ALBERT

Description: Background: Bendamustine (Treanda®) is a purine analog/alkylator hybrid with single-agent activity in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), multiple myeloma, and breast cancer. The objective of this phase 3 multicenter study was to evaluate the efficacy and safety of single-agent bendamustine HCl in patients with relapsed, rituximab-refractory NHL. Methods: Eligible patients had previously treated, rituximab-refractory, indolent-histology NHL. Rituximab-refractory was defined as no response or progression within 6 months of first dose of rituximab induction, completion of rituximab maintenance therapy or progression before the next scheduled rituximab dose, or completion of a combination of rituximab and chemotherapy. Patients received bendamustine 120 mg/m2 intravenously over 60 minutes on days 1 and 2 every 21 days for 6 cycles (2 additional cycles at investigator discretion; max 8). Tumor response was determined by modified International Working Group Response Criteria for NHL. The primary endpoint was overall response rate (ORR) with secondary endpoints of response duration (RD) and progression-free survival (PFS). Results: Results for the first 38 of 100 enrolled patients are presented. The median age was 60 years, 63% were male, and 63% had stage III/IV disease. Histologies included follicular (53%), CLL/small lymphocytic lymphoma (26%), and marginal zone (21%) lymphoma. Patients had received a median of 3 prior courses of treatment (range 1–10) and 2 prior rituximab-containing courses (range 1–6). Prior alkylator or purine analog-based treatment was administered to 79% and 37% of patients, respectively. Eighteen (47%) patients were considered to be chemoresistant. Four (11%) patients received prior radioimmunotherapy. The ORR in the primary analysis population was 84%, including 29% complete responses (CR), 3% CR unconfirmed, and 53% partial responses. The median RD was 9.3 months and the median PFS was 9.7 months. The primary hematologic toxicity was reversible myelosuppression; grade 3/4 hematologic side effects included leukopenia (60%), neutropenia (60%), thrombocytopenia (24%), lymphocytopenia (95%), and anemia (5%). Febrile neutropenia was not observed. Common nonhematologic adverse events (grades 1/2, 3, 4) were nausea (68%, 5%, 0%), vomiting (42%, 0%, 0%), and fatigue (42%, 13%, 3%). Conclusions: In this multicenter study, single-agent bendamustine was well tolerated and produced a high rate (84%) of durable responses. It is the first chemotherapeutic agent to demonstrate significant clinical activity in rituximab-refractory indolent lymphoma. These results compare favorably with prior reports of radioimmunotherapy in this patient population. An updated analysis of all 100 patients will be available for the annual meeting.

Description: Abstract 155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). Methods Previously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg/m2 on day 1 of each 28-day cycle) or R-CHOP/R-CVP (rituximab 375 mg/m2 and vincristine 1.4 mg/m2 (up to maximum 2 mg) on day 1 and prednisone at 100 mg on days 1–5 (of a 21-day cycle), plus either [1] cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 or [2] cyclophosphamide 750 mg/m2 or 1000 mg/m2(investigator choice) on day 1. QLQ-C30 was administered at screening (baseline); after cycles 1, 3, 6, 8; and at the end-of-treatment visit. Linear transformation to standardize raw scores was performed. The QLQ-C30 is composed of 5 multi-item functional scales, 1 global health status (GHS)/QOL scale, 3 symptom scales, and 6 single-item measures; all scores could range from 0 to 100. Rising scores for functional scales and GHS/QOL indicate improvement. Rising scores for symptom scales/single items indicate worsening. GHS/QOL score change at last QLQ-C30 administration postbaseline was interpreted using