scholarly journals Ibrutinib in Mantle Cell Lymphoma Patients: Analysis of the Czech Lymphoma Study Group

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4526-4526
Author(s):  
Aleš Obr ◽  
Pavel Klener ◽  
Andrea Janíková ◽  
Heidi Mocikova ◽  
David Belada ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
World Population ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Mantle Cell ◽  
Heavily Pretreated

Abstract Introduction: Mantle cell lymphoma (MCL) is usually an aggressive B-cell lymphoma subtype characterized by frequent relapses and is still considered to be incurable. Ibrutinib (iBTK), a first-in-class inhibitor of Bruton′s tyrosine kinase, demonstrated promising outcomes in heavily pretreated MCL patients in several prospective trials. But only limited data on its effect is available in real-world population. Methods: We performed an analysis of 77 MCL patients (pts) from five Czech university centers diagnosed from 11/1997 to 12/2019. iBTK was initiated no later than 7/2020. The database was locked 7/2021. Bone marrow (BM) was examined by immunohistochemistry and/or flowcytometry at time of iBTK initiation. Overall and progression free survival (OS, PFS) were calculated from the beginning of iBTK therapy. Duration of response (DoR) to iBTK was calculated from response to relapse/progression/death. Results: The median age at diagnosis was 68 (40-81) years. Eighty percent of pts had advanced disease (III and IV). MIPI score was low, intermediate and high in 15.3%, 20.3% and 64.4% pts, respectively. BM involvement had 27 (56.3%) of 48 evaluated pts. Frontline regimens used were as follows: R-CHOP/R-CHOP-like in 54.5%, intensive R-HDAC-containing in 32.5% and non-anthracycline regimen in 13.0% pts. Autologous stem cell transplant consolidation had 24.7% pts. Rituximab maintenance was administered in 53.2% pts. Sixty-one percent of pts had relapse/progression of disease within 24 months (POD24). Median of treatment lines before iBTK was 2 (1-8). The overall response rate to iBTK by PET/CT was 66% with 30% complete remissions. After median follow-up of 12.6 months, 26 (33.8%) pts are alive. Median PFS and median OS were 7.9 months (95% CI 1.1-65.6) and 12.4 months (95% CI 1.2-80.0), respectively. Median DoR was 8.8 months (95% CI 0.7-64.1). Pts with 1 line of therapy before iBTK experienced significantly superior OS compared to those with 2 or more previous lines (2-year OS [2-y OS] 66.0% vs 37.4%, p=0.03), but there was no difference in PFS (p=0.46) and DoR (p=0.83). We found a trend toward improved OS in patients without POD24 (2-y OS 51.1% vs 41.0%, p=0.08), but no difference neither in PFS (p=0.97), nor DoR (p=0.16). Survival analysis according to BM involvement status (BM +/-) showed 2-fold lower risk of relapse/progression (HR=1.81, p=0.06) and death (HR=2.18, p=0.02) in BM+ pts. No difference in DoR was found (p=0.72). Pts with iBTK failure had almost 4-fold higher risk of death (HR 3.6, p=0.003) [Fig. 1]. Conclusions: Our data confirm promising efficiency of ibrutinib also in heavily pretreated unselected R/R MCL patients but iBTK failure portends a dismal outcomes. Surprisingly, BM involvement at time of iBTK initiation seems to have favorable impact on prognosis and requires further investigation. Acknowledgement: Supported by IGA_LF_2021_001, MZ ČR - RVO (FNOL, 00098892), PROGRES Q40/08 (FN HK), AZV NU21-03-00386 Figure 1 Figure 1. Disclosures Belada: Genmab: Research Funding. Trněný: Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria.

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.

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.

Herpes Zoster (HZ) Complicating Bortezomib Therapy of Relapsed/Refractory Indolent B-Cell and Mantle Cell Lymphoma: An Analysis of Two Phase II Trials.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2818-2818
Author(s):  
Vicki A. Morrison ◽  
Richard I Fisher ◽  
Andre Goy ◽  
Sven de Vos ◽  
Steven H. Bernstein ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Purine Analog

