Retrospective Analysis of 149 Unselected Patients with Mantle Cell Lymphoma Confirms Prognostic Relevance of Mantle Cell Lymphoma International Prognostic Index: Single Center Experience

Abstract Introduction: Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma with distinguishes clinical, biologic, and molecular characteristics. The MCL-International Prognostic Index (MIPI) incorporates age, EGOC performance status, normalized LDH level and WBC and has improved discriminatory power. The aim of this retrospective single-center study was to evaluate the clinical characteristics and response to treatment of patients with mantle cell lymphoma. Methods: This single center retrospective study included 297 adult patients diagnosed with MCL between December 2005 and May 2018. The diagnosis of MCL was rendered in accordance with the later World Health Organization (WHO) classification. Outcome was determined as response to treatment, progression free survival (PFS) and overall survival (OS) by Kaplan-Meier analysis using SPSS (IBM SPSS Statistics 21; IBM Corp., Chicago, IL) statistical tool kit. We also compared the PFS and OS according to simplified MIPI (s-MIPI) index. Results: All clinical data were available in 149 cases and these patients were further evaluated. There were 38 (26%) female and 208 (74%) male patients. The median age at diagnosis of MCL was 66 years (range, 31-93 years). The median time of follow-up was 14.5 months (range, 3-139.3 months). The median s-MIPI was 6 points (range 2-11). Most patients were in the high-risk group (62.2%). Induction chemotherapy was administered in 128/146 patients and remaining two patients had deceased after diagnosis of MCL. Altogether 115 out of 146 patients (78.8%) were treated with a combination of chemotherapy and anti-CD20 monoclonal antibody rituximab.One elderly patient received Rituximab immunotherapy only. The majority (56.5%) of the patients received CHOP with rituximab as induction chemotherapy. Thirty-one patients underwent ASCT after remission was obtained in relapse setting. Sixty-four patients (43.8%) had bone marrow involvement and 23 patients (15.7%) had extra-nodal involvement. In total 40 patients (41.2%) achieved a complete remission (CR) with an overall response rate of 63.9% after the induction therapy. During follow up, 20 relapses and 28 deaths were noted. Infection was the most common cause of death (50%). Following ASCT, OS was significantly improved; estimated median OS in transplant cohort was 115.7 months vs. 60 months compare with non-transplant group (p=0.013) (Figure-2). According to the long-rank test, estimated 5-year OS was not significantly different between intermediate-risk and high-risk s-MIPI categories (72.4%±1.2% vs. 72.6%±0.7%; p=0,202). Estimated 5-year PFS was significantly different between intermediate-risk and high-risk s-MIPI cohorts (47.1%±1.3% vs. 33%±10.3%; p=0,05). Among the transplanted patients, there is no differences between the OS of s-MIPI groups (p=0.952). No patient died or progressed in the low-risk group. Conclusion: We have confirmed the validity of the MIPI and simplifed MIPI for the prognosis of patients with MCL even in the era of rituximab. e general results of both indexes are fully comparable, facilitating the broad application of s-MIPI as a simple bedside prognostic tool. Disclosures Civriz Bozdag: MSD: Research Funding; TAKEDA: Consultancy; NOVARTIS: Consultancy. Özcan:Janssen: Other: Travel Support, Research Funding; Abbvie: Other: Travel payment; Novartis: Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; Bayer: Research Funding; BMS: Honoraria; Celgene: Other: Travel support, Research Funding; Roche: Honoraria, Research Funding; Archigen: Research Funding; MSD: Other: travel support, Research Funding; MSD: Research Funding; Jazz: Other: Travel support; Jazz: Other. Beksac:Takeda: 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, Speakers Bureau; Deva: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ilhan:Roche: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau.

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

Blood ◽

10.1182/blood-2019-124192 ◽

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.

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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 ◽

10.1182/blood.v116.21.110.110 ◽

2010 ◽

Vol 116 (21) ◽

pp. 110-110 ◽

Cited By ~ 20

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.

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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 ◽

10.1182/blood-2020-134875 ◽

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>T/A(W) and VEGFA c.2055A>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<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<0.05). Actually, ABCB1 HET/POL predicted for a more favorable PFS vs WT in LM (3yPFS 85% vs 69% p<0.05, Fig.1A), as well as VEGFA HET/POL (3yPFS 85% vs 59% p<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<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

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Mutations Affecting RNA Binding Proteins Are a Novel Feature of Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2019-129136 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1478-1478

Author(s):

Krysta M Coyle ◽

Prasath Pararajalingam ◽

Sarah E Arthur ◽

Nicole Thomas ◽

Miguel Alcaide ◽

...

