cairo et al BMT 2012). However, less than 15% of eligible SCD patients have an unaffected MSD with a 10-15% increase of graft failure and TRM (Talano/Cairo et al, EJH, 2015). Similarly, most patients lack a matched related donor and UCB is an inferior source in SCD recipients (Radhakrishman/Cairo et al, BBMT 2013). Haploidentical familial donors with SCD trait offers an opportunity for a new donor source for children with high risk SCD. To overcome HLA barriers, Geyer/Cairo et al (BJH, 2012) demonstrated that T cell depletion using CD34 enriched HPC products with PB MNC addback transplanted in pediatric recipients utilizing MUD was associated with sustained engraftment, low risk of aGVHD but limited by delayed immune reconstitution. Efforts to use FHI donors and T replete AlloSCT in patients with SCD were associated with high rates of graft failure (Bolanes-Meade J et al Blood 2012; Ruggieri et al BBMT 2011). We previously reported FHI CD34 enriched/PB MNC addback AlloSCT is feasible and well tolerated in patients with high risk SCD (Abikoff/Cairo, ASBMT 2015). Objective: To characterize immunological reconstitution following FHI AlloSCT with CD34 enriched grafts with PB MNC addback in children and adolescents with high risk SCD. Methods: 15 patients were evaluatedpretransplant at D+30, 60, 100 and 180 following FHI AlloSCT. GCSF mobilized HPC were collected by apheresis (Spectra OPTIA, Terumo BCT) and products underwent CD34 enrichment using the CliniMACS cell separation system (materials generously supplied by Miltenyi Biotec, Cambridge , MA) with a PB MNC addback dose of 2x10*5 CD3/kg. Immune cell and subset reconstitution was assessed by flow cytometry. NK function was determined by cytotoxic activity against K562 tumor targets at 10:1 E:T ratio by europium release assay and intracellular LAMP-1 (CD107a) and granzyme B expression by flow cytometry. Whole blood, T cell and RBC chimerism (CD71) determined by flow cytometry and by STR. Results: Patients achieved neutrophil and platelet engraftment in a median time of 10 and 16 days, respectively. By D+30, median whole blood donor chimerism was ≥93% and ≥95% at most recent followup (D+30-730). Median donor chimerism in the erythroid lineage was 95% by D+60, with 7 of 13 patients ≥99% at D+30. This was maintained at most recent followup (D+30-730). Median T cell chimerism was 90% (D+60-550) and median NK cell chimerism was 90% by D+30 and maintained at ≥95% through D+730. NK (CD3-/56+) and NKT (CD3+/56+) cell reconstitution following FHI AlloSCT was rapid and peaked at D+30 (35.5±8.6%, 271x10*3/ul; 14.2±4%, 179x10*3/ul, respectively). Moreover, there was robust NK cell receptor expression reconstitution with high levels of activating receptors, NKp46, NKG2D and KIR2DS and inhibitory receptors NKG2A, CD94 and KIR2DL2/3 at D+30 [Fig 1]. NK cytotoxicity against K562 at E;T 10:1 peaked at D+30 (26±3%) and D+180 (28±3%) compared to pretransplant (16±2%, p<0.01). NK activation marker, CD107a, peaked at D+30 (37±9%) and D+180 (41±6%) and there was robust granzyme B degranulation at D+30. CD3+, CD4+, CD8+ and CD19+ immune reconstitution occurred between D+180 and D+270. One year absolute (mean±SEM) cells/ul of CD3+, CD4+, CD8+, CD19+ and CD56+ was 795±168, 408±102, 375±90, 815±352 and 204±37, respectively. [Fig 2] Conclusion: Immune reconstitution and donor chimerism was relatively rapid after FHI AlloSCT with CD34 enriched grafts with PB MNC addback in high risk SCD patients. The donor MNC addback after CD34 selection may in part contribute to rapid engraftment and immune reconstitution along with sustained donor chimerism. This research was supported by FDA grant 5R01FD004090. Disclosures Cairo: Celgene: Research Funding.

