scholarly journals Characterization of Mechanisms Underlying Acquired Venetoclax-Resistance in Mantle Cell Lymphoma: BDA-366 As a Potential Treatment Option

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1580-1580
Author(s):  
Daniela Steinbrecher ◽  
Felix Seyfried ◽  
Johannes Bloehdorn ◽  
Billy Michael Chelliah Jebaraj ◽  
Lüder Hinrich Meyer ◽  
...  
Keyword(s):  
Cell Death ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Resistant Cell ◽  
Advisory Committees ◽  
Apoptotic Protein ◽  
Mantle Cell ◽  
Resistant Cells

Abstract In many cancers the equilibrium of pro- versus anti-apoptotic BCL-2 proteins is deregulated. BCL-2 inhibitors like Venetoclax (VEN) have been shown to be highly active drugs in BCL-2 dependent cancers like chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Despite being highly efficient in cell killing, resistance to VEN can be acquired over time. In addition to understanding the underlying mechanisms of resistance to VEN it is important to identify additional treatment options. BDA-366 is a BCL-2 inhibitor with a different mode of action than the BH3 mimetic VEN. BDA-366 acts by inhibiting the BH4 domain and thereby inducing a conversion of anti-apoptotic BCL-2 into a pro-apoptotic protein. BDA-366 showed high effectivity in inducing apoptosis in CLL cells, in primary as well as in cell lines, while all of the CLL cell lines (n=7) tested were resistant to VEN. Furthermore all of the MCL cell lines (n=5) tested were sensitive to the treatment with BDA-366 while only a subset (3 out of 5) responded to treatment with VEN. In order to investigate whether BDA-366 would be a treatment option for VEN-resistant patients, we generated VEN-resistant MCL cell lines (MINO and MAVER-1) by chronic exposure to the drug. In the resistant cell lines, BCL-2 protein levels were not deregulated. In variance to previous reports in diffuse large B cell lymphoma (DLBCL) (Choudhary et al, Cell Death Dis 2015), resistance in MCL cell lines was not mediated by MCL-1 upregulation. In VEN-resistant MINO cells, MCL-1 expression was similar to the parental cells, while MCL-1 was significantly downregulated in VEN-resistant MAVER-1 cells. In contrast, VEN-resistant MCL cell lines showed BCL-XL upregulation as compared to parental cells, which is in line with results obtained in DLBCL (Choudhary et al, Cell Death Dis 2015). Furthermore, dynamic BH3 profiling validated a dependency on BCL-XL in resistant cells and confirmed that resistance was not mediated by MCL-1. The significance of BCL-XL in mediating resistance to VEN was underlined by additional experiments using navitoclax. In contrast to VEN, navitoclax inhibits BCL-2, BCL-XL and BCL-W and was sufficient to induce apoptosis in both parental and resistant cells. In contrast to the BH3 domain inhibitor VEN, the BCL-2 inhibitor BDA-366 acts by converting BCL-2 into a pro-apoptotic molecule. BDA-366 efficiently induced dose dependent apoptosis in VEN-resistant cells. MINO as well as MINO VEN-resistant cells showed the same sensitivity to BDA-366 while VEN-resistant MAVER-1 cells showed reduced sensitivity to BDA-366 as compared to the parental cells. However, with increased BDA-366 concentrations efficient cell killing was achieved in the VEN-resistant cell lines Overall, these results suggest that VEN-resistance is mostly mediated by permanent upregulation of BCL-XL. BCL-2 levels are not deregulated upon development of resistance to VEN. The inhibition of the BH4 domain and thereby converting BCL-2 into a pro-apoptotic protein proved to be a promising therapeutic option even in cancers with acquired resistance to VEN. Disclosures Döhner: Pfizer: Research Funding; Amgen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Pfizer: Research Funding; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stilgenbauer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Targeting Hypersumoylation in Mantle Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4060-4060 ◽  
Author(s):  
Walter Hanel ◽  
Liudmyla Tsyba ◽  
Dennis Huszar ◽  
Alex Prouty ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Advisory Committees ◽  
Human B Cells ◽  
Mantle Cell ◽  
Normal Human ◽  
Protein Sumoylation

Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell Non-Hodgkin's lymphoma (NHL) characterized by genetic dysregulation of CyclinD1. Despite the improvement in response rates with current therapies, MCL patients inevitably relapse and outcomes remain poor. This is particularly true for MCL patients progressing on novel targeted therapies such as ibrutinib, highlighting the continued need for new therapeutic approaches. SUMOylation is a post-translational modification regulated by SUMO Activating Enzymes 1 and 2 (SAE1/2) affecting function, stability, and subcellular localization of a multitude of proteins such as Cyclin D1 and regulating multiple cellular functions such as cell cycle control and DNA damage response. While not yet explored in MCL, it is known that hyper-SUMOylation is associated with augmented cell proliferation and tumor growth of a number of cancers including B-cell NHL. We evaluated the expression levels of SAE1/2, total SUMO1, and SUMO 2/3 in normal human B cells, primary MCL patient samples, and a panel of 8 MCL cell lines via immunoblotting. We found significantly increased levels of SAE1/2 and total protein SUMOylation in 4 out of 5 MCL patient samples and all MCL cell lines compared to normal human B-cells. To validate the SAE complex as a potential therapeutic target in MCL, we performed genetic knockdown of SAE1 and SAE2 using both shRNA and an inducible CRISPR/Cas9 system and found significant reduction in viability of MCL cells (p < 0.001) thus confirming that SUMOylation is essential for MCL survival. TAK-981 (Takeda Pharmaceuticals) is a potent and selective inhibitor of the SAE1/2 complex currently in a phase 1 clinical trial (NCT036483). We found that treatment of MCL cell lines with TAK-981 resulted in time- and dose-dependent cell death in 7 of 8 MCL cell lines (IC50 17 - 62.5 nM at 72 hr) which was associated with relevant decrease in protein sumoylation. MCL cells were sensitive to TAK regardless of ATM or p53 mutations. Finally, TAK-981 treatment prolonged the survival of SCID mice engrafted with a human MCL cell line (Jeko) compared with placebo control [median overall survival (OS): TAK-981, 34 days; placebo, 29 days, p = 0.008] and also extended the survival of a novel patient derived xenograft (PDX) mouse model of ibrutinib-resistant MCL (median OS: TAK-981, 60 days; placebo, 55 days, p = 0.001), thus establishing the in vivo efficacy of TAK-981 in models of aggressive MCL. Mechanistically, 24 hours of treatment with TAK-981 resulted in a profound G2M cell cycle arrest in 6 out of 7 TAK-981-sensitive MCL cell lines. Cell synchronization with palbociclib followed by release into TAK-981 showed significant apoptosis upon G2M re-entry. In addition, in p53-deficient MCL cell lines, we found rapid accumulation of polyploid and aneuploid cells followed by rapid cell death following 48 hours of drug exposure. These findings strongly support mitotic catastrophe as a significant mechanism of tumor cell death mediated by TAK-981. Upon fractionation of cells at distinct phases of the cell cycle, we found significantly increased levels of protein SUMOylation by both SUMO1 and SUMO2/3 at the G2M transition. Further mechanistic data will be presented at the meeting. Given the multiple immune dampening mechanisms of SUMOylation, we are currently studying the anti-MCL immune effects of TAK-981. To do this, we are employing a novel immunocompetent mouse model of MCL in which murine lymphoma cells from Eμ-SOX11/CCND1 double transgenic animals are adoptively transferred into syngeneic mice. These mice develop a systemic lymphoma with morphological, molecular, and phenotypic features characteristic of MCL resulting in death within 3-4 weeks. Preliminary results with this model show that treatment with TAK-981 leads to decrease in lymphoma burden and significant prolongation of survival. Studies into the immune mediated anti-lymphoma effects of TAK-981 using this model are ongoing and will be presented at the meeting. Together, our data strongly support further development of TAK-981 as a novel MCL therapeutic. Disclosures Huszar: Takeda Pharmaceuticals: Employment, Equity Ownership. Parekh:Karyopharm Inc.: Research Funding; Foundation Medicine Inc.: Consultancy; Celgene Corporation: Research Funding. Maddocks:BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. Baiocchi:Prelude: Consultancy.

