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 CD5 Negative Mantle Cell Lymphoma: Clinicopathologic Correlations and Outcome in 58 Cases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2964-2964
Author(s):  
Annapurna Saksena ◽  
Yuan Miao ◽  
Pei Lin ◽  
Michael Wang ◽  
C. Cameron Yin ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
P Value ◽  
Clinicopathologic Features ◽  
Advisory Committees ◽  
Mantle Cell

Abstract Introduction: Mantle cell lymphoma (MCL) is a B-cell neoplasm that has a characteristic immunophenotype of being positive for CD5, B-cell antigens and cyclin D1. A small subset of cases of MCL can be negative for CD5, approximately 5% in the literature. The clinicopathologic features and prognosis of patients with CD5-negative MCL are poorly characterized. Here, we study a group of patients with CD5- MCL and compare them with a group patients with CD5+ MCL. Methods: From a total of 270 cases of MCL accessioned from 2004-2015, 58 CD5- cases (study group) and 212 CD5+ cases (control group) were identified. All cases of MCL were positive for cyclin D1 by immunohistochemistry and, in most patients, CCND1-IGH was shown FISH. Cases negative for CD5 were assessed by flow cytometry and/or immunohistochemistry. Fisher exact test was utilized to analyze differences between the CD5- and CD5+ groups. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards model analyses for OS and PFS were performed (SPSS 22 software). A P-value of less than 0.05 was considered statistically significant. Results: The CD5- group included 39 men and 19 women with a median age of 66 years (range, 36- 88 years) at time of diagnosis. The CD5- and CD5+ groups shared overlapping clinicopathological features, but CD5- cases showed a lower percentage of men (P=0.006) than CD5+ cases. Treatment information was available for 50 patients. Twenty-nine (58%) patients were treated initially with R-Hyper CVAD therapy (rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine). Seventeen (34%) patients were treated initially with less aggressive therapy: 7 with R-CHOP; 8 had other rituximab-based chemotherapy regimens; 2 received rituximab as a single agent. Four patients (8%) were observed without therapy. After induction, 34 patients achieved complete remission (CR), 5 patients achieved partial remission (PR), 6 patients showed no response (NR) or progressive disease (PD), and 5 patients lost follow-up. Ten patients also underwent stem cell transplantation (SCT): 5 patients received allogeneic SCT, the other 5 autologous SCT. With a median follow-up of 45.7 months (range, 2.0-174.3 months), 13 of 56 (23.2%) patients died, 43 of 56 (76.8%) patients were alive at last follow-up, and the rest of 2 patients lost follow up. The induction chemotherapy regimens and CR and PR rate were not significantly different between the CD5- and CD5+ groups (p>0.05). Survival analysis showed patients with CD5- MCL had a tendency for longer OS (Figure 1A, P=0.078). Further analysis showed that lack of CD5 expression predicted a superior OS in a few subsets of MCL patients defined with 1) normal WBC count (p=0.049); 2) Stage I/II disease (p=0.046); 3) Low/intermediate MIPI (p=0.041) and 4) Ki67≥30% (at a borderline p value of 0.05). Patients with CD5- MCL also showed a significantly longer progression-free survival (PFS) (Figure 1B, P=0.01). Absence of CD5 expression was associated with a better PFS in MCL patients with advanced disease (stage III-IV) (P=0.035), a normal leukocyte count (P=0.018), a normal serum lactate dehydrogenase level (P=0.046), classical morphology (P=0.029), and low/intermediate MIPI (p=0.0004). Multivariate Cox regression analysis revealed that MIPI was the only independent prognostic factor for both OS and PFS (P=0.026 and P=0.001 respectively) and CR/PR also predict a better OS (P=0.004) in CD5- MCL patients. Conclusion: The clinicopathologic features were similar between patients with CD5- MCL and those with CD5+ MCL, except that less men in the CD5- MCL group. Lack of CD5 expression was associated with a favorable PFS in MCL patients. Recognizing this subgroup of CD5- MCL has not only a diagnostic significance, but also a prognostic significance. Figure Figure. Disclosures Wang: Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Onyx: 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.

Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1518-1518 ◽  
Author(s):  
Jackie Vandermeer ◽  
Allison M Winter ◽  
Ajay K. Gopal ◽  
Ryan D. Cassaday ◽  
Brian T. Hill ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

scholarly journals Systematic Reviews of the Clinical Efficacy and Safety of First-Line Treatments for Patients with Mantle Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5868-5868
Author(s):  
Neerav Monga ◽  
Jamie Garside ◽  
Matthew S. Davids ◽  
Constantine S. Tam ◽  
Katherine Ward ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Eligible Patient ◽  
High Dose ◽  
Efficacy And Safety ◽  
First Line ◽  
Advisory Committees ◽  
Treatment Regimens ◽  
Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL) is a rare and aggressive form of Non-Hodgkin's lymphoma (NHL) with poor survival outcomes. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended as first-line therapy in younger patients. However the comparative efficacy of such regimens, and of alternative therapy options (for patients unable to tolerate chemotherapy + ASCT), remain unclear. A comprehensive understanding of the current evidence is therefore required. Methods Two systematic reviews (SRs) were developed to identify efficacy and safety data for therapies used in the first-line treatment of MCL. One review identified randomised controlled trials (RCTs) and the other non-randomised studies (NRSs). Searches were carried out in EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials electronic databases. Additionally, conference materials were screened from ASH, EHA, ESMO and ASCO proceedings from the last 2 years. All review methodologies were performed according to Cochrane best practice guidelines Results The RCT SR was run in August 2017 and updated in April 2018. Overall, 2,787 abstracts were screened. The SR included 9 full-text articles and data from 2 conference proceedings, together reporting a total of 7 independent studies. Across the RCTs, the most commonly investigated treatment regimens were rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), and bendamustine + rituximab (BR). Frequently reported primary endpoints were response rates and progression-free survival (PFS). Table 1 presents the PFS and overall survival (OS) data reported in the included RCTs. Data from the RCT reporting on intensive induction chemotherapy followed by ASCT are separated from regimens that did not include ASCT. There were notable differences in median PFS rates, between both patients receiving ASCT versus patients not receiving ASCT and also between the two ASCT treatment arms. In pharmacotherapy studies, PFS ranged from 14.4 to 35.4 months, whereas the two arms of the ASCT RCT reported 51.6 and 109.2 months, respectively. Similar trends were observed in OS: the only result for patients undergoing ASCT (117.6 months) was higher than any result reported in patients not receiving transplant (range 40 - 60 months). However, study heterogeneity may affect the appropriateness of directly comparing these results. Frequently reported grade 3-4 adverse events included anemia, infusion-related reactions, nausea, neutropenia and thrombocytopenia (four of seven RCTs reported each event). The NRS SR was run in April 2018. A total of 3,290 abstracts were screened and 75 full papers were assessed. The SR included 25 full-text articles and 6 conference proceedings, together reporting a total of 18 independent single-arm studies. Several of the NRSs investigated treatment regimens that have not been described in RCT studies, including: R-CHOP with alternating or sequential rituximab + cytarabine (maxiCHOP), and cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high dose methotrexate or cytarabine + rituximab (hyperCVAD + R). Across the NRSs, the longest median PFS was 8.5 years (102 months), in patients treated with maxiCHOP (who were young/ASCT-eligible patients). This outcome was reported in a patient population who had responded to induction therapy and were treated with consolidative ASCT. Across all studies there was heterogeneity in the eligible patient population, with some studies focusing on unfit patients and others focusing on high-dose-therapy-eligible patient populations. Many studies also reported maintenance or consolidation treatments, which would influence the long-term outcomes of the patients. Conclusions These SRs highlight the paucity of directly comparable evidence on the efficacy and safety of therapies for patients with MCL. Although there are some marked differences in patient outcomes according to therapy regimen, considerable heterogeneity in study design and patient populations make direct comparison difficult. Despite this, these SRs highlight that MCL remains a difficult subtype of NHL to treat, with short survival highlighting the high unmet need. With new and emerging therapies, additional research is essential to understand optimal regimens for first-line MCL. Table 1. Table 1. Disclosures Monga: Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Davids:Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ward:Janssen Pharmaceutica NV: Consultancy. Quigley:Janssen Pharmaceutica NV: Consultancy. Parisi:Janssen: Employment. Tapprich:Janssen Pharmaceutica NV: Employment.