Abstract Introduction Ruxolitinib is a selective JAK 1/2 inhibitor, which shows an excellent treatment outcome in myelofibrosis (MF) patients. Main side effect of JAK 1/2 inhibitors is an increased risk of infection. JAK1/2 inhibition may interfere with the differentiation of interferon-γ (IFN-γ) producing Th1 cells and IFN-γ is a key cytokine involved in protective immunity against Mycobacterium tuberculosis(TB). During COMPORT-II trial, a case of disseminated TB with ruxolitinib was reported. Here, we analyze the efficacy and safety of ruxolitinib in Korean MF patients and report cases of TB lymphadenitis during the treatment. Methods Forty-nine patients diagnosed with PMF, PPV-MF or PET-MF have been enrolled and at this time twenty patients are evaluable (median age; 63 years, 37-80). Starting dose of ruxolitinib was determined based on each patient’s baseline platelet count (20 mg bid/d for a baseline platelet more than 200,000/µL, 15 mg bid/d for 100,000-200,000/uL). To determine the efficacy of ruxolitinib, we serially assessed the spleen size by palpation, myelofibrosis symptom assessment using MFSAF and BM examination with JAK2V617Fmutation allele burden. Among 20 evaluable patients, 16 assessed IFN-γ release assays (IGRAs, quantiFERON-TB Gold test) before starting ruxolitinib. Results Of total twenty patients, 12 (60.0%), 3 (15.0%) and 5 (25.0%) were PMF, PPV-MF and PET-MF, respectively. By DIPSS, 13 (65.0%) was Int-2 risk, 3 (15.0%) and 4 (20.0%) were Int-1 and high risk. Eleven patients started with 20 mg bid/d (median baseline platelet: 302,000/uL, 206,000-814,000) and nine were 15 mg bid/d (median; 139,000/uL, 100,000-194,000). Median baseline total symptom score (TSS) was 12 (1-36) and palpable spleen length was 19 cm (1-30). JAK2V617Fmutation was positive in 13 (65.0%) patients (median allele burden; 87.1%, 26.2-93.7). Median time of ruxolitinib exposure was 2.0 ms. (0.8-6.2). Two patients increased TSS following ruxolitinib treatment, however, median maximal reduction in TSS was above 90.9% (27.8-100) and 64.7% of patients showed more than 50% reduction of TSS with ruxolitinib. In an aspect of spleen length, all except two patients showed decreased palpable spleen length. Median maximal reduction in spleen length was 70.2% (0-100) and 72.2% of patients showed more than 35% reduction in spleen length with ruxolitinib. Three patients (15.0%) experienced gr. 3/4 thrombocytopenia and one (5.0%) gr. 3 neutropenia. Among patients who assessed pre-treatment IGRAs, only one revealed positive IGRAs. Since there was no evidence of active TB in symptom and radiologic examination, he was diagnosed as latent TB infection (LTBI) and started 9 ms.-isoniazid (INH) treatment. He had a huge hepatosplenomegaly combined with large amount of ascites which needed frequent paracentesis, hence, we started ruxolitinib with INH treatment. He showed no evidence of active TB and achieved negative IGRAs result on 5 ms. of ruxolitinib treatment. On 1 m. and 5 ms. of ruxolirinib treatment, two patients developed pyrexia and neck masses which were diagnosed as TB lymphadenitis. All of them had no previous history of TB and showed negative results in pre-treatment IGRAs and radiologic examinations. First patient discontinued ruxolitinib by herself and eventually died of MF progression 2 ms. later. Second patient continued ruxolitinib treatment with TB medication and there was no evidence of active TB or MF progression on 5 ms. of ruxolitinib treatment. Conclusions Ruxolitinib was generally well tolerated and showed an excellent treatment outcome in Korean MF patients. By 2008 WHO report, intermediate burden of TB cases exist in Korea, hence, TB is still endemic in Korea. According to 2011 Korean Guidelines for TB, LTBI should be treated in patients receiving immunosupressive agents including TNF-α inhibitors. Although further prospective investigations on the incidence of TB with JAK 1/2 inhibitors in TB endemic countries are warranted, it seems to be reasonable to check the possibility of LTBI before starting JAK 1/2 inhibitors. LTBI confirmed patients receiving JAK 1/2 inhibitors may be deemed a high risk of active TB and consider LTBI treatment. Furthermore, it is necessary to use a caution for active TB infection during the treatment of JAK 1/2 inhibitors in such countries. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Outcomes have improved in treating lymphoid malignancies but relapse remains an ongoing issue. The mTOR inhibitor, everolimus (RAD) and lenalidomide (LEN) have both shown clinically significant activity as single agents in patients with relapsed and refractory (R/R) Hodgkin (HL) and non-Hodgkin (NHL) lymphomas. The low toxicity and differing mechanisms of action were explored further by combining these active agents. A phase I/II clinical trial of the mTOR inhibitor everolimus (RAD) and lenalidomide (LEN) was designed to explore the tolerability, toxicity and to determine the MTD of this combination for Phase II study. The phase I data is reported here. Methods This Phase I/II trial for patients with R/R lymphoid malignancy opened at Mayo Clinic between January 2011 and May 2013 and utilized a standard cohort of 3+3 design to determine the MTD of the combination. Eligibility required age≥18, biopsy proven relapsed or refractory NHL or HL, ECOG PS 0, 1 or 2, measurable disease, Hb >9g/dl, ANC ≥1200/uL, platelet ≥ 50,000/uL, creatinine ≤1.5xULN and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Dose limiting toxicity was defined in cycle 1 as Gr 4 neutropenia ≥7days or platelets ≤ 25,000 ≥7days, grade 4 infection or grade ≥3 non-Heme toxicity at least possibly related to treatment per CTCAE v4.0. The starting dose (level 0) was RAD 5mg daily + LEN 10 mg/d X 21d in a 28-day cycle. Results Twenty-five patients were enrolled on the phase I portion and 23 are evaluable for analysis. The median age was 63 years (23-82) and 18 (78%) were male. Sixty-five percent had stage IV disease and 43% had 4 or more prior treatments (1- ≥5) including stem cell transplantation in 39%. Histologies included HL (n=3) and NHL (n=20)(DLBCL = 11, FL-III = 2, LPL = 3, MCL = 1, MF = 1, and other = 2). Two DLTs (rash, Gr4 neutropenia) were reported at the starting dose (level 0) and the protocol was amended for DLT definition change. At dose level -1 (RAD 5mg daily + LEN 5mg/d X 21d) a DLT (Gr4 neutropenia) was seen in only 1 of 6 patients so the study was re-opened to dose level 0 and 3 additional patients were treated without developing a DLT. At dose level +1 (RAD 5 mg daily + LEN 15mg/d X 21d) 1 Gr3 rash occurred and 2 patients experienced Gr4 neutropenia. Therefore the MTD was determined to be RAD 5mgdaily + LEN 10 mg/d X 21d. At least 1 Gr≥3 adverse event was seen in 91% of patients. The most common Gr≥3 toxicities were neutropenia (57%), leucopenia (52%), thrombocytopenia (39%), fatigue (22%), and anemia (13%). Eight of 23 patients (35%) had Gr≥3 infection. Five patients discontinued study due to adverse events. One death on study occurred due to disease progression. Three patients continue on therapy. Responses have been seen in 4 patients and 10 patients have stable disease, encouraging signs in this heavily pretreated population. Conclusions This phase I/II trial of everolimus and lenalidomide in malignant lymphoma shows the combination to be tolerable with neutropenia as the main dose limiting toxicity. The MTD of this combination is RAD 5mg daily and LEN 10 mg/d X 21 d. Encouraging responses were seen. The phase II study has opened with 2 patients accrued to date. Updated results will be presented. This trial is sponsored by Novartis and Celgene Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding. Off Label Use: lenalidomide and everolimus are not approved for treatment of lymphoma. Nowakowski:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Witzig:Celgene: Research Funding.

