ALBERT

Description: Background: Multiple myeloma disproportionately affects the elderly and is currently an incurable malignancy. New therapies for myeloma, particularly oral therapies, are urgently needed. Objectives: To determine if thalidomide with or without other agents, improves response rate (≥ 50% reduction in monoclonal protein), survival, and/or progression in patients with previously untreated myeloma. To determine the frequency and significance of major adverse events associated with thalidomide in this setting. Methods: A literature search of Medline (1966–June 2006), Embase (1980–June 2006), the Cochrane Library, abstracts from the annual meetings of the American Society of Hematology (1999–2005) and the American Society of Oncology (1999–2006) was completed with a pre-specified search strategy. No language restrictions were applied. Randomized controlled trials of induction thalidomide (any dose, any duration) for adults with previously untreated multiple myeloma were included. Trials of exclusively maintenance therapy were excluded. Two reviewers independently extracted data. The methodological quality of selected trials was assessed and summarized. Weighted data was expressed as relative risk, risk difference, number needed to treat (NNT), and number needed to harm (NNH). A random-effects model was used. Results: Six eligible studies involving almost two thousand patients (N=1875) were identified and meta-analyzed. Two studies were published and four were reported in abstract form only. Five studies reported overall response rate (ORR); the four largest trials reported statistically significant improvements in ORR with the addition of thalidomide to standard therapy. The weighted relative risk of responding to a thalidomide-containing regimen versus control was 1.50 (95% CI 1.21 to 1.86). The NNT to achieve one additional response with thalidomide was 4 (95% CI 2.9 to 8.3). Two trials reported improvements in EFS/PFS. One trial reported an improvement in OS. The risk of VTE, peripheral neuropathy, and constipation was consistently elevated with thalidomide such that for every 50 patients treated with a thalidomide-containing-regimen, one could expect 12 to 13 additional patients to respond, 4 additional patients to develop VTE (NNH 12.5; 95% CI 8.3 to 20), 2 additional patients to develop peripheral neuropathy (NNH 25; 95% CI 16.7 to 50), and 4 additional patients to develop constipation (NNH14; 95% CI 10 to 25). In our analyses, prophylactic anticoagulation appeared to decrease, but not abolish, the risk of VTE with thalidomide. Conclusions: Thalidomide improves response rate and possibly progression free and overall survival in patients with previously untreated myeloma. It also increases the incidence of VTE, neuropathy, constipation and other adverse events. Further studies are required to confirm the survival advantage seen in one study, and to determine the optimum strategy for VTE prophylaxis.

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: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agent with a purine-like ring system and novel mechanisms of action that exhibits impressive single-agent activity in multiple hematologic and solid tumors. In vitro data indicate that bendamustine induces cell death as a result of both apoptosis and mitotic catastrophe, resulting in potent cell-killing activity in cancer cells that are resistant to traditional chemotherapy (alkylating and fludarabine-containing regimens). In vitro data have also demonstrated a synergistic effect with rituximab for the treatment of non-Hodgkin’s lymphomas (NHL). A Phase II multicenter study (SDX-105-02) was conducted to determine the efficacy and toxicity of the combination of bendamustine with rituximab in relapsed NHL patients. Methods: The intent-to-treat (ITT) population consists of 54 patients with relapsed indolent CD20-positive B-cell or mantle cell NHL, enrolled from 22 sites in the US and Canada. Median age of the patients was 60 years (range 40–84); 59% had follicular NHL, 6% had small lymphocytic lymphoma, 4% had lymphoplasmacytoid lymphoma, 4% had marginal zone lymphoma, and 17% had mantle cell lymphoma; and 72% of all patients had Stage III/IV disease. Patients relapsed from a median of 1 prior therapy. Patients received rituximab, 375 mg/m2 IV on day 1, and bendamustine, 90 mg/m2 on days 2 and 3, every 28 days for 4–6 cycles. All patients received an additional dose of rituximab 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: Of the 54 ITT patients, 37% had prior treatment with rituximab. Forty-three patients are currently evaluable for response, as defined by the International Working Group. The overall response rate was 84%, with complete response in 21% and partial response in 63% of patients. The median duration of response has not yet been reached after a median follow up of 3.6 months. Minimal toxicity was observed. The most common nonhematologic toxicities included grade 1/2 gastrointestinal complications. The primary grade 3/4 hematologic toxicity was neutropenia (with no neutropenic fever), observed in 22% of patients. Grade 3/4 anemia and thrombocytopenia were observed in only 1 patient. No alopecia was observed. Conclusions: Bendamustine, administered in combination with rituximab, produced high objective response rates with minimal toxicity in patients with refractory indolent and mantle cell NHL, including patients that previously failed alkylating and fludarabine-containing regimens. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.

Description: Objective: The objective of this study was to evaluate the efficacy and safety of bendamustine HCl (TREANDA®) in combination with rituximab in patients with relapsed non-Hodgkin’s lymphoma (NHL). Background: Bendamustine is a novel hybrid, alkylating agent with single-agent activity in multiple hematologic and solid tumors. It induces cell death via both apoptosis and the apoptosis-independent pathway of mitotic catastrophe. The combination of bendamustine and rituximab has been shown to exhibit a synergistic antitumor effect on NHL cells. Methods: This Phase II, multicenter study enrolled adult patients with relapsed, indolent B-cell or mantle-cell NHL who were not refractory to rituximab (defined as progression ≤6 months of last rituximab dose). Patients received rituximab 375 mg/m2 intravenously (IV) on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week before the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat (ITT) population included 66 patients (59% men) with a median age of 60 years (range, 40–84). Indolent histologic phenotype was seen in 54 patients with the following histologic subtypes: follicular center cell (61%), small lymphocytic (15%), lymphoplasmacytic (3%), and marginal zone (3%); 18% had mantle-cell lymphoma (MCL). A total of 85% of patients had stage III/IV disease. These patients relapsed from a median of 1 prior chemotherapy (range: 0–5), with 56% having had prior treatment with rituximab. Patients with no prior chemotherapy relapsed following biologic therapy. In the ITT population, the overall objective response rate (ORR) was 94% (complete response [CR]/complete response unconfirmed [CRu], 41%; partial response [PR], 53%); 6% had stable disease. The ORR for the 12 MCL patients was 92% (CR/CRu, 42%; PR 50%). For all patients, the median duration of response and progression-free survival has not been reached after a median follow-up of 8.3 months (range, 0.14–31 months). Grade 3/4 neutropenia was seen in 41% of patients (7%, febrile neutropenia). Common nonhematologic toxicities (grade 1/2, grade 3, grade 4) were nausea (68%, 0%, 0%) and fatigue (53%, 5%, 0%); one patient had grade 3 sepsis. No alopecia was observed. Conclusions: Bendamustine administered in combination with rituximab produced a high objective response rate and was generally well tolerated in patients with relapsed indolent and mantle-cell NHL who were not refractory to rituximab. These results suggest that the combination of bendamustine and rituximab may be comparable in activity to R-CHOP, and further studies of this combination are warranted.