analysis of covariance. Data from the last observation (end-of-treatment visit) were analyzed. Results The 447 enrolled patients were randomly assigned to 1 of the 2 treatments; 224 to BR (NHL n=187, MCL n=36, missing n=1) and 223 to R-CHOP/R-CVP (NHL n=184, MCL n=38, missing n=1). Treatment groups were well matched for demographic and clinical characteristics. Among all randomized patients, mean change in GHS/QOL score from baseline to final visit was significantly higher (indicating relative improvement) for patients treated with BR than those treated with R-CHOP/R-CVP (3.6 vs −5.1 respectively, P=0.0005). For patients with indolent NHL, mean change in GHS/QOL score by final visit was significantly higher in patients treated with BR than those receiving R-CHOP/R-CVP (2.1 vs −6.3, respectively, P=0.0021); in patients with MCL, mean change in GHS/QOL score was numerically higher in the BR group, but the difference was not statistically significant (10.9 vs 1.6, P=0.0654). All randomized patients receiving BR showed greater improvement in QLQ-C30 Emotional Functioning (from baseline to final visit), compared with patients receiving R-CHOP/R-CVP. Mean change from baseline scores (± SEM) for QLQ-C30 for Cognitive, Physical, Role, and Social Functioning scales of the QLQ-C30 decreased (signifying deteriorating effect) in both treatment groups, with patients treated with BR deteriorating less than patients treated with R-CHOP/R-CVP (Figure). For symptom scales/item measures, patients treated with BR showed larger reductions in mean scores from elevated baseline levels (signifying greater improvement), compared with R-CHOP/R-CVP for Appetite Loss (−2.9 for BR vs −1.1 for R-CHOP/R-CVP), Pain (−5.6 vs −1.7), and Constipation (−0.7 vs 1.8). For symptom scales/item measures of Dyspnea, Fatigue, and Financial Difficulties, both treatments showed deteriorating effects, with BR showing less than R-CHOP/R-CVP: Dyspnea (0.8 vs 4.8), Fatigue (0.5 vs 7.2), and Financial Difficulties (0.9 vs 1.3). Patients receiving R-CHOP/R-CVP had larger reductions in mean scores for Insomnia (−2.1 for BR vs −6.7 for R-CHOP/R-CVP), Diarrhea (0.5 vs −1.3), and Nausea and Vomiting (1.8 vs 0.9). Conclusions In this study, BR significantly improved GHS/QOL, compared with R-CHOP/R-CVP treatment, in previously untreated patients with indolent NHL or MCL. In addition, BR provided improved patient QOL scores for most aspects of functioning and symptoms, as measured by the QLQ-C30. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Burke: Spectrum Pharmaceuticals: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Roche: Consultancy, Sponsorship, Sponsorship Other; Teva: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb: Consultancy. Kahl:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Teva Pharmaceutical Industries Ltd.: Employment. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Flinn:Teva: Research Funding.

Description: Background: Previously the CLSG studied response adapted rx (RA) using idarubicin 12mg/m2 d1-3/cytarabine 200mg/m2 d1-7(IDAC); followed by IDAC and mitoxantrone 10mg/m2/etoposide 100mg/2 d1-5(NOVE) if in CR afer IDAC, or NOVEx2 if they had persistent blasts at d 14 or on recovery. The 10 year follow-up demonstrated that RA rx appeared to have an encouraging response and lead to longer survival. We elected to compare consolidation with RA vs high dose ara-c(HDAC). Methods: Pts. with newly dx’d AML were included who were: age 15–80, with ECOG performance status 0–2, with no hx of HIV, CML or MDS〉3 mos, and had bilirubin60. Median follow-up since randomization was 64 mos. Comparing RA(arms A+D) vs HDAC(armsC+D), DFS in pts60 was 20 vs.13 mos following HDAC(p=.15). For those pts 〉60 disease free at 6 mos, median DFS was 27 mos after RA vs.10 mos post HDAC(p=.05). There was a trend towards higher mortality in BMT patients 60 and in those 60.

