Nonmyeloablative Unrelated Donor Hematopoietic Cell Transplantation to Treat Patients with Poor-Risk, Relapsed, or Refractory Multiple Myeloma

AbstractThe purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in patients with poor-risk multiple myeloma. A total of 24 patients were enrolled; 17 patients (71%) had chemotherapy-refractory disease, and 14 (58%) experienced disease relapse or progression after previous autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43–135 days later with unrelated transplantation, whereas 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m2) and 2 Gy of total body irradiation before HLA-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced nonfatal graft rejection. The incidences of acute grades II and III and chronic graft-versus-host disease were 54%, 13%, and 75%, respectively. The 3-year nonrelapse mortality (NRM) was 21%. Complete responses were observed in 10 patients (42%); partial responses, in 4 (17%). At 3 years, overall survival (OS) and progression-free survival (PFS) rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior OS and PFS (77% and 51%) compared with patients proceeding directly to unrelated donor transplantation (44% and 11%) (PFS P value = .03). In summary, for patients with poor-risk, relapsed, or refractory multiple myeloma, cytoreductive autologous HCT followed by nonmyeloablative conditioning and unrelated HCT is an effective treatment approach, with low NRM, high complete remission rates, and prolonged disease-free survival

Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin after Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse

Abstract Introduction The AETHERA trial is a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov #NCT01100502), which evaluated whether post-ASCT consolidation treatment with brentuximab vedotin (BV) could prevent disease progression in Hodgkin lymphoma (HL) patients at high risk for relapse. The study met its primary endpoint: significant improvement in progression-free survival (PFS) per independent review with BV versus placebo (hazard ratio [HR]=0.57, P=0.001) (Moskowitz, 2015). The 2 most common adverse events (AEs) in the BV- treatment group were peripheral sensory neuropathy (56%) and neutropenia (35%). We are presenting updated efficacy and safety data after approximately 1 additional year of follow-up after the primary analysis. Methods Patients were randomized to receive BV 1.8 mg/kg q3wk or placebo for 16 cycles (approximately 12 months), 30-45 days after transplantation. Randomization was stratified by response to frontline therapy and by best clinical response to pre-ASCT salvage therapy. Patients whose disease had progressed after salvage treatment were not eligible. Patients received CT scans quarterly for the first year and then at 18 and 24 months during long-term follow-up (LTFU). Clinical lymphoma assessments were performed at each cycle of treatment, quarterly during the first year of LTFU, and every 6 months thereafter. AEs were collected for 30 days after the end of treatment, except for peripheral neuropathies and secondary malignancies, which were followed throughout LTFU. Clinical responses to subsequent BV treatment received after progression were also recorded. Results A total of 329 patients were randomized to the BV- (n=165) or placebo- (n=164) treatment arms. Median PFS per investigator assessment was not reached (95% CI not estimable [NE]-NE) in the BV arm and was 15.8 months (95% CI 8.5-44.0) in the placebo arm (HR=0.52, 95% CI 0.37-0.71). A sustained plateau with substantial separation is evident between both treatment groups, with improved PFS at 3-years post-randomization with BV consolidation versus placebo (Figure). The 3-year PFS rate was 61% (95% CI 52-68) for the BV arm and 43% (95% CI 36-51) for the placebo arm. Six PFS events (2 progressions and 4 deaths) were recorded after the 24-month evaluation period in the BV arm and 3 in the placebo arm (2 progressions and 1 death). The HR for PFS per independent review was 0.58 (95% CI 0.41-0.82). No new secondary malignancies have been observed since the primary analysis. The number of cases were comparable between the 2 treatment arms (n=4 BV, n=2 placebo). Malignancies on the BV arm included bladder cancer, lung cancer, pancreatic cancer, and myelodysplastic syndrome (n=1 each). In the placebo arm, secondary malignancies included mantle cell lymphoma and myelodysplastic syndrome (n=1 each). Among the 112 patients on the BV arm who experienced treatment-emergent peripheral neuropathy based on a Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) analysis, 99 patients (88%) experienced some improvement (23%) or complete resolution (65%) of neuropathy symptoms at the time of analysis. Discontinuation of treatment due to an AE occurred in 54 patients (33%) on the BV arm, most commonly due to peripheral sensory and motor neuropathies (14% and 7%, respectively). Patients who discontinued treatment as a result of an AE received a median of 9.5 cycles (range, 1 to 15) on the BV arm. The 2-year PFS rate in these patients was 69% (95% CI 54-79) versus 82% (95% CI 71-89) for patients who completed all 16 treatment cycles. Conclusions Consolidation treatment with BV in HL patients at high risk of relapse after ASCT showed an improvement in PFS versus placebo, approximately 3 years since the last patient was randomized. Kaplan-Meier analysis of PFS per investigator assessment showed a continued benefit of BV consolidation. No additional secondary malignancies have been observed in either treatment arm and most patients experienced resolution of peripheral neuropathy symptoms. We are currently analyzing clinical responses to BV treatment after disease progression. Figure 1. Progression-Free Survival per Investigator Assessment Figure 1. Progression-Free Survival per Investigator Assessment Disclosures Sweetenham: Seattle Genetics Inc.: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. This study investigates the use of brentuximab vedotin for consolidation therapy soon after ASCT. . Walewski:Mundipharma; Roche; Takeda: Honoraria, Other: Travel expenses; Amgen; Boehringer Ingelheim; Celgene; Janssen-Cilag; Mundipharma; Roche; Takeda; Teva: Consultancy; Bayer (Inst); Bayer/Onyx (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celltrion (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); GlaxoSmithKline (Inst); Mundipharma (Inst); Pfizer (Inst); Roche (Inst); Roche/Genentech (Inst); Seattle Geneti: Research Funding. Nademanee:Celgene: Consultancy; Seattle Genetics Inc.: Research Funding; Spectrum: Research Funding; Gilead: Consultancy. Masszi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Agura:Seattle Genetics Inc.: Research Funding. Holowiecki:Seattle Genetics Inc.: Research Funding; Takeda: Other: Travel expenses. Abidi:Seattle Genetics Inc.: Research Funding. Chen:Gilead: Consultancy, Other: Advisory Board; Janssen: Consultancy, Other: Advisory Board; Seattle Genetics: Consultancy, Other: Advisory Board; Genentech, Inc.: Consultancy, Other: Advisory Board. Stiff:Seattle Genetics Inc.: Consultancy, Honoraria, Research Funding. Viviani:Italfarmaco SpA: Consultancy; Teva Italia SpA: Consultancy; Takeda Italia SpA: Consultancy; Takeda International: Consultancy. Carella:Seattle Genetics Inc.: Research Funding. Osmanov:Seattle Genetics Inc.: Research Funding. Bachanova:Seattle Genetics Inc.: Consultancy, Research Funding. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Hunder:Seattle Genetics Inc.: Employment, Equity Ownership