scholarly journals Simultaneous Inhibition of BCL-2 and PI3K Signaling Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2950-2950
Author(s):  
Haige Ye ◽  
Shengjian Huang ◽  
Dayoung Jung ◽  
Changying Jiang ◽  
Krystle Nomie ◽  
...  
Keyword(s):  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Resistant Cell ◽  
Tumor Burden ◽  
Pi3k Signaling ◽  
Advisory Committees ◽  
Apoptotic Pathway ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses to frontline therapy. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase (BTK) has achieved a 68% overall response rate in relapsed/refractory MCL patients (Wang et al., NEJM, 2013). However, the vast majority of MCL patients experience disease progression; therefore, novel therapies to overcome ibrutinib resistance are urgently needed. Ibrutinib resistance is associated with the dysregulation of alternative signaling pathways such as the apoptotic pathway and PI3K/AKT signaling; therefore, combinatorial therapeutic strategies may prove fruitful in overcoming ibrutinib resistance via the blockade of these compensatory pathways. Based on the upregulation of the PI3K signaling pathway and the anti-apoptotic pathway in ibrutinib resistance, we co-inhibited both pathways with the dual PI3K-delta and -gamma inhibitor duvelisib and the BCL-2 inhibitor venetoclax to assess the ability of this combination to overcome ibrutinib resistance in MCL. Methods: Cell viability and apoptosis assays were conducted to assess the effects of venetoclax and duvelisib on 4 ibrutinib-resistant cell lines (Jeko BTK KD, Jeko-R, Z-138 and Maver-1) and 4 primary patient samples. We also confirmed the synergistic effect of this combination on two ibrutinib-resistant cell lines (Jeko BTK KD and Z-138) by western blotting. Aberrant protein expression between single agents and drug combination in Jeko BTK KD cells was detected using Reverse Phase Protein Array (RPPA) analysis with confirmation by western blotting. Cell migration of Jeko BTK KD cells was assessed. A Jeko-1 cell xenograft (which is resistant to ibrutinib in vivo) was established in NSG mice, and drug testing was performed in this model with tumor burden assessed viain vivo imaging. Results: We observed synergistic activity with the combination of venetoclax and duvelisib in 4 ibrutinib-resistant cell lines (Jeko BTK KD, 0.36; Jeko-R, 0.47; Z-138, 0.66; Maver-1, 0.41) and in 4 ibrutinib-resistant patient samples (PT1, 0.14; PT2, 0.43; PT3, 0.52; PT4, 0.41) by calculating the synergistic index (Ki value). We confirmed the synergistic effects of this combination by observing apoptosis at 72 hours post-treatment in Jeko BTK KD and Z-138 cells. Moreover, the combination of venetoclax and duvelisib synergistically reduced the cell migration of Jeko BTK KD cells. RPPA analysis of Z-138 MCL cells post-treatment demonstrated that multiple pathways, including the apoptotic pathway as well as the PI3K/AKT and BCR signaling pathways, were synergistically altered by venetoclax and duvelisib. Moreover, venetoclax and duvelisb synergistically reduced tumor burden in a Jeko-1 cell xenograft model resistant to ibrutinib. Conclusion: PI3K signaling and BCL-2-related pathways are activated in ibrutinib-resistant MCL cells, and targeting these pathways using a combinatorial approach may potentially overcome ibrutinib resistance. Disclosures Wang: AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; MoreHealth: Consultancy; Juno: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria.