Abstract Abstract 2818 Background: The use of bortezomib-based therapy is known to be associated with an increased risk of HZ in patients (pts) with multiple myeloma, who have disease-related inherent immune defects. A 13% incidence of HZ occurrence in pts with relapsed/refractory MM who received single agent bortezomib has been previously reported (J Clin Oncol 2008; 26:4784-4790). However, the occurrence of HZ in bortezomib-treated pts with non-Hodgkin lymphoma (NHL) has not been previously examined. Methods: We reviewed clinical data from two phase II trials in which bortezomib therapy was administered to pts with relapsed/refractory mantle cell NHL or indolent B-cell NHL. The occurrence of HZ complicating their treatment course was delineated, and an analysis for potential predisposing risk factors was undertaken. Results: A total of 236 relapsed/refractory pts, median age 65 years (yrs), enrolled on these trials was examined. Mantle cell NHL pts (n=155) received single-agent bortezomib, 1.3 mg/m2, days (D) 1, 4, 8, 11, 21-D cycles; those with indolent B-cell NHL (n=81) received either bortezomib, 1.3 mg/m2, D 1, 4, 8, 11, 21-D cycles, plus rituximab, 375 mg/m2, D 1, 8, 15 (cycle 1) and D 1 (cycle 2) (n=41), or bortezomib, 1.6 mg/m2, D 1, 8, 15, 22, 35-D cycles, and rituximab, 375 mg/m2, D 1, 8, 15, 22 (cycle 1) (n=40). HZ occurred in 24 pts (10.2%) overall, with a comparable incidence in both disease subgroups. Median time to HZ occurrence was 39 (range, 11–206) days (< 2 cycles). Overall, 11% of pts had had a prior episode of HZ. Baseline demographic and clinical variables were examined, including age, gender, disease stage, baseline absolute neutrophil and lymphocyte counts, hemoglobin, lactate dehydrogenase, prior HZ, and number and types of prior therapies, to determine if any may predict for subsequent development of HZ. With regard to age, 71% of pts with HZ were age ≥65 yrs, compared to 48% without HZ (p=0.03). 63% of pts with HZ had received ≥2 lines of prior therapy, compared to 47% in those without HZ (p=0.15). 4% of pts with HZ had undergone prior stem cell transplantation, compared to 13% of pts without HZ. Of the pts with HZ, 25% had received prior purine analog therapy, compared to 9% of pts without HZ. The other baseline variables had no impact on the occurrence of HZ. In the 77 pts who responded to bortezomib protocol therapy (complete/partial responses), the incidence of HZ was 14%, compared to an 8% incidence of HZ in the 159 non-responders (p=0.15). Conclusions: HZ may complicate the course of relapsed/refractory indolent or mantle cell NHL pts receiving bortezomib-based therapies, with an incidence similar to the myeloma population. Pts who are elderly, more heavily-pretreated, or have received prior purine analog therapy may be at greater risk of this complication, and should be strongly considered for antiviral prophylaxis during such therapy. Disclosures: Morrison: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Pfizer: Speakers Bureau. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Fisher:Allos Therapeutics: Consultancy; CytoKinetics: Consultancy; GSK: Consultancy; MundiPharma: Consultancy; Seattle Genetics: Consultancy; Millennium Pharmaceuticals, Inc,: Consultancy. Goy:Millennium, Celgene, GSK and Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bernstein:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Speakers Bureau. Boral:Millennium Pharmaceuticals, Inc.: Employment; Takeda Pharmaceuticals: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: 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

The Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Mantle Cell Lymphoma Previously Treated with Bortezomib: Pooled Data from Two Phase II Studies (NHL-002 and NHL-003).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1560-1560 ◽  
Author(s):  
Craig B. Reeder ◽  
T.E. Witzig ◽  
Julie M. Vose ◽  
Pier Luigi Zinzani ◽  
Rena Buckstein ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Prior Treatment ◽  
Cell Transplant ◽  
Phase Ii Trials ◽  
Phase Ii Studies ◽  
Mantle Cell

Abstract Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma that if not cured with aggressive chemoimmunotherapy and stem cell transplant is usually fatal. The intravenous proteasome inhibitor bortezomib produces an overall response rate (ORR) of 33% in patients with relapsed MCL (J Clin Oncol2006;24(30):4867–74). Unfortunately, most patients eventually relapse and new agents are needed for this disease. Two recently conducted phase II trials (NHL-002 and NHL-003) tested single-agent lenalidomide for patients with relapsed MCL. Fifty-four patients with MCL were enrolled into the two studies; 26% (14/54) had received prior bortezomib and they are the subject of this report. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least one prior treatment regimen including prior bortezomib were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Therapy was continued as tolerated or until disease progression. The 1999 IWLRC methodology was used to assess response and progression. Results: The 14 patients in this study were heavily pretreated with a median of 4 (2–6) prior treatments (including bortezomib) and 50% were bortezomib-refractory. Median age was 66 (45–84) years and 6 (43%) patients were female. Median time from diagnosis to lenalidomide treatment was 3.3 (0.7–7.6) years. The ORR with lenalidomide was 57% (8/14), including 21% (3/14) complete response (CR)/unconfirmed CR and 36% (5/14) partial responses. One (7%) patient had stable disease. The most common grade 3 or 4 adverse events were neutropenia (50%), thrombocytopenia (43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenic fever occurred in 7% of patients. Conclusion: These results demonstrate that lenalidomide oral monotherapy is very effective with manageable side effects in patients with relapsed or refractory MCL who had received prior treatment with bortezomib.