Keyword(s):

Alternative Splicing ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cell Lymphoma ◽

Advisory Committees ◽

Mantle Cell

Objectives Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. We sought to extend our understanding of the molecular etiology of this malignancy using an integrative genomic analysis of diagnostic biopsies. Methods We performed exome sequencing on 51 frozen MCL tumors and analyzed these alongside previously published exome cohorts. We sequenced tumour genomes and matched constitutional DNA from 34 frozen MCLs, along with matched constitutional DNA, to more broadly identify the pattern of non-coding mutations. Based on mutations identified in this discovery cohort, we re-sequenced 18 recurrently-mutated genes in 212 archival MCLs, each having clinical follow-up data. We also performed RNA-seq on 110 of these cases and analyzed these data for alternative splicing and differential expression, including the differential splicing of HNRNPH1 in the context of recurrent intronic mutations. We investigated the functional and phenotypic effect of mutations and deregulated HNRNPH1 protein through ectopic expression of full-length HNRNPH1 and a mini-gene containing the exons and introns affected by mutations. Using custom droplet digital PCR (ddPCR) assays, we validated alternative splicing patterns in HNRNPH1 itself and other targets identified through re-analysis of available CLIP-seq data. Results In addition to confirming the prognostic association of TP53 and NOTCH1 mutations in MCL, we identified two additional genes associated with outcome: EWSR1 with poor outcome (HR = 5.6) and MEF2B with good outcome (HR = 0.2). By comparing mutation patterns to diffuse large B-cell lymphoma (DLBCL), we identified an MCL-specific missense hot spot in MEF2B, non-specific truncating mutations in EWSR1, and truncating mutations affecting the DAZAP1 C-terminus in both MCL and DLBCL. The DAZAP1 mutations are predicted to alter protein sub-cellular localization and disrupt protein-protein interactions. We also identified the focal recurrence of non-coding mutations surrounding a single exon of the HNRNPH1 gene that were largely restricted to MCL. These mutations affected a region bound by HNRNPH1 protein and disrupted the preferred binding motif of this protein. Intronic mutations were significantly associated with alternative splicing of the HNRNPH1 mRNA and appear to disrupt a negative regulatory loop that normally limits the level of HNRNPH1. Using cell-based assays, we have evaluated the role of HNRNPH1 in cell survival and proliferation. Our interrogation of alternative splicing events in downstream targets implicate HNRNPH1 as a master splicing regulator which may broadly perturb the transcriptome and proteome to favor lymphomagenesis in MCL. Conclusions We discovered three novel MCL-related genes with roles in RNA trafficking or splicing, namely EWSR1, DAZAP1, and HNRNPH1. Mutations in these RNA-binding proteins were identified in 49 of 291 (17%) samples analyzed. Our results improve the current understanding of the MCL mutational landscape, highlight the similarities and differences between MCL and DLBCL, and strongly implicate a role for aberrant regulation of RNA metabolism in MCL pathobiology. We elucidated a functional role for recurrent non-coding HNRNPH1 mutations specific to MCL and identified multiple downstream targets. We continue to explore putative trans targets of HNRNPH1, a novel oncoprotein in MCL. Disclosures Steidl: Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Bayer: Consultancy; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Juno Therapeutics: Consultancy; Tioma: Research Funding. Connors:Bristol-Myers Squibb: Consultancy; Seattle Genetics: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria. Villa:Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Johnson:Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding. Scott:Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Celgene: Consultancy; Roche/Genentech: Research Funding.

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A Phase I/II Study of Ibrutinib and Ixazomib in Relapsed/Refractory Mantle Cell Lymphoma: PrE0404

Blood ◽

10.1182/blood-2019-127494 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1541-1541

Author(s):

Jonathon B. Cohen ◽

Craig A. Portell ◽

Mehdi Hamadani ◽

Opeyemi Jegede ◽

Catherine Diefenbach ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Proteasome Inhibitors ◽

