ALBERT

Description: This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels 〈 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

Description: SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of 〉50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

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: MDS are a heterogeneous group of clonal disorders characterized by the development of one or more symptomatic cytopenias. We evaluated the role of erythropoietin (EPO) with or without granulocyte colony stimulating factor (G-CSF) for the treatment of anemic patients with MDS. Patients with refractory anemia (RA n=40), RA with ringed sideroblasts( RARS n=36), and RA with excess blasts (RAEB n= 29) were initially randomized to either supportive therapy (ST) or EPO, 150 u/kg/d. Patients on the ST arm could cross over to the EPO arm if after at least a 4 month period of observation they had a ≥ 50% increase in their transfusion requirement. In patients who did not respond to or did not maintain their response to EPO( 150 u/kg) , G-CSF, 1mcg/kg/d was administered in addition to the EPO. Patients who did not respond after 4 months received an increased dose of EPO at 300u/kg/d + G-CSF. Bone marrow studies and iron stores were evaluated before each change in treatment. Response criteria were CR (complete response), GR (good erythroid response), which required a sustained increase of the pre-transfused Hgb value of 〉 2 g/dl or loss of the transfusion requirement or PR (partial response), defined as a decrease in the transfusion requirement by ≥ 50% or an increase in the Hgb by 〉 1 g/dl above the pretreatment level. A GR or PR must be sustained for at least 4 months. Transformation to acute leukemia was defined as ≥ 30% blasts in the bone marrow. 118 patients were enrolled , 109( 53 EPO, 56 ST) were eligible and 105 were evaluable for response. The median age was 73 (range 37–88 years). The response rate (CR+GR+PR) in the EPO arm was 35% vs. 9% in the ST arm (p=. 002). Of the 23 patients who crossed over from the ST arm, 30% responded to EPO (GR+PR). Six of 27 patients (22%) who received EPO 150u/kg + G-CSF responded (CR+GR+PR). Ten patients received EPO 300 u/kg + G-CSF and 6(60%) responded (CR+GR+PR). Transformation to acute leukemia occurred in 3.6% and 0% in the supportive therapy and EPO arm respectively( P=.50). A complete response (CR) was documented in 2 patients, 1 each on EPO and EPO+G-CSF. There was a survival difference for patients who had an erythroid response: median survival 53 months for responders vs 26 months for non-responders (p=.009). Neither EPO nor the addition of G-CSF was associated with an increase rate of transformation to acute leukemia. Toxicities were comparable in all the treatment arms. The pretreatment serum EPO level correlated with the response to treatment (P=.004): median EPO of 48 vs. 140 mu/ml for responders versus non-responders. Responses were observed in all subtypes. Responses were greater in RA〉RARS〉RAEB. In conclusion, EPO administration was associated with a significant increase in Hgb and a decrease in the transfusion requirement in anemic patients with MDS. Low doses of G-CSF + EPO were effective in EPO nonresponsive or refractory patients. In MDS patients EPO + low dose G-CSF was not associated with progression or transformation to acute leukemia.

Description: BACKGROUND: Lenalidomide has immunomodulatory and anti-neoplastic properties, with demonstrated activity in myelodysplastic syndrome and multiple myeloma. Preliminary reports indicate that lenalidomide has activity against cutaneous T-cell lymphoma (mycosis fungoides) and chronic lymphocytic leukemia. We hypothesized that lenalidomide should be studied as a non chemotherapy approach for Peripheral T- Cell Lymphoma (PTCL). STUDY DESIGN AND METHODS: In this Canadian multi-center, open label, single-arm, phase II clinical trial, patients with PTCL were treated with lenalidomide 25 mg po qd × 21 days on a 28-day cycle until disease progression, death or unacceptable toxicity. Patients with ECOG 0-2 and relapsed/refractory disease were eligible, as well as patients who had not previously had systemic therapy but who were ineligible for standard curative chemotherapy regimens due to comorbid illness. We report on the first ten patients enrolled. The primary endpoint is response rate defined according to the 1999 Cheson criteria. RESULTS: Median age of participants was 56y (range, 42–76y), 9M, 1F. Histologies included PTCL not otherwise specified (n=4), angioimmunoblastic (n=4), cutaneous anaplastic large cell (n=1), hepatosplenic gamma/delta (n=1). 8 were relapsed, 2 previously untreated. 2 were refractory to their previous regimen. Median number of prior lines of systemic therapy is 1 (range, 0–3). Median number of cycles delivered to date, 2 (range: 1–8). Therapy has generally been well tolerated. 3 patients experienced grade 3–4 hematological toxicity, 3 experienced grade 3+ infectious complications and 1 had grade 3 rash. No thrombotic events have been seen to date. Best responses to date include 0 CR, 4 PR (2 angioimmunoblastic, 2 PTCL NOS), 1 SD (PTCL NOS), 2 PD (1 angioimmunoblastic, 1 PTCL NOS). Three deaths have occurred on study, due to disease progression (n=2) and pneumonia during cycle 1 (n=1, angioimmunoblastic). One patient has withdrawn from study post cycle 1 due to treatment related asthenia. One previously untreated patient still awaits the first response assessment; the overall response rate (CR+PR) to date in the remaining patients on an intent-to-treat basis is 4/9 (44%). 5 of 9 (56%) patients have achieved stable disease or better, for 2+, 3+, 5, 6 and 8+ months. For the two patients with previously refractory disease, best response was 1 PR for 6 months and 1 PD. CONCLUSION: Lenalidomide appears to be an active agent in the treatment of relapsed PTCL with an acceptable tolerability profile. Further recruitment and follow-up will allow us to better define the response rate, tolerability, TTP and OS with this regimen.

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.