ALBERT

Description: The success of adoptive immunotherapy for the treatment of leukemia depends on the generation of T cells that can specifically react with malignant cells. Dendritic cells (DCs) are important antigen-presenting cells in the development of antileukemic T-cell responses. In this study, we generated DCs from peripheral blood cells of patients with chronic myelogenous leukemia (CML). CML cells incubated concurrently with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α in vitro developed morphologic and phenotypic characteristics of DCs. Fluorescence in situ hybridization showed the presence of t(9; 22) in the nuclei of these cells, indicating that they were leukemic in origin. These cells were potent stimulators of lymphocyte proliferation in specific in vitro assays for DC function. Autologous T cells stimulated with in vitro-generated, leukemic DCs displayed vigorous cytotoxic activity against CML cells but low reactivity to major histocompatability complex-matched normal bone marrow cells. Cytotoxic activity against CML targets was fourfold to sixfold higher using DC-stimulated autologous T cells than with autologous T cells expanded by culture with interleukin-2 alone. DC-stimulated T cells also inhibited growth of CML clonogenic precursors in colony-forming assays in vitro. These results suggest that cytokine-driven in vitro differentiation of CML cells results in generation of DCs with potent T-cell stimulatory function. In vitro-generated DCs can be effectively used as antigen-presenting cells for the ex vivo expansion of antileukemic T cells.

Description: In myeloablative unrelated donor allogeneic hematopoietic cell transplantation (HCT) a 1-locus HLA-mismatch (-A, -B, -C, -DRB1) is associated with lower survival compared to fully matched pairs. However data in reduced-intensity and non-myeloablative conditioning (together called RIC) HCT are limited. We analyzed adult AML/ALL/CML/MDS recipients of first 8/8 HLA-matched or 1-locus mismatched unrelated donor (MUD, MMUD) RIC HCT performed in the period 1999-2011 and registered in the CIBMTR. HLA-A, -B, -C and -DRB1 loci were typed in all pairs at high resolution; -DQB1 and -DPB1 loci could not be evaluated in all pairs. Transplants involving ex-vivo T-cell depletion, CD34+ selection, or post-transplant cyclophosphamide were excluded. Overall survival (OS) was the primary outcome. Secondary outcomes included non-relapse mortality (NRM), relapse, disease-free survival (DFS) and acute and chronic GVHD. Individual locus mismatch was also assessed. Apart from HLA matching, variables related to patient (age, race, sex, KPS, diagnosis, disease-risk), donor (age, parity), both (sex match/ABO match/CMV match) treatment (conditioning intensity, TBI use, in-vivo T-cell depletion (ATG), graft source (PB, BM) and GVHD prophylaxis (CyA-, Tac-based)) were considered. 2588 RIC HCT (8/8 MUD: 2025; 7/8 MMUD: 563) from 144 centers and 12 countries were analyzed. Median follow up in 8/8 MUD and 7/8 MMUD was 38 and 48 months respectively. Diagnoses were AML (65%), ALL (8%), CML (7%), MDS (20%). Conditioning intensity was RIC (79%), NMA (21%). 58% received in-vivo T-cell depletion. Graft source was PBSC (85%), BM (15%). GVHD prophylaxis was Tac-based (70%), CyA-based (27%). Mismatches involved HLA-A (188), -B (81), -C (219), and -DRB1 (75); with -DPB1 and -DQB1 typing available in 1382 and 2502 cases respectively. Compared to 8/8 MUD, 7/8 MMUD recipients were more likely to be younger and ethnic minorities and to have older and parous donors. In univariate analyses DQB1- and -DPB1 mismatch was not associated with worse OS, DFS, or NRM and was not further evaluated. There was a trend toward more grade II-IV acute GVHD in -DPB1 double (p=0.02) but not single mismatches. In multivariate models 7/8 MMUD RIC HCT had worse grade II-IV and III-IV acute GVHD, NRM, DFS and OS, but not relapse or chronic GVHD (Table). No significant interactions were identified between degree of HLA matching and other clinical variables. Adjusted 1- and 3-year NRM for 8/8 MUD vs. 7/8 MMUD was 20.4% vs. 28.9% (p