Phase 2 ◽

Advisory Committees ◽

Mantle Cell ◽

Duration Of Response

Background: The Bruton's tyrosine kinase inhibitor ibrutinib is highly effective as a monotherapy in relapsed/refractory mantle cell lymphoma (MCL) with an overall response rate of 68% (Wang et al, NEJM 2013), but the duration of response is shorter than what is seen in chronic lymphocytic leukemia, and the survival of patients who progress after receiving ibrutinib is as short as 3 months (Martin et al, Blood, 2016). In addition, the complete response (CR) rate is only 21%. Ibrutinib-containing combinations may improve depth and duration of response in patients with relapsed/refractory MCL. While use of the proteasome inhibitor, bortezomib, can be limited due to the development of peripheral neuropathy, it has an ORR of 33% (CR rate 8%) in MCL, and preclinical models suggest a synergism between proteasome inhibitors and ibrutinib in MCL cell lines (Axelrod et al, Leukemia 2014). We developed a phase 1/2 trial of ibrutinib combined with the oral proteasome inhibitor ixazomib in patients with relapsed/refractory MCL. Methods: PrE0404 will be open at 18 sites nationwide and is registered at clinicaltrials.gov (NCT03323151). It is currently enrolling patients with relapsed/refractory MCL who have received at least 1 prior line of combination therapy. Patients receiving prior BTK or proteasome inhibitors are eligible, and patients may have received prior autologous or allogeneic transplantation as long as they do not have active graft versus host disease. Patients must have ≤ grade 1 peripheral neuropathy. For phase 1, patients are required to have been off of a BTK inhibitor for 3 months. Starting dose of ibrutinib for all patients is 560mg daily, and dose levels of ixazomib for the phase 1 trial range from 3mg to 4mg days 1, 8, and 15 of a 28 day cycle. Patients continued therapy until disease progression or unacceptable toxicity. For the phase 1 portion of the study, patients are monitored for a dose limiting toxicity (DLT) during cycle 1, defined as grade 3 thrombocytopenia with significant bleeding, select grade 3 non-hematologic toxicities, grade 4 thrombocytopenia, grade 4 febrile neutropenia, grade 4 non-hematologic toxicity, or any grade 5 toxicity. In addition, any toxicity-related dose delay > 7 days of ibrutinib or ixazomib or an inability to receive all 3 doses of ixazomib during cycle 1 are considered DLT's. The maximum tolerated dose/recommended phase 2 dose will be the dose at which fewer than 1/6 patients experience a DLT, with the maximum dose of ixazomib will be 4mg. The primary endpoint for the phase 2 portion of the study is CR rate, and patients will be assigned to one of two cohorts based on prior BTK-inhibitor exposure. For ibrutinib-naïve patients, we will target a CR rate of 40% (based on a historical CR rate of 21% for ibrutinib), and for ibrutinib-pretreated patients, we will target a CR rate of 23% (based on a historical CR rate of 8% for bortezomib). There is 86% statistical power & a one-sided 10% alpha to test each hypothesis. We will accrue 31 patients to each cohort in order to detect this difference. Secondary and exploratory endpoints will include progression-free and overall survival, overall response, toxicity, frequency of BTK mutations, and response based on molecular risk stratification. As of July 2019 the study is open to accrual at 14 sites and is expected to move to phase 2 in fall 2019, at which time it will be expanded to 18 sites. Disclosures Cohen: Hutchison: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Astra Zeneca: Research Funding; LAM Therapeutics: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; UNUM: Research Funding; Gilead/Kite: Consultancy; Takeda Pharmaceuticals North America, Inc.: Research Funding. Portell:Infinity: Research Funding; Roche/Genentech: Research Funding; Xencor: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; Bayer: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; BeiGene: Consultancy, Research Funding. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Otsuka: Research Funding; Celgene: Consultancy; Merck: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Triphase: Research Funding; Takeda: Research Funding; Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau. Kahl:Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Ixazomib is not currently approved for mantle cell lymphoma.

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T-Cell Clonal Expansion and Activation Associated with Durable Clinical Response to Dual BTK and CDK4/6 Inhibitor Therapy in Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2019-122322 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3973-3973

Author(s):

Christina Y. Lee ◽

Maurizio Di Liberto ◽

Yang Hu ◽

Xiangao Huang ◽

Nancy L Bartlett ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Committees ◽

