High Anti-Lymphoma Activity of Bendamustine/Mitoxantrone/Rituximab (BMR) in Rituximab Pretreated Relapsed or Refractory Indolent Lymphomas. A Multicentre Phase II Study of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2480-2480
Author(s):  
Rudolf Weide ◽  
Georg Hess ◽  
Hubert Koeppler ◽  
Jochen Heymanns ◽  
Joerg Thomalla ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Observation Time ◽  
Low Grade ◽  
Multicentre Phase ◽  
Not Otherwise Specified ◽  
Mantle Cell ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Lymphoma Study Group ◽  
Indolent Lymphomas

Abstract Purpose: Bendamustine is a new anti-lymphoma agent with promising activity. Based on a preceeding phase I study the current trial explored Bendamustine in combination with Mitoxantrone and Rituximab (BMR) in patients with relapsed or refractory indolent lymphomas. Patients and Methods: Patients with relapsed or refractory symptomatic stage III/IV indolent lymphomas with or without prior treatment with Rituximab were eligible. Therapy consisted of Bendamustine 90 mg/m2 days 1+2, Mitoxantrone 10 mg/m2 day 1, Rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of 4 cycles. Results: Between 04/03 and 07/04 62 patients were recruited from 24 participating institutions, 40% of whom had received prior Rituximab therapy. Median age was 67 years (40–83). Lymphoma subtypes were 30 follicular (FL), 18 mantle cell (MCL), 4 B-CLL with plasmacytic differentiation, 3 lymphoplasmacytic (LPL), 3 marginal zone (MZL), 2 diffuse large B-cell (DLBCL), 1 high grade lymphoma not otherwise specified and 1 hairy cell leukemia. The overall response rate (ORR) was 88% with 36% CR and 53% PR. ORR in Rituximab pretreated patients was 75% (38% CR, 38% PR). After a median observation time of 17 months (1 – 33), the estimated median progression free survival is 19 months. Treatment related toxicities of grade 3/4 comprized a reversible myelosuppression (10 % anemia, 78 % leukocytopenia, 46 % granulocytopenia, 16 % thrombocytopenia). However, unexpected hospitalisations were necessary after 10 of 231 cycles (4%) only. Conclusion: BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory indolent lymphoma. Response rates All patients FL MCL pretreated with Rituximab n 62 30 18 25 end of therapy without staging 3 3 0 1 evaluable patients 59 27 18 24 CR 21 (36%) 13 (48%) 6 (33%) 9 (38%) PR 31 (53%) 12 (44%) 8 (44%) 9 (38%) MR 1 (2%) 0 (0%) 1 (6%) 1 (4%) SD 0 (0%) 0 (0%) 0 (0%) 0 (0%) PD 6 (10%) 2 (7%) 3 (17%) 5 (21%) EX 0 (0%) 0 (0%) 0 (0%) 0 (0%) CR+PR 52 (88%) 25 (93%) 14 (78%) 18 (75%) Figure Figure

Rituximab Maintenance Prolongs Response Duration after Salvage Therapy with R-FCM in Patients with Relapsed Follicular Lymphomas and Mantle Cell Lymphomas: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 920-920 ◽  
Author(s):  
Wolfgang Hiddemann ◽  
Roswitha Forstpointner ◽  
Martin Dreyling ◽  
Martin Gramatzki ◽  
Hans-Peter Böck ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Progression Free Survival ◽  
Response Duration ◽  
Initial Response ◽  
Remission Induction ◽  
Low Grade ◽  
Mantle Cell ◽  
Lymphoma Study Group ◽  
Follicular Lymphomas ◽  
The Impact

Abstract Preceding studies have shown that Rituximab prolongs the time to treatment failure (TTF) and response duration (RD) in follicular lymphoma (FL) when given either together with chemotherapy or as maintenance after a no R containing therapy. In the current study the impact of R maintenance on RD was evaluated after remission induction by an R-chemo combination. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized a first randomization between 4 courses of chemotherapy with Fludarabine (25mg/m2/d days 1–3), Cyclophosphamide (200mg/m2/d days 1–3) and Mitoxantrone (8mg/m2/d day 1) (FCM) versus FCM plus Rituximab (375mg/m2/d on day 0) (R-FCM). Patients entering a complete (CR) or partial remission (PR) underwent a second randomzation for observation only versus R maintenance with 4 weekly doses of R (375mg/m2/d) to be given at three and nine month after end of therapy. Both randomizations were stratified for histology and preceding therapy. The first randomization was stopped after 147 patients demonstrating a significant improvement for the R-FCM therapy in initial response, progression free survival and even overall survival (OS). So all subsequent patients received R-FCM. 174 cases are currently evaluable for the second randomization, 136 of whom had received R-FCM for remission induction. In these patients the median RD has not been reached in the R-maintenance arm whereas it is 17 months in patients with no further treatment after R-FCM (p=0.0024). This improvement was seen both in FL and MCL. This study demonstrates that R maintenance after R-FCM salvage therapy is highly effective and improves the outcome of patients with relapsed FL and MCL.

Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 405-405 ◽  
Author(s):  
Mathias J Rummel ◽  
Norbert Niederle ◽  
Georg Maschmeyer ◽  
Andre Banat ◽  
Ulrich von Gruenhagen ◽  
...  
Keyword(s):  
Early Death ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Mantle Cell ◽  
Phase Iii Study ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Abstract 405 Introduction: Promising results have been observed in two phase-II studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas (Rummel et al., JCO 2005; Robinson et al., JCO 2008). In order to further investigate the role of the combination B-R we initiated a multicenter randomized phase-III study in October 2003 to compare efficacy and safety of B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for patients with follicular (FL), indolent and mantle cell lymphomas (MCL). Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine 90 mg/m2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement did not statistically significant differ between both arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76,9% in BR and 77,5 in CHOP-R) and stage III (19,2% in B-R and 18,6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol. Results: Of the 549 pts 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 × DLBCL, 3 × CLL, 2 × MM, 1 × HD, 3 × solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these 9 pts were not evaluable for response evaluation: 4 pts (3 × CHOP-R, 1 × B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT). A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93,8% vs 93,5%, respectively). The CR rate was significantly higher with 40,1% for B-R compared to 30,8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54,8 months for B-R versus (vs) 34,8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40,7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33). CHOP-R treatment was more frequently associated with serious adverse events (SAE) (n=49 in B-R vs n=74 in CHOP-R). Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10,7% vs CHOP-R 46,5%; p<0.0001) and for leukocytopenia grade 3+4 (BR 12,1% vs CHOP-R 38,2%; p<0.0001). G-CSF was more often used in CHOP-R treated pts (20,0% of all cycles) than it was used in the B-R group (4,0%) (p<0.0001). The B-R regimen was better tolerated by the pts as evidenced by a lower rate of alopecia (15% (only grade 1) in B-R vs 62% CHOP-R), a lower number of infectious complications (95 in BR vs 121 in CHOP-R, p=0.0403), a lower incidence of peripheral neuropathy (B-R n=18; CHOP-R n=73; p<0.0001), and fewer episodes of stomatitis (B-R n=16; CHOP-R n=47; p<0.0001). Only drug-associated erythematous skin reaction (urticaria, rash) was more often seen with B-R (n=42) than with CHOP-R (n=23) (p=0.0122). Conclusions: In this final analysis the combination of Bendamustine plus Rituximab improves PFS and CR rates while showing a better tolerability profile. These promising results suggest that B-R does have the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Disclosures: Rummel: Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Maschmeyer:OrthoBiotech: .

Bendamustine Plus Rituximab Is Effective and Has a Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma

2005 ◽  
Vol 23 (15) ◽  
pp. 3383-3389 ◽  
Author(s):  
Mathias J. Rummel ◽  
Salah E. Al-Batran ◽  
Soo-Z. Kim ◽  
Manfred Welslau ◽  
Ralf Hecker ◽  
...  
Keyword(s):  
Response Rate ◽  
Remission Rate ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Low Grade ◽  
Free Survival ◽  
Highly Active ◽  
Major Toxicity ◽  
Mantle Cell ◽  
Grade 3

Purpose The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment. Patients and Methods A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma. Results Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4. Conclusion These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.

scholarly journals Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial

2020 ◽  
Vol 38 (3) ◽  
pp. 248-256 ◽  
Author(s):  
Hanneke C. Kluin-Nelemans ◽  
Eva Hoster ◽  
Olivier Hermine ◽  
Jan Walewski ◽  
Christian H. Geisler ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Interferon Alfa ◽  
Random Assignment ◽  
Free Survival ◽  
Rituximab Maintenance ◽  
Mantle Cell ◽  
Grade 3