scholarly journals Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2865-2865
Author(s):  
Sudhakiranmayi Kuravi ◽  
Janice Cheng ◽  
Kishore Polireddy ◽  
Gabrielle Fangman ◽  
Roy A Jensen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Advisory Board ◽  
Advisory Committees ◽  
Apoptotic Protein ◽  
Large Cell Lymphoma ◽  
Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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

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

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

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

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

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

Outcome and Prognostic Factors in Patients with Mantle Cell Lymphoma Relapsing After Autologous Stem Cell Transplantation: A Retrospective Study of the EBMT

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 474-474 ◽  
Author(s):  
Sascha Dietrich ◽  
Herve Finel ◽  
Ariane Boumendil ◽  
Irit Avivi ◽  
Liisa Volin ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Mantle Cell ◽  
One Year

Abstract Abstract 474 BACKGROUND: Autologous stem cell transplantation (autoSCT) is considered as standard treatment for non-frail patients with mantle cell lymphoma (MCL). However, little is known about outcome of MCL recurrence after autoSCT. We therefore conducted a retrospective analysis of patients with MCL who failed autoSCT using the EBMT database. PRIMARY OBJECTIVE was to analyse outcome and prognostic factors after relapse following autoSCT for MCL in the rituximab era. PRIMARY ENDPOINT was overall survival (OS) from relapse. ELIGIBLE were patients aged 18 years or more who relapsed following an autoSCT for MCL performed between 2000 and 2010 and who were registered with the EBMT. Centres were contacted to provide additional information on relapse treatment. STATISTICAL ANALYSIS was based on log-rank comparisons and multivariable testing using Cox regression models. RESULTS: 1054 patients meeting the eligibility criteria could be identified in the EBMT registry. Of these, a full data set could be retrieved for 382 patients. Sixteen patients had to be excluded due to loss of follow up (n=7), wrong diagnosis (n=6), or falsely reported relapse (n=3). Median age at autoSCT of 366 evaluable patients was 59 years (range: 37 to 76), 290 patients (79%) were men. 64% had undergone autoSCT as part of 1st-line therapy; 68% and 49% had documented exposure to rituximab (RTX) and high-dose ara-C (HA) before autoSCT; and 12% had had refractory disease at autoSCT. Median time from autoSCT to relapse was 20 months (range: 0.4 to 117). 21 relapses (6%) occurred beyond 5 years after autoSCT. With a median observation time of 37 months (95% CI 32–43), median OS after relapse of the whole study group was 20 months. By univariate analysis, a long (>12mo) interval between autoSCT and relapse (p<0.001; HR 0.26; Figure 1A), 1st-line autoSCT (p=0.006; HR 0.7) refractory disease at autoSCT (p<0.001, HR 2.0) and more recent year of relapse (p<0.001, HR per year 0.9) significantly influenced OS from relapse, whereas age, gender, RTX and HA exposure did not. By multivariate analysis refractory disease at autoSCT (p<0.001, HR=2.14), remission duration after autoSCT (p<0.001 HR per 3 months 0.88) and calendar year of relapse (p<0.03, HR per year 0.93) were confirmed to be predictors for OS. In addition, HA exposure prior autoSCT adversely affected OS from relapse (p=0.06, HR 1.38). Salvage chemotherapy after relapse resulted in only 31% complete responses and 29% partial responses, whereas 40% of patients have been refractory to first salvage chemotherapy. 83 patients (23%) received an allogeneic SCT (alloSCT), whereas only 7 patients (2%) received a second autoSCT after relapse. Median time after relapse to second SCT was 7 months (range: 1 to 40). Survival after relapse for patients who received a second autoSCT was poor with no long-term survivor. AlloSCT performed for late relapse (>12mo) after autoSCT was associated with superior OS compared to patients who received an allograft upon a shorter remission duration after autoSCT (5-year OS from alloSCT 50% vs 0%; p=0.001; Figure 1B). Achievement of CR before alloSCT (p=0.05 HR=0.5), but not donor source, T-cell depletion or conditioning intensity affected OS after alloSCT. CONCLUSIONS: Patients with MCL who relapse within one year after autoSCT have an extremely dismal outcome even with alloSCT. In contrast, about half of the patients who have MCL recurrence beyond one year after autoSCT and can undergo salvage alloSCT enjoy long-term survival. It remains to be shown if a similarly good outcome can be achieved without alloSCT in this favourable selection of patients. A 2nd autoSCT does not appear to be a promising option in patients with MCL failing a 1st autoSCT. Disclosures: Walewski: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding.