Introduction Acute Promyelocytic Leukemia (APL), a distinct subtype of acute myeloid leukemia is a relatively rare disease, characterized by a severe coagulopathy which is often present at the time of diagnosis. Mortality due to bleeding complications during induction is more common in this subtype than in other FAB classifications. The number of newly diagnosed cases in the US is estimated to be 600 to 800 cases a year. The introduction of all-trans retinoic acid (ATRA) into the therapy of APL has completely revolutionized the management and outcome of this disease. The treatment and cure of patients with APL depend not only on the effective use of combination therapy but also involves critical supportive care measures. Aim The aim of this study was to analyze the number of red cells, platelets, plasma and cryoprecipitate transfused during the induction phase of treatment until time to response. Method Patient and transfusion data was retrospectively collected from the Leukemia Department files and Blood bank records at the UT MD Anderson Cancer Center from 2010 to 2011. Results There were 28 newly diagnosed APL patients ([16F: 12 M]; 2 AA/6 Hispanic/20 White), median age 49 (21-84) and included patients who did not go on to clinical trials due to early complications. Karyotyping was obtained on 26 (93%) patients. Confirmation of the PML-RARα short or long transcripts was obtained in 25 (89%) patients by quantitative RT-PCR all of whom showed the PML-RARα fusion transcript. Induction therapy was started on day -1 to day 0 from the date of diagnosis in 5 (18%) patients, Day 1 in 13 (46%), Day 2 in 1 (3%), Day 3 in 3 (11%), Day 4 in 2 (7%), Day 6 in 3 (11%) and Day 7 in 1 (3%) patient. 24 (86%) patientsreceived Arsenic + ATRA, 3 (11%) received Arsenic + ATRA + Idarubicinand 1 (3%)received Arsenic + ATRA + Gemtuzumab Ozogamicin. 4 (14%) patients died early from complications of severe coagulopathy. Response to therapy was noted in 24 (86%) patients, median 25 (range 19-63) days from start of treatment. Red cells were transfused to 25 (89%) patients, median 6 (range 1-29) units, platelets to 23 (82%) patients, median 5 (1-47) units, plasma to 11 (39%) patients, median 8 (2-38) units and cryoprecipitate to 14 (50%) patients, median 10 (2-20) units. There was 1 (3%) patient who did not require blood or blood products, 3 (11%) did not require red cell transfusions, 5 (18%) platelet transfusions, 17 (61%) plasma transfusions and 14 (50%) did not require cryoprecipitate. Of the 24 patients who responded to therapy, 22 (79%) patients are alive. One patient has been lost to follow up. The remaining 21 (75%) patients are in molecular remission with a median follow-up of 714 (256-1110) days from the date of response. Two (7%) patients died in molecular remission from unrelated non-hematologic causes (204, 283 days from their date of response). Table 1 The results of the laboratory studies at the time of diagnosis/ time of response are as follows; WBC median 1.2 K (0.5-17.9)/median 3.3 K/UL (1.0-5.5), Hgb median 8.39 G/Dl (5.9-12.1/median 10.3 G/Dl (8.1-12.1), platelet count median 31 K/UL (3-87)/median 180 K/UL (49-1335), BM blast median 1% (0-64), median 1% (0-4), BM progranulocytes median 59% (0-93)/median 1% (0-7), BM normoblast median 9% (1-35)/median 28% (0-72%), PT median 16.2 secs (14.7-21.0)/ median 14.3 sec (13.1-15.5), INR median 1.29 (1.12-1.76)/median 1.10 (0.97-1.20), aPTT median 29.9 secs (26.0-41.0)/ median 32.2 secs (24.1-47.4), D -Dimer median 19.83 mcg/ml (3.71->20.00)/median 0.96 mcg/ml (0.39-6.09), Fibrinogen median 172 MG/DL (77-461)/ median 399 MG/DL (164-856) and LDH median 883 IU/L (374-2561)/median 591 IU/L (444-1084). Conclusion In conclusion, our review found that the majority of cases required red cells and platelet transfusion but only 50% of the patients required plasma or cryoprecipitate transfusion support for their coagulopathy. Disclosures: No relevant conflicts of interest to declare.

