Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 626-626 ◽  
Author(s):  
Marek Trneny ◽  
Thierry Lamy ◽  
Jan Walewski ◽  
Wojciech Jurczak ◽  
David Belada ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Advisory Committees ◽  
First Response ◽  
Mantle Cell ◽  
Grade 3 ◽  
Prognostic Profile

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with poor outcome, especially after failure of first-line treatment. Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, has shown activity in single-arm phase II studies of patients with relapsed/refractory (R/R) MCL. The present controlled randomized study compared the efficacy and safety of lenalidomide vs investigator’s choice (IC) in patients with R/R MCL. Methods: MCL-002 (SPRINT), a European multicenter, open-label, phase II study enrolled patients with up to 3 relapses or who failed prior therapy and were ineligible for intensified treatment or stem cell transplantation (NCT00875667). Oral lenalidomide was given at 25 mg/day on days 1-21 of each 28-day cycle until progressive disease (PD) or intolerability. The IC treatment consisted of single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil. Patients who progressed on IC per investigator judgment were allowed to crossover to lenalidomide. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), time to first response, duration of response (DOR), overall survival (OS), and safety. Response assessments were centrally reviewed using the modified IWG criteria. Results: 254 patients with R/R MCL were randomized 2:1 to lenalidomide (n=170) or IC (n=84). Patients had median age 68.5 years, were predominantly male (73%), and had received a median of 2 prior therapies. 91% had stage III/IV disease at diagnosis, with 34% high-risk MIPI, 43% high tumor burden, and 20% bulky disease at baseline. Overall, patients on the lenalidomide arm had a worse prognostic profile than the IC arm due to higher tumor burden and disease risk (>5 percentage points for a number of parameters). After a median time of 2.9 months, 39 patients (46%) from the IC arm crossed over to lenalidomide due to PD. Overall, 84 patients remain on lenalidomide (15 having crossed over from IC) and 11 patients on IC without PD. At a median follow-up time on study of 15.9 months, the risk reduction for PFS was 39% (HR=0.61 [95% CI, 0.44-0.84]; P=0.004; Table) in favor of lenalidomide (median PFS: 8.7 months lenalidomide vs 5.2 months IC). ORR was significantly improved for lenalidomide vs IC (40% vs 11%; CR/CRu 5% vs 0%). Median time to first response was 4.3 months for lenalidomide (not reached for IC). Median DOR (16.1 vs 10.4 months) and OS on mature data (27.9 vs 21.2 months) were longer for lenalidomide vs IC. Efficacy results were consistent among subgroups. Safety data in 250 patients receiving ≥1 dose showed more dose reductions in lenalidomide-treated patients (41%) vs IC (17%), due in part to a longer median duration of lenalidomide treatment vs IC, and to strict dose modification rules for lenalidomide. The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34% [without increased risk of infection]), thrombocytopenia (18% vs 28%), and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); 1 patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively. Conclusions: The MCL-002 study demonstrated a statistically significant and clinically meaningful improvement in PFS for lenalidomide over best IC monotherapy in patients with advanced R/R MCL despite a worse prognostic profile in the lenalidomide arm at baseline. In addition, ORR and CR rates, TTR, DOR, and OS were improved for lenalidomide over IC. The DOR has been remarkably consistent in various studies with lenalidomide in MCL patients. The safety profile for lenalidomide was as expected and no new safety signals were identified. The results of this first randomized, controlled study of lenalidomide showed superior efficacy compared to IC in patients with R/R MCL with a manageable toxicity profile. Table Efficacy of lenalidomide vs IC in R/R MCL Efficacy Lenalidomide (n=170) IC (n=84) P PFS (Lenalidomide vs IC)  Median PFS, mo (95% CI) 8.7 (5.54-12.14) 5.2 (3.67-6.95)  Sequential HR (95% CI) 0.61 (0.44-0.84)  Sequential log-rank test p-value 0.004 ORR, n (%) 68 (40) 9 (11) <0.001 CR/CRu, n (%) 8 (5) 0 (0) 0.043 Median DOR, mo 16.1 10.4 0.421 Median OS, mo 27.9 21.2 0.52 Disclosures Trneny: Celgene, Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Walewski:Celgene: Consultancy, Other, Research Funding; Janssen-Cilag: Consultancy; Mundipharma : Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other, Research Funding. Jurczak:Celgene, Eisai, Gilead, Janssen, Pharmacyclics, Pfizer, Roche, Novartis, Spectrum, Takeda, Teva: Research Funding. Belada:Celgene: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Biyukov:Celgene: Employment. Patturajan:Celgene: Employment. Casadebaig Bravo:Celgene: Employment. Arcaini:Celgene, Roche, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Phase II Multicenter Study of the Safety and Efficacy of Single-Agent Lenalidomide in Subjects with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Follow-up Analysis of the NHL-003 Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2738-2738
Author(s):  
Pier Luigi Zinzani ◽  
Julie M Vose ◽  
Myron S. Czuczman ◽  
Craig Reeder ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 2738 Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin's lymphoma (NHL) with poor prognosis that necessitates the development of new treatments. Lenalidomide is a unique immunomodulatory agent with antiproliferative and tumoricidal effects on MCL cells. NHL-003 was a phase II, open-label, multicenter trial for subjects with relapsed aggressive NHL that tested single-agent lenalidomide 25 mg PO days 1–21 every 28 days. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), survival, and safety. At the time of the initial publication (Witzig et al. Ann Oncol.2011;22:1622–1627), MCL subgroup analysis showed an ORR of 42%; the median DOR had not been reached. The purpose of this report is to provide long-term efficacy and safety results for the MCL subgroup from NHL-003. Results: Subjects with MCL (N=57) had a median age of 68 y (range, 33–82), were predominantly male (77%) with good ECOG performance status (89% PS 0–1) and advanced-stage disease (88% stage III/IV). Subjects had received a median of 3 (range, 1–13) prior systemic therapies. According to the current central review at a median follow-up of 12.4 mo, subjects achieved an ORR of 35% (CR/CRu 12%) following lenalidomide, including a median DOR of 16.3 mo (Table 1). The ORR to single-agent lenalidomide was 44% (CR/CRu 21%) by independent assessment, with a median DOR not yet reached. Median PFS was 8.8 mo by central review and 5.7 mo according to investigators. Subjects responded quickly, with a median time to first response of 1.9 mo (central and investigator). Median DOR for subjects in CR and overall survival for all subjects have not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), fatigue (9%), and diarrhea (5%). Other AEs included one subject with grade 1 to 2 tumor flare reaction, one subject with grade 3 deep vein thrombosis, and two subjects with second primary malignancies suspected of being related to treatment (one grade 3 squamous cell carcinoma of the skin that resolved and one grade 4 AML in a heavily pretreated individual with 5 prior cancer therapies). Conclusions: This subset analysis from a phase II study further confirms the efficacy of lenalidomide in subjects with relapsed MCL. Responders have a long DOR with manageable side effects. These results support continued investigation of lenalidomide alone or in combination for the treatment of MCL. Disclosures: Zinzani: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Czuczman:Celgene: Consultancy, Consultant Celgene Advisory Board Other. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding. Haioun:Celgene: Celgene Advisory Board Consultant Other, Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pietronigro:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Li:Celgene: Employment. Witzig:Celgene: Research Funding.