PURPOSE In an update of the randomized, open-label, phase III European Mantle Cell Lymphoma (MCL) Elderly trial (ClinicalTrials.gov identifier: NCT00209209 ), published in 2012, we aimed to confirm results on long-term outcome focusing on efficacy and safety of long-term use of rituximab maintenance. PATIENTS AND METHODS Five hundred sixty patients with newly diagnosed MCL underwent a first random assignment between rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, fludarabine, and cyclophosphamide (R-FC) induction, followed by a second random assignment in 316 responders between rituximab and interferon alfa maintenance, to be continued until progression. We compared progression-free survival from the second randomization and overall survival (OS) from the first or second randomizations. RESULTS After a median follow-up time of 7.6 years, the previously described difference in OS between the induction arms persisted (median, 6.4 years after R-CHOP [n = 280] v 3.9 years after R-FC [n = 280]; P = .0054). Patients responding to R-CHOP had median progression-free survival and OS times of 5.4 and 9.8 years, respectively, when randomly assigned to rituximab (n = 87), compared with 1.9 years ( P < .001) and 7.1 years ( P = .0026), respectively, when randomly assigned to interferon alfa (n = 97). In 58% and 32% of patients treated with R-CHOP, rituximab maintenance was still ongoing 2 and 5 years from start of maintenance, respectively. After R-FC, rituximab maintenance was associated with an unexpectedly high cumulative incidence of death in remission (22% at 5 years). Toxicity of rituximab maintenance was low after R-CHOP (grade 3-4 leukopenia or infection < 5%) but more prominent in patients on rituximab maintenance after R-FC, in whom grade 3-4 leukopenia (up to 40%) and infections were frequent (up to 15%). CONCLUSION The excellent results of R-CHOP followed by rituximab maintenance until progression for older patients with MCL persisted in a mature follow-up. Prolongation of rituximab maintenance beyond 2 years is effective and safe.

Allogeneic Stem Cell Transplantation with Dose-Reduced Conditioning in Relapsed Follicular and Mantle Cell Lymphoma - A Prospective Phase II Trial of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3058-3058 ◽  
Author(s):  
Martin H. Dreyling ◽  
D.-W. Beelen ◽  
Michael Schleuning ◽  
Anthony D. Ho ◽  
Martin Gramatzki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Survival Rates ◽  
Unrelated Donor ◽  
Low Grade ◽  
Mantle Cell ◽  
Prospective Phase ◽  
Lymphoma Study Group

Abstract Background: Conventional therapy achieves high initial response rates in follicular (FL) and mantle cell lymphoma (MCL), but even after introduction of combined immuno-chemotherapy, a continuous relapse pattern has been observed. The introduction of dose-reduced conditioning prior to allogeneic peripheral blood stem cell transplantation significantly reduced early treatment-associated toxicity of this curative approach. In 2003, the German Low Grade Lymphoma Study Group initiated a prospective phase II trial to investigate the feasibility and efficacy of this approach in a multi center approach. Methods: Patients with a high risk profile (bulky disease, 3 lymph nodes >3 cm, elevated LDH, >20% bone marrow infiltration, hematopoietic insufficiency) received a conventional salvage chemotherapy, e.g. 2–4x (R-)FCM. Subsequently, all patients received a dose-reduced conditioning (30 mg/m2 fludarabine d-7-4, 30 mg/m2 cyclophosphamide d-4-3) and an optional low dose TBI (2–4 Gray, d-8). Immunosupression consisted of ATG-Fresenius (10mg/m2 bs d-3-1 if unrelated donor), cyclosporine A starting day −1 and mycophenolat (2× 15mg/kg). If T-cell chimerism was established after discontinuation of immunosuppression, donor lymphocyte infusion was applied on days +120, +150 and +180 with increasing doses (2× 105–107/kg) in cases of persistent lymphoma. Results: After a median follow-up of 17 months, a total of 32 patients are evaluable (21 FL and 11 MCL). Median age was 48.5 years (34–62) with a median of 3 prior therapies (1–8). Eigth patients had a family donor and 24 were transplanted from an unrelated donor (no mismatch in 25 and 1 mismatch in 8 cases). 2 early infectious deaths were observed at day 30 and 87 resulting in a treatment-associated mortality (d100) of 6% and another death after 1014 days. After 2 years follow-up, failure-free and overall survival rates were 73% and 77%, respectively. As expected, failure-free survival rates differed significantly between FL (80%) and MCL patients (60%). Discussion: This multicenter trial confirms allogeneic stem cell transplantation with dose-reduced conditioning achieving long-term remissions especially in patients with relapsed FL with rather low mortality. Thus, in younger high risk patients, this therapeutic option should be discussed in relapsed disease. Randomized or case-control trials are warranted to exactly define the role of allogeneic transplantation in FL and MCL.