Description: Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma that usually presents as advanced-stage disease. Relapse is common, and management of relapsed/refractory MCL is difficult due to a limited number of approved agents and numerous comorbidities seen in this typically elderly patient population. We conducted a study of bendamustine plus rituximab (BR) in patients with relapsed/refractory MCL and presented preliminary results (Czuczman et al, ASH 2012, Abstract 3662). Final data are being analyzed in a multivariate analysis of baseline demographic and disease factors affecting outcomes for this study, and we present below the final data for individual subgroups for best overall response, DOR, and progression free survival (PFS). Patients and Methods: This multicenter, open-label, single-arm, phase 2 study was conducted to evaluate the efficacy, tolerability, and safety of BR in adults with relapsed or refractory CD20-positive B-cell MCL. Relapsed disease was defined as having achieved CR with a previous therapy but demonstrating recurrent disease 〉6 mo after the last dose. Refractory disease was defined as either a lack of CR while undergoing previous therapy or the loss of CR 5 was 44% (n=4; CR 2, PR 2). DORs based on risk category: ≤3, 20.6 mo (14.3, 35.5); 4–5, 11.1 mo (5.1, 21.3); 〉5, NC (5.1, NC). PFS results were: ≤3, 23.2 mo (16.2, 40.4); 4–5, 12.8 mo (8.3, 24.0); 〉5, 7.9 mo (2.0, NC). Main treatment-emergent grade 3/4 adverse events (〉10%) were hematologic: neutropenia (n=15), lymphopenia (n=6), and leukopenia (n=5). Conclusion: The multivariate analysis is intended to indicate which patient characteristics are most closely associated with efficacy endpoints such as durability of response to BR. BR showed efficacy across a wide range of patient subgroups with relapsed/refractory MCL. In the subgroup of patients with relapsed MCL, CR was more common than PR, while patients with refractory MCL were more likely to achieve PR than CR. This information may be used to help guide treatment decisions when considering BR in heavily treated MCL patients. The BR regimen is generally well-tolerated and may serve as the backbone to which other active agents can be added in the study regimens to further improve anti-lymphoma activity. Support: Teva BPP R&D, Inc. Disclosures Czuczman: Teva: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.. Goy:JNJ: Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution, Research funding for clinical trials through institution Other, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution, Research funding for clinical trials through institution Other; Millennium: Membership on an entity's Board of Directors or advisory committees, Research fundiing for clinical trials through institution, Research fundiing for clinical trials through institution Other, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution Other, Speakers Bureau. Munteanu:Teva: Employment, Equity Ownership. van der Jagt:Teva: Consultancy, Honoraria, Research Funding, Speakers Bureau; Lundbeck: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Background Given the widespread use of bendamustine, data on long-term outcomes are essential for patients and clinicians to understand potential risks and benefits of therapy. Despite a long history as treatment for indolent non-Hodgkin lymphoma (iNHL), such information has been limited. We retrospectively reviewed the registration SDX-105-01 and SDX-105-03 trials (bendamustine 120 mg/m2 days 1+2 q21 days) and SDX-105-02 trial (bendamustine 90 mg/m2 days 1+2 plus rituximab 375 mg/m2 day 1 q28 days) to characterize long-term toxicity and efficacy of patients treated with bendamustine. Methods Patient level data was retrospectively collected from patients treated on the SDX-01, 02, and 03 trials. Descriptive statistics were used to summarize patient characteristics and events. The Kaplan-Meier method was used to report time-to-event outcomes. Wilcoxon Rank sum test was used to test the