ALBERT

Description: Background: Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods: Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results: We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was 〉3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (〉 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion: Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. Table Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Nieto:Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy; Novartis: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Autolous: Consultancy; Bioclinica: Consultancy; Speaker: Other: Speaker; Amgen: Other: Advisory Board. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. OffLabel Disclosure: Fludarabine & Busulfan as conditioning agent prior to transplant

Description: Disease relapse remains the major cause of treatment failure following hematopoietic transplantation for AML/MDS. A major goal is to develop more effective antileukemic regimens without excessive toxicity. Busulfan (Bu)-fludarabine (Flu) is a widely used preparative regimen. We demonstrated that targeting a relatively high busulfan systemic exposure pharmacokinetic (PK) dose adjustment was superior to fixed busulfan dosing. Clofarabine (Clo) has improved antileukemic activity compared to fludarabine. We previously reported a phase I/II study of different dosing combinations of busulfan with Flu and Clo; the best results were obtained with Bu with Flu 10 mg/m2 and Clo 30 mg/m2 daily for four daily doses. We performed a phase III randomized controlled trial to determine if Flu/Clo/Bu improved progression free survival compared to the Flu/Bu regimen. Busulfan was given with PK dose adjustment AUC 6000 mM x min for age

Description: Key Points Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments. This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.

Description: Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for patients with severe aplastic anemia (SAA), but graft-versus-host disease (GVHD) has been a major impediment to success. Cyclosporine (CSP) has been widely used as GVHD prophylaxis after HCT for SAA, while both CSP and tacrolimus (TAC) have been used after HCT for hematological malignancies. The aim of this study was to compare transplant outcomes according to TAC+methotrexate (MTX) vs. CSP+MTX as GVHD prophylaxis after HCT for SAA using large registry data. Patients and methods:The retrospective cohort included 949 patients who had a first allogeneic bone marrow or growth factor-mobilized peripheral blood cell transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) for treatment of SAA using GVHD prophylaxis with MTX in combination with either TAC or CSP from 2001 to 2011. Patients who had ex-vivo T cell depletion were excluded. Study endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, overall mortality, hematopoietic recovery and graft failure. Multivariate Cox regression models were used to evaluate hazard ratios for endpoints with TAC+MTX as compared with CSP+MTX. A stepwise procedure was used in developing models for each outcome, using a P value threshold of 0.05, with GVHD prophylaxis and year of HCT forced in all models. Analyses were performed separately in SIB (n=631) and URD (n=318) recipients. Results: The median age of patients was 19 (range, 0.5 to 70) years. TAC+MTX was used in 62 SIB recipients (10%) and in 120 (38%) URD recipients, and was used more frequently in older patents than in younger patients in both groups. Multivariate analysis showed a decreased risk of overall mortality with TAC+MTX in URD group and an increased probability of neutrophil recovery with TAC+MTX in SIB group, but other outcomes did not differ statistically between TAC and CSP prophylaxis (Table). Center effect was not statistically associated with overall mortality, and results were similar even after adjustment for center effect. Causes of death were similar between CSP and TAC prophylaxis in both SIB and URD recipients. Conclusion: Based on adjusted multivariate analyses, the use of TAC+MTX was associated with a decreased risk of mortality among URD recipients and with earlier neutrophil recovery among SIB recipients. Results showed no statistically significant differences in other outcomes with the 2 prophylaxis regimens, although power was limited by the number of patients treated with TAC. Our results support the use of either prophylaxis regimen for SIB recipients. TAC+MTX may be favored for URD recipients, but the interpretation of the survival difference remains uncertain, since TAC was not associated with a reduction in the risk of GVHD, causes of death were similar between the 2 prophylaxis regimens, and the actual difference in survival was small between the 2 prophylaxis regimens. Table. Multivariate analysis of outcomes with TAC+MTX compared to CSP+MTX Outcome Identical Sibling (n=631) Unrelated (n=318) HR* (95% CI) P HR* (95% CI) P Grades II-IV acute GVHD 1.79 (0.92-3.47) 0.09 1.17 (0.76-1.80) 0.48 Grades III-IV acute GVHD 0.79 (0.19-3.34) 0.75 1.52 (0.81-2.86) 0.19 Chronic GVHD 1.79 (0.92-3.47) 0.09 1.23 (0.80-1.88) 0.35 Overall mortality 1.38 (0.74-2.55) 0.31 0.45 (0.25-0.81) 0.008 ANC recovery 1.47 (1.04-2.08) 0.03 1.29 (0.95-1.75) 0.10 Platelet recovery 1.26 (0.93-1.71) 0.13 0.89 (0.66-1.20) 0.44 Graft failure 1.08 (0.45-2.56) 0.87 0.48 (0.16-1.48) 0.20 *Adjusted for other covariates. Disclosures No relevant conflicts of interest to declare.