scholarly journals Pharmacogenomics Drives Lenalidomide Efficacy and MRD Kinetics in Mantle Cell Lymphoma after Autologous Transplantation: Results from the MCL0208 Multicenter, Phase III, Randomized Clinical Trial from the Fondazione Italiana Linfomi (FIL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Simone Ferrero ◽  
Daniele Grimaldi ◽  
Elena Arrigoni ◽  
Gian Maria Zaccaria ◽  
Beatrice Alessandria ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Treatment Efficacy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Autologous Transplantation ◽  
Phase Iii ◽  
Strong Linkage Disequilibrium ◽  
Advisory Committees ◽  
Mantle Cell

Background and Aims. Prediction of treatment efficacy is an active and growing field of pharmacology. In the Fondazione Italiana Linfomi (FIL) MCL0208 phase III trial (NCT02354313), a 24 months lenalidomide maintenance (LM, 15 mg days 1-21 every 28 days) after high-dose immuno-chemotherapy followed by autologous transplantation (ASCT) in 300 frontline mantle cell lymphoma (MCL) patients showed substantial clinical activity in terms of Progression-Free Survival (PFS) vs observation (OBS). However, this benefit seemed not uniform across patient series. To deeper investigate the differential pattern of response to lenalidomide, a wide analysis of the host pharmacogenomics (PG) background was planned, in order to dissect whether specific germline polymorphisms of transmembrane transporters, metabolic enzymes or cell surface receptors (ABCB1, ABCG2, VEGFA, FCGR2A, NCF4, GSTP1, CRBN) might predict the drug efficacy. Actually, several single nucleotide polymorphisms (SNPs) of ABCB1 exert an effect on substrate affinity of lenalidomide for the transmembrane transporter. Moreover, VEGFA is involved in the anti-angiogenic activity of lenalidomide and might eventually upregulate ABCB1 expression, too. Patients and methods. Genotypes for SNPs were obtained through allele-specific (ASO) probes on germline DNA from peripheral blood. Minor allele frequencies (MAFs) were obtained and the Hardy-Weinberg equilibrium (HWE) was checked. Genotypes were used to infer individual haplotypes by Arlequin and Haploview softwares. Minimal residual disease (MRD) was assessed with ASO primers on either IGH or BCL-1/IGH rearrangements by RQ-PCR in bone marrow samples. TP53 disruption was identified by NGS targeting resequencing and copy number variation analysis. Clinical-biological correlations were screened by automated machine learning methods and validated by both Kaplan-Meier at univariate level and Cox models for multivariate analysis (MV). A logistic regression was implemented to investigate correlations between polymorphisms and MRD kinetics. Results. 