scholarly journals CSF1R and BTK Inhibitions As Novel Strategies to Disrupt the Dialogue between Mantle Cell Lymphoma and Macrophages

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2855-2855
Author(s):  
Antonin Papin ◽  
Benoit Tessoulin ◽  
Céline Bellanger ◽  
Anne Moreau ◽  
Yannick LE Bris ◽  
...  

Abstract The aggressive clinical behavior of mantle cell lymphoma (MCL) and its short-term response to treatments highlight a need for novel options. The microenvironment strongly controls MCL cell survival, proliferation and chemoresistance, nevertheless little is known regarding the interactions that occur in the tumor niches. Here, we studied the interplay between primary MCL cells (n=55) and macrophages and identified mechanism-based targeted strategies to disrupt this dialogue. Using ex vivo co-cultures of peripheral blood MCL cells and monocytes (healthy donors), we showed that monocytes greatly improved MCL cell survival, whereas MCL cells poorly survived when cultured alone (co-culture, 85.9%; alone, 6.5%; D7; n=17; p<0.001). We also demonstrated that monocytes supported the proliferation of conventional (n=7) and blastoid (n=4), but not leukemic non-nodal MCL subtypes (n=5) (p<0.05). During co-culture, primary MCL cells polarized monocytes into MCL-associated-macrophages (MϕMCL). To define the nature of MϕMCL, we studied their phenotype and function with 12 markers differentially expressed in M1 and M2 macrophages (CD14, CD68, CD163, CD11b, CD86, HLA-DR, CD16, CD23, IL10, IL6, IGF1, BAFF). The analysis showed that even though MϕMCL distinctly clustered from both M1 and M2, they shared more similarities with M2 (CD163high, CD11blow, IL10+, IGF1+). To determine how MCL cells polarized monocytes into CD163high MϕMCL, we analyzed the expression of known M2-polarizing factors and observed that CSF1 and IL10 were overexpressed in MCL cells compared to normal B cells (GEP, p<0.01). CSF1 and IL-10 were detected at the protein level in co-culture (ELISA), and CSF1, but not IL-10, neutralization significantly blocked MϕMCL polarization ex vivo. Previous studies reported modulations of the MCL secretome upon BTK inhibition. Here, we demonstrated that both CSF1 and IL-10 were inhibited upon ibrutinib treatment (0.5 µM) in sensitive MCL cells, whereas no modulation was observed in ibrutinib-resistant cells. Reduction of the CSF1 level by ibrutinib consequently inhibited M2-like polarization and resulted in the inhibition of MϕMCL-dependent tumoral survival (n=8/14) and proliferation (n=4/4). Nevertheless, 6 MCL samples cocultured with MϕMCL appeared resistant to ibrutinib. To test whether targeting the CSF1R could bypass this resistance, we treated MCL/MϕMCL coculture with the inhibitor GW2580. We showed that CSF1R inhibition efficiently reduced the viability of ibrutinib-resistant MCL cells. Moreover, the combination in low concentrations of ibrutinib/GW2580 (125nM) induced a supra-additive effect in ibrutinib-sensitive samples. In vivo, we showed higher levels of CSF1 and IL-10 in the plasma of MCL patients (n=28) compared to match-aged HD (p<0.01). We also showed that CD163 was overexpressed at the surface of circulating monocytes in MCL compared to HD (n=32; p < 0.05), which was consistent with the CD163-inducing properties of CSF1 and IL-10. Taking advantage of a local clinical trial (NCT02558816), we evaluated modulations of CSF1 and IL-10 plasma concentrations as well as CD163 expression on monocytes from 8 patients treated with ibrutinib. We observed a reduction of CSF1 and IL-10 as well as inhibition of CD163 expression in 7/8 patients after 8 days (D8) of treatment (median CD163+ reduction, - 58%). We performed longitudinal follow-up of 4 patients treated with ibrutinib, 3 were characterized by a dramatic reduction in CD163 at D8 and achieved a durable complete response. In contrast, 1 patient who displayed an increase in CD163 at D8, progressed upon treatment. In conclusion, through secretion of IL-10 and CSF1, MCL cells polarized monocytes into M2-like macrophages (MϕMCL), which in turn support tumor survival and proliferation. Ibrutinib counteracts the MCL/MϕMCL dialogue through inhibition of CSF1 production and, consequently, impairs the MϕMCL-dependent expansion of ibrutinib-sensitive MCL cells. Of note, our in vivo retrospective analysis highlights that CSF1, IL-10 and CD163 modulations might be early markers of ibrutinib response. A larger cohort of MCL patients treated with ibrutinib is now necessary to confirm the strength of this soluble and cellular signature. Lastly, targeting the CSF1R is an alternative to disrupt the MCL/MϕMCL pro-tumoral dialogue, especially for ibrutinib-refractory patients for which no therapeutic alternative is available. Disclosures Moreau: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5263-5263
Author(s):  
Karin Hohloch ◽  
Christine Windemuth-Kieselbach ◽  
Pier Luigi Zinzani ◽  
Roberto E. Cacchione ◽  
Wojciech Jurczak ◽  
...  