Description: Because of potential synergy with chemotherapy and non-overlapping toxicity, we investigated the addition of Rituximab or Campath 1-H to the standard myeloablative conditioning regimen of cyclophosphamide (60 mg/kg daily x 2) and total body irradiation (12.0 Gy in four fractions) prior to allogeneic transplantation for ALL. Transplantation was performed on day 0. Rituximab was added if patients’ disease expressed CD20+ 〉 20% by flow-cytometry. It was administered (375 mg/m2 ) on days −6, −1, +7 and +14. Campath I-H (10 mg daily intravenously, days −6 to −2) was added if patients’ CD20 expression was 20%. Thirty-two adult consecutive patients were studied. Eleven were in first remission with poor prognostic features, 11 in 2nd remission, and 10 were ≥ 3rd remission, or in relapse. Twenty-nine patients had B-cell, two had T-cell and one had an undifferentiated phenotyping. The study group included 19 males and 13 females of median age 35 yrs (range, 19–57). Median # of prior chemoregimens received was 2 (range, 1–6). In both groups of patients, prophylaxis for GVHD consisted of a combination of tacrolimus and methotrexate. Pharmacokinetic studies in patients who received Campath I-H showed no detectable level of the antibody one-day prior to- or after the infusion of the donor graft. Median follow-up for survivors was 19 months. Outcomes were: Campath-study group Rituximab-study group P -value Prior Chemoregimens (range) 2(1–6) 2(1–3) 0.04 Donor Type     Matched unrelated 3(28%) 8(38%) 0.2     Matched sibling 7(63%) 12(57%)     Mismatched sibling 1(9%) 1(5%) Cell Source     PB 8(73%) 11(52%) 0.2     Marrow 3(27%) 10(48%) Disease Status     CR1/CR2 5(45%) 17(81%) 0.05     Others 6(55%) 4(19%) Median time ANC 〉500 13 12 0.07     (range) (11–17) (10–24) Median time Platelets 〉20K 13 13 0.8     (range) (6 – 31) (7 – 34) Day 100 TRM 0 1(5%) Acute GVHD II–IV (N,% kM) 2 (18%) 5 (24%) 0.7 Acute GVHD III–IV (N, % kM) 0 2 (9%) Chronic extensive GVHD (N, cumulative incidence) 3 (27%) 9 (54%) 0.4 Overall Survival (18 mos) (95% CI) 53% (21 – 77) 52% (26 – 73) 0.9 Disease-free survival (18 mos) (95% CI) 54% (23 – 75) 37% (15 – 60) 0.8 No prognostic factor was found to be of significance for survival, disease-free survival, or relapse. This included: age (

Description: Background: Hemorrhagic cystitis (HC) is a known complication of high-dose cyclophosphamide, which is part of the conditioning regimen for stem cell transplantation, and is associated with significant morbidity. Treatment of HC is frequently unsatisfactory, leading to prolonged hospitalization and utilization of health care resources. High-dose recombinant factor VIIa (rFVIIa) is used as a hemostatic agent in patients with hemophilia with inhibitors. As rFVIIa enhances the generation of thrombin on activated platelets and facilitates the formation of a stable fibrin plug that is resistant to premature lysis, we conducted a pilot study to assess its efficacy and safety in the treatment of HC. Methods: Subjects between 18–65 years with severe HC that was judged unresponsive to (a) optimization of hemostatic parameters, and (b) a trial of at least 24-hours of continuous bladder irrigation using a standardized protocol were eligible. Consented subjects were administered 80 μg/kg of rFVIIa for the first dose, and 120 μg/kg every 3 hours for up to 2 additional doses if hematuria was persistent. Response was evaluated by monitoring urine color photographically and by measuring urine hemoglobin content, using spectrophotometer. Subjects were followed for 24 hours. Complete response was defined as complete clearing of the color of urine at any time point in the 24-hour study period, and partial response was defined as slowing of hematuria, as evidenced by lightening of the color of urine. Results: Of the 7 subjects who participated in the study, 4 had a complete response, 2 had a partial response, and 1 had no response. The response duration was temporary, and all the subjects required the administration of the three doses of rFVIIa. No major adverse effects were encountered. Conclusion: rFVIIa appears to be effective in temporarily abating bleeding in HC. Further trials should include multiple dosing and/or addition of antifibrinolytic agents for a more durable effect.