278 out of 300 patients (93%) were fully genotyped. The MAF values of the SNPs were very similar to published data and the HWE was confirmed. Most notably, ABCB1 c.2677G&gt;T/A(W) and VEGFA c.2055A&gt;C were significantly associated to outcome and are thus described in this abstract. In the case of ABCB1, the three loci were in strong linkage disequilibrium (p&lt;0.001). 31% of patients were homozygous for ABCB1 wild type alleles (GG, "WT"), 53% heterozygous (GW, "HET") and 16% polymorphic on both chromosomes (WW, "POL"). 20% were VEGFA WT (AA), 47% HET (AC) and 33% POL (CC). PG did not impact on induction therapy and randomization rates of this trial, as superimposable polymorphism frequencies were described between the enrolled and randomized population. Conversely, both ABCB1 HET and POL and VEGFA HET/POL associated with higher MRD clearance rates vs WT after 6 months of LM (93% vs 71% and 91% vs 67%, respectively). Interestingly, the risk of MRD reappearance during LM was 86% lower for patients harboring either polymorphism vs WT (odds ratio 0.14, 95% CI 0.02-0.99; p&lt;0.05). Actually, ABCB1 HET/POL predicted for a more favorable PFS vs WT in LM (3yPFS 85% vs 69% p&lt;0.05, Fig.1A), as well as VEGFA HET/POL (3yPFS 85% vs 59% p&lt;0.01, Fig.1B). The two polymorphisms co-occurred in 57% of patients, being 12% ABCB1 HET/POL only, 23% VEGFA HET/POL and 8% ABCB1/VEGFA WT. Interestingly, patients with either polymorphism had superimposable outcome to patients in whom both co-occurred (Fig.1C). Finally, MV showed that either polymorphism was protective for PFS among randomized patients (HR=0.42; 95% CI 0.20-0.85; p&lt;0.05). According to this hypothesis, among the 17 ABCB1/VEGFA WT patients LM did not improved PFS vs OBS (Fig.1D), independently from TP53 disruption. Conclusions. The first PG data on LM after ASCT in MCL suggested that: 1) ABCB1 and VEGFA polymorphisms did not impact on the chemotherapeutic efficacy of FIL-MCL0208 trial; 2) both polymorphisms favored sustained MRD clearance during LM; 3) either polymorphism conferred a survival advantage during LM. Taken together, these observations hint that a variable excretion of lenalidomide through ABCB1 (heralded by SNPs), as well as an altered VEGFA pathway, could predict treatment efficacy. This observation might be very useful in the future to tailor lenalidomide therapy to MCL patients. Disclosures Ferrero: Servier: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Maria:Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses; BMS: Consultancy; MSD: Consultancy; Janssen: Consultancy, Other: travel, accomodations, expenses; Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding. Ferreri:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Hutchinson: Research Funding; BMS: Research Funding. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. OffLabel Disclosure: Lenalidomide maintenance in mantle cell lymphoma