difference between events for continuous variables. Results Out of the total 245 subjects at 45 sites, data were available for 149 subjects (60 men, 89 women; SDX-01 N = 40, SDX-02 N = 43, SDX-03 N = 66) at 21 sites (included based on willingness to participate). The median age was 60 years at the start of bendamustine (range 39-84). The histologies included grade 1-2 follicular lymphoma (FL; N = 73), grade 3 FL (N = 23), SLL (N = 20), marginal zone lymphoma (N = 15), mantle cell lymphoma (N = 9), transformed lymphomas (N = 5), lymphoplasmacytic lymphoma (N = 2), and not reported (N = 2). The average time from diagnosis to study entry was 41 months (range 2-229). The median number of therapies prior to bendamustine was 2.5 (range 1-8). Patients received a median of 6 cycles and a median total dose of bendamustine of 1408 mg (max 5216, min 240). With a median follow up of 8.8 years after study entry, 80 patients had experienced progression. The median PFS was 18.4 months (95% C.I. 11.9-27.8); the 3-year PFS was 37%. During follow up, 93 patients had died at a median time of 22.3 months after the start of bendamustine. The median OS after start of bendamustine was 65.9 months (95% C.I. 38.8-91.8). The causes of death were lymphoma (N = 45), bendamustine toxicity (N = 2), subsequent treatment toxicity (N = 8), MDS/AML (N = 5), other cancer (N = 2), other (N = 6), and unknown (N = 25). A total of 98 patients received a median of 2 therapies following bendamustine (range 1-9), with the first treatment occurring a median of 13.2 months (range 0-111.3) following the final dose of bendamustine. The reported best response to the first subsequent treatment was CR (N = 11), PR (N = 6), SD (N = 21), PD (N = 12), not evaluable (N = 25), and unknown (N = 22) and the median OS of these patients was 51.3 months (95% C.I. 33.4-80.3). Fourteen patients had attempted stem cell collection following bendamustine, 10 of which had stem cells collected successfully. Eight patients had stem cells collected with GCSF alone (N = 7) or GCSF plus chemotherapy (N = 1). Twenty-three patients developed 25 cancers following bendamustine. Six patients developed MDS and 2 more developed AML. The median time to MDS/AML following bendamustine was 24 months (range 10-103) with an annualized incidence rate of 0.52%/year. One of patient had a prior myeloid neoplasm and one had a prior germ cell tumor. In univariate analysis, neither age at lymphoma diagnosis (P=0.438), nor total number of systemic regimens (P=0.443), nor total dose of bendamustine (P=0.291) was associated with MDS/AML. Other cancers included adenocarcinoma (colon N = 2; prostate N = 2; lung N = 2; breast N = 1), non-melanoma skin cancer (N = 6), squamous cell carcinoma (N = 2), hepatocellular carcinoma (N = 1), and bladder cancer (N = 1). None of these occurred in the 12 patients with a history of solid tumor before bendamustine. Conclusions With a median follow up of survivors of 〉 8 years, there was no evidence that bendamustine in the setting of previously treated iNHL was associated with a high rate of long-term bone marrow toxicity. Rates of MDS/AML and failure to collect stem cells were lower than expected. However, roughly half of all patients died within 5 years of starting bendamustine, thereby limiting the long-term follow up. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for many patients with relapsed or refractory iNHL. Disclosures Martin: Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Cheson:AstraZeneca: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Astellas: Consultancy; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; Teva: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding. Williams:Celgene: Consultancy, Other: Research funding to my institution; Takeda: Consultancy, Other: Research Funding to my institution; Genentech: Other: Research funding to my institution. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Szer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy.