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 110-110 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
High Dose ◽  
Advisory Committees ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 110 Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008). Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A. Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Disclosures: Walewski: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier:roche: Consultancy, Honoraria. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Gisselbrecht:Roche: Research Funding.

Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on An Ongoing Phase I/II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2697-2697 ◽  
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Christian Buske ◽  
Peter Borchmann ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3 ◽  
Entire Treatment ◽  
Ongoing Phase

Abstract Abstract 2697 Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods: This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results: Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary: In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures: Hess: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Increases Overall Survival When Compared to 6 Courses of CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in Mantle Cell Lymphoma: Final Analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 151-151 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Final Analysis ◽  
High Dose ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 151 Background MCL outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggest that the addition of rituximab and/or high dose ARA-C may significantly improve outcome. A phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an ORR of 95% with a CR rate of 61%, a median EFS of 83m and a 75% survival rate at 5 years (Delarue et al Blood 20012). Two years ago we presented preliminary results of the the MCL randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B) and have shown that after a follow up (FU) median of 27m patients of Arm B experienced a significantly better time to treatment failure (TTF) (49m vs NR; p=0.0384, HR 0.68), but no overall survival difference. Here, we present final results after a longer FU. Methods Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point TTF was monitored continuously by a sequential procedure based on a one sided triangular test. Stable diseases after induction, progression or death from any causes were considered as treatment failure. Sample size was calculated to detect a relative risk of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 455 patients evaluable for the primary analysis (19 no MCL, 13 not yet documented, 7 lost of follow up, 2 stage 1, and 1 R bendamustine chemotherapy) displayed the following characteristics (A vs B): median age 54 vs 56 year, male 79% vs 79%, stage IV 82% vs 81%, B symptoms 43% vs 31%, ECOG >2 4% vs 4%, elevated LDH 39% vs 35%, and MIPI low/int/high risk 60%/25%/15% vs 64%/23%/13%, respectively. After induction overall response (OR) was similar in both arms (90% vs 95%; p=0.19) but CR and CR/CRu rates were significantly higher in arm B (25% vs 36%; p=0.012 and 40% vs 54%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%). After transplantation OR and CR rates were comparable in both arms (98% vs 97% and 63% vs 61%). After a median FU of 51 months, TTF was longer in Arm B (46m vs 88m; p=0.0382, HR 0.68) mainly due to a lower number of relapses after CR/CRu/PR (n= 81 vs 40). The rate of ASCT-related death in remission was similar in both arms (4% vs 4%). Although CR rate after ASCT was similar in both arms, remission duration (RD) after ASCT was superior in Arm B (49m vs 84m; p=0.0001). At the time of final analysis, OS was superior in Arm B (NR vs 82m, p=0.045). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 9% vs 30%, WBC 50% vs 75%, platelets 10% vs 74%), renal toxicity (creatinine grade 1/2: 10% vs 44%, grade 3/4: none vs 1%), and grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar. Conclusions With a longer FU, we confirmed that high dose ARA-C in addition to R-CHOP increases significantly complete response rates, TTF and in addition overall survival without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients <65 y. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.

scholarly journals Temsirolimus in Combination with Three Different Immuno-Chemotherapy Regimens in Relapse and Refractory Mantle Cell Lymphoma, Final Results of the T3 Phase IB Trial of the Lysa Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2987-2987 ◽  
Author(s):  
Steven Le Gouill ◽  
Krimo Bouabdallah ◽  
Barbara Burroni ◽  
Thierry Lamy ◽  
Remy Gressin ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Advisory Committees ◽  
Phase Ib ◽  
Mantle Cell ◽  
Grade 3

Abstract Temsirolimus has shown clinical activity in heavily pretreated patients with mantle cell lymphoma (MCL) leading to evaluate tolerability and efficacy of combinations regimens. The T3 trial is a multicenter, Phase IB, dose escalation study (3+3) of Temsirolimus administered in combination with three chemotherapy regimens in relapse or refractory (R/R) mantle cell lymphoma (MCL) patients. The primary objective was to determine the maximum tolerated dose (MTD). DLT was assessed during the first two cycles. Study design: Temsirolimus was added for 6 cycles to R-CHOP (R-CHOP-T) administered every 3 weeks or to or R-FC (R-FC-T) and R plus high dose cytarabine and dexamethasone (R-DHA-T) administered every 4 weeks. Temsirolimus was administered IV at day 2, 8 and 15. Three dose levels of Temsirolimus was tested: 15 mg, 25 mg (starting dose) and 50 mg. Patients were treated with one of these 3 chemotherapy regimens according to the choice of local investigator and no randomization was performed. LYSARC was the sponsor and the trial was conducted with a financial support of Pfizer Results: forty-one patients (R-CHOP-T n=10; R-FC-T n=14 and R-DHA-T, n=17)were enrolled. At time of inclusion, median age of patients was 68y (56-79), 32 patients were male, median time from last therapy to inclusion was 23,1m (2-143), MIPI score was low in 8, intermediate in 13 and high in 19 cases (missing=1). Previous lines of treatment included autologous stem cell transplantation in 18 patients. Among patients treated in the R-CHOP-T arm, all patients (n=4) presented grade 3 toxicities at the 25mg dose level. At the 15mg dose level (n=6), one DLT occurs (Thrombopenia). Consequently, the maximum tolerated dose (MTD) of Temsirolimus in the R-CHOP-T was 15 mg. Among patients of the R-FC-T arm (n=14) and R-DHA-T, the recommended dose of Temsirolimus has not been found because of toxicities that occurred at all Temsirolimus doses (25 and 15mg). Hematologic grade 3/4 toxicities were the most frequent, mainly thrombocytopenia (n=28). In term of efficacy, ORR (CR/CRu/PR) during treatment period was 40% for R-CHOP-T including 2 patients who reached CR, 35,7% for R-FC-T including 3 patients who reached CR and 47,1% for R-DHA-T including 6 patients who reached CR. For all patients, mFU is 30.5 m (23-39). The mPFS and mOS according to treatment arms and for all patients (n=41) are as followed: 15,1m and not reached for R-CHOP-T (n= 10); 8.6m and 17.8 m for R-FC-T (n=14) ; 11.9m and 24.2m for R-DHA-T (n=17). In conclusion, the recommended dose of Temsirolimus for R-CHOP-T is 15mg D1,8,15. We are not able to recommend a dose of Temisrolimus for both R-DHA-T and R-FC-T. Hematologic toxicity was the main concern in all arms. A good efficacy in term of response rates PFS and OS was observed in all arms suggesting that Temsirolimus-based chemotherapy regimen should be further investigated in prospective trials but dose of Temsirolimus should be carefully investigated. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Thieblemont:Roche: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Hermine:AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