Description: Since 1988 we have treated 66 patients with relapsed, refractory, or high-risk Hodgkin lymphoma (HD) with high-dose CEP consisting of cyclophosphamide 1,500 mg/m2/day × 4 (total dose, 6,000 mg/m2), etoposide 400 mg/m2 twice daily × 6 doses (total dose, 2,400 mg/m2), and cisplatin 50 mg/m2/day × 3 by continuous i.v. infusion (total dose 150 mg/m2) followed by infusion of autologous peripheral blood stem cells (n=49), bone marrow (n=16), or both (n=1). The patient population included 41 males and 25 females. The median age at transplant was 33 years (range, 17–64 years). Twenty-three patients (35%) had never achieved complete remission prior to transplant, 36 (55%) had previously achieved a complete remission but subsequently relapsed, and 3 (5%) were in first complete remission. Information regarding the disease status at transplant was unavailable for 4 patients (6%). Twenty-seven patients (41%) remain alive and free of any post-transplant relapse or progression as of the most recent follow-up, and an additional 10 patients (15%) manifested active disease post-transplant but are currently in remission following additional post-transplant therapy, yielding a total of 37 patients (56%) currently in CR. In addition, 5 patients (8%) remain alive with active disease, 23 patients (35%) died of progressive disease, and only 2 patients (3%) died of treatment-related causes including diffuse alveolar hemorrhage (1 patient) and hepatic veno-occlussive disease (1 patient). With a median follow-up of 4.4 years among surviving patients, the Kaplan-Meier 5-year estimates for event-free survival and overall survival are 34% and 60%, respectively, and five-year survival was superior among patients who had achieved at least one CR prior to transplant versus patients who had never been in CR prior to transplant (71% versus 43%, p = 0.03). Detailed adverse events data is available regarding all patients transplanted since September 1996: Of these, only 3 (7%) suffered grade 3 or greater pulmonary toxicity, 12 (29%) exhibited grade 3 or higher mucositis, and 10 (24%) had grade 3 or higher nausea or vomiting. The median number of days from transplant to neutrophil recovery (500 cells/uL) was 10 days, whereas the median number of days to platelet recovery (20,000 cells/uL) was 12 days. We conclude that high- dose CEP followed by autologous transplant is an active and well-tolerated treatment program in patients with relapsed or refractory HD. The low incidence of pulmonary toxicity is noteworthy given that a high percentage of patients had been exposed to bleomycin and/or thoracic XRT prior to transplant, and appears to be superior to that reported with conventional CBV-conditioned transplants in patients with HD.

Description: We present preliminary data of haploidentical transplant for 12 patients (pts) with relapse of refractory acute leukemia using a chemotherapy only preparative regimen of 140 mg/m2 Melphalan on day −8; 10 mg/kg Thiotepa on day −7; 160 mg/m2 Fludarabine on days −6, −5, −4, −3; 1.5 mg/kg of rabbit ATG/day days −6, −5, −4, −3 and T-cell depleted peripheral blood progenitor cells, processed using the CliniMACS® device. All products had 1 x 107 CD34+ cells/kg recipient body weight. Pts received: intensive PCP prophylaxis with bactrim and pentamidine prior to transplant and during pancytopenia; CMV prophylaxis with valcyte during the BMT prep and foscarnet while pancytopenic; and with ambisone for fungus. The last 4 pts enrolled were treated with cancidas prophylactically instead of ambisome. 10 of 12 pts engrafted (83%). 2 pts had protocol deviations and primary graft failure - 1 survived disease free and 1 relapsed. Median time to engraftment was 14 days (range, 9–26) to 500 neutrophils and 13 days to platelets 20,000 (range, 10–25). Among engrafting patients, two died within 100 days due to disease progression and multiple organ failure. Six-month overall survival is 50% (21–74). One year overall and progression-free survival is 33% (95% CI 10–59). 7 pts had disease relapse at a median of 10 months (range 2–13 months). Two of 10 pts who engrafted developed grade 1 acute graft-versus-host disease (GVHD) and 4/8 pts who engrafted and survived beyond day 100 had chronic GVHD. The 2 patients who engrafted and survived beyond 1 year post transplant had chronic GVHD. This report for haploidentical transplant demonstrates that a chemotherapy only preparative regimen achieved a high rate of engraftment. Infectious complications were minimal. 25% of patients survived progression free. If these results are sustained in a larger study, haploidentical transplant may offer hope of allogeneic transplant for every individual needing such therapy.