Description: Background: Approximately 20–40% of pts with NDMM present with RI, which is associated with a negative impact on survival (Rajkumar, 2005). In the pivotal phase 3 FIRST trial (median follow-up 37 months [mos]), continuous Rd improved progression-free survival (PFS) vs. melphalan-prednisone-thalidomide (MPT) in elderly NDMM pts by 28% (25.5 vs. 20.7 mos; HR = 0.72; P 〈 0.01) (Facon, Blood 2013). Although 121 pts receiving continuous Rd are still on Tx, the interim overall survival (OS) analysis showed a 22% reduction in the risk of death in favor of continuous Rd vs. MPT (HR = 0.78; P = 0.02). The present analysis was conducted to determine the impact of RI on PFS, OS, and time to 2nd antimyeloma Tx (AMT) as clinical study outcomes. Methods: Pts were randomized to 3 Tx arms: continuous Rd until progression (n = 535); Rd for 18 cycles (72 weeks) (Rd18; n = 541); or MPT for 12 cycles (72 weeks) (n = 547). Enrolled NDMM pts were categorized according to their renal function: 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (≥ 50 and 〈 80 mL/min), 23% had moderate RI (≥ 30 and 〈 50 mL/min), and 9% had severe RI (〈 30 mL/min). Pts requiring dialysis were excluded. Lenalidomide starting dose was 25 mg QD for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg QOD for severe RI. Melphalan dose was reduced by 50% in pts with moderate or severe RI. The primary endpoint was PFS (continuous Rd vs. MPT); secondary endpoints were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety, and improvement in renal function from baseline. Improvement in RI was defined as shifts from baseline to most extreme post-baseline value of the calculated CrCl as a measure of renal function during the active Tx (N = 1484). Results: A PFS benefit favored continuous Rd vs. MPT irrespective of the degree of renal function (Table 1): there was a benefit in pts with normal renal function (HR = 0.72 (0.51–1.02); P = 0.06), and better in pts with mild RI (HR = 0.79 (0.62–1.00); P = 0.05) and moderate RI (HR = 0.62 (0.45–0.85); P 〈 0.01). A PFS benefit was also seen with continuous Rd vs. Rd18 (a secondary comparison) in pts with mild RI and moderate RI (P 〈 0.01 for both). An interim OS benefit with continuous Rd vs. MPT was observed in most renal subgroups. Similar results were observed between Rd18 and MPT in terms of PFS or interim OS in any of the renal subgroups. Continuous Rd, compared with Rd18 or MPT, extended time to 2nd AMT in most renal groups except severe RI (CrCl 〈 30mL/min) (Table 2). Improvement in RI was observed more frequently in pts treated with continuous Rd than those with Rd18 or MPT: improvement of mild RI, 48%, 43%, and 48%, respectively; of moderate RI, 67% 61%, and 62%; and of severe RI, 64%, 59%, and 56%. Overall, 〈 5% of pts in any Tx group experienced a worsening in renal function status during Tx (continuous Rd 2.2%; Rd18 2.8%; MPT 2.7%). The most common grade 3–4 adverse events (AEs) for these Txs were anemia, neutropenia, thrombocytopenia, deep-vein thrombosis/pulmonary embolism (DVT/PE), and peripheral sensory neuropathy (Table 3). Tx discontinuation due to AEs increased in pts with moderate and severe RI, regardless of the type of Tx (Table 3). Conclusions: PFS, OS (at interim analysis), and time to 2nd AMT outcomes generally improved continuous Rd vs. Rd18 or MPT in transplant-ineligible NDMM pts with normal renal function, and in those with mild or moderate RI. The small number of pts in the severe RI group precluded a meaningful conclusion. Continuous Rd was generally well tolerated and renal function improved in the majority of pts during Tx with continuous Rd vs. Rd18 or MPT. Disclosures Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Roussel:Celgene: Consultancy, Lecture fees Other, Research Funding. van der Jagt:Celgene Corporation: Research Funding. Jaccard:Celgene Corporation: Honoraria, Research Funding. Tosikyan:Celgene: Consultancy. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Celgene Corporation: Consultancy, Research Funding. Schots:Celgene: Research Funding. Chen:Celgene Corporation: Employment. Marek:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Background Patients with T-cell lymphomas face a poorer prognosis when compared to patients with B-cell lymphomas. New therapeutic approaches need to be developed in order to improve outcomes for these patients. We report the final results of a phase 2 multicenter clinical trial evaluating lenalidomide monotherapy in T-cell lymphomas. Methods Forty patients with relapsed and refractory T-cell lymphomas other than mycosis fungoides, as well as patients with untreated T-cell lymphoma who were not candidates for combination chemotherapy, were prescribed oral lenalidomide (25mg daily) on days 1 to 21 of each 28 day cycle, with standardized dose reductions for toxicity. Treatment continued until disease progression, death or unacceptable toxicity. The