Introduction: JAK2 is located on chromosome 9p24 and includes 25 exons encoding a protein of about 1132 amino acids. JAK2 is one of the four Janus family non-receptor protein tyrosine kinases. JAK2V617F is by far the most prevalent mutation in BCR-ABL1-negative Myeloproliferative neoplasms (occurs in ∼95% of patients with polycythemia vera, in ∼55% with essential thrombocythemia and in ∼65% with primary myelofibrosis) 1, 2. More than 80% of hemochromatosis patients are homozygous for a C282Y mutation in HFE gene, and a smaller proportion are compound heterozygous for both the C282Y mutation and an H63D mutation3. Here we present the first case of an elderly female with concomitant diagnosis of Polycythemia Vera (PV) and hemochromatosis. To our knowledge, there is no literature about the co-existence or associations of these diseases. Case Reports: 75 year old female, former smoker with PMH of hemochromatosis and COPD with recent exacerbation, presented to the oncology clinic after hospital discharge for continuing care of her hemochromatosis requiring phlebotomy. She reports to have had multiple phlebotomies in the past fifteen years. Patient denied any history of liver disease, diabetes, arthralgia, skin pigmentation or sleep problems. Vital signs and examination were within normal limits. Her initial work up reported significantly elevated hemoglobin of 17.4gm/dl, hematocrit of 56.1%, RBC count of 6.98M/UL with MCV 80.4 fl, MCH 24.9 pg and platelet count of 673 K/UL. Peripheral smear showed normal red cell morphology and few giant platelets. Subsequently, further lab testing revealed ferritin of 25.7ng/ml. Her elevated hematocrit was further evaluated and erythropoietin was surprisingly <1mIU/ml. Genetic testing for HFE gene mutation screen was positive for homozygous C282Y mutation. Due to high suspicion for Polycythemia Vera, JAK2 mutation was also tested, which to our surprise, came back positive for JAK2 V617F point mutation. Patient is diagnosed with Polycythemia Vera and Hereditary Hemochromatosis and is recommended to start Aspirin, continue phlebotomy to maintain Hematocrit below 45% and take hydroxyurea for thrombocytosis. Discussion: It is interesting to note the co-existence of two un-related diseases. Franchini M et al analyzed 52 patients with PV for 12 HH gene mutations and found no significant association between the two conditions4. Hannuksela J et al studied C282Y and H63D mutations in 232 patients with hematological malignancies and reported no significant association5. Beaton and Adams in their review article about the myths and realities of hemochromatosis reports an elevated hemoglobin, in hemochromatosis's patient as a myth, based on their review of 634 C282Y homozygous patients at London health Science center, with mean hemoglobin of 145±13 g/L6. Our case re-iterates the importance of clinical suspicion of polycythemia Vera in a hemochromatosis patient with elevated hematocrit and undetectable erythropoietin. The coincidence is, phlebotomy is the treatment for both conditions as long as patient is fairly asymptomatic. References: 1. Ayalew Tefferi; Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1; J Cell Mol Med. 2009 Feb; 13(2): 215-237. 2. Cross NC (2011); Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2011:208-214. 3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet1996; 13:399-408. 4. Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera. Franchini M1, de Matteis G, Federici F, Solero P, Veneri D. Hematology. 2004 Oct-Dec;9(5-6):413-4. 5. Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders. Hannuksela J, Savolainen ER, Koistinen P, Parkkila S. Haematologica. 2002 Feb;87(2):131-5. 6. The myths and realities of hemochromatosis Melanie D Beaton, Paul C Adams Can J Gastroenterol. 2007 February; 21(2): 101-104. PMCID: PMC2657669 Disclosures No relevant conflicts of interest to declare.