Description: Introduction - Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for patients with myelofibrosis (MF). MF is stratified into various risk groups based on Dynamic International Prognostic scoring system (DIPSS plus), which determines the eventual prognosis of the disease at any time. Previous studies and expert opinion indicate that for patients with Intermediate-2 risk (INT-2) and High risk (HR) disease, HCT is a reasonable option. How applicable is this to all patients with MF and what are the barriers to doing a transplant are not known. We therefore reviewed medical records of all patients who were referred for HCT. The main purpose of this study was to determine the proportion of patients who underwent transplantation as well as to ascertain the major reasons why patients referred for transplantation did not receive it despite its reported benefit. Methods- This was a retrospective, single institution, observational study. We analyzed patients referred for HCT with a diagnosis of MF. One hundred and ninety-eight consecutive patients with a preliminary diagnosis of MF were seen at the stem cell transplantation and cellular therapy (SCTCT) clinic of MD Anderson cancer center (MDACC) from 1/1/2004 to 12/31/2012. Out of the 198 patients, 26 had a diagnosis other than MF and hence were excluded. We stratified the remaining patients according to their DIPSS plus score at the initial consult and also traced their progression. For the non-transplanted patient with HR and INT-2 DIPSS plus scores, the major reason for deferring transplant was retrieved from the chart. Results & Discussion- Out of 172 patients seen in the stem cell transplant clinic with MF, 70(41%) underwent transplantation and 102(59%) did not receive HCT. Of the 102 patients who did not undergo SCT, 72(70%) had INT-2 or HR disease at the initial consultation (transplant eligible). Of the remaining 30 patients with low risk or intermediate-1 risk disease, 7(23%) patients eventually progressed to INT-2 or HR disease and became transplant eligible. The median time from MF diagnosis to consultation for non-transplanted patients was 331days (11 months) (Range-0-8675). For patients with INT-2 and HR disease (79/102), the major reasons for not receiving a transplant (Figure) are patient choice (36/79; 46%), financial issues (23/79; 29%), comorbidities (9/79; 11%), lack of donor (7/79; 9%) and poor performance status (4/79; 5%). Patient choice of not pursuing transplant is understandable because there was limited data on efficacy of HCT for MF in early years. The most common insurance provider not covering transplantation was Medicare (20/23; 87%). The co-morbidities that precluded HCT were cardiopulmonary disease (4/9; 44%), liver dysfunction due to advanced disease (3/9; 33%) and other comorbidities (2/9; 22%). Of note 5/7 (72%) patients who were not transplanted due to lack of appropriate donor were non-Caucasian patients. Conclusion- Only 41% of patients referred for transplant with MF receive HCT. The major barriers to wider application and usage of HCT for MF were patient choice and lack of coverage by Medicare. Patient education, coverage by Medicare, use of alternative donors, and earlier transplant referrals can further increase the accessibility of transplantation and improve outcomes of patients with MF. Figure 1. Figure 1. Disclosures Alousi: Therakos, Inc: Research Funding.

Description: Introduction: Age at diagnosis is of prognostic value in Hodgkin's lymphoma (HL) patients. However, there is paucity of data on the impact of age on outcomes of autologous hematopoietic transplantation (auto-HCT) for patients with relapsed and refractory HL. We studied impact of age at diagnosis on long-term outcomes of patients with HL undergoing auto-HCT. Patients and Methods: All consecutive patients with relapsed/refractory HL who underwent auto-HCT at our center between January 1996 and December 2010 were included. Baseline patient and disease characteristics were collected. As HL has bimodal peak incidence betweenages of 15 and 34 years and over age of 50 to 55 years, we stratified patients into 3 groups: 〉 55, 26 to 55 years, and ≤ 25 year age groups. We compared overall survival (OS), progression free survival (PFS), relapse rate and rates of secondary malignancies between these groups. As the outcomes were similar between ≤ 25 and 26 to 55 years groups, subsequent analysis of these two groups was done together as ≤ 55 years vs. 〉 55 years groups. Baseline patient and disease-related characteristics were compared using the chi-square test for categorical variables and Mann Whitney's rank-sum test for continuous variables. Actuarial OS was estimated using the Kaplan-Meier method. Prognostic factors for OS, disease progression and non-relapse mortality (NRM) were assessed on univariate and multivariate analyses using Cox proportional hazards regression analysis. Results: 30 (9.7%) patients were 〉 55, 168 (54.1%) patients were between 26 to 55, and 112 (36.1%) were ≤ 25 years of age. At a median follow-up of 80 months, patients 〉 55 were at significantly higher risk for mortality with hazard ratio (HR) of 2.3 (95% CI, 1.3-4.2; P = 0.007) compared to patients ≤25 years of age. There was no difference in mortality when between age 26 to 55 years and ≤ 25 years group (HR 1.0; 95% CI, 0.6-1.6; P = 0.9). Risk for progression was similar between the 3 groups, with HRs of 1.3 (95% CI, 0.7-1.5; P = 0.5) and 1.2 (95% CI, 0.8-1.8; P = 0.3) for 〉 55 group and 26 to 55 groups, respectively compared to ≤ 25 years group (Table 1). Patients 〉 55 years at diagnosis had significantly higher incidence of secondary malignancies mostly MDS/AML(30% vs. 8%; P55 years at diagnosis who receive auto-HCT for relapsed/refractory HL experience higher mortality from secondary malignancies. Table 1. Outcomes of Auto-HCT at Median Follow-Up of 80 Months Outcomes Entire Cohort 〉 55 yearsN = 30 ≤ 55 yearsN = 280 P value OS 65% (59-71) 27% (9-49) 69% (63-74) 0.003 PFS 54% (48-60) 31% (12-53) 56% (50-62) 0.2 CI of progression 41% (26-64) 52% (36-75) 37% (32-44) 0.7 CI of NRM 8% (5-12) 33% (16-65) 5% (3-9) 0.001 CI of second malignancy 11% (7-16) 30% (16-57) 8% (5-14) 〈 0.001 CI of second malignancy excluding skin cancers 9% (6-13) 22% (10-49) 7% (4-12) 0.003 SHAPE P=0.001 P