primary endpoint was overall response rate, and secondary endpoints were complete and partial response rates, progression-free and overall survival (PFS, OS), and safety. We also determined duration of response (DoR). Results Forty patients were enrolled in the study; one was subsequently deemed ineligible. In the 39 eligible patients, the median age was 65. ECOG PS was 0-1 (n=29), 2 (n=8), and 3 (n=2). The histology of the studied cases included peripheral T-cell unspecified (PTCL-u, n=14), angioimmunoblastic (n=9), anaplastic large cell (n=10), enteropathic T-cell (n=2), Hepatosplenic gamma/delta (n=2), and lymphoblastic T-cell lymphoma (n=2). The number of prior therapies was 0 (n=8), 1 (n=14), 2 (n=8), 3 (n=6), 4 (n=2), and 5 (n=1). Five patients had previous autologous stem cell transplant. Eleven patients were refractory to their previous treatment. The median time from diagnosis until the start of treatment was 14 months (range, 1-204 months). The median time from completion of prior therapy to the start of lenalidomide was 5 months (range, 1-48 months). The ORR was 10/39 (26%); 3 (8%) were complete responses and 7 were partial responses. Responses occurred in anaplastic, angioimmunoblastic, and PTCL-u histologies. Three additional patients had SD ≥5 cycles. The median OS was 12 months (range

Description: Abstract 2681 Poster Board II-657 Background: Although initially very responsive to therapy, indolent non-Hodgkin's lymphomas (NHLs) are generally incurable. Therefore, it is important to identify active and tolerable treatments for patients (pts) with relapsed or refractory disease. Bendamustine (B, Treanda®), a mechlorethamine alkylator with novel mechanisms of action, is approved in the US for the treatment of indolent B-cell NHL that has progressed during or after rituximab (R) or an R-containing regimen. Methods: Data from 2 North American, multicenter studies with similar design and enrollment and response assessment criteria were pooled to examine safety and durability of response and allow meaningful comparisons between groups receiving prior therapies. B 120 mg/m2 was given IV on D 1, 2 q 21 days × 6-8 cycles to pts with R-refractory indolent NHL. Pts with transformed disease were excluded from efficacy analyses. Endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: The primary analysis set consisted of all randomized pts (N=176; median 61 yr; 81% stage III/IV; median 2 prior chemotherapy- and 2 R-containing courses) and comprises the population for safety analyses. Histologies included follicular (68%), small lymphocytic (20%), marginal zone (11%), and lymphoplasmacytic (1%) lymphomas. Fifty-four (35%) pts were refractory to their last chemotherapy; 49 (28%) were refractory to their last alkylator-based regimen. Sixty-six (38%) pts received prior purine analogs (PA); 22 (33%) of these pts were PA refractory. Ninety-four (53%) pts received ≥6 cycles of B; early withdrawals were primarily due to adverse events (AEs, 28%, mostly myelosuppression [18%]) or disease progression (14%). Dose reduction occurred in 14% of cycles; 18% of cycles involved a treatment delay. Common nonhematologic AEs, primarily grade 1/2, were nausea (75%), fatigue (57%), vomiting (40%), and diarrhea (37%). 97% of pts received antiemetic therapy during study treatment. Grade 3/4 hematologic AEs included neutropenia (58%), thrombocytopenia (25%), and anemia (11%). Overall, 50 opportunistic infections in 48 pts were reported: herpes zoster (HZ, 18), herpes simplex (7), candidiasis (16), cytomegaloviral infection (5), Pneumocystis jiroveci pneumonia (2), atypical mycobacterial infection (1), and tuberculosis (1). HZ reactivation tended to be higher in pts with prior PA exposure (13% vs 8 %, P=NS); pts receiving prophylactic antivirals (n=18) did not experience HZ outbreaks, while an 11% incidence of outbreaks was observed in those not prophylaxed. Second malignancies occurred in 6 pts: 3 MDS, 1 CMML, 1 squamous cell carcinoma, and 1 AML. Two pts had tumor lysis syndrome (1 each grades 3 and 4) in the first cycle. Grade 3/4 AE frequencies were similar by prior PA exposure, except for neutropenia (41% vs 29%) and infection rate (26% vs 14%), which were higher in PA-pretreated pts. Grade 3/4 AEs were higher in pts '60 yr vs 65 yr), gender, histology, prior chemotherapy (' or 〉1). Conclusions: Durable responses and acceptable safety support the use of bendamustine in R-refractory pts with indolent NHL, even those who were refractory to prior alkylator- and PA-based treatments. PFS will be updated and pooled, and presented at the ASH meeting. Disclosures: Cheson: Cephalon, Inc.: Consultancy, Honoraria. Friedberg:Cephalon, Inc.: Research Funding. Kahl:Cephalon, Inc.: Consultancy, Research Funding. van der Jagt:Cephalon, Inc.: Research Funding. Tremmel:Cephalon, Inc.: Employment, Equity Ownership. Zaks:Cephalon, Inc.: Employment, Equity Ownership.