Description: Criteria for the selection of HLA mismatched donors are needed when an HLA matched unrelated donor is not available. To define the risks associated with mismatching at HLA loci, and the impact of number of HLA mismatches on outcome, we studied 1933 patients receiving URD peripheral blood stem cell (PBSC) transplants facilitated by the National Marrow Donor Program between 1999–2006 for treatment of AML, ALL, CML or MDS. Myeloablative (65%) and reduced intensity (35%) regimens were included. The transplanted PBSC grafts were T cell-replete, and most patients received calcineurin-inhibitor based GVHD prophylaxis (99%) with T replete grafts. Median follow-up was 2 years. Pairs were typed for HLA-A, B, C, DRB1, DQA1 and DQB1 by high resolution typing methods. Matching was classified as low resolution (antigen-equivalent) or high resolution (allele) involving HLA-A, B, C, and DRB1 (8/8 match). Because of multiple comparisons, p-values

Description: Abstract 2390 Burkitt lymphoma (BL) is an aggressive B cell lymphoma primarily affecting children and young adults and is characterized by the highest doubling time of any tumor. Cyclical intensive chemotherapy and rituximab confer high complete remission (CR) rates and 80% long term disease free survival in chemotherapy sensitive disease. The role of autologous (autoHCT) or allogeneic (alloHCT) transplant is not well described in BL. We report the outcomes of 241 recipients of HCT for BL between 1985 and 2007 reported to the CIBMTR. Five patients (pts) received syngeneic twin grafts in addition to autoHCT in 113 pts, HLA identical sibling alloHCT (SIB) in 80 pts and mismatched related or unrelated donor (UNR/MM) alloHCT in 48 pts. Baseline patient and disease related risk factors varied significantly between cohorts (table1). The autoHCT cohort had a higher proportion of pts with chemotherapy sensitive disease (86%), peripheral blood grafts (73%) and HCT in first CR (42%). In the UNR/MM cohort, 25% pts were chemotherapy resistant and only 6% were in CR1. The use of autoHCT has declined in recent years with the majority (81%) performed before 2001. Conditioning regimen for alloHCT was myeloablative in 88% (86% and 92% in SIB and UNR/MM respectively). Treatment related mortality (TRM) was higher in alloHCT recipients (table1). Cumulative incidence of relapse/progression at 5 yrs (95% CI) was 44 (35-53)% for autoHCT, 42(31-53)% for SIB and 48 (34-62)% for UNR/MM. For autoHCT, 5-yr progression free survival (PFS) was 48(39-58)%, 78% for those in first CR versus 27% for disease beyond CR1 (p