The Aethera Trial: An Ongoing Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at High Risk of Residual Hodgkin Lymphoma Following Autologous Stem Cell Transplant

n/

Progress in the treatment of acute myeloid leukemia

Significant progress in understanding the mechanisms leading to the development of acute myeloid leukemia (AML) has led to the identification of numerous molecular abnormalities that may be responsible for leukemogenesis. Over the same period, large trials have established standard regimens combining cytotoxic agents for the treatment of patients with AML. Current research is attempting to better stratify patients by identifying risk factors responsible for resistance, and to discern ways for incorporating newer agents with specific and targeted activity into our standard regimens, Herein the recent developments in the diagnosis and treatment of AML are reviewed

Preliminary Results of Fixed-Dose Oral Clofarabine (CLO) In Patients Who Have Failed Hypomethylating Agents for the Treatment of Myelodysplastic Syndromes (MDS)

Abstract Abstract 1869 Background: Three disease-modifying drugs have been approved by the US Food and Drug Administration for first-line therapy of myelodysplastic syndromes (MDS). There is no accepted standard of care for patients (pts) who fail currently approved therapies, particularly the hypomethylating agents. This is the first study designed to determine the appropriate dose, and to assess the efficacy and safety of oral clofarabine (CLO) specifically in higher-risk MDS or secondary acute myeloid leukemia (sAML) pts who failed treatment with a hypomethylating agent. Methods: This phase IIa, open-label, multi-center study of fixed-dose oral CLO (daily × 5 days of a 4-week cycle) enrolled adult pts with pathologically confirmed MDS or sAML (following a history of MDS) who failed up to 2 prior treatment regimens (including ≥ 1 hypomethylating agent) with failure defined as no evidence of response or being progressive under therapy (pts must have received 4 cycles of hypomethylating agents). The primary endpoints were unacceptable drug-related toxicities and overall response rate (ORR) defined as complete remission (CR) + marrow CR + partial remission (PR) + hematological improvement (HI) for MDS pts and CR + CR with incomplete peripheral blood count recovery (CRi) + PR for AML pts. Initially, pts were randomized to receive 55mg or 35mg of oral CLO daily × 5 days. Based on emerging safety data, primarily renal and infectious complications, the protocol was amended and randomization into the 55mg cohort was closed. After review of the initial data for 35mg cohort (n=8), the dose of CLO was reduced to 25mg, with the intent of improving the adverse event profile observed in these pts. Patients could receive a maximum of 8 cycles and response was assessed after cycles 2, 4, 6, and 8. Results: Of the 27 pts enrolled in the study from Sep 2007 - Jan 2010 (55mg [n=4], 35mg [n=8] and 25mg [n=15]) demographic and safety data are available for 22 pts (55mg [n=4], 35mg [n=8] and 25mg [n=10]). Median age was 70 years (range 41–82) with 55% male. IPSS scores at study entry were (median=2.0): 1.5–2.0 (n=16), ≥2.5 (n=6); 8 pts (36%) had intermediate, 6 pts (27%) had poor risk and 8 pts (36%) had favorable cytogenetics; and 11 pts (50%) were transfusion dependent at baseline. Previous treatment with hypomethylating agents included: decitabine (n=10 [45%], azacitidine (n=11 [50%]), or both agents (n=1 [5%]). At study entry 8 pts (36%) had relapsed disease while 13 pts (64%) were refractory and 1 pt (5%) had prior inadequate treatment. Grade 3 or higher hematologic adverse events (regardless of relationship) reported in ≥10% of pts included anemia (54%), thrombocytopenia (41%), neutropenia (36%), febrile neutropenia (32%), leukopenia (32%). Grade 3 or higher non-hematologic toxicities (regardless of relationship) included pneumonia (36%), hypokalemia (27%), hypertension (23%), renal failure (18%), asthenia (14%), fatigue (14%), respiratory distress and/or failure (14%). Serious adverse events (SAE, regardless of relationship) were reported in 77% of pts. The most frequently reported SAE was febrile neutropenia (32%). The 30-day mortality was 50% in the 55 mg cohort (n=2), 13% in the 35 mg cohort (n=1) and 0% in the 25 for an overall 30-day mortality rate of 14%. Pts came off study for the following reasons: adverse event (n=8), progressive disease (n=7), other (n=5). Preliminary efficacy data are available for 16 pts, 35mg (n=6) and 25mg (n=10). Efficacy data are not available for pts enrolled in the 55mg cohort, because no pts completed the required two cycles for efficacy assessment, before the protocol was amended to allow for bone marrow evaluation at the end of cycle 1. The ORR is 31% (5/16 pts). Complete remission was achieved in 1 pt (35mg cohort) and marrow CR in 4 pts (25mg cohort). Among pts with marrow CR, 1 achieved HI-Erythroid and became transfusion independent and 1 pt had unconfirmed HI-Neutrophil. The median number of treatment cycles for the 16 patients with response assessment was 2 with a majority of responses occurring after the first cycle. Conclusions: These preliminary data suggest that fixed-dose oral CLO administered at 25mg daily × 5 days in pts previously treated for MDS with hypomethylating agents has an acceptable response rate and safety profile and warrants continued investigation. Disclosures: Sekeres: Genzyme: Research Funding. Off Label Use: Clofarabine injection (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of oral clofarabine in patients with MDS. Roboz:Genzyme Corporation: Research Funding. Odenike:Genzyme Corporation: Research Funding. Agura:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Powell:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ewesuedo:Genzyme Corporation: Employment, Equity Ownership. Vasconcelles:Genzyme Corporation: Employment, Equity Ownership. Faderl:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding

Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse

The phase 3 AETHERA trial established brentuximab vedotin (BV) as a consolidative treatment option for adult patients with classical Hodgkin lymphoma (cHL) at high risk of relapse or progression after autologous hematopoietic stem-cell transplantation (auto-HSCT). Results showed that BV significantly improved progression-free survival (PFS) vs placebo plus best supportive care alone. At 5-year follow-up, BV continued to provide patients with sustained PFS benefit; 5-year PFS was 59% (95% confidence interval [CI], 51-66) with BV vs 41% (95% CI, 33-49) with placebo (hazard ratio [HR], 0.521; 95% CI, 0.379-0.717). Similarly, patients with ≥2 risk factors in the BV arm experienced significantly higher PFS at 5 years than patients in the placebo arm (HR, 0.424; 95% CI, 0.302-0.596). Upfront consolidation with BV significantly delayed time to second subsequent therapy, an indicator of ongoing disease control, vs placebo. Peripheral neuropathy, the most common adverse event in patients receiving BV, continued to improve and/or resolve in 90% of patients. In summary, consolidation with BV in adult patients with cHL at high risk of relapse or progression after auto-HSCT confers a sustained PFS benefit and is safe and well tolerated. Physicians should consider each patient's HL risk factor profile when making treatment decisions. This trial was registered at www.clinicaltrials.gov as #NCT01100502