ALBERT

Description: Abstract 4532 Introduction: In an unicenter analysis we investigated the impact of allogeneic hematopoietic cell transplantation (RIC-HCT) after reduced intensity conditioning on the kinetics of engraftment and predictor of outcome in 50 patients with advanced CLL. Patient and Methods: Patients in advanced stage CLL (n=50) received Fludarabine 30mg/m2 on day -4 to -2 and 2Gy TBI on day 0 followed by cyclosporine and MMF from unrelated (n=40) or related (n=10) donors between June 1999 and March 2010 at the University of Leipzig. The majority of patients (n= 35) were male, had Binet C (n=37, 74%) at RIC-HCT. The median age was 58 (range 44–69) years. Of 48 patients for whom cytogenetic analyses were available, 22 (46%) had unfavourable cytogenetics including del 17 or del 11q. Three (6%) patients had CR, 27 (54%) PR, 7 (14%) progressive disease, 12 (24%) stable disease and one (5%) relapse at RIC-HCT. Resistance to first line therapy was present in 25 (50%) patients, whereas 12 (24%) were resistant to Fludarabine. Richter’s transformation was found in six patients (12%). Chimerism was detected in bone marrow and peripheral blood on T-lymphocytes and B-lymphocyte subpopulation after sorting at monthly intervals in the posttransplant period and than in 6 months interval. Results: Hematological toxicities after RIC-HCT were moderate. The majority of patients (96%) engrafted with neutrophiles 〉500/μ L median at day 22 after HCT. Six (12%) and 15 (30%) patients maintained absolute neutrophil counts (ANC) 〉0,5 × 109/L and platelet counts 〉50 × 109/L, respectively. T-cell donor chimerism increased to 〉95% at day 56 and B-cell donor chimerism to 94% at day +360, respectively. B-CLL cells disappeared completely on day +360 (median 0%). Overall survival (OS) at 4 years was 51%, Non relapse related mortality (NRM) 30%, Progression-free survival 33% and progression/relapse 37%. The most common causes of NRM were GvHD (n= 7; 14%) and sepsis (n=3, 6%). Factors significantly associated with increased risk of relapse/progression were intermediate/advanced disease vs. CR/PR1 (p=0.022) and lymphocytes ≥ 5 × 109/L vs. 〈 5 × 109/L (18% vs. 58%, p= 0.00) at 12 months in univariate analysis. Conclusion: Full donor T-cell chimerism was reached early after HCT, while B-cell reconstitution was observed only 1.5 years after RIC-HCT despite the absence of evident disease by 360 days after RIC-HCT. Best predictor for Progression-free survival (PFS) was CR or PR1. Disclosures: Pönisch: Mundipharma: Honoraria, Research Funding.

Description: Conventional allogeneic hematopoietic cell transplantation (HCT) is effective treatment for AML, but its use has been restricted to younger patients in good medical condition. However, AML is increasingly common with advancing age, and older patients have more adverse prognostic features than younger patients. The vast majority of older patients who reach a CR with chemotherapy relapse within two years from diagnosis and die within three years. The situation is similar in patients with secondary AML or with AML in CR2, more advanced remission status or in partial remission, where median duration of disease-free survival (DFS) is generally