Description: The CHOP-R regimen is the standard regimen for first-line therapy of patients with DLBCL. Pixantrone (BBR 2778) is a novel aza-anthracenedione with structural similarities to mitoxantrone. In a phase 1/2 study of CPOP in 65 patients with relapsed NHL who had received a first-line anthracycline-containing regimen, patients received pixantrone at 80–180 mg/m2. This study indicated substantial activity with an overall response rate of 77% and complete response (CR) rate of 54% with acceptable toxicity. Studies in indolent NHL demonstrated that the combination of pixantrone with rituximab is well tolerated and more active than rituximab alone (JCO, 24(18S), 2006:7578). To evaluate the safety and activity of CPOP-R with special regard to cardiac safety in the first-line setting, a randomized phase 2 study in untreated patients with DLBCL comparing CPOP-R to CHOP-R is being conducted. Patients with untreated, histologically confirmed CD20-positive DLBCL receive CHOP-R or CPOP-R every 21 days for 6–8 cycles. An interim analysis for efficacy was prospectively planned to be performed when 40 patients had completed 4 cycles of therapy to test whether the CR rate of CPOP-R (pixantrone dose of 150 mg/m2) is, with 95% confidence, not more than 15% less than the CR rate of CHOP-R. We report the results of this analysis, which included 40 patients (21 CPOP-R and 19 CHOP-R) who had completed 4 cycles or had prematurely withdrawn from the study. Preliminary safety data (CPOP-R=27 patients, CHOP-R=30 patients) were also evaluated. CR rates after 4 cycles based on investigators’assessment were similar between arms (CPOP-R=33%, CHOP-R=37%). In general, adverse events were equal between arms. There were no more grade 3–4 adverse events (41% CPOP-R vs 50% CHOP-R) and no more grade 3–4 treatment-related adverse events (33% in CPOP-R vs 40% in CHOP-R) in the CPOP-R arm compared to the CHOP-R arm. 8 patients in each arm had asymptomatic absolute LVEF declines of ≥10%. 3 patients in the CPOP-R arm had a LVEF decline of 〉15% and ≤20% compared to 5 patients in the CHOP-R arm. No patients in the CPOP-R arm had a 〉20% LVEF decline compared to 2 patients in the CHOP-R arm. No heart failure or deaths resulting from heart failure have been reported. Infections reported as serious adverse events occurred in 1 patient (4%) in the CPOP-R arm and 3 patients (10%) in the CHOP-R arm. Grade 3–4 neutropenia was similar (CPOP-R = 34%, CHOP-R = 30%). Febrile neutropenia was less frequent in the CPOP-R arm (4% vs 23%). There were 2 deaths within 30 days of the last dose of study drug on CPOP-R arm. Both patients were 〉 80 years; 1 of the events was attributed to study treatment secondary to neutropenic infection. No deaths were reported in the CHOP-R arm. Based on this preliminary analysis, we conclude that for 1st-line therapy of patients with DLBCL, CPOP-R has similar activity to CHOP-R with no more toxicity. Further follow-up is required.

