Academic literature on the topic 'K 46.5 UL 2010 B718'

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.

Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

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.

Abstract Allogeneic hematopoietic cell transplantation (HCT) from HLA-matched sibling (MS) or unrelated donors (MU) is a well-established treatment for patients with intermediate/high-risk acute myelogenous leukemia (AML) in remission. When HLA-matched donors are not available, however, use of haploidentical family (HF) donors for HCT remains controversial. Therefore, we performed a prospective study, where patients with AML in complete remission (CR) underwent allogeneic HCT according to the donor priority of MS, MU, or HF donors. Conditioning regimen for MS-HCT was busulfan (3.2 mg/kg • 4 days)-cyclophosphamide (60 mg/kg • 2 days) or, for patients >55 years or with co-morbidity, busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (1.5 mg/kg • 3 days). Patients undergoing MU- or HF-HCT received busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (3 mg/kg • 3 days) (Lee K-H et al; Blood 2011;118:2609-2617; Am J Hematol 2011;86:399-405). Ex-vivo T cell depletion was not performed. GVHD prophylaxis included cyclosporine plus a short course of methotrexate. Between January 2010 and December 2014, 244 patients enrolled. Of those, 16 patients were excluded from the analysis (12 patients relapsed before HCT; 3 with major protocol violation; and 1 with incomplete data). Of remaining 228 patients, 81 underwent HCT from MS donors, 90 from MU donors, and 57 from HF donors. The donors for MU-HCT were younger and more male-dominant than those for MS- or HF-HCT. The characteristics of patients and their donors were summarized in Table 1. Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P* Median age, yr (range) 48 (19-66) 43 (16-66) 46 (17-69) Sex, male/female 37/44 44/46 29/28 0.824 CR1/CR2 76/5 82/8 47/10 0.098 Chromosome risk,low**/intermediate/high/high-monosomal 6/57/10/5 4/65/16/3 2/40/7/5 0.751 Donor median age, yr (range) 45 (18-63) 28 (20-45) 29 (15-58) Donor age, yrup to 2526-45over 45 44136 29610 19326 0.000 Donor sex, male/female 46/35 76/14 36/21 0.000 Donor relation, parents/sibling/offspring 7/24/26 HLA allele mismatch/8 (GVH direction), 0/1/2/3/4 81/0/0/0 51/26/10/2/1 0/0/5/22/30 0.000 Graft, bone marrow/peripheral blood 28/53 0/90 0/57 0.000 Median nucleated cell count, •108/kg (range) 8.0 (0.9-19.0) 10.8 (4.1-31.4) 10.8 (5.1-19.3) Median CD34+ count, •106/kg (range) 4.9 (0.8-18.0) 8.0 (1.4-26.2) 6.4 (2.4-25.7) *by Chi-square test; **Twelve patients with AML of low-risk chromosomal abnormality included 6 patients in CR2, 3 with c-kit mutation, and 3 with persistent aml1-eto or cbf beta-myh11 after induction chemotherapy. The median follow-up duration of 164 survivors in the study was 34.7 months (range, 3.7-63.6) after HCT. The donor-group effect on the HCT outcomes was described in Table 2. Patients who underwent MS-HCT showed slightly slower neutrophil engraftment and higher incidence of chronic GVHD. Otherwise, in terms of disease recurrence, NRM, graft failure, EFS, and OS, there was no significant difference according to the donor-type. For AML recurrence, cytogenetic risk was an independent prognostic factors (P =0.003; hazard ratio of low-risk to; intermediate-risk, 1.42; high-risk, 2.53; high-risk with monosomal karyotype, 5.47). Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P Cumulative incidence ( 95% confidence interval)* AML recurrence 29% (19-40%) 26% (17-36%) 35% (20-51%) 0.785 Non-relapse mortality (NRM) 8% (3-16%) 7% (2%-16%) 11% (4-21%) 0.435 Graft failure 1% (0.1-6%) 6% (2-12%) 5% (1-13%) 0.293 ANC>500/uL median days (range) 100% 13 (9-20) 99%12 (10-45) 98% 12 (6-22) 0.049 Platelet>20,000/uL median days (range) 99% (86-100%) 14 (0-83) 97% (88-99%) 13 (0-77) 96% (83-99%) 14 (0-106) 0.352 Grades 2-4 acute graft-versus-host disease (GVHD) 12% (6-21%) 13% (7-21%) 23% (13-34%) 0.176 Moderate to severe chronic GVHD 39% (28-50%) 22% (13-30%) 23% (13-35%) 0.0452 4-year survival** Event-free (EFS) 63% 69% 54% 0.381 Overall (OS) 62% 74% 64% 0.077 *compared by Gray's method; **compared by log-rank test Our study showed that, despite heterogeneity of baseline donor characteristics (age and sex), conditioning regimen, and graft source (bone marrow vs. peripheral blood), overall post-transplant outcomes were similar among recipients from MS-, MU-, and HF-donors. Therefore, for patients with AML in CR but without an HLA-matched donor available, HCT from a haploidentical family member may be considered. Disclosures No relevant conflicts of interest to declare.