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

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

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

scholarly journals Tolinapant (ASTX660), a Non-Peptidomimetic Antagonist of cIAP1/2 and XIAP, and the HDAC Inhibitor Romidepsin Are Synergistic in in Vitro Models of T Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4356-4356
Author(s):  
John S Manavalan ◽  
Ipsita Pal ◽  
Aidan Pursley ◽  
George A. Ward ◽  
Tomoko Smyth ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Tnf Alpha ◽  
Sensitive Cell ◽  
Advisory Committees

Abstract Background: The PTCL are a heterogeneous group of non-Hodgkin lymphomas originating from mature T-lymphocytes. They are aggressive diseases, often resistant to conventional chemotherapy. Despite the fact that a number of new agents have been approved, treatment paradigms tailored to the biology of the disease have yet to emerge. Tolinapant (ASTX660) is a potent antagonist of both cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), and is presently in phase I/II trials in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis (Ward GA, et al. Mol Cancer Ther. 2018), are potent anti-tumor immune enhancers and induce markers of immunogenic cell death such as damage associated molecular patterns (DAMPs; Ye W, et al, Oncoimmunology, 2020). Objectives: We explored the sensitivity of a range of T-cell lymphoma (TCL) cell lines to tolinapant. We establish the synergy coefficient between tolinapant and the HDAC inhibitor, romidepsin, and interrogated the molecular basis of their synergistic interaction. Methods: A panel of human T-cell lymphoma cell lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10ng/ml of TNF alpha. For combination studies, with tolinapant and romidepsin, each drug was tested at the IC10 and IC40 concentrations in the presence or absence of TNF alpha. Synergy scores using the Excess over Bliss (EOB) model were calculated using SynergyFinder (Aleksandr Ianevski et al; Nucleic Acids Research, 2020). Additionally, the effects of tolinapant and romidepsin on the IAPs and caspases were analyzed by western blots. TNFR1 receptor expression and induction of DAMPs were also analyzed by flow cytometry. Results: TCL Lines demonstrated varying sensitivities to tolinapant in the presence or absence of TNF alpha. The most sensitive cell lines, ALK+ ALCL and SUP-M2, had IC50 concentrations ranging from 200nM ± 100nM to 20nM ± 1nM in the absence or presence of TNF alpha, respectively, at 24, 48 and 72hrs, while a resistant CTCL cell line HH had an IC50 concentration of over 20mM, even in the presence of TNF alpha. Interestingly, using western blot analysis, we found that the presence of TNF alpha increased the levels of cIAP1 in the tolinapant sensitive SUP-M2 cell line, but not in the resistant HH cell line. However, there was a concentration dependent decrease in cIAP1 but not in XIAP in both cell lines treated with tolinapant. Flow cytometry analysis demonstrated that tolinapant increases the expression of TNFR1 and DAMPs in a dose dependent manner on the sensitive SUP-M2, but not in the resistant HH cells. In combination experiments, using the EOB model, tolinapant plus romidepsin was found to be synergistic in the absence of TNF alpha, at 36hrs, in both the sensitive cell line SUP-M2 and the resistant cell line HH. In the presence of TNF alpha, synergism was seen only in the sensitive cell line SUP-M2 and antagonistic in the HH cell line (Fig. 3). In the tolinapant plus romidepsin treated samples, cIAP1 levels decreased in the SUP-M2 cell line, in the absence of TNF alpha, however, addition of TNF alpha did not alter the levels of cIAP1 in the SUP-M2 cells. The cIAP1 levels decreased in the HH cells treated with the combination, in both the presence or absence of TNF alpha (Figure). Our findings indicate that the synergy of the tolinapant plus romidepsin is not dependent on the presence of TNF alpha. Conclusion: Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha. These data provide the rationale to continue to explore the combination of tolinapant and romidepsin in vivo and to investigate additional combinations with T-cell specific agents (e.g. pralatrexate, belinostat, azacitidine and decitabine). Figure 1 Figure 1. Disclosures Smyth: Astex Pharmaceuticals: Current Employment. Sims: Astex Pharmaceuticals: Current Employment. Loughran: Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioniz Therapeutics: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Marchi: Kyowa Kirin: Honoraria; Myeloid Therapeutics: Honoraria; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; Kymera Therapeutics: Other: Scientific Advisor.