B-Cell Depletion for Two Years after Autologous Stem Cell Transplant Reduces Lymphoma Relapse but Induces Prolonged Hypogammaglobulinemia beyond the Rituxan Maintenance Period.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4480-4480
Author(s):  
Seah H. Lim ◽  
William V. Esler ◽  
Yana Zhang ◽  
Jian Zhang ◽  
Phillip O. Periman ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Maintenance Period ◽  
Mantle Cell

Abstract Although autologous stem cell transplant (ASCT) may benefit patients with relapsed or high risk non-Hodgkin’s lymphoma (NHL), many patients still relapse and die of their disease. Most relapses occur during the first three years after transplant. In an attempt to reduce disease relapses, we have applied a maintenance regimen to patients after ASCT for B-cell NHL. In this regimen, all patients received low dose rituximab infusion (375 mg/m2 for one day only) every three months starting D+100 for a total of 2 years or until disease relapse. We reasoned that rituxan infusion given for only one day every three months may be sufficient to prevent disease relapse during this post-transplant period when any residual tumor bulk is likely low. Fifteen patients (eight men, seven women) with high-risk B-cell lymphoma have been treated. Their diagnoses: advanced mantle cell lymphoma in first complete remission (CR1) (8), refractory advanced marginal zone lymphoma (2), refractory follicular large cell lymphoma (1), high risk T-cell rich B-cell NHL in CR1 (1), Stage IV diffuse large cell lymphoma in CR1 (1) and relapsed B-cell NHL in CR2 (2). The median age was 59 years (range 38–72 years). CR was achieved using R-CHOP (10) or R-DHAP/R-ICE (5) and autologous hematopoietic stem cells were harvested during hematopoietic recovery from the last course of chemo-immunotherapy. With a median follow-up of 46 months (range 12–66) for the group and 47 months (range 16–66) for patients with advanced mantle cell lymphoma, the projected 5.5 years relapse-free survival for the group is 100% and the overall survival 80%. Two patients with mantle cell lymphoma died, one due to metastatic breast cancer and another a stroke at 40 and 41 months respectively. Unlike patients who underwent ASCT without rituximab, in whom B-cell recovery occurred between 3–6 months, we observed severe delays in the immunoglobulin recoveries in these patients (Figure 1). With a median immunoglobulin follow-up of 28 months (range 6–64), none of the fifteen patients showed normalization of total IgG. Two patients achieved a normalized total IgA and two a normalized total IgM. This hypogammaglobulinemia persists beyond the rituxan maintenance period. The median time to attainment of 75% normal level of immunoglobulin is 36 months for IgG, 48 months for IgA and not reached for IgM. The severe immunoglobulin deficiencies may be clinically relevant. Six of fifteen patients developed recurrent upper respiratory tract infection. No fatal infection was observed among any of the patients. Our results, therefore, suggest that low dose rituximab administration every three months after ASCT for high-risk B-cell lymphoma may prevent lymphoma relapse. However, this is associated with severe and prolonged delays in immunoglobulin recovery beyond the rituxan maintenance period. Careful monitoring of the immunoglobulin recovery and intervention as appropriate should be done routinely in these patients. Figure Figure

Safety and Efficacy of Bendamustine with or without Rituximab in the Treatment of Heavily Pretreated Patients with Haematological Malignancies: A Multicenter Retrospective Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4945-4945 ◽  
Author(s):  
Luigi Rigacci ◽  
Benedetta Puccini ◽  
Alberto Bosi ◽  
Sergio Cortelazzo ◽  
Sergio Storti ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Large B Cell