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.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 110-110 ◽  
Author(s):  
Olivier Hermine ◽  
Eva Hoster ◽  
Jan Walewski ◽  
Vincent Ribrag ◽  
Nicole Brousse ◽  
...  

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.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2818-2818
Author(s):  
Vicki A. Morrison ◽  
Richard I Fisher ◽  
Andre Goy ◽  
Sven de Vos ◽  
Steven H. Bernstein ◽  
...  

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.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Simone Ferrero ◽  
Daniele Grimaldi ◽  
Elena Arrigoni ◽  
Gian Maria Zaccaria ◽  
Beatrice Alessandria ◽  
...  

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


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4526-4526
Author(s):  
Aleš Obr ◽  
Pavel Klener ◽  
Andrea Janíková ◽  
Heidi Mocikova ◽  
David Belada ◽  
...  

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


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2856-2856 ◽  
Author(s):  
Tiziana Vaisitti ◽  
Katti Jessen ◽  
Thanh-Trang Vo ◽  
Mira Ko ◽  
Francesca Arruga ◽  
...  

ROR1 is a transmembrane receptor with tightly controlled expression during development. It is present on multiple tumor types but not on normal adult tissues. Hematological malignancies are often ROR1-positive, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B cell lymphoma (DLBCL). Given its unique pattern of expression, ROR1 represents a tumor-specific therapeutic target. The anti-ROR1 antibody, UC-961, is ahumanized IgG1 monoclonal antibody (mAb) that binds with high affinity to a specific extracellular epitope of human ROR1 receptor and can block Wnt5a-induced ROR1 signaling. Nonclinical studies document that UC-961 does not react with normal adult human tissues and selectively binds to tumor cells. Because of the antibody high specificity, rapid internalization, and trafficking to lysosomes, UC-961 appears ideally suited to serve as the targeting moiety for an anti-ROR1 ADC. Accordingly, we have developed VLS-101, a UC-961-linker-monomethyl auristatin E (MMAE) ADC that preserves the high-affinity binding and specificity of UC-961 and allows for ROR1-targeted intracellular release of MMAE. RS is an aggressive lymphoma, typically of DLBCL type, arising as transformation of CLL. Despite, progressive improvements in the therapy of CLL, very few effective treatment options exist for patients with RS. Using our recently established RS patient-derived xenografts (RS-PDXs), we explored the expression and signaling properties of ROR1 in RS and investigated the ex-vivo and in vivo effects of VLS-101. When assessed by flow cytometry (FACS), immunohistochemistry (IHC), and reverse-transcriptase-polymerase chain reaction (RT-PCR), 3 of 4 RS-PDXs showed ROR1 positivity (2 highly positive: 99% and 80% of cells; 1 medium/low positive: 25% of cells by FACS). The extent of ROR1 expression correlated among the 3 assays methods and was consistent with ROR1 expression data reported for non-RS DLBCL samples. When engaged by its ligand Wnt-5a, ROR1 activated downstream targets, Rac1 and RhoA, and induced phosphorylation of the p65 subunit of NF-kB and Jnk in RS cells. When cells purified from RS-PDX tumor masses were exposed to VLS-101 ex-vivo, the drug induced time- and dose-dependent apoptosis, as shown by increases in annexin V/propidium iodide and by Caspase-3 and PARP cleavage. VLS-101 efficacy was then assessed in vivo in both subcutaneous and systemic RS-PDX models. When palpable masses had formed in subcutaneous models, mice were randomly assigned to vehicle or VLS-101, bi-weekly treated for 3 consecutive weeks, and then compared for tumor growth and survival. In the 3 ROR1-expressing RS-PDX models, VLS-101 caused highly significant disease regressions. Complete regressions were observed even in RS-PDXs without universal ROR1 expression, suggesting a MMAE bystander effect. After treatment discontinuation, VLS-101-treated animals showed no tumor regrowth for several months and had significantly extended survival. Data were confirmed in systemic ROR1-expressing RS models in which tumor cells were intravenously injected and allowed to engraft for ~14 days before starting treatment. VLS-101 was administered with the same schedule adopted for the subcutaneous model. VLS-101 eliminated RS cells in bone marrow, peripheral blood, and spleen, increasing survival in VLS-101-treated animals relative to controls (approximately 20-50 days, depending on the RS-PDX model). Of note, no in vivo VLS-101 efficacy was observed in the ROR1-negative RS-PDX, confirming the specificity of VLS-101 targeting. VLS-101 showed no adverse effects on animal well-being or body weight. Collectively, these results indicate that ROR1 is expressed on RS cells where it can transduce pro-survival signals and can be diagnostically evaluated for selective targeting. Nonclinical data document that the MMAE-containing ADC, VLS-101, can cause RS-PDX apoptosis in vitro and can safely and selectively induce complete tumor regressions in in vivo models of RS derived from patient tumors with heavy prior clinical treatment and variable levels of ROR1 expression. Building on these types of results, a Phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with lymphoid cancers. Disclosures Vaisitti: VelosBio Inc.: Research Funding; Verastem Inc: Research Funding. Jessen:VelosBio Inc.: Employment. Vo:VelosBio Inc: Employment. Ko:VelosBio Inc: Employment. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Bayer: Consultancy. Furman:Acerta Pharma: Consultancy; Pharmacyclics: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Oncotracker: Consultancy; Verastem: Consultancy; Abbvie: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Miller:VelosBio Inc.: Employment. Lanutti:VelosBio Inc.: Employment. Deaglio:iTeos Therapeutics: Research Funding; Verastem Inc: Research Funding; VelosBio Inc.: Research Funding. OffLabel Disclosure: The drug used in this project is an anti-ROR1-toxin-conjugated antibody


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Pavel Klener ◽  
Marek Trněný ◽  
Ladislav Andera ◽  
Zuzana Nahacka ◽  
Magdalena Klanova ◽  
...  