scholarly journals Bendamustine, Obinutuzumab and Venetoclax As Induction Therapy for Untreated Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Irl Brian Greenwell ◽  
Jeffrey M. Switchenko ◽  
Kami J. Maddocks ◽  
Brad S. Kahl ◽  
Alexander F. M. Craig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Advisory Committees ◽  
Tumor Lysis ◽  
Phase 2 Study ◽  
Mantle Cell ◽  
Grade 3 ◽  
Stage 1

Bendamustine-rituximab (BR) is a standard of care for patients with mantle cell lymphoma (MCL) with median progression free survival (PFS) of approximately 3 years. Venetoclax has proven activity both as a single agent and in combination with other targeted therapies in relapsed MCL. We developed a phase 2 study of bendamustine, obinutuzumab, and venetoclax (BOV) for untreated patients with MCL to determine the efficacy and toxicity of this combination (NCT03872180). Patients ≥ 18 years old with untreated MCL received up to six 28-day cycles of BOV, consisting of bendamustine (90mg/m2 on D1-2) and obinutuzumab (1000mg, C1: D 1,8,15 and C2-6: D1) with a venetoclax ramp up from 20mg to 200mg during the first cycle and then 400mg on days 1-10 of cycles 2-6. Post-induction therapy is determined by the treating physician and is not dictated by the study. The primary endpoint was CR rate at the end of induction, per Lugano criteria. We assumed a historical CR rate of 60% with BR, with a goal CR rate of 85% with the BOV regimen and plan to accrue 23 total patients to assess for this difference. This was a two-stage design that included 9 patients in stage 1 with a requirement of 7 CR's in the first 9 patients to justify continued accrual. Secondary and correlative endpoints include PFS/overall survival, toxicity (including frequency and severity of tumor lysis syndrome), and MRD negativity using both commercial IgHTS assays as well as CAPP-Seq. Supportive care included G-CSF, antimicrobial prophylaxis, and prescribed monitoring for and management of tumor lysis syndrome. 11 patients have initiated therapy. Median age is 70 years (45-80), with 7 males and 4 females. All 11 patients had marrow involvement. Five patients had Ki67 index ≥30%, and TP53/17p abnormalities were found in 2 patients. Eight patients have completed 6 cycles, one patient discontinued study therapy after 5 cycles due to thrombocytopenia and 2 patients remain on therapy after 5 cycles of treatment. Of 9 patients who have completed end of treatment restaging, the ORR was 100%, including 8 CR's (89%) and 1 PR. The two patients currently completing study therapy have completed their interim PET/CT's and both have achieved CR. Three patients experienced grade 3+ obinutuzumab infusion reactions on cycle 1 day 1, with both patients requiring admission but subsequently fully recovering. One of these patients chose to forgo additional obinutuzumab while a second patient safely completed 6 cycles of treatment. The third patient initiated treatment in the hospital and experienced atrial fibrillation requiring ICU transfer, as well as grade 2 hyperkalemia while receiving day 1 treatment. Cardiology did not feel AFib was a result of TLS. She was ultimately able to safely complete 6 cycles of obinutuzumab. Although this event was not clear clinical TLS, the protocol was subsequently amended to incorporate venetoclax administration beginning on day 8 of cycle 1 to prevent overlapping infusional and TLS toxicities from venetoclax and obinutuzumab on day 1. No other patients have had TLS to date. Grade 3/4 hematologic toxicities include neutropenia (n=4), anemia (n=1), thrombocytopenia (n=4) leukopenia (n=3), and lymphopenia (n=10). Grade 3/4 non-hematologic toxicities included rash (n=2), hypophosphatemia (n=2). One patient has experienced prolonged leukopenia 2 months after finishing 6 cycles of therapy and was unable to collect stem cells after cycle 4 for a planned post-induction autologous transplant. To date, 2 patients have relapsed at 7 and 8 months after completing therapy, and one patient died suddenly while in remission of unknown causes at 6 months post-treatment. Of the two relapses, one patient chose not to receive any obinutuzumab during treatment due to a grade 3 reaction during cycle 1, and both patients initially presented with aggressive leukemic phase disease with Ki67 &gt; 30%. Here we report the pre-planned stage 1 of this phase 2 study, the BOV regimen has resulted in CRs in 8 of the first 9 patients, and accrual continues to stage 2. Expected hematologic and infusional toxicities have been manageable. One patient has discontinued therapy due to toxicity, and the prescribed venetoclax ramp-up has successfully avoided clinically significant tumor lysis syndrome. Accrual continues, and additional follow-up of currently treated patients will provide insights into response duration, OS, and rate of MRD negativity with this regimen. Disclosures Greenwell: Acrotech Biopharma LLC, Kyowa Kirin: Consultancy; Lymphoma Research Foundation: Research Funding. Maddocks:Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Kahl:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding. Allen:Curio Sciences: Honoraria; Bayer: Consultancy, Other; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy.