Abstract Bendamustine is an purine analog alkylating agent with marked efficacy in haematological malignancies either when given as monotherapy or in combination with rituximab. The efficacy and safety of this drug was investigated in heavily pretreated patients (pts) with hematological malignancies. A total of 44 patients (median age 63 years ranging from 22–87) from 6 Italian centers treated with bendamustine alone or in combination with rituximab were analyzed in this retrospective study. The diagnoses were multiple myeloma (n=2), chronic lymphocytic leukemia or small lymphocytic lymphoma (n=19), diffuse large B cell lymphoma (n=7), follicular lymphoma (n=8), mantle cell lymphoma (n=4), marginal zone lymphoma (n=2), Hodgkin’s disease (n=1) and peripheral T cell lymphoma (n=1). All pts received bendamustine 60–90 mg/m2 at day 1+2, alone or in combination with rituximab 375 mg/m2 (n=35) at day 1 of each cycle given every 21 or 28 days. The pts were heavily pretreated with a median of 3 previous treatments (range 1–8); 37 pts had previously received rituximab and 9 pts had undergone autologous transplantation. Prior to receiving bendamustine, 14 pts had relapsed disease, 7 had refractory disease and 23 were progressing during therapy. The median number of bendamustine cycles was 3 (range 1–8); 11 pts were still on treatment at the time of this analysis. Patients who completed therapy with at least 1 cycle of chemotherapy were evaluated for response and toxicity; pts in continuous therapy were evaluated for toxicity only. Of 33 pts evaluable for response 7 pts achieved a CR (21%) and 14 a PR (42%) resulting in an ORR of 64%. The remaining 12 pts were non-responders. No differences in the results were observed between groups with different bendamustine doses or scheduling. The best results were obtained in 10 evaluable pts with indolent lymphoma (4 CR, 6 PR) and in 9 pts with chronic lymphocytic leukemia (1 CR, 6 PR). Two evaluable pts with mantle cell lymphoma obtained a response (1 CR, 1 PR). By contrast, only 1 pt with diffuse large B cell lymphoma of 6 patients evaluable for response obtained a CR: the other 5 were non-responders. No pt with myeloma, Hodgkin’s disease or T cell lymphoma achieved a response. After a median follow-up of 4 months, 80% of pts were alive. During 150 treatment cycles, 2 pts experienced grade 4 thrombocytopenia and 1 experienced grade 4 neutropenia; non-hematological toxicity was mild. In conclusion, this retrospective analysis shows that treatment with bendamustine, alone or in combination with rituximab, is a safe and effective regimen in heavily pretreated pts. The best results were obtained in indolent lymphoma: the data in mantle cell lymphoma were also encouraging. No lack of efficacy can be inferred in pts with diffuse large B cell lymphoma, due to the refractory nature of their disease and the advanced age of this particular group (median age 76 years ranging from 67–87).

Ofatumumab Monotherapy for Treatment of Patients with Relapsed/Progressive Diffuse Large B-Cell Lymphoma: Results From a Multicenter Phase II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3955-3955 ◽  
Author(s):  
Bertrand Coiffier ◽  
André Bosly ◽  
Ka Lung Wu ◽  
Gregor Verhoef ◽  
Van Eygen Koen ◽  
...  
Keyword(s):  
B Cell ◽  
Disease Progression ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Large B Cell