Description: Abstract 1971 Introduction: While the role of lenalidomide monotherapy in the treatment of relapsed/refractory patients with multiple myeloma (MM) is established, combination therapies with Lenalinomide are still under investigation. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective in combination with steroids, thalidomide and bortezomib for the treatment of patients with MM. In the current trial, combination therapy of bendamustine, lenalinomide and prednisolone (RBP) was tested for feasibility and safety in patients with relapsed or refractory MM. Patients and Methods: This is a phase I trial examining dosing of lenalidomide in combination with bendamustine and prednisolone. The first cohort of patients received a starting dose of 10mg/d d1-21 lenalidomide, 60mg/m2/d d1-2 bendamustine and 100mg/d d1-4 prednisolone. Escalation steps in the next cohorts included 15, 20 and 25mg of lenalidomide followed by an escalation step of 75 mg/m2 bendamustine. Three patients were enrolled at each dose level and the first two cycles were evaluated for maximum tolerable dose. Patients received RBP in 4-week cycles for a maximum of 8 cycles in order to evaluate efficacy. Patients with stable or responding disease following 8 cycles of RBP received single-agent oral lenalidomide 10 mg once daily on days 1–21 of each 28-day cycle as maintenance. Results: : Nine patients (3 at each dose level of 10 mg, 15 mg or 20 mg lenalidomide) have been enrolled to date and 9 patients have completed at least 2 cycles. Response was assessed using modified EBMT criteria to include near complete remission (nCR) and very good partial remission (VGPR). 8 of 9 patients responded after at least 2 cycles with 2 VGPR, 4 PR, 1 MR and 1 stable disease. One patient experienced progressive disease. None of the 9 patients developed dose-limiting hematoxicity as defined by an ANC 〈 1,0 × 109/l with fever for 〉 3 days or an ANC 7 days or platelet count 〈 25 × 109/l for 〉 3 days. Neutropenia was reported in 4 patients (CTC grade ≥ 3) but no thrombocytopenia (CTC grade ≥ 3) was observed. No grade 3 or 4 non hematological toxicity was encountered and no dose modification was required. Conclusions: RBP with a dose of 20 mg lenalidomide d 1–21 and 60 mg/m2 bendamustine d 1–2 is well tolerated in patients with relapsed or refractory MM. Maximum tolerable dose was not reached. Further dose increase according to the protocol is in progress. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Description: Abstract 128 The treatment of elderly patients (pts) with AML remains challenging. High treatment associated mortality using protocols developed for younger patients and high relapse rates for pts reaching CR are frequent causes of failure, while many pts are assessed as ineligible for intensive chemotherapy. Patient registration at diagnosis to check for patient allocation or the use of age-adjusted induction protocols to reduce treatment related mortality may improve the management of these pts. In a prospective German Intergroup Study for patients ≥ 60 years, comparable to a completed study for patients 〈 60 years (Büchner JCO 2012 in press), the outcomes from two study groups using specific induction and consolidation protocols were compared to a common standard arm (CSA). By October 2011, 1041 pts had been randomized to the study-specific regimens or CSA in a 9:1 ratio. Eighty four patients (8%) were excluded due to incorrect diagnosis, secondary neoplasias or other reasons. Treatment in the CSA consisted of araC [100 mg/m2 continuous infusion (c.i.) d1-7] and daunorubicin (60 mg/m2 i.v. on d3- 5). A second induction was given if marrow blasts ≥5% on d15. Pts in CR received two consolidations with araC (1 g/m2 i.v. bid on d1, 3 und 5). The OSHO study group (group A) investigated araC (1 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m2 d1-3) for induction and araC (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m2 d1-2) for consolidation, while the AMLCG (group B) analyzed TAD (ara-C 100 mg/m2 c.i. d1,2; ara-C 100 mg/m2 bid i.v. d3-8)-HAM (ara-C 1g/m2bid i.v. d1-3) vs HAM-HAM ± G-CSF in pts with ≥5% blasts and TAD as consolidation followed by maintenance. Of 957 eligible pts, the median age was 69 (range: 60–87) years (68, 70 and 67 years for A, B and CSA, respectively; p

Description: Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m2/d from days −4 to −2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day −3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56+ cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.