Abstract Introduction Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2 and good sensitivity to a small molecule BCL2 inhibitor venetoclax. In the present study we analyzed molecular mechanisms of venetoclax resistance in MCL cells, and tested strategies to overcome it based on concurrent targeting of BCL2 a MCL1. Methods Cell death was determined by flow cytometry using Annexin-V/PI staining. Establishment of MCL cell clones with knock-down or transgenic overexpression of MCL1, BIM and NOXA, western blotting, immunohistochemistry of formalin-fixed paraffin-embedded tissue sections, and immunoprecipitation experiments were carried out as previously described (Klanova et al, Clin Cancer Res, 2016). All PDXs were derived in our laboratory from patients with relapsed MCL. All PDX were confirmed by NGS to keep majority of somatic mutations with the primary MCL cells from which they were derived. Samples were sequenced using SureSelectXT Human All Exon V6+UTR (Agilent Technologies, Santa Clara, CA) on the NextSeq 500 (Illumina, San Diego, CA) instrument according to manufacturer's protocols. Experimental therapies were implemented using NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice purchased from Jackson Laboratory (Bar Harbor, Maine, USA). Therapy was initiated when all mice developed palpable subcutaneous tumors (= day 1, D1). Venetoclax (VTX) and S63845 were from MedchemExpress, carfilzomib (CFZ) was from Charles University General hospital pharmacy. Carfilzomib (4 mg / kg) was administered intravenously (IV) on days 1 and 6. Venetoclax (40 mg / kg) was given by oral gavage on days 1, 2, 3, 6 and 7. S63845 (25 mg / kg) was administered IV on days 1, 2, 3, 6 and 7. Tumor volumes were calculated using the following formula: π / 6 × tumor length × width × height. Results By transgenic overexpression or shRNA-mediated knock-down we confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. We demonstrated that both BIM and NOXA are differentially expressed between MCL cell lines on one side, and primary MCL cells and patient-derived xenograft (PDX) cells on the other side. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, biallelic deletions of BIM harbored by three commonly used MCL cell lines (JEKO-1, MINO and Z138), and previously reported to be present in approx. 30% of MCL patients, were not found in primary MCL cells. As a consequence, vast majority of the in vitro data was implemented on venetoclax-sensitive cell lines HBL2 and MAVER-1, whose patterns of expression of BCL2, MCL1, BIM and NOXA are similar to primary MCL cells. We demonstrated that MCL1, another key anti-apoptotic protein, plays an essential role in mediating resistance to venetoclax. First, MCL1 functions as a buffer for BIM released from BCL2 upon binding of venetoclax thereby preventing activation of BAX and induction of apoptosis. Second, marked upregulation of MCL1 protein was associated with acquired resistance to venetoclax in two most sensitive MCL cell lines HBL2 and MAVER-1. Based on the in vitro data we proposed two experimental treatment strategies that co-targeted MCL1 (along with inhibition of BCL2 with venetoclax): a direct blockage with a highly specific small molecule MCL1 inhibitor S63845, and an indirect blockage achieved by proteasome inhibitor carfilzomib that upregulates the proapoptotic protein NOXA that specifically binds and blocks MCL1. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo inducing the longest "remissions" of MCL bearing mice (i.e. temporary disappearance of subcutaneous MCL tumors) using a panel of four different PDXs derived from patients with relapsed / refractory MCL with complex karyotype changes (Figure 1). The combination of carfilzomib and venetoclax was far less effective, and at the same time more toxic suggesting functional blockage of MCL1 induced by overexpressed NOXA is either incomplete or insufficient. Conclusions Our data strongly support investigation of venetoclax in combination with S63845 as an innovative proapoptotic treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds. Figure 1 Figure 1. Disclosures Trněný: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1478-1478
Author(s):  
Krysta M Coyle ◽  
Prasath Pararajalingam ◽  
Sarah E Arthur ◽  
Nicole Thomas ◽  
Miguel Alcaide ◽  
...  

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


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1541-1541
Author(s):  
Jonathon B. Cohen ◽  
Craig A. Portell ◽  
Mehdi Hamadani ◽  
Opeyemi Jegede ◽  
Catherine Diefenbach ◽  
...  

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


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3973-3973
Author(s):  
Christina Y. Lee ◽  
Maurizio Di Liberto ◽  
Yang Hu ◽  
Xiangao Huang ◽  
Nancy L Bartlett ◽  
...  

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


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