Abstract Abstract 3955 Background: Patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) or relapsing after ASCT have a poor prognosis and limited therapeutic options. New treatment options are needed for these pts. Ofatumumab is a human monoclonal antibody that targets a membrane-proximal epitope comprising both the large loop and small loop of CD20, and has shown effective lysis of chemotherapy-refractory DLBCL cells in vitro (Teeling et al. Blood 2004; Cillessen et al. Blood 2007; abstract 2346). We report the first results from an open-label, single-arm, international Phase II trial that evaluated ofatumumab monotherapy in relapsed or progressive DLBCL. Methods: Pts (age ≥18 years) with relapsed or progressive CD20+ DLBCL ineligible for ASCT or with relapsed or progressive disease after ASCT were enrolled between December 2007 and August 2009 (N=81). Relapsed or progressive disease was defined as relapse after a complete remission (CR) or disease progression after partial remission (PR). Pts received 8 weekly infusions of ofatumumab (dose 1, 300 mg; doses 2–8, 1000 mg). The primary endpoint was overall response rate (ORR) evaluated during the 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee according to the revised response criteria (Cheson et al. J Clin Oncol 2007). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety. Results: Baseline characteristics are shown in the Table. Pts were heavily pretreated (median 3 prior systemic therapies), and 32% of pts did not respond to their last prior therapy. Nearly all pts (96%) had received prior rituximab-containing treatment; 54% had received 2 or more courses of prior rituximab therapy (Table). Overall, 58% of pts completed all 8 infusions of ofatumumab, 65% received at least 6 infusions, and 81% received at least 4 infusions. The primary reason for treatment discontinuation was disease progression. The ORR (95% CI) was 11% (4–18%), including 3 CRs (4%) and 6 PRs (7%). Of these 9 responding pts, 8 had responded to their last systemic therapy. The median duration of response (95% CI) was 6.9 months (5.3–6.9) and median PFS (95% CI) was 2.5 months (2.3–2.9). Infusion-related events occurred in 59% of pts, primarily occurred during infusion 1 (40% of pts) and infusion 2 (22%), and subsided during subsequent infusions; these events were predominantly grade 1–2 in severity (96% of pts). The most common (>10% of pts) adverse events (AEs; any grade) were diarrhea (17%), fatigue (15%), peripheral edema (15%), neutropenia (14%), abdominal pain (12%), constipation (12%), nausea (12%), pyrexia (11%), anemia (11%) and leukopenia (11%). Of these, ≥ grade 3 events included neutropenia (10%), leukopenia (6%), anemia (5%) and fatigue (1%). Grade 3 or greater thrombocytopenia and febrile neutropenia were reported in 6% and 4% of pts, respectively. The most common infectious events were upper respiratory tract infections (7% of pts), all of which were grade 1–2 events. In total, 13 pts died during the study; 3 pts died during the treatment period and 10 pts died during post-treatment follow up (until 24 months from study start). Deaths were due to disease progression (n=10), sepsis (n=1), circulatory collapse (no further details; n=1) and multi-organ failure (n=1). Conclusions: Single-agent ofatumumab was well tolerated with an ORR of 11% in heavily pretreated pts with relapsed or progressive DLBCL, nearly all of whom had received prior rituximab therapy. Response to last systemic treatment appeared to influence response to ofatumumab in this pt population. Further studies of ofatumumab in combination with chemotherapy in relapsed DLBCL are currently underway. Disclosures: Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Davies:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Davis:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Radford:GlaxoSmithKline: Equity Ownership; Genmab: Consultancy, Honoraria.

Prolongation of Progression Free Survival In Mantle Cell Lymphoma After RHCVAD: ASCT Consolidation or Rituximab Maintenance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3570-3570
Author(s):  
Jennifer McQuade ◽  
Tahamtan Ahmadi ◽  
David Porter ◽  
Noelle Frey ◽  
Alison Wakoff Loren ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Primary Study ◽  
Cell Transplant ◽  
Data Set ◽  
Bulky Disease ◽  
Rituximab Maintenance ◽  
Mantle Cell

Abstract Abstract 3570 Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. The best initial treatment regimen remains unclear. Although it is generally acknowledged that aggressive approaches using combination chemotherapy and/or high dose chemotherapy can prolong survival, consensus on upfront treatment strategies for advanced MCL is currently lacking without randomized controlled data to guide treatment decisions. We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-HCVAD (N=43) with or without autologous stem cell transplant (ASCT) or Rituximab maintenance. The primary study endpoints were PFS and OS as assessed by chart review and confirmed by SSDI database. Median follow up for all pts was 3 years. The median age was 53.7, and 76.7 % (n=33) were stage IV at diagnosis. 15 patients underwent consolidative ASCT. 11 pts received Rituximab maintenance. Comparing patients treated with R-HCVAD vs R-HCVAD + R maintenance vs. R-HCVAD + ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. Median PFS for all patients was 3.9 years: R-HCVAD alone 2.1 years vs. R-HCVAD+R 3.9 years (P=0.02, HR 3.51, 95%CI: 1.2–10.2) vs R-HCVAD + SCT not reached (p=0.017, HR 3.7, 95%CI: 1.26–10.63). PFS survival rates at 2 years were 50%, 88% and 70%; 33%, 71/% and 63% respectively at 3 years, and 0%, 33% and 33 % at 5 years. 3 year OS for all patients was 84% (95% CI: 65–94) with no significant differences among the three approaches. Notably, only 1/8 patients treated with R-HCVAD + SCT relapsed after 2 years, with a median follow up of 4.8 years for these patients. Our data suggest a further improved PFS when R-HCVAD is consolidated with either Rituximab maintenance or ASCT. While neither of the two consolidative approaches appears superior in our limited data set, both show significant PFS prolongation when compared to R-HCVAD alone. Further prospective investigation of consolidative approaches after RHCVAD in a randomized fashion is warranted. Figure 1: Figure 1:. Disclosures: No relevant conflicts of interest to declare.

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