Mantle Cell ◽

Progression Of Disease

Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma characterized by the chromosomal translocation (11;14)(q13;q32), resulting in aberrant expression of cyclin D1 and dysregulated cell cycle progression. In a phase I clinical trial in patients with previously treated MCL, the combination of the cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor palbociclib and the Bruton tyrosine kinase inhibitor ibrutinib was safe and active. We hypothesized that clinical responses are in part attributed to dynamic changes in the immune landscape and tumor-immune interaction, given accumulating evidence that inhibition of CDK4/6 augments anti-tumor immunity. In a patient (Pt 17) treated with palbociclib and ibrutinib for over 3 years and experiencing a complete response (CR), there was an over 4-fold increase in circulating CD3+ T cells over time. For the first 19 treatment cycles, the absolute CD3+ T cell count was 862 ± 322 compared to 4,027 ± 253 between cycles 31 and 40, with no clinical suspicion of infection for at least 3 months prior. To investigate the T-cell receptor (TCR) repertoire over the course of treatment, high-throughput sequencing of the TCRB CDR3 region was performed, revealing a more oligoclonal repertoire in the peripheral blood over time. The cumulative frequency of the top 10 TCR clones during cycles 3, 7, and 31 were 3.9%, 6.5%, and 25.8%, respectively. These clones were mapped to single-cell RNA sequencing (scRNA-seq) data and determined to be CD8+ effector and central memory T cells. Furthermore, there appears to not only be increased numbers of CD4+ and CD8+ T cells but also enhanced activation as evidenced by scRNA-seq expression of CD69. These findings suggest a predominant cytotoxic T-cell response, which is consistent with recent preclinical studies using CDK4/6 inhibitors. A similar, less dramatic, pattern of T cell expansion was observed in three additional responding patients, including one with non-leukemic MCL (Pt 25) who achieved a CR with subsequent progression of disease at cycle 25. This patient had a 2-fold increase in the absolute number of circulating CD3+ T cells with a baseline count of 442 ± 168 during cycles 1 to 2 compared to 915 ± 104 between cycles 4 and 23, prior to a substantial decrease to 452 during cycle 24 and further to 114 during cycle 25. There was no evidence of clonal T cell expansion in the peripheral blood samples from cycles 4, 20, and 24. Whether this is related to a lack of circulating tumor cells remains to be determined. Interestingly, scRNA-seq analysis revealed a remarkable increase in PDCD1 (encoding PD-1) expression upon disease progression (abstract by Di Liberto et al.). Our findings offer potential new insights into the tumor-immune interaction associated with a durable treatment responses and drug resistance in targeting CDK4/6 and BTK in MCL. In preclinical models, CDK4/6 inhibition has been linked to changes in the tumor microenvironment to enhance the immune response, and here we present the first longitudinal data obtained from patients within the context of a clinical trial. Expansion of the cohort from the ongoing phase II trial, cytokine profiling, and functional assays are underway to further characterize the oligoclonal CD8+ T cell and other immune populations as well as to explore the potential therapeutic role of combinations with immune checkpoint blockade in lymphoma. Figure 1. Differential T-cell responses in relapsed/refractory MCL patients on palbociclib and ibrutinib combination therapy, including a leukemic MCL patient with a CR (Pt 17) and a non-leukemic MCL patient with a CR and subsequent progression of disease (Pt 25). A, Absolute B-cell and T-cell counts during various treatment cycles for Pt 17 (top) and Pt 25 (bottom). B, Cumulative productive frequency of the top 10 clonal TCR rearrangements in a given treatment cycle. C, Change in abundance of the top 10 TCR clones across a given treatment cycle. D, Differential abundance of productive TCR clones that have significantly increased or decreased in frequency between treatment cycles. Abbreviations: CR, complete response. MCL, mantle cell lymphoma. PD, progression of disease. Pt, patient. TCR, T-cell receptor. Figure 1 Disclosures Bartlett: Pharmacyclics: Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Genentech, Inc.: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Research Funding. Leonard:MorphoSys: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Merck: Consultancy; Miltenyi: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Sandoz: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; Karyopharm Therapeutics: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Gilead: Consultancy. Galluzzi:Luke Heller TECPR2 Foundation: Consultancy; Astra Zeneca: Consultancy; Inzen: Consultancy; OmniSEQ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:I-MAB: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy; Sandoz: Consultancy. OffLabel Disclosure: Palbociclib, a CDK4/6 inhibitor, was used off-label in combination with ibrutinib in a phase I clinical trial in patients with relapsed/refractory mantle cell lymphoma.