Abstract Thrombotic microangiopathy (TMA) is seen in up to 30% of patients receiving solid organ transplantation and almost always occurs in the setting of calcineurin inhibitor (CNI) therapy. The underlying pathophysiology of calcineurin induced TMA is poorly understood. Long term follow up in non renal transplant patients with TMA suggests that in spite of plasma exchange therapy the 1 year mortality following TMA is up to 70%. Between November 2010 and August 2012, 7 patients at our institution who underwent organ transplants ( 5 small bowel, 2 orthotopic liver) developed clinical and laboratory evidence of TMA while receiving CNI therapy. TMA was diagnosed from 3 to 13(median 11) months post transplant and none of the patients responded symptomatically or by laboratory parameters to a reduction in dose of CNI. Other unsuccessful therapies included substitution of other immunosuppressive agents (N=1) and 11 daily plasma exchanges (N=1). At the time of TMA diagnosis notable laboratory values included platelets 22-73 (median 46) K/UL, hemoglobin 4.5 to 8.1(median 6.9) GM/DL, serum creatinine 1.16-5.4 (median 2.66)MG/DL, LDH 262-2903(median 435) Units/L, and ADAMSTS13 37-137%. All patients had a negative DAT, schistocytes on peripheral smear and all but one had undetectable haptoglobin. ( Table 1 ) Clinical symptoms at diagnosis included nausea, vomiting, abdominal pain, fever, hypertension, cerebral vascular accident (N=1), acute coronary syndrome (N=1). None of the patients had evidence of graft rejection on biopsy of the transplanted organ at the time of TMA diagnosis however 2 patients with small bowel transplants had pathologic evidence of ischemic changes and vascular thrombi on biopsy of the small bowel graft.Table 1Comparison of Medians of TMA Laboratory ParametersMedian ValuesPreTransplantTMA Diagnosis4 weeks post eculizumabPlatelet count K/UL12046202Hemoglobin GM/DL11.06.99.0Serum Creatinine MG/DL0.832.661.7LDH Units/L174435322HaptoglobinNT<3190 Eculizumab is a monoclonal antibody which binds with high affinity to C5 and is highly effective in disorders associated with abnormalities in the regulation of complement such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS) another TMA disease. Due to the clinical and laboratory similarities of post transplant CNI associated TMA and aHUS all patients in our series were treated with the standard induction dose of eculizumab 1200mg weekly for 4 weeks and 900mg every 2 weeks thereafter. Treatment duration ranges from 4 weeks to 107 weeks. All patients were successfully maintained on adequate immunosuppression with calcineurin inhibitor (tacrolimus in all cases) to inhibit graft rejection. All patients demonstrated a rapid and complete resolution of laboratory and clinical manifestations of TMA. After the fourth dose of eculizumab platelet counts ranged from 104-291(median 202), hemoglobin 8.1-10.9(median 9.0), serum creatinine 0.70-4.08(median 1.7), LDH 157-475(median 322) and haptoglobin 23-204(median 90). Only 1 of the 4 patients requiring dialysis at TMA diagnosis remained on dialysis at 4 weeks of therapy.( Table 1) No patients show evidence of recurrent TMA or increase in infectious complications on continued eculizumab plus calcineurin inhibitor therapy at greater than 2 years of eculizumab therapy. The excellent clinical and laboratory response of our patients to eculizumab strongly suggests a central role for complement dysregulation in the pathophysiology of calcineurin induced TMA. There are multiple theories regarding the mechanism by which CNIs induce complement dysregulation including: (1) an underlying genetic predisposition to complement dysregulation worsened or exacerbated by CNI therapy, (2) CNI therapy may induce widespread and significant endothelial damage which serves as a stimulus for chronic complement activation, or (3) chronic over stimulation of complement production secondary to CNI inhibition of T-cell function .While the mechanism remains to be elucidated the clinical implications seem clear: CNI induced TMA is mediated by complement and is treated very effectively with eculizumab allowing patients to continue on graft function preserving CNI therapy. Disclosures: Broome: Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Off Label Use: Eculizumab for the treatment of calcineurin induced TMA.