Description: Background: Primary mediastinal (PMBL), GCB and non-GCB B-cell lymphoma are three major subtypes of DLBCL with distinct clinical outcomes. PMBL and DLBCL of GCB immunophenotype have a higher chance of cure than patients with non-GCB DLBCL when treated with conventional chemotherapy. In the relapsed/refractory setting, there is paucity of data regarding the impact of histological classification of DLBCL on survival following alloSCT in patients who were not eligible for or who have failed a prior autologous SCT (ASCT). Herein, we compare outcomes of alloSCT in these patients. Methods and Patients: We identified 101 de novo DLBCL patients who were treated at our center from January 1, 1998 to December 31, 2011. Seventeen (17%) tumors were PMBL. We determined the cell-of-origin in the remaining patients, based upon the Visco/Young and Choi immunohistochemical algorithms, and classified 62 (61%) as GCB and 22 (22%) as non-GCB tumors. GCB patients were older than non-GCB [median (range): 54 (21-70) vs 48(24-58) years, p=0.003)] and PMBL [26(19-48), P

Description: Key Points After HSCT with in vivo T-cell depletion using ATG, HLA-DPB1 nonpermissive mismatches at the GVH direction increase the risk for aGVHD. HLA-DPB1–matched pairs have an increased risk for disease progression if intermediate risk by the Disease Risk Index.

Description: Abstract 2283 Poster Board II-260 Background: Reduced intensity allogeneic transplantation was developed to harness graft versus leukemia immune effect to treat older patients and patients with comorbidities who are not eligible for conventional myeloablative transplant. Aim: To prospectively study the safety and efficacy of reduced intensity HCT in patients with myelofibrosis. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Fifteen patients were conditioned with Fludarabine 40mg/m2 × 4 (days -5, -4, -3 -2) and Busulfan 130mg/m2 × 2 (day -3,-2). Thymoglobulin 2.5 mg/kg x 3 (day -3,-2 and 1) was additionally given to patients receiving unrelated donor graft. Because of high incidence of relapse, Busulfan dose was increased to a target AUC of 4000 μmol/L or a fixed dose of 100mg/m2 × 4 (days -5, -4, -3 -2) in 11 patients. Tacrolimus and mini Methotrexate were used as graft versus host disease prophylaxis. All patients received standard supportive care. Results: Between 6/2005 and 07/2009, 26 consecutive patients with myelofibrosis were treated. There were 13 males and 13 females with a median age of 58 (range 27-74). Seventeen patients had primary MF, 3 post PV MF and 6 Post ET MF. Based on Lille criteria, 14 patients had intermediate risk disease and 12 had high risk disease. Ten patients had splenectomy prior to transplant; remaining 16 patients had enlarged spleen at the time of transplant. Fourteen patients had mutated Jak 2. Median peripheral blood CD 34 count was 57/μl(range 1-3770/μl). Karyotype was abnormal in 11 patients and diploid in 15. Donors were matched siblings for 10 patients, matched unrelated for 12, and one antigen or allele mismatched unrelated for 4 patients. Stem cell source was marrow in 3 and peripheral blood in 23. All patients engrafted with a median time to neutrophil engraftment of 13 days (0-27) days) and a median time to platelet engraftment of 24 (0-105) days. Jak 2 positive patients achieved molecular remission post transplant with negative JaK 2. With a median follow up of 21 (1-43) months, 2 year overall and event free survival are 71% (SE 10%) and 46% (SE 11%), respectively. Cumulative incidence of non relapse mortality was 14% (SE 7%). Cumulative incidence of relapse was 39% (SE10%). Eight patients relapsed; 3 in blast phase and 5 in chronic phase. Four of these 8 are currently disease free after a second transplant. Including these 4 patients, 18 out of 26 patients are currently disease free. These include 10 of 11 patients treated with higher dose of busulfan compared with 8 of 15 patients treated with lower busulfan dose. Conclusion: RISCT induces molecular remission with very low non relapse mortality in older patients with myelofibrosis, but the relapse rate is high. Increasing the intensity of conditioning regimen may reduce the relapse risk and needs to be studied further. Disclosures: No relevant conflicts of interest to declare.