scholarly journals Non-Bcl2 Mutations Are Predominant in Patients (pts) with Venetoclax Resistant Mantle Cell Lymphoma (MCL) - Response and Clinical Outcomes in Ultra-Refractory MCL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2815-2815 ◽  
Author(s):  
Preetesh Jain ◽  
Shuangtao Zhao ◽  
Rashmi Kanagal-Shamanna ◽  
Lucy Navsaria ◽  
Holly Hill ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Advisory Board ◽  
Advisory Committees ◽  
Ki 67 ◽  
Mantle Cell ◽  
Btk Inhibitors

Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax. Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax). Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance. In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by > 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented. Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.

scholarly journals Outcomes, Causes of Discontinuation and Mutation Profile of Patients with Mantle Cell Lymphoma Who Progressed on Acalabrutinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4151-4151 ◽  
Author(s):  
Preetesh Jain ◽  
Rashmi Kanagal-Shamanna ◽  
Shaojun Zhang ◽  
Chi Young Ok ◽  
Makhdum Ahmed ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Median Number ◽  
Copy Number Alterations ◽  
Advisory Committees ◽  
Mantle Cell

Abstract Introduction: Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed patients (pts) with mantle cell lymphoma. We have reported previously that ibrutinib refractory MCL pts have poor survival. However, outcomes, causes of discontinuation, management and the genomic landscape of MCL in pts who discontinued acalabrutinib are rarely reported. Method: We reviewed charts from all MCL pts treated with single agent acalabrutinib (n=28) in the relapsed setting and identified 15 pts who discontinued acalabrutinib and who are described in this analysis. Outcome after discontinuing acalabrutinib is reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on 10 tumor specimens and 5 matched germline samples collected from 9 pts whose MCL progressed on acalabrutinib; among these pts 4 tumors were collected at baseline and 6 were collected after disease progression. One patient had sufficient DNAs available for both time points (baseline and progression). Results: The median duration on treatment with acalabrutinib was 6.5 months (1 to 29 months) and the median number of cycles of acalabrutinib treatment was 6 (range, 1-30). Seven pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. In 12 pts (80%) acalabrutinib was discontinued due to disease progression (2 pts transformed from classic to blastoid and pleomorphic type at progression) and 3 pts were discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis and another for cytopenias secondary to therapy related myelodysplasia; all three pts were in CR). Nine pts had classic and 3 pts each had blastoid or pleomorphic features before starting acalabrutinib. Overall, median Ki-67 expression was 50% (range, 5-100) and all pts had high a MIPI score. The median number of prior treatments was 1 (range, 1-3); all chemo-immunotherapy (10 pts were previously treated with rituximab-hyper-CVAD) and none with ibrutinib. Two pts who transformed on acalabrutinib received acalabrutinib for a median duration of 12 months (range, 8-16.5). Median follow up after discontinuation was 27 months and the median survival was 25 months (26 months for progression and 1.5 months for intolerance; p <0.001, Figure-1A). Patients who discontinued due to intolerance did not get subsequent treatment for MCL. Among the 12 pts who progressed on acalabrutinib, 11 pts received systemic therapy for MCL [seven received ibrutinib based therapies (2 non responders, 3 achieved CR and 2 were PR and all pts progressed subsequently), 3 got chemo-immunotherapy and progressed and one pt did not receive any treatment and was lost to follow up and died. Six patients received a clinical trial with CAR-T cells (results will be reported separately). Overall, at the time of last follow up, 8 pts were alive and 7 were in CR. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Fig. 1B). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. Compared to tumors at baseline, ATM was mutated at a higher frequency in samples at progression (67% vs. 50%; p=NS). To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from pt-1 (Fig. 1C). Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. In pt-1, both the NLRC5 and β2M mutations acquired at disease progression were truncating, suggesting loss-of-function alterations. Copy number analysis reveals frequent whole-genome doubling and intensive copy number alterations in all tumors, including recurrent losses of chromosome 9p, 17p, and chromosome 13, indicating chromosomal instability as a driver of disease progression. Conclusion: Patients who progress on acalabrutinib have a poor outcome, and newer therapies are required for their treatment. In this small cohort, we observed non-BTK mutations associated with acalabrutinib resistance and disease progression. Disclosures Nastoupil: Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Merck: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Wang:Acerta Pharma: Honoraria, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

scholarly journals Prognostic Value of Circulating Bcl-2/Igh Levels before and after Treatment in 415 Patients with Advanced Follicular Lymphoma Receiving First-Line Immuno-Chemotherapy in 2 Prospective StiL Trials - the Effect of Rituximab Maintenance

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4149-4149
Author(s):  
Guido Kobbe ◽  
Sabrina Pechtel ◽  
Fabian Zohren ◽  
Jürgen Barth ◽  
Alexander Christoph Burchardt ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
The Other ◽  
First Line ◽  
Advisory Committees ◽  
Rituximab Maintenance