Description: Background: Minimal residual disease (MRD) status reflects treatment efficacy and may predict prognosis after first-line therapy in patients (pts) with follicular lymphoma (FL). GALLIUM (NCT01332968) is an ongoing, randomized global Phase 3 study evaluating the efficacy and safety of obinutuzumab (GA101; GAZYVA/GAZYVARO; G) vs rituximab (R) as induction (with chemotherapy [chemo]; bendamustine, CHOP or CVP) and maintenance (in responders) in previously untreated pts with indolent non-Hodgkin lymphoma. In GALLIUM, the primary endpoint of investigator-assessed PFS in pts with FL was significantly improved with G- vs R-based treatment. We report the results of MRD assessment at mid induction (MI) and end of induction (EOI) in FL pts in GALLIUM. Methods: Diagnostic peripheral blood (PB) and bone marrow (BM) samples from FL pts were screened by consensus PCR to detect a t(14;18) translocation and/or clonal Ig variable domain rearrangement suitable for MRD assessment. In pts with a detectable clonal marker, allele- or translocation-specific real-time quantitative (RQ)-PCR assays were designed with a sensitivity ≤10-4. RQ-PCR data were evaluated by European Study Group criteria for MRD detection (van der Velden, Leukemia 2007). MRD status was assessed at MI in PB, and at EOI in PB and BM, and defined as negative (MRD response) if RQ-PCR and subsequent nested PCR were negative in all samples analyzed at the respective time point. Results: Of the 1202 FL pts enrolled in GALLIUM, 1138 provided consent for MRD analyses. Baseline PB or BM samples were available for 1101 pts; a clonal marker was detected in 968 (88%) of these pts and 815 (74%) had an RQ-PCR assay fulfilling sensitivity criteria. Pts with a detectable clonal marker had baseline characteristics comparable to pts without a marker, with the exception of higher-stage disease (61% vs 34% Ann Arbor stage IV), reflecting increased BM involvement. Among 696 pts with an available PB or BM sample at EOI, MRD response was significantly higher in the G-chemo arm than the R-chemo arm (92% vs 85%; p=0.0041; Table 1). BM clearance of residual tumor cells at EOI was higher in the G-chemo vs R-chemo arm (93% [199/214] vs 83% [165/200]; p=0.0014), whereas PB clearance at EOI was similarly high in both arms (96% [323/336] vs 94% [320/341]; p=0.22). MRD clearance occurred early during treatment: at MI, 94% of pts in the G-chemo arm achieved MRD-negative status in PB compared with 89% in the R-chemo arm (p=0.013; Table 2). The anti-lymphoma activity of G-chemo induction was confirmed by analyzing quantitative MRD data in PB at MI: all 20 (100%) pts who remained MRD-positive at MI in the G-chemo arm had low-level MRD (below the limit of quantification) compared with 24/38 (63%) pts in the R-chemo arm. The chemo backbone in the R-chemo arm affected MRD status in PB at EOI giving an MRD response rate of 96% (201/209) after R-bendamustine (B), 93% (100/108) after R-CHOP, and 79% (19/24) after R-CVP. No such effect was seen in the G-chemo arm, where MRD response rates in PB at EOI were high and similar with all three chemo regimens: 96% (187/194), 96% (105/109), and 94% (31/33), respectively. Similarly, in BM, chemo had a large influence on MRD-negative status at EOI in the R-chemo arm (87% [100/115] after R-B, 74% [55/74] after R-CHOP), but negligible impact in the G-chemo arm (93% [109/117] after G-B, 93% [76/82] after G-CHOP). Achievement of MRD negativity at EOI in PB/BM for pts with CR/PR at EOI was associated with longer subsequent PFS, with a hazard ratio of 0.35 (95% CI, 0.22, 0.56; p