Description: Abstract 1933 Introduction: Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other alkylating drugs. Treatment of patients with newly diagnosed multiple myeloma using Bendamustine and Prednisone in comparison to Melphalan and Prednisone results in superior complete response rate and prolonged time to treatment failure (Poenisch et al, Res Clin Oncol 132: 205–212;2006). So far, however, reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after Bendamustine therapy is missing. Material and Methods: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 63 patients with multiple myeloma who had received Bendamustine pretreatment at the university Hospitals Leipzig and Heidelberg over a period of sixteen years. Patients had a median age of 59 (range, 31–72) years. The cumulative dosis of Bendamustine per patient ranged between 120 and 2400mg/qm and was administered during a median of three (range 1–10) cycles. The mobilization regimen consisted of Cyclophosphamide 4g/qm (n=41) or 7g/qm (n=4) and G-CSF (2×5ug/kg). Alternative regimens such as CAD, CED, TCED and others were also used in the remaining patients. Apheresis was started as soon as peripheral blood CD34+ counts exceeded 10×106/l with a harvest target of 4×106 CD34+/kg using 4 times the blood volume. The minimal accepted target was 2×106 CD34+/kg. Results: Stem cell mobilization and harvest was successful in 60 of the 63 patients (95 %). In 19 of 60 patients (32 %) a single apharesis was sufficient to reach the target. The median number of aphareses was two (range 1–7) and the median CD34+ cell-count/kg was 5.9 (range 1.7–20.4) x106. Information on autologous SCT is available from all 60 patients with successful harvest. Engraftment was successful in 59 of 60 patients. The median time to leucocytes count 〉 l ×109/l was reached after 12 days and the time to untransfused platelet count of 〉50×109/l was 14 days. 54 patients (90%) responded after the autologous SCT with 6 CR, 4 nCR, 12 VGPR, and 32 PR. The event free survival at 36 months was 31 % and overall survival was 68 %. In conclusion, the stem cell mobilization and autologous SCT is feasible in multiple myeloma patients who have received Bendamustine pretreatment. Disclosures: Pönisch: Mundipharma: Honoraria, Research Funding. Niederwieser:Mundipharma: Research Funding.

Description: Abstract 3544 The prognosis of patients with aggressive relapsed or refractory B- or T-cell lymphomas is poor with conventional chemotherapy. Therefore, high-dose chemotherapy followed by autologous or allogeneic transplantation is the treatment of choice in these patients. We investigated the outcome of patients with aggressive B- or T-cell lymphomas transplanted between 1998 and 2009 in one centre. A total of 104 patients with diffuse large B-cell lymphoma (DLBCL) (n=69) and T-lymphoblastic lymphoma (T-LBL) (n=35) received autologous (auto) (n=66; DLBCL: 68%; T-LBL: 32%) or allogeneic (allo) (n=38; DLBCL: 63%; T-LBL: 37%) HSCT. Patients ineligible for auto transplantation, who did not respond to prior chemotherapy or had bone marrow involvement, were assigned to allo transplantation. Allo HSCT recipients were more likely to have high risk disease (higher disease stage, more prior chemotherapy regimens, resistant disease). Recipients of auto HCT were more likely to have chemosensitive disease at HSCT compared to patients at allo HCT (70% vs. 30%). Median age at transplantation was 52 years for auto and 42 years for allo HSCT. Median follow up was 12.7 (0.2-106) months after auto and 6.4 (0.4-111) months after allo transplantion. All patients with auto HSCT received BEAM and patients with allo HSCT TBI-based preparative regimen (myeloablative: n=23; reduced intensity: n=15). In the cohort of 104 patients the estimated 5-years overall (OS) and progression free survival (PFS) were 38% and 44%, respectively. There was no difference in OS and PFS between DLBCL and T-LBL (p=0.44). The estimated OS and PFS after allo HCT were significant lower (25% and 37%) than after auto HCT (45% and 47%; p=0.008 and p=0.03) caused by outcome differences in patients with DLBCL (p=0.02). Interestingly, OS and PFS were not different in patients with T-LBL transplanted with auto or allo HSCT (p=0.55 [OS] and p=0.34 [PFS]). The estimated PFS was significantly better in chemosensitive than chemorefractory patients (p=0.0001), however the OS and PFS were similar in chemosensitive group of patients regardless auto or allo HSCT (PFS: 50% vs. 51%; p=0.57; OS: 49% (auto) vs 32% (allo); p=0.19). Treatment related mortality (TRM) at day 100 was 18% after allo HSCT compared to 8% after auto. In conclusion, allo HSCT in patients with aggressive B- or T-cell lymphoma ineligible for auto transplantation is an attractive treatment option for these patients with high risk of relapse with a considerably low TRM. The response status at the moment of HSCT is the most important parameter affecting either OS or PFS. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Description: Abstract 4439 Introduction The alkylating agent bendamustine has structural similarities to both alkylating agents and purine analogs, and is effective in the treatment of patients with multiple myeloma. So far, no data are available on stem cell toxicity or on stem cell mobilization. Since autologous stem cell transplantation is an established treatment for multiple myeloma after primary treatment, we were interested in analysing the experience of stem cell mobilization after bendamustine treatment. Material and Methods A retrospective analysis over a period of fifteen years was carried out in 56 (34 male and 22 female) patients with multiple myeloma after bendamustine pretreatment at the university hospitals Leipzig and Heidelberg. Patients had a median age of 58 (range 31–72) years. The median number of cycles was 3 (range 1–10) and the cumulative bendamustine dose ranged from 120 to 2400 mg/qm. The mobilization regimen in 37 cases was either cyclophosphamide 4 g/qm (n=33) or 7 g/qm (n=4) followed by G-CSF (2×5 ug/kg s.c.). Alternative regimens such as CAD, CED, TCED and others were used for mobilization in the remaining 19 patients. Apheresis was started as soon as peripheral blood CD34+ counts exceeded 10×106/l with a harvest target of 4×106 CD34+/kg using 4 times the blood volume. The minimal accepted target was 2×106 CD34+/kg. Results Stem cell harvest was successful in 54 of the 56 patients. In one patient the peripheral blood CD34+ cell count failed to reach 10 × 106/l and no apheresis was performed. In one further patient a rapid decrease in peripheral blood CD34+ counts resulted in insufficient recovery of stem cells in the apheresis product. In 18 out of 54 patients (33%) the target was reached with a single apharesis. The median number of aphareses in the 54 patients was 2 (range 1–7) and the median CD34+ cell-count obtained was 5.5 (range 1.7–20.4) × 106/kg. Engraftment was successful in 52/53 patients receiving a stem cell transplant. One patient was successfully harvested and did not receive the transplant yet. Conclusion From this retrospective analysis we conclude that mobilization of PBSC is possible after intensive bendamustine pretreatment. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Research Funding; Celgene: Research Funding; Chugai Pharma: Research Funding; Amgen: Research Funding.