Abstract Introduction New treatment strategies are improving outcomes for patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL) but achieving durable responses and cure in the relapsed patient remain a challenge. Both the mTORC1 inhibitor everolimus (RAD001) and the IMiD, lenalidomide (LEN) have efficacy as single agents in patients with relapsed and refractory (R/R) HL and NHL. Individually, LEN and RAD present a low toxicity profile and in combination may offer synergistic therapeutic efficacy by unique mechanisms of action. A phase I/II clinical trial of RAD and LEN was designed to explore the tolerability, toxicity and to determine the maximum tolerated dose (MTD) of this combination for the Phase II study. The results of phase I/II data are reported here. Methods MC0981 was activated on January 10, 2011. In phase I, the study enrolled a total of 25 patients and RAD 5 mg daily + LEN 10 mg/d X 21d in a 28-day cycle was defined as the MTD. The phase II opened on May 14, 2013, and closed on Feb 19, 2014, during which 33 patients were enrolled and were treated until progression of disease. Eligibility required age ≥18, biopsy proven relapsed or refractory NHL or HL, ECOG PS 0- 2, measurable disease, Hb >9g/dl, ANC ≥1200/uL, platelet ≥ 50,000/uL, creatinine ≤1.5xULN and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Follow up data was analyzed as of July 2014. Results A total of 58 patients were enrolled to this study and fifty five are evaluable for analysis (2 never started therapy, 1 deemed ineligible). The median age was 62 years (21-82) and 38 (69.1%) were male. Sixty-five percent had stage IV disease and 42% had 4 or more prior treatments including stem cell transplantation in 49%. Histologies included HL (n=10) and NHL (n=45 with 23 DLBCL, 2 FL-III, 5 LPL, 3 MCL, 2 MF, and 3 other). At least 1 Gr≥3 adverse event was seen in 74.5% of patients. The most common Gr≥3 toxicities were hematologic - neutropenia (30.9%), and thrombocytopenia (21.8%), and anemia (10.9%). Nine of 55 patients (16%) had Gr≥3 infection; 2 with skin infection, 1 with cholecystitis, 1 with lung infection, 1 with pharyngitis 1 with otitis externa, 1 with otitis media, and 1 with pleural infection and 1 with upper respiratory tract infection. Seven patients discontinued treatment due to adverse events. At this time, 44% (25/55) remain progression-free. A documented tumor response, as overall response rate (ORR) was seen in 20% (11/55) with 1CR, 8PR, and 2MR; 17 remain on therapy; and 22 deaths have occurred with a median survival of 15.0 months (95% CI 7.5-NR). Median follow up time was 5.5 (range, 0.7- 41.0) months. The median duration of response (DOR) in those responding is 19.4 months. Conclusions In a heavily pretreated population with baseline compromised bone marrow function, the combination of everolimus and lenalidomide is feasible with a modest ORR and a surprisingly long DOR. Future studies in more defined groups of NHL or HL are necessary to better predict which patients will be long-term responders. This trial is sponsored by Novartis and Celgene Disclosures Off Label Use: mTORC1 inhibitor (Everolimus) and the Immunomodulatory (IMiD) drug Lenalidomide for patients with Heavily Pretreated Relapsed Lymphoma . Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Nowakowski:Celgene, Morphosis: Consultancy. Witzig:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Introduction. Limited data exist regarding the role of haploidentical HCT (haplo-HCT) in hemoglobinopathies, whereas long-term outcomes and late effects among these patients are largely unknown. We compared long-term outcomes in two groups of patients underwent halpo-HCT using different in vitro depletion strategies. Methods . Fifty four consecutive patients, aged &lt;17 years, received a haploidentical (≥2 HLA-mismatched antigens) transplant for thalassemia (n=45) or sickle cell disease-SCD (Hb SS, n=7 and HbS/beta thalassemia, n=2). Among these patients 32 received CD34+ selected PBSC and bone marrow grafts, and 8 patients received CD34+ selected