Description: INTRODUCTION: Despite recent advances in treatment for MDS, allogeneic hematopoietic stem cell transplantation (alloHCT) remains the only curative therapy. Historically, patients (pts) 65 and older with Medicare did not have coverage for HCT. On August 4th 2010, the Centers for Medicare and Medicaid services (CMS) established coverage for HCT for MDS through coverage with evidence development (CED). A Center for International Bone Marrow Transplant Research (CIBMTR) study comparing outcomes of pts 55-64 vs. 65 and older was approved. Herein we report the survival outcomes of the first 688 pts enrolled on the study. RESULTS: From 12/15/2010 to 5/14/2014, 688 pts 65 years and older (65+) underwent alloHCT for MDS compared with 592 pts 55-64 years (55-64). Median follow-up was 12 and 18 months for the 65+ and 55-64 group respectively. Median age was 68 and 61 for the 65+ and 55-64 group respectively. In the 65+ group, 76%, 22% and 2% were ages 65-69, 70-74 and 〉 74 years old. At the time of diagnosis, 30%, 10%, 42% were diagnosed with RA/RARS/RCMD/RCMDRS/5q-, CMML and RAEB respectively. The IPSS score at diagnosis was Low risk/intermediate-1 and intermediate-2/high risk in 39% and 31% respectively, and 23% had t-MDS. In the 55-64 group, 43% and 57% were 55-59 and 60-64 years old respectively. Otherwise, patient and disease characteristics were similar in both groups. More patients in the 55-64 group compared to 65+ group received a myeloablative alloHCT (49% vs. 29%). The donor was an HLA identical sibling in 24% vs. 34% in the 65+ vs. the 55-64 groups. Because of confounding between age and selection of transplant procedures (including preparative regimen intensity, graft source, gvhd prophylaxis) we chose to adjust only for patient and disease characteristics in the multivariate analysis (MVA). Age group 65+ vs. 55-64 had no significant impact on 100-day mortality (HR 1.26; CI 0.91-1.75 p=0.16) or overall survival (HR 1.14; CI 0.98-1.33 p=0.1) in the MVA. The adjusted 100 day survival was 84% vs. 87%, one year survival was 60% vs. 56% and 2 year survival was 42% vs. 46% in the 65+ group vs. 55-64 group respectively. As expected, MVA for 100 day mortality identified that poor cytogenetics (HR 1.85; CI 1.28-2.68) compared to good cytogenetics, patients with stable disease/no response to therapy (HR 3.35; CI 1.59-7.07), disease progression/relapsed disease (HR 2.91; CI 1.13-7.51), patients who did not receive any therapy prior to preparative regimen (HR 2.9; CI 1.17-7.21) compared to patients in complete remission and platelet count

Description: Alemtuzumab is an effective agent in the treatment of various B- and T-cell malignancies that express CD52. Patients with advanced or refractory ALL have poor outcome after allogeneic stem cell transplantation (SCT). We investigated whether the addition of alemtuzumab to a standard myeloablative conditioning regimen would have any additional therapeutic effect and improve outcome after SCT in CD52+ ALL. Patients and Methods: Patients were eligible if their disease expressed CD52 in 〉20% blasts by flow cytometry. The conditioning regimen consisted of cyclophosphamide (Cy, 60 mg/kg daily x 2 doses) and total body irradiation (TBI, 12 Gy in four daily fractions). Alemtuzumab at 10 mg was intravenously administered daily on days -6 to -2 prior to day of stem cell infusion. Patients received additional graft versus host disease (GVHD) prophylaxis with tacrolimus and methotrexate. Results: Fifteen patients (9 M/6 F) with median age 33 years (range 22–57) were studied. Twelve patients had B-lineage and 3 had T-lineage disease. Cytogenetic data were available for 12 patients; all had high-risk cytogenetics, including 5 with Ph+ disease. The median number of prior chemotherapy regimens was 3 (range 1–6). At time of study entry, 3 patients were in CR1, 3 were in ≥ CR1, and 9 were in primary or refractory relapse. Five patients received a matched related donor transplant and 10 received an unrelated donor graft. The source of stem cells was bone marrow (n=7) or peripheral blood (n=8). The median CD34+ cell dose infused was 4.67 x 106/kg (range 1.85–6.43). Median time to ANC ≥ 0.5 x 109/L was 15 days (range 11–20). Median time to platelet count ≥ 20 x 109/L was 19 days (range 13–34). The cumulative incidence of non-relapse mortality at 2 years was 13% (95% CI, 4%–43%). The incidence of grade II-IV acute GVHD was 7% (95% CI, 1%–38%); no grade III/IV acute GVHD was observed. The incidence of chronic extensive GVHD was 20%. Overall survival at 2 years was 16% (95% CI, 3%–40%). Failure was related mainly to progression; thirteen of 15 patients had disease progression at a median time of 4 months (range 1–22). Conclusion: These data suggest that alemtuzumab can be safely added to the standard transplant conditioning regimen for ALL without delayed engraftment or increased regimen-related toxicity. However, any potential direct antileukemia effect in CD52+ ALL patients with advanced disease appears to be negated by in-vivo T-cell depletion of the donor graft. Strategies to restore the graft-versus-leukemia effect in this setting are needed.