scholarly journals Novel BET Protein Proteolysis Targeting Chimeras (BETP-PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1058-1058
Author(s):  
Baohua Sun ◽  
Warren Fiskus ◽  
Liang Zhang ◽  
Kanak Raina ◽  
Kevin Coleman ◽  
...  
Keyword(s):  
Research Funding ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Gene Expressions ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Bet Protein

Abstract Mantle Cell Lymphoma (MCL) exhibits pathogenetic mutations or deletion of RB1, ATM, p53, deletion of INK4a/ARF, as well as copy number gains of MYC, CDK4 and BCL2. Activated B cell receptor (BCR) signaling, and the ensuing downstream pro-growth and pro-survival NFkB activity, is also a notable feature of MCL. Collectively, the genetic alterations and the ensuing deregulated signaling and activity of transcription factors, including c-MYC and NFkB, creates the MCL-specific 'transcriptome' that promotes growth and survival of MCL cells. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase (BTK), exhibits unprecedented single-agent activity in relapsed/refractory MCL, however approximately 40% of patients demonstrate primary refractory/resistant disease with a one-year survival rate of only 22%. Mutations in CARD11/IKBKB/TRAF2/BIRC3/NIK or the C481S mutation in BTK, despite ibrutinib treatment, sustain classical or alternative NFkB signaling and transcriptional activity, as well as confer resistance to ibrutinib in MCL. We previously reported that the BET protein (BETP) bromodomain inhibitors (BETis), which disrupt the binding of BRD4 with acetylated chromatin, inhibit the in vitro growth and induce apoptosis of cultured and patient-derived (PD) primary MCL cells. This was associated with BETi-mediated attenuation of c-MYC, BCL2, CDK4/6 as well as of NFkB target gene expressions, including cIAP2, XIAP, cFLIP, TNFAIP3, Bcl-xL, IL10, TNFα and BTK. Concomitantly, BETi treatment induced HEXIM1, p21, p27 and NOXA levels in MCL cells. Co-treatment with BETi and ibrutinib was synergistically lethal and improved the median survival of the immune-depleted mice engrafted with human MCL cells. However, treatment with BETi leads to the accumulation of BRD4, which could promote the deregulated transcriptional activity of c-MYC, NFkB and other transcription factors. Here, we compared the anti-MCL activity of the novel BETP-PROTACs (proteolysis targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) that degrade BRD4 with the BETi OTX015 against cultured and primary MCL cells. ARV-825 and ARV-771 recruit and utilize the E3 ubiquitin ligase activities of cereblon and VHL, respectively, to effectively degrade BET proteins including BRD4. At equimolar concentrations (10 to 500 nM) ARV-825 and ARV-771 were significantly more potent than the BETi OTX015 in inducing apoptosis of cultured and primary MCL cells (p < 0.01), while sparing the CD19+ normal B and CD34+ hematopoietic progenitor cells. Notably, whereas OTX015 treatment increased, BETP-PROTACs markedly attenuated (> 90%) the levels of BRD4 in the MCL cells. BETP-PROTAC treatment caused more profound up and down regulation of mRNA and protein expressions, utilizing the RNAseq and reversed phase protein array (RPPA) analyses, respectively. BETP-PROTAC treatment also caused greater and more sustained depletion of c-MYC, CDK4/6, PIM1, cyclin D1, as well as of the NFkB transcriptional targets Bcl-xL, XIAP, MCL1 and BTK, while concomitantly inducing the level of NOXA and p21. As compared to treatment with OTX015, ARV-771 treatment dramatically inhibited the growth and improved survival of NSG mice engrafted with luciferase-transduced, ibrutinib-resistant, Z138 MCL cells. Also, notably, co-treatment of ARV-825 or ARV-771 with ibrutinib or the BCL2-antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of cultured and primary MCL cells. We have also generated, ex vivo, ibrutinib-resistant (e.g., Mino/IR and JeKo1/IR) and ibrutinib-persister/resistant (Mino/IPR) cultured MCL cells, with >10-fold higher IC50 value for ibrutinib than the parental MCL cells. BETP-PROTAC treatment more potently induced lethality than BETi in the Mino/IR and Mino/IPR cells, associated with attenuation of c-MYC, BCL2, CDK4/6 and NFkB target gene expressions including BTK. BETP-PROTAC and BETi also induced synergistic lethality with venetoclax and palbociclib against the Mino/IR, Mino/IPR and Z138 MCL cells. These findings underscore the superior in vitro and in vivo activity of BETP-PROTACs versus BETi against ibrutinib-sensitive and ibrutinib-refractory MCL cells, as well as highlight a promising new class of agents to be developed for the therapy of human MCL. Disclosures Raina: Arvinas, LLC: Employment. Coleman:Arvinas, LLC: Employment. Winkler:Arvinas, LLC: Employment. Qian:Arvinas, LLC: Employment. Crew:Arvinas, LLC: Employment. Shen:Arvinas, LLC: Employment. Wang:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; BeiGene: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Asana BioSciences: Research Funding; Kite Pharma: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