Description: Abstract 2938 Introduction: Renal impairment is one of the most severe complications of Multiple Myeloma (MM) at diagnosis. These patients are at increased risk for infections and have a significantly worse prognosis. Small phase I/II studies suggest that treatment with chemotherapy and/or new substances results in recovery of renal function in up to 25%. The window of opportunity to reverse renal impairment is rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as Bendamustine have turned out to be effective, rapid action drugs in the treatment of MM. Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks of DNA, and shows only partial cross resistance with other alkylating drugs. Methods: Between June 2006 and May 2011, 18 patients (median age 69; range 43 – 86 years) with newly diagnosed/untreated MM and renal insufficiency (creatinine clearance 〈 35 ml/min) were treated with Bendamustine 60 mg/qm day 1 and 2, Prednisone 100 mg on day 1, 2, 4, 8 and 11, and Bortezomib 1.3 mg/qm on day 1, 4, 8 and 11 (BPV). Cycles were repeated every 21 days up to the stage of maximum response or disease progression. MM response was assessed using IMWG criteria modified to include near complete response (nCR) and minimal response (MR). Eight patients were on dialysis at the time of diagnosis. Results: Fifteen patients (83%) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow up of 17 months, PFS at 12 months was 57 % and OS was 61 %. The median number of the BPV-treatment cycles was 2 (1–5) cycles. The myeloma protein decreased rapidly, reaching the best response after the first cycle in 4 patients and after the second cycle in a further 7. Six patients showed a complete remission of the kidney function (creatinine clearance 〉 60 ml/min) and in seven patients a partial remission (creatinine clearance 〉 30 ml/min) was attained. Transient grade 3 – 4 neutropenia was reported in one patient, and grade 3 – 4 thrombocytopenia occurred in 6 patients. One patient experienced a new grade 3 polyneuropathy. Summary: These results indicate that the combination of Bortezomib, Bendamustine and Prednisone is effective and tolerated in patients with newly diagnosed/untreated MM and renal failure. Disclosures: Pönisch: Mundipharma: Honoraria, Research Funding. Niederwieser:Mundipharma: Research Funding.