PBSC and CD3+/CD19+ depleted bone marrow grafts between December 2005 and December 2011(group A), whereas 14 patients received TCRαβ+/CD19+ depleted PBSC grafts between June 2012 and March 2017 (group B). The conditioning regimen consisted of oral/weight-based IV BU, Thiotepa (10 mg/kg/d), CY (200 mg/kg) and rabbit ATG preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −59, and fludarabine (30-35 mg/m2/d) from D −16 through D −11. Short-course CSA/methylprednisolone or CSA/MMF was given as GVHD prophylaxis until D+60. Eighty and 85% of patients received hematopoietic cells from mother in group A and group B, respectively. The two groups showed similar patient demographics. Results. The median follow-up among surviving patients was 90 months (range, 68-139) for group A and 46 months (range, 5-62) for group B. Median CD34+ cell dose in group A and B was 16x106/kg (range, 4.3-28.1) and 15.7 x106/kg (range, 8.1-39.2) (P=0.43), respectively. The grafts of group A patients contained median of 2.8 x105/kg CD3+ and 0.21x106/kg CD19+ cells. The grafts of group B patients contained median of 4x104/kg (range, 1-10.0) αβ T cells, 9x106/kg (range, 2.8-40.2) γδ T cells, 0.06x106/kg (range, 0.01-1.7) CD19+ cells, and 28.67x106/kg (range, 9.8-194.3) CD16+/56+ cells. Sustained engraftment occurred in 55% versus 86% in group A and B (P=0.05), respectively. Group B patients showed significantly faster platelet and neutrophil recovery. Graft failure (GF) occurred in 18 group A (primary GF in 12 and secondary GF in 6 patients) and one patient each in group B had PGF and SGF. The incidence of GF was significantly higher among patients of group A (45%) than of group B (14%) (P= 0.048). Respective OS and DFS were 78% versus 84% (P=0.9), and 39% versus 69% (P=0.085) (Figure 1). The incidence of grade 2-4 aGVHD in groups A and B were 29% and 28%, respectively. Three patients in group A and one in group B developed grade 3-4 acute GVHD with visceral involvement. The remaining patients in both groups had grade 2 acute skin GVHD. The incidence of moderate chronic GVHD was 10% and 21% in group A and B (P= 0.1), respectively. Both groups showed similar CD3+, CD4+, CD8+, CD19+ and CD56+ immune reconstitution with suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ in group A and B at D+180 were 148±43 and 169±36, respectively (P=0.64). Respective one year absolute cells/ul of CD3+, CD4+, CD8+, CD19+ and CD56+ were 1014±238, 423±97, 559±147, 600±241, 413±151 vs 832±250, 295±74, 415±140, 307±103, 182±49. In group A, 8 patients died due to pneumonia (D+29), perianal abscess (D+33), CMV pneumonia (D+190 ), diffuse large B-cell lymphoma (DLBCL) (D+199), disseminated aspergillosis (D+243), toxic megacolon (+1.2 years), acute heart failure (+ 4 years) and overwhelming postsplenectomy sepsis (+7.4 years). In group B 2 patients died from gastrointestinal bleeding (D+222) or DLBCL (+1.7 years). The frequency of complications were similar in both groups. The incidence of EBV reactivation/PTLD was significantly higher in patients who did not receive prophylactic rituximab (26%) than who did (4%) (P=0.03). Conclusions. This study showed that the use of TCRαβ+/CD19+ depleted grafts was associated with a reduced rate of GF and improved DFS compared with CD34+selected/CD3+CD19+- depleted grafts in hemoglobinopathies. However, delayed immune reconstitution and infectious complications remain major causes of morbidity and mortality in these patients. Additional strategies to improve immune recovery are needed. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1259 Severe aplastic anemia (SAA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. As most patients lack a histocompatible donor, the majority of patients are treated with immunosuppressive therapy (IST) with horse anti-thymocyte globulin plus cyclosporine (h-ATG/CsA). The current limitations of IST in SAA are: 1) most responses are not complete; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) hematologic relapses occur in 30–35% of responders following initial response ATG/CsA; 4) and clonal evolution is observed in about 15% of patients at 10 years after first therapy (Scheinberg and Young 2012). Efforts to improve initial IST in treatment-naïve patients with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or use of lymphocytotoxic agents such as rabbit ATG or alemtuzumab have not yielded better outcomes when compared to standard h-ATG/CsA (Scheinberg and Young 2012). Cyclophosphamide (Cy) has been proposed as an alternative IST regimen to h-ATG/CsA. A pilot and single institution phase II study suggested that high dose Cy (200 mg/kg) yielded similar results to that observed for h-ATG/CsA but with fewer relapses and clonal evolutions (Brodsky, Chen et al. 2010). However, in a randomized study at NHLBI comparing high dose Cy (200 mg/kg) and h-ATG/CsA in treatment-naïve patients excess toxicity and deaths from invasive fungal infections were observed in the Cy arm, which led to the discontinuation of this regimen (Tisdale, Dunn et al. 2000). In a recent Chinese protocol introduced by Dr. Zhang (Institute of Hematology & Blood Disease Hospital, China), lower doses of Cy (30 mg/kg/d * 4 days, 120 mg/kg total) plus CsA, were reported to achieve similar results as with high-dose Cy at 200 mg/kg with reduced toxicity (Kojima, Nakao et al. 2011). Because of the marked improvement in survival in SAA, especially among patients who did not respond to IST, likely due at least in part to improved antifungal drugs (Valdez, Scheinberg et al. 2011), we considered it reasonable to investigate “moderate” dose Cy + CsA as proposed by the Chinese as first line in SAA. The main objective was to assess the safety and efficacy of Cy at 120 mg/kg + low dose CsA, at doses aimed to achieve plasma levels of 100 – 200 mg/L, in treatment-naïve SAA, and the primary hematologic endpoint was response, defined as no longer meeting criteria for SAA, at 6 months. The study was designed to show an increase in complete response rate > 30%, in our experience a surrogate for fewer late events. Prophylactic voriconazole was administered with target levels between 1 – 5.5 ug/L, with ciprofloxacin and Bactrim. From October 2010 to April 2012, 22 patients were accrued. Toxicity from Cy + CsA was considerable and in some cases unexpected, with absolute neutrophil levels of 0/uL universal regardless of pre-therapy blood counts. Granulocyte transfusions were required in 5 participants for uncontrolled infections, and to date 5 patients have died, all from infections. Confirmed fungal infections were documented in 4 participants. In 10 patients with a pre-treatment ANC > 500/uL, 5 remained with severe neutropenia at 6 months as salvage therapies were being sought. In a companion protocol using Cy at 60 mg/kg + fludarabine at 125 mg/m2, neutropenia was also prolonged and severe in a patient leading to pulmonary murcomycosis and need for frequent granulocyte transfusions. In total 9 patients responded to “moderate” dose Cy (120 mg/kg total dose) + CsA, with 4 complete and 5 partial responders. In the relative short follow-up period, cytogenetic abnormalities have been observed in 4 patients: 1 to monosomy 7, 1 del20q, 1 trisomy 15, and 1 del7q. We conclude that Cy at 120 mg/kg + CsA, while capable of producing meaningful hematologic responses in some cases, results in significant toxicity, despite maximum prophylactic and intensive supportive care. The regimen led to very prolonged hospitalizations and frequent bacterial and fungal infections. Hematologic relapses with a higher than expected number of clonal evolution events were observed in our cohort. Due to the high toxicity of Cy (120 mg/kg) + CsA, without likelihood of benefit from decreased relapse and clonal evolution, both protocols using “moderate” dose Cy were terminated by our data and safety monitoring board. Although Cy has activity in SAA, its toxicity is not justified when far less toxic alternatives, such as h-ATG, are available. Disclosures: Off Label Use: Cyclophosphamide in aplastic anemia.

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.