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

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

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

scholarly journals Novel Bruton's Tyrosine Kinase Inhibitor Bgb-3111 Demonstrates Potent Activity in Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5374-5374 ◽  
Author(s):  
Carrie J Li ◽  
Yang Liu ◽  
Taylor Bell ◽  
Jack Wang ◽  
Hui Guo ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Viability ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Mantle Cell ◽  
Btk Inhibitor ◽  
Dose Dependent

Abstract Background: Aberrant B-cell receptor signaling is an important contributor to lymphomagenesis in mantle cell lymphoma (MCL). Bruton's Tyrosine Kinase (BTK), a component of the BCR signaling axis, has been validated as a clinically relevant target, and BTK inhibitor ibrutinib received FDA approval for treatment of MCL in 2013. Growing concerns that single agent ibrutinib exerts off-target effects that interfere with other treatments such as rituximab-induced antibody-dependent cell cytotoxicity limit its utility in combination treatments. In this study, we assessed the in vitro and in vivo effects of BGB-3111in MCL models. Methods: We performed cell viability assays with BGB-3111 treated MCL cell lines to determine inhibition of cellular proliferation. The same assays were conducted on primary human MCL cells and patient-derived xenograft (PDX) tumor samples. Dose-dependent inhibition of BTK auto-phosphorylation and inhibition of downstream targets such as PLC-γ were determined by phospho-protein immunoblotting and immunoprecipitation. A reverse-phase protein assay (RPPA) was conducted on BGB-3111-treated Mino cells to evaluate changes in MCL oncogenic signaling. Induction of apoptosis in MCL cells treated with increasing doses of BGB-3111 was quantified using flow cytometry. For in vivo experiments, an ibrutinib-sensitive MCL PDX mouse model was treated with 50 mg/kg/day BGB-3111 and monitored for mean tumor burden and survival. Results: BGB-3111 potently inhibited cell viability in a panel of MCL cell lines, with an activity range of 1-10 uM, and induced apoptosis in a dose-dependent manner in several MCL cell lines.BGB-3111 treatment of MCL cells demonstrated a dose-dependent decrease in p-BTK (Y223) and inhibition of downstream effectors without impacting total protein levels, while RPPA revealed upregulation of the PI3K-Akt signaling axes. In addition, BGB-3111 treatment did not impact phosphorylation of off-target kinases affected by ibrutinib treatment. In vivo, BGB-3111 suppressed tumor growth and prolonged tumor survival in BGB-3111 treated mice. Conclusion: The second generation BTK inhibitor BGB-3111 demonstrates selectivity for BTK in vitro and BTK inhibition in vivo. BGB-3111-treated PDX mouse models examining survival, tumor growth, and other factors point to BGB-3111 as an effective single agent BGB-3111 is being investigated in Phase I clinical trials. Disclosures Wang: Beigene: Employment. Wang:Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Acerta: Consultancy, Research Funding; Kite Pharma: Research Funding; BeiGene: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding.

