abt-199 and Lymphoma--Mantle-Cell

Mantle cell lymphoma (MCL), an aggressive, but incurable B-cell lymphoma, is genetically characterized by the t(11;14) translocation, resulting in the overexpression of Cyclin D1. In addition, deregulation of the B-cell lymphoma-2 (BCL-2) family proteins BCL-2, B-cell lymphoma-extra large (BCL-X

Topics: Adult; Antineoplastic Agents; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Microenvironment

There is no standard approach to sequencing novel therapies in mantle cell lymphoma (MCL). For initial treatment, intensive induction chemotherapy followed by autologous stem cell transplant and rituximab maintenance remains our preferred approach in young, fit patients. We consider bendamustine plus rituximab or lenalidomide plus rituximab in patients who are ineligible for intensive chemotherapy-based approaches. Bruton's tyrosine kinase inhibitors are our preferred class of agents to use in the second-line setting. When patients inevitably relapse on one of these agents, we proceed with chimeric antigen receptor T-cell (CAR T) therapy in eligible patients, often with the use of bridging therapy with corticosteroids, lenalidomide, or venetoclax. We treat patients who are ineligible for CAR T or clinic trial with venetoclax, lenalidomide, or proteosome