High Remission Rates and Prolonged Progression Free Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma Treated with R-MACLOIVAM-T

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3597-3597 ◽  
Author(s):  
Peter J Hosein ◽  
Daniel Morgensztern ◽  
Francine Coleman ◽  
Gail Walker ◽  
Maricer Escalon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Relapse Rate ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable subtype of B-cell non-Hodgkin lymphoma characterized by median progression-free survival (PFS) and median overall survival (OS) of only 1.5 and 3–4 years respectively. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a need for novel therapeutic approaches for this entity. Methods: We conducted a single-arm phase II study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO1996;14:925). The study size of 22 patients was based on precision of a two-sided 95% confidence interval for the 18-month progression free survival rate. Eligible subjects had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS ≤ 2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures as well as esophagogastroduodenoscopy and colonoscopy. Prior to initiating thalidomide maintenance, subjects were enrolled in the STEPS® program. Cycle 1 consisted of R-MACLO: rituximab 375 mg/m2 IV on day 1, doxorubicin 45 mg/m2 IV on day 1, cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2/day on days 2–5, vincristine 1.5 mg/m2 on days 1 and 8 capped to 2mg, methotrexate 1.2 g/m2 IV on day 10 over 1 hour followed by 5.52 g/m2 IV over 23 hours followed by leucovorin 36 hours later. G-CSF was begun on day 13. When the ANC was >1.5×109/L, cycle 2 with R-IVAM was begun: rituximab 375 mg/m2 IV day 1, cytarabine 2 g/m2 IV every 12 hours on days 1 and 2, etoposide, 60 mg/m2 on days 1–5 and ifosfamide 1.5 g/m2 on days 1–5 with mesna. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, subjects were re-staged and responses were assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide 200 mg/day until MCL relapse or intolerable toxicity. Results: Accrual started in 4/2004 and ended in 3/2008 when the planned 22 subjects were enrolled. All subjects were evaluable for toxicity and 21 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage 3 disease with bone marrow involvement in 19 and gastrointestinal involvement in 10. Distribution according to IPI: 0–1 factor, 3; 2 factors, 8; 3 factors, 8; and 4 factors, 3. Twenty subjects had diffuse variant and 2 had blastic variant. Nineteen subjects completed all 4 cycles of therapy; treatment was stopped in 2 subjects after 2 and 3 cycles respectively, and one subject died during the first cycle. Of the 21 subjects completing 2 cycles of therapy, 20 achieved CR and one PR. Two subjects relapsed at 9 and 33 months respectively, while 19 remain relapse free after median follow-up of 25 months (range 5–51). With a total follow-up of 545 months, the estimated relapse rate is 4.4 per 100 patients per year. There were two deaths: 1 from sepsis on cycle 1 day 8 and the other in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL. Common severe toxicities were grade 3–4 neutropenia, thrombocytopenia and anemia in 33%, 19% and 17% of R-MACLO cycles and in 50%, 88% and 68% of R-IVAM cycles respectively. There were 14 bacteremias in 82 cycles, 12 of which were after R-IVAM therapy. Six episodes of reversible grade 1–2 renal toxicity occurred after methotrexate. The thalidomide maintenance dose was reduced in 6 subjects due to grade 3–4 neutropenia and reduced or stopped in 8 subjects because of grade 3–4 peripheral neuropathy. Patients remain under follow-up for relapse and survival. Conclusions: R-MACLO-IVAM-T results in a high overall response rate of 100% (95% CR and 5% PR) and a low relapse rate. At a median follow-up of 25 months, median PFS and OS were not reached. The 2-year actuarial PFS of 94% compares favorably with previously reported 2-year actuarial PFS of 40% and 67% for CHOP-like regimens without and with upfront bone marrow transplantation (Blood2005;105: 2677). The contribution of thalidomide maintenance to this outcome requires additional study. A multicenter clinical trial is suggested.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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