scholarly journals Initial Report of a Multi-Institution Phase I/Ib Study of Ibrutinib with Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2958-2958 ◽  
Author(s):  
Craig A. Portell ◽  
Robert W Chen ◽  
Nolan Wages ◽  
Jonathon B. Cohen ◽  
Michael J. Weber ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Complete Response ◽  
Targeted Agents ◽  
Advisory Committees ◽  
Second Stage ◽  
Optimal Dosing ◽  
Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL) which relapses or becomes refractory to frontline chemotherapy can be a clinical challenge. There have been several targeted agents approved in relapsed MCL including bortezomib, lenalidomide and ibrutinib (IBR) with the best single-agent responses seen with IBR. IBR is an oral, Bruton tyrosine kinase (BTK) inhibitor which has an overall response rate (ORR) of 67% with a median duration of response of 17.5 months in relapsed MCL (Wang, Blood 2015). While these responses are impressive in this population, only 1/3 of patients will have a complete response and only 1/3 of responding patients will have a 24 month PFS. Thus, improvements are needed. Venetoclax (VEN) is an oral selective BCL2 inhibitor which is currently FDA approved in relapsed 17p-deleted chronic lymphocytic leukemia. We and others have shown synergistic cytotoxicity with VEN and IBR (Axelrod Leukemia 2014) which prompted us to explore the combination in a Phase I/Ib clinical trial (clinicaltrials.gov ID: NCT02419560). This study was supported by a grant from AbbVie Inc. Methods Given overlapping toxicities with VEN and IBR, namely neutropenia and GI toxicities, potential for drug-drug interactions given both are metabolized by CYP3A, and a wide range of therapeutic dosing for the two drugs, a dose finding study is appropriate. A continual-reassessment model was designed to test six dosing strategies (table 1). Subjects start treatment with single agent VEN at 100mg PO daily and increase to the allocated dose per table 1. After 1 week of VEN, subjects start the allocated dose of IBR. Subjects are monitored closely for tumor lysis syndrome (TLS) and hospitalized for TLS monitoring when starting IBR. Subjects are treated with the combination for 6 months and are encouraged to continue IBR after that time. The study enrolls in 2 stages. In the first stage, subjects are enrolled one at a time to sequential arms. Up to 2 subjects are allowed on each arm in a zone before enrollment in the zone is paused. Subsequent zones are enrolled once at least one subject in every arm of the zone does not have a DLT during the DLT window. The second stage begins when a subject has a DLT or all arms have enrolled at least 1 subject. In the second stage, subsequent subjects are allocated to an arm based on DLT's and ORR at 2 months occurring in prior patients on the study, thus the study aims to find the optimal dosing combination of IBR and VEN for both toxicity and response. Enrollment will continue until 10 subjects are allocated to an arm or 28 total subjects are enrolled. Eligible patients must have documented relapsed MCL after at least 1 line of chemotherapy. Subjects must not have bulky disease, no evidence of TLS, and must not have been previously treated with IBR. Results Enrollment began 10/2015 and at the time of submission, we have treated 8 subjects and have finished stage I of the study. Subjects were enrolled on arms A to E. Mean age is 63 years (range 49-81). 7 of the 8 subjects are male. 5 subjects were refractory to their prior treatment and 3 subjects have progressed after an autologous bone marrow transplant. Seven of the 8 subjects are evaluable for adverse events. 5 subjects have completed the 6-week DLT window. There have been 15 related adverse events reported with 14 of these being grade 1 or 2. No TLS has been reported. One DLT at arm E was identified (grade 4 neutropenia) which prompted us to move to stage II of the study. Three subjects (arm A, B, and C) are evaluable for response with all achieving at least a partial response. One subject on arm C, had a complete response at 4 months of the combination. Conclusion: Early results suggest tolerability for the combination of IBR and VEN in Relapsed MCL. There have been no signs of TLS, though subjects with high risk for TLS are excluded. One DLT (neutropenia) has been reported in Arm E and thus modeling will start to find the optimal combination using both toxicity and response. Responses have been seen across the various treatment arms. Continual re-assessment modeling is an adequate study design for combination studies with targeted agents to identify optimal dosing, accounting for both toxicity and response. Disclosures Portell: Infinity: Research Funding; Roche/Genentech: Research Funding; Acerta: Research Funding; AbbVie: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Cohen:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kahl:Seattle Genetics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Gilead: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy. Williams:Jansen: Research Funding; Pharmacyclics: Research Funding.