Abstract Introduction. The prognosis of patients with follicular lymphoma (FL) has improved during recent years following the introduction of immuno-chemotherapy and Rituximab maintenance. Nevertheless, some patients still relapse early and have a poor prognosis. Several prognostic scoring systems have been developed using clinical, laboratory as well as molecular data, while the early identification of high-risk patients remains a challenge. In this context, the relevance of circulating bcl2/IgH levels for patient stratification is not clear. We could show that high circulating bcl2/IgH levels in the peripheral blood (PB) before therapy were an independent adverse prognostic factor for progression free survival (PFS) in patients receiving R-CHOP or Bendamustine-Rituximab (B-R) in the NHL1 study of the German StiL group (Zohren et al, Blood 2015). Methods. Using a sensitive quantitative PCR method as previously described (Zohren et al, Blood 2015), a total of 2,491 circulating bcl-2/IgH level analyses were performed on PB samples before (n=415) and after (n=305) 6 cycles first-line immuno-chemotherapy and during follow-up (n=1,771). Results of these molecular studies were correlated with clinical outcome. We first present a 10-year update of the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial. Secondly, we report the results from the StiL-NHL7-trial including bcl2/IgH analyses of 308 bcl2/IgHpositive patients who received B-R and Rituximab maintenance. Results. With a median follow-up of 10 years in the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial, high PB bcl-2/IgH levels (bcl-2/IgH to reference gene (tPA) ratio >1) before treatment as compared to low (ratio <1) levels remained a major independent prognostic factor for PFS (median 22 vs 71 months, HR 2.27, 95% CI 1.37-3.75; p=0.001). We also confirm that patients who were still bcl-2/IgHpositive after six cycles of immuno-chemotherapy had significantly inferior PFS (13 vs 79 months, Hazard Ratio (HR) 2.97, 95% CI 1.53-5.78; p=0.001) and overall survival (OS, 128 months vs not reached , HR 3.90, 95% CI 1.39-11.00; p=0.010). In contrast, among the 308 bcl-2/IgHpositive patients of the StiL-NHL7-trial, who all received B-R and Rituximab maintenance, PB bcl-2/IgH levels (ratio >1 vs <1) before therapy were no longer prognostic for PFS (99 months vs not reached, HR 1.06, 95% CI 0.66 - 1.69; p=0.814) or OS. On the other hand, being bcl-2/IgHpositive after 6x B-R remained a poor prognostic factor for PFS (43 months vs not reached, HR 2.44, 95% CI 1.18-5.04; p=0.016 ) and OS (72 months vs not reached, HR 4.03, 95% CI 1.82-8.96; p=0.001) despite Rituximab maintenance. When comparing StiL-NHL1 and StiL-NHL7 patients with respect to bcl-2/IgH levels and the effect of Rituximab maintenance, we found that Rituximab maintenance led to a significantly better PFS. In patients with low (ratio <1) bcl-2/IgH levels before therapy the hazard ratio of 1.7 was modest (71 months vs not reached, HR 1.70, 95% CI 1.16-2.50; p=0.006) in comparison to 3.46 as observed in patients with high (ratio >1) bcl-2/IgH levels (22 vs 99 months, HR 3.46, 95% CI 1.93-6.20; p<0.000). These findings suggest that patients with high bcl-2/IgH levels before therapy have a greater benefit from Rituximab maintenance therapy. There was no difference with regard to OS between StiL-NHL1 and StiL-NHL7 patients who were still bcl-2/IgHpositive after 6 cycles of immuno-chemotherapy implying that these patients may not benefit from Rituximab maintenance. Conclusion. High circulating bcl-2/IgH levels in the PB before first line therapy identify a subgroup of patients with advanced FL who have significantly shorter PFS after standard immuno-chemotherapy. These patients greatly benefit from the addition of Rituximab maintenance, because pre-treatment bcl-2/IgH levels lose their predictive value with Rituximab maintenance therapy. On the other hand, patients who remain bcl-2/IgHpositive after standard immuno-chemotherapy have short PFS and OS despite treatment with Rituximab maintenance and therefore are candidates for experimental treatment approaches. Disclosures Kobbe: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Zohren:Pfizer Inc.: Employment. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Greil:Sandoz: Honoraria, Research Funding; Roche: 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; MSD: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Symbio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Rituximab Plus Bendamustine and Cytarabine (R-BAC) in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma: Long Term Follow-up and Mrd Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 384-384
Author(s):  
Maria Chiara Tisi ◽  
Luca Nassi ◽  
Caterina Patti ◽  
Michele Spina ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Mantle Cell

Abstract The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes. After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p&lt;0.05), elevated Ki67 &gt; 30% (p&lt;0.05), and failure to achieve CR after 2 cycles (p=0.03). Early-progression of disease (&lt;24 months from start of R-BAC) was associated with impaired overall survival (p&lt;0.05). Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia. Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses. As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p&lt;0.05 for them both). In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.

scholarly journals Bendamustine and Rituximab As Induction Therapy in Both Transplant Eligible and Ineligible Patients with Mantle Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2814-2814
Author(s):  
Diego Villa ◽  
Laurie H Sehn ◽  
Kerry J Savage ◽  
Cynthia L Toze ◽  
Kevin Song ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Patient Preference ◽  
Systemic Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
First Line ◽  
Treatment Characteristics ◽  
Mantle Cell ◽  
Induction Regimen