scholarly journals Ibrutinib, Venetoclax Plus Obinutuzumab in Newly Diagnosed Mantle Cell Lymphoma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1530-1530 ◽  
Author(s):  
Steven Le Gouill ◽  
Franck Morschhauser ◽  
Kamal Bouabdallah ◽  
Guillaume Cartron ◽  
Olivier Casasnovas ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Dose Intensity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Good Safety Profile ◽  
Mantle Cell ◽  
Grade 3

Background. Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor, is currently under investigation in prospective trials in R/R MCL. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody approved in frontline and R/R follicular lymphoma which has shown efficacy in MCL (Chiron Blood 2016, Le Gouill ICML/EHA 2019). Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016) The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study that was designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. The study is divided into three steps (A, B,C, respectively) : step A enrolled nine R/R MCL who were treated with Ibrutinib plus Obinutuzumab and step B enrolled 24 R/R MCL patients who were treated with Ibrutinib/Venetoclax/Obinutuzumab (Venetoclax dose from 200 to 800mg ). The Ibrutinib/Venetoclax/Obinutuzumab combination demonstrated a good safety profile and high response rates in R/R MCL (step B). No DLT was reported in either step (Le Gouill et al, ASH 2018). Herein, we present the safety (primary objective), clinical and MRD results for Oasis step C where Ibrutinib/Venetoclax/Obinutuzumab was given to newly-diagnosed, untreated MCL patients. Methods: Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment. Results. Fifteen untreated MCL patients were enrolled from August 2018 to April 2019, in 6 participating centers (France and UK). Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass &gt;5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 13 patients (one was not informative and two are ongoing) of these one presented TP53 mutation. IGHV status (assessed in 13 patients, ongoing in 2) was mutated in two cases including the p53mutcase and not mutated in 8 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis - grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 7 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 8 patients (others are ongoing) were assessed at end of cycle 3 and all were MRD negative in BM (n=6) and/or in blood (n=8), including the p53mutpatient. Seven patients completed 6 cycles, all reached CR according to Lugano criteria (6 in CR/Cru according to Cheson criteria) and were MRD neg (in blood in all cases and in BM in 6 cases -one not done), including the P53mut patient. At date of last monitoring (Jul 2019), no disease progression is reported and all patients remain under the planned treatment. Conclusion. Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL. Disclosures Le Gouill: Janssen-cilag: Consultancy, Honoraria; Novartis: Consultancy; Abbvie: Consultancy, Honoraria; Roche Genentech: Consultancy, Honoraria; Gilead-Kite: Consultancy, Honoraria; Servier: Consultancy; loxo: Consultancy, Honoraria; Takeda: Consultancy. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Napp: Consultancy; TG Therapeutics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. OffLabel Disclosure: Venetoclax, obinutuzumab in mantle cell lymphoma

scholarly journals Results of the Mantle Cell Lymphoma Subset from a Phase 2a Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent and Aggressive Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3935-3935 ◽  
Author(s):  
David Cunningham ◽  
Pier Luigi Zinzani ◽  
Sarit E. Assouline ◽  
Krimo Bouabdallah ◽  
Dominique Bron ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Median Number ◽  
Aggressive Lymphoma ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Duration Of Response ◽  
Grade 3