scholarly journals Overcoming CAR T Resistance with Non-Covalent BTK Inhibitor Loxo-305 in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Yang Liu ◽  
Vivian Changying Jiang ◽  
Joseph McIntosh ◽  
Alexa A Jordan ◽  
Yijing Li ◽  
...  
Keyword(s):  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Annexin V ◽  
Car T ◽  
Mantle Cell ◽  
Btk Inhibitor

Background: Mantle cell lymphoma (MCL) is a distinctive B-cell non-Hodgkin's lymphoma characterized by poor prognosis. Despite clinical success of the covalent Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a subset of patients need to discontinue ibrutinib therapy due to treatment related adverse events, which are primarily caused by off-target effects. Furthermore, primary or acquired resistance to ibrutinib continues to emerge and often leads to dismal clinical outcomes. Therefore, exploration of more target-specific BTK inhibitors is crucial to minimize the adverse events and provide clinical benefit. CAR T therapy has achieved unprecedented response in patients with relapsed or refractory MCL. However, the development of resistant phenotypes is a new emerging medical challenge in MCL patients with unknown mechanisms. Here, we characterize the therapeutic efficacy of LOXO-305, a next generation non-covalent small molecule inhibitor with high selectivity for BTK. Preclinical efficacy of LOXO-305 alone or in combination with venetoclax (ABT199), a selective Bcl-2 inhibitor, was evaluated in MCL using in vitro and in vivo CAR T-resistant PDX models. Methods : In vitro cell viability was measured after 72 hour treatment with LOXO-305 alone and in combination with ABT-199 in MCL cell lines using Cell Titer Glo luminescent cell viability assay (Promega). To determine whether LOXO-305 induces cell death through cell apoptosis, we used annexin V/PI staining followed by flow cytometry analysis. To evaulate in vivo drug efficacy we used patient-derived xenograft (PDX) models established from primary patient samples. Results: LOXO-305 treatment, as a single agent, resulted in effective MCL cell growth inhibition in a panel of MCL cell lines including ibrutinib and/or ABT-199-resistant cell lines (IC50=6.6-24.4μM), except for JeKo BTK KD cells with BTK knockdown (KD) via CRISPR/Cas9 technology (IC50&gt;30 μM). To improve the efficacy, we decided to investigate the potential of LOXO-305 in combination with ABT199, since the combo of ibrutinib and ABT199 is clinically beneficial in MCL patients. Indeed, LOXO-305 significantly improved the inhibitory effect of ABT-199 in the ABT-199 resistant Mino-R and JeKo BTK KD cells, suggesting that this combination could be further explored in overcoming ABT-199 resistance in MCL. The compelling synergistic effect was further confirmed by annexin V/PI apoptosis assay. Next, we assessed the in vivo efficacy of LOXO-305 in an ibrutinib-CAR T dual-resistant PDX model. LOXO-305 effectively reduced tumor size after 40 days of treatment as a single agent. Moreover, LOXO-305 treatment showed significant anti-tumor effects in an ibrutinib-ABT199-CAR T triple-resistant PDX model that recapitulates the most aggressive human MCL variants invivo. In this model, LOXO-305 treatment effectively decreased the tumor load in mice spleen and liver (p&lt;0.05) as well as in bone marrow and peripheral blood, compared to vehicle-treated mice (p&lt;0.001). Conclusions: By using various in vitro and in vivo multiple resistant MCL models we determined that LOXO-305 holds great promise for an effective single agent or combined treatment of the most eggressive forms of MCL, and that a continued investigation of the rationale for a combined therapy with ABT-199 is imperative to understand its role in overcoming ibrutinib-ABT199-CAR T triple resistance. Disclosures Wang: OMI: Honoraria, Other: Travel, accommodation, expenses; MoreHealth: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Targeted Oncology: Honoraria.

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

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

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

scholarly journals BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000387 ◽  
Author(s):  
Chiara Tarantelli ◽  
Elena Bernasconi ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Valentina Restelli ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Antitumour Activity ◽  
Single Agent ◽  
Treatment Strategies ◽  
Bet Inhibitor ◽  
Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

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

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

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

scholarly journals Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Alexa A Jordan ◽  
Joseph McIntosh ◽  
Yang Liu ◽  
Angela Leeming ◽  
William Lee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Publicly Traded ◽  
In Vivo Efficacy ◽  
Mantle Cell ◽  
Xenograft Models

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.

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.

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