Background Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma associated with poor outcomes. First-line treatment incorporates cytotoxic chemotherapy and rituximab, but there is no single standard of care regimen. In British Columbia (BC), between January 2003 and May 2013, R-CHOP was the preferred induction regimen. Based on results from the STIL-1 trial (Rummel et al, Lancet 2013) demonstrating improved CR rate and prolonged progression-free survival (PFS) of bendamustine and rituximab (BR) compared with R-CHOP, in June 2013, BR became the standard first-line therapy for all patients with MCL regardless of age. In both eras, fit patients generally ≤65 years of age responding to induction were eligible for high-dose BEAM and autologous stem cell transplantation (ASCT). Maintenance rituximab (MR) has been offered to responding patients post ASCT since 2004 and for transplant ineligible patients since 2012. The aim of this study was to assess the efficacy of BR as an induction regimen for MCL. Methods Patients with MCL treated with first-line BR were identified in the BC Cancer clinical and pathology databases as well as the Leukemia/BMT Program of BC transplant database. BR was initiated no later than December 2018. Treatment received was verified using the BC Cancer Provincial Pharmacy database, and clinical characteristics were verified using the BC Cancer Information System. Radiotherapy for localized disease, splenectomy, or a period of observation prior to systemic therapy were permitted. PFS and overall survival (OS) were calculated from the date of initiation of systemic therapy. In the subgroup of patients ≤65 years of age, results were compared to a historical cohort uniformly treated with R-CHOP. Baseline and treatment characteristics associated with PFS or OS (p<0.05) as well as the treatment variable (BR vs. R-CHOP) were included in Cox regression multivariate models using a backward likelihood ratio approach. Results A total of 190 BR-treated patients were identified. Table 1 shows clinical and treatment characteristics. Excluding 4 patients with an unknown response to BR, 101 (54%) patients achieved a complete response and 62 (33%) a partial response, for an 87% overall response rate. 23 (12%) patients progressed during or within 3 months after BR, and all had highly proliferative MCL (Ki-67 ≥30%) or blastoid/pleomorphic histology. Among the 89 BR-treated patients ≤65 years of age, 60 (67%) underwent ASCT and 29 (33%) did not (10 PD, 10 patient preference, 7 comorbidities, 2 pending). Among the 101 patients >65 years old, 9 underwent ASCT (age 66-71) and 92 did not. 63/69 patients received MR after ASCT, and 77/121 received MR after BR (without ASCT). Reasons for not receiving MR (6 after ASCT, 44 after BR) were 25 PD, 10 ASCT/BR toxicity, 7 pending, 3 patient preference, 3 early deaths, 2 physician preference. With a median follow-up of 2.4y (range 0.2 - 6.1) in living patients the 3y OS was 69.5% (95% CI 69.4-70.6) and 3y PFS 62.8% (95% CI 62.4-63.6). Baseline characteristics and outcomes were similar between patients ≤65y treated with BR vs. R-CHOP (Table 1, Figure 1A and 1B). 81/140 (58%) patients treated with R-CHOP underwent ASCT. In the subgroup of patients who underwent ASCT, outcomes calculated from the point of ASCT were not statistically different between BR vs. R-CHOP. In univariate analysis, age >65y, ECOG performance status >1, elevated LDH, blastoid/pleomorphic morphology, no ASCT, and no MR were associated with worse PFS and OS. In multivariate analysis including these variables as well as chemoimmunotherapy regimen, treatment with BR was not associated with PFS or OS. Conclusions In this population-based analysis, BR is an effective induction regimen for both transplant eligible and ineligible patients. ASCT is feasible in patients treated with BR induction. Even though BR was associated with a numerical improvement in PFS compared to R-CHOP in patients ≤65y, differences in PFS and OS were not statistically significant. Longer follow-up is necessary to fully understand the impact of BR in the frontline setting. We observed PD in 12% patients, suggesting that BR may not be an optimal induction regimen across all patients with MCL, particularly in those with aggressive or highly proliferative disease. Disclosures Villa: Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Sehn:Morphosys: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Song:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Freeman:Seattle Genetics, Janssen, Amgen, Celgene, Abbvie: Consultancy, Honoraria. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria.

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