Abstract Introduction: Mantle cell lymphoma (MCL) is an aggressive disease that is incurable with conventional therapy and the outcome of which remains the poorest amongst B-cell lymphomas. Phosphoinositide-3 kinase (PI3K) pathway activation contributes to MCL pathogenesis, but early-phase studies of the PI3K-δ selective inhibitor idelalisib have reported lower responses in MCL compared with indolent non-Hodgkin lymphoma (NHL) subtypes (Kahl et al., Blood 123:3398-405, 2014; Gopal et al., NEJM 370:1008-18, 2014). In addition, although PI3K-δ is highly expressed in MCL, PI3K-α shows wide variation and expression increases with relapse (Iyengar et al., Blood 121;2274-84, 2013). Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-α and PI3K-δ isoforms. Preliminary results from a phase 2a study of copanlisib in patients with relapsed/refractory NHL or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort in patients with aggressive lymphoma ongoing. We report here the final results of the MCL subset. Methods: Patients with histologically confirmed indolent and aggressive NHL and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Copanlisib was administered at the starting dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244, 1999). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability. Results: As of February 28, 2015, of the 81 patients enrolled, a total of 11 patients with MCL were treated. Median age was 70 years (range 60-85), M/F= 8/3. The median number of prior lines of treatment was 3 (range 3-9) with a median time of 1.4 months since last systemic anti-cancer therapy. All patients previously received rituximab and 8 patients (73%) were refractory to the last therapy. The median duration of treatment was 17 weeks (range 3-59), corresponding to a median number of 4 cycles (range 1-15), with a close adherence to planned dose (median 92%). The most common drug-related adverse events (AEs) of all grades were hyperglycemia (8 patients, 73%), hypertension (6 patients, 55%), neutropenia (5 patients, 46%) and fatigue (4 patients, 36%). Grade 3-4 AEs occurring in 2 or more patients included: neutropenia (2 patients with grade 3, 18%; 3 patients with grade 4, 27%), hypertension (3 patients with grade 3, 27%), hyperglycemia (2 patients with grade 3, 18%), and fatigue (2 patients with grade 3, 18%). One grade 5 AE of acute respiratory failure, was assessed as drug-related by the investigator. Dose reductions and delays possibly due to study drug-related adverse events (AE) were reported in 2 (18%) and 6 (55%) patients, respectively. Two patients were discontinued from study treatment due to adverse events (lung infection and non-melanoma skin cancer). All 11 patients were included into efficacy assessment, although one clinical PD was not confirmed by radiologic measurement. The ORR as determined by independent radiologic review was 64% (2 CRu and 5 PRs). The median duration of response was 150 days (95% CI: 56, 434); 33% of responders had a DOR of at least 270 days. PFS ranged from 7 to 547 days [median 112 days (95% CI: 42, 377)]. Conclusions: Copanlisib was active as a single-agent, with an ORR of 64%, and had a manageable safety profile in patients with heavily pretreated, advanced refractory/relapsed MCL. These results support the potential role of inhibiting both PI3k-α and PI3K-δ in relapsed MCL. Based on these results, a phase 2 trial of copanlisib in ibrutinib-pretreated patients with MCL is under way (NCT02455297). Disclosures Cunningham: Astra Zeneca: Research Funding; Merrimack: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding; Medimmune: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding. Zinzani:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Mollica:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Giurescu:Bayer Pharma AG: Employment. Gorbatchevsky:Bayer HealthCare Pharmaceuticals: Employment. Neves:Bayer HealthCare: Employment. Lemos:Bayer HealthCare: Employment. Grunert:Bayer Pharma AG: Employment. Hiemeyer:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

scholarly journals Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5263-5263
Author(s):  
Karin Hohloch ◽  
Christine Windemuth-Kieselbach ◽  
Pier Luigi Zinzani ◽  
Roberto E. Cacchione ◽  
Wojciech Jurczak ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Therapy ◽  
First Line ◽  
Advisory Committees ◽  
Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: 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; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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