scholarly journals Inhibition of B-Cell Receptor Signaling Disrupts Cell Adhesion in Mantle Cell Lymphoma Via RAC2

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1369-1369
Author(s):  
Weige Wang ◽  
Franzen Carrie ◽  
Hui Guo ◽  
Jimmy Lee ◽  
Yan Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Receptor ◽  
Resistant Cell ◽  
Advisory Committees ◽  
Tumor Tissues ◽  
Mantle Cell ◽  
Bcr Signaling

Abstract Background: B-cell receptor (BCR) signaling pathway is recognized as a crucial pathway for the pathogenesis of neoplastic B-cells. Inhibition of the BCR signaling and the downstream pathway is highly effective in B-cell malignancy through Bruton tyrosine kinase inhibition by ibrutinib. In addition to cell proliferation inhibition, ibrutinib disrupts cell adhesion between tumor and its microenvironment through unknown molecular mechanisms, resulting in peripheral lymphocytosis with accompanying lymphadenopathy reduction in patients who receive ibrutinib. Methods and materials: In an effort to elucidate the link between BCR signaling and cell adhesion phenotype, we first characterized ibrutinib sensitive and resistant mantle cell lymphoma (MCL) cell lines. We measured cell proliferation and cell growth, and correlated ibrutinib sensitivity with cell adhesion disruption. We then used RNA-sequencing to identify differential pathways between sensitive or resistant cell lines in response to ibrutinib treatment. We validated RNA-Seq findings using cell lines, as well as animal models and human primary MCL tumor tissues and cells. Results: We found that intrinsic sensitivities of MCL cell lines to ibrutinib correlated well with their cell adhesion phenotype. RNA-sequencing revealed that BCR and cell adhesion gene signatures were simultaneously down-regulated by ibrutinib in ibrutinib-sensitive but not ibrutinib-resistant cell lines. Among the differentially expressed genes in the BCR gene signature, we identified and validated that RAC2, a regulator of cell adhesion, was down-regulated at both RNA and protein levels by ibrutinib only in ibrutinib-sensitive cells. Physical association of RAC2 with BLNK, an early BCR pathway adaptor, was disrupted by ibrutinib uniquely in sensitive cells. RAC2 knockdown with siRNA impaired cell adhesion while RAC2 over-expression rescued ibrutinib-induced reduction in cell adhesion. In a xenograft mouse model, mice treated with ibrutinib demonstrated tumor growth retardation along with down-regulation in RAC2 protein expression. Using immunohistochemical staining, we demonstrated that RAC2 was expressed in ~65% primary MCL tumor tissues with majority of RAC2-positive tumors characterized as being the more aggressive subtypes. Finally, primary MCL cells treated with ibrutinib demonstrated reduced RAC2 that is accompanied by cell adhesion impairment. Conclusions: Our findings uncover a novel cross-talk between BCR signaling and cell adhesion. Ibrutinib inhibits cell adhesion via down-regulation of RAC2. Our study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and new drug development. Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; AstraZeneca: Consultancy, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding.

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

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

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

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