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A Phase II, Open-Label, Single Arm Trial to Assess the Efficacy and Safety of the Combination of Tisagenlecleucel and Ibrutinib in Mantle Cell Lymphoma (TARMAC)

Blood ◽

10.1182/blood-2020-138946 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Adrian Minson ◽

Nada Hamad ◽

Jason P Butler ◽

David Alan Westerman ◽

David Ritchie ◽

...

Keyword(s):

T Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

Complete Response ◽

Advisory Committees ◽

Car T ◽

Mantle Cell

Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.

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Triangle: Autologous Transplantation after a Rituximab/Ibrutinib/ara-c Containing Induction in Generalized Mantle Cell Lymphoma - a Randomized European MCL Network Trial

Blood ◽

10.1182/blood-2019-127863 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2816-2816 ◽

Cited By ~ 1

Author(s):

Martin Dreyling ◽

Marco Ladetto ◽

Jeanette K. Doorduijn ◽

Eva Gine ◽

Mats Jerkeman ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Mantle Cell ◽

Scientific Advisory

Background: Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma with a wide variation of clinical course. Based on randomized trials of our network, current standard of care is a cytarabine-containing immunochemotherapy induction (Hermine, Lancet 2016) followed by autologous stem cell transplantation (SCT; Zöllner, ICML 2019) and rituximab maintenance for 3 years (Le Gouill, NEJM 2018). In relapsed MCL the BTK inhibitor ibrutinib achieves high response rates and ongoing remissions (Wang, NEJM 2013; Dreyling, Lancet 2016). This approach achieved especially longer remission durations in earlier treatment lines (Rule, Hamatologica 2019). We aim to clarify whether ibrutinib added to induction and as maintenance with or without autologous stem cell transplantation might improve outcome. Study design and methods: In this international, randomized three-arm phase III trial (EudraCT-no. 2014-001363-12) young, fit patients ( up to 65 years) with histologically confirmed, untreated mantle cell lymphoma advanced stage II-IV qualify for 1:1:1 randomization after written informed consent according to ICH/EU GCP. In the control arm A, patients receive an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (either BEAM or THAM: TBI, high dose Ara-C and melphalan). In arm A+I Ibrutinib is added to the R-CHOP cycles (560 mg day 1-19) and applied as maintenance (continuous dosing) for 2 years. In arm I the same induction and maintenance is applied but high dose consolidation and autologous SCT is skipped. A rituximab maintenance (single doses every 2 months up to 3 years) may be added in all study arms according to national clinical routine. The primary study aim is to show superiority of one of three study arms as future standard of care based on the comparison of the investigator-assessed failure-free survival (FFS), i.e. to investigate if the addition of ibrutinib improves the efficacy of standard 1st line treatment, and can even challenge the use of high-dose chemotherapy with autologous SCT. Secondary study aims include the efficacy of the three treatment arms and the safety and tolerability of ibrutinib during induction immuno-chemotherapy and maintenance. Accordingly, overall and complete response rates, progression-free and overall survival will be determined as well as adverse events during induction immuno-chemotherapy and follow-up including the cumulative incidence rates of SPMs. In addition, minimal residual disease is regularly determined based on patient-specific PCR assay according to the standardized Biomed-2 procedure. Results: As of July 30th, 511 of up to 870 patients have been randomized from 12 different European countries. In a meanwhile completed safety run-in of the initial 50 patients, feasibility of the two experimental arms was confirmed with no major differences in hematological and other toxicities and no major delays during induction. Disclosures Dreyling: Acerta: Other: Scientific advisory board; Novartis: Other: Scientific advisory board; Mundipharma: Other: Scientific advisory board, Research Funding; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Bayer: Other: Scientific advisory board, Speakers Bureau; Sandoz: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; Pfizer: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria. Doorduijn:Roche: Honoraria, Research Funding. Gine:Janssen: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Roche: Other: Travel expenses, Research Funding. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Mey:Janssen-Cilag: Consultancy; Roche: Consultancy, Research Funding. Hutchings:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Kolstad:Merck: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trneny:Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Gomes da Silva:AbbVie: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support; Janssen-Cilag: Consultancy, Other: Travel support; Celgene: Consultancy; Gilead Siences: Other: Travel support, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hoster:Janssen: Research Funding; Roche Pharma AG: Other: Travel Support.

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

Blood ◽

10.1182/blood.v128.22.2964.2964 ◽

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.

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Effectiveness of Lenalidomide in Patients with Mantle Cell Lymphoma Who Relapsed/Progressed after or Were Refractory/Intolerant to Ibrutinib: The MCL-004 Study

Blood ◽

10.1182/blood.v128.22.1786.1786 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1786-1786 ◽

Cited By ~ 4

Author(s):

Michael Wang ◽

Peter Martin ◽

Tycel Phillips ◽

Andre Goy ◽

Izidore S Lossos ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Cell Lymphoma ◽

Unknown Primary ◽

Employment Equity ◽

Advisory Committees ◽

Mantle Cell ◽

Equity Ownership

Abstract Background: Mantle cell lymphoma (MCL) remains challenging particularly in the relapsed/refractory setting, where patients often show chemoresistance. Novel molecular-based therapies have shown impressive and durable activity in that setting, although primary and acquired resistance remains problematic. A recent retrospective series of 114 patients who had failed ibrutinib (median of 4.7 month exposure) showed very short median overall survival of 2.9 months after ibrutinib cessation (Martin et al. Blood 2015). Here we report the results from the observationalMCL-004 study investigating outcomes of patients treated with lenalidomide (an IMiD® immunomodulatory agent) after failing ibrutinib; patients were either relapsed, progressed, refractory, or intolerant to ibrutinib. The objective here is to evaluate the clinical effectiveness of lenalidomide monotherapy or a lenalidomide-containing regimen in relapsed/refractory MCL after ibrutinib failure or intolerance. Methods: MCL-004 is a multicenter study in patients with MCL who relapsed/progressed after or were refractory/intolerant to ibrutinib, and were subsequently treated with lenalidomide. With patient informed consent, data were collected retrospectively from patients who, after their disease failed to respond to ibrutinib, received lenalidomide-based therapy from March 1, 2009 to June 9, 2015. The primary endpoint was investigator-assessed overall response rate (ORR) based on 2007 International Working Group criteria, with required patient monitoring and routine imaging. Results: Thirty patients were enrolled at 7 US sites and 1 EU site, including patients receiving lenalidomide monotherapy (n=8), lenalidomide + rituximab (n=8), and lenalidomide + other treatment (n=14). Lenalidomide + other treatment included combination with rituximab, carfilzomib, and dexamethasone (n=3); other combinations were given in ≤2 patients. Patients had a median age of 69 years (range, 50-84), and median time from last dose of ibrutinib to first dose of lenalidomide was 1.3 weeks (range, 0.1-21.7). All patients received ≥2 prior lines of therapy, and 83% received ≥3 prior therapies (median prior therapies, 3.5; range, 2-8). With prior ibrutinib, the best responses achieved were 10% complete response (CR), 43% partial response (PR), 3% stable disease, 40% relapse/progressive disease (PD), and 3% unknown. Primary reasons for ibrutinib discontinuation were 50% relapse/PD, 40% refractory, and 10% intolerance. Patients received a median of 2 cycles (range, 1-11) of lenalidomide-based treatment. Eight patients' disease responded (4 CR, 4 PR), resulting in an ORR of 27% (95% CI, 12%-46%). Five of 8 maintained their response at data cut-off (3 CR, 2 PR). ORR was similar for patients with relapse/PD vs. those refractory to ibrutinib (29% vs. 33%, respectively). Median duration of response (DOR) was 18 weeks (95% CI, 2.9-25+) for all patients. Median DOR was not reached in patients who previously relapsed/progressed with ibrutinib compared with a median of 11 weeks for those whose disease was refractory to ibrutinib. Most common treatment-emergent adverse events (TEAEs) were 33% fatigue; 27% nausea; and 23% each dyspnea, neutropenia, dizziness, or rash. In general, TEAEs were less common with lenalidomide monotherapy. The most frequently reported serious AEs were pneumonia, dyspnea, deep vein thrombosis, hypotension, and acute kidney injury (7% each). At data cutoff, 15 patients (50%) had died, mostly due to MCL and none due to second primary malignancy. Conclusions: Most patients received ≥3 prior lines of treatment, and median time from last dose of ibrutinib to first dose of lenalidomide was short. Lenalidomide-based treatment showed clinical activity in this difficult-to-treat patient population, including 27% ORR and 13% CR. No new safety signals for lenalidomide were identified. Overall, our results show that lenalidomide is active in a selected group of patients with relapsed/refractory MCL that previously failed ibrutinib. Disclosures Wang: BeiGene: Research Funding; Asana BioSciences: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Onyx: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin:Acerta: Consultancy; Teva: Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda: Research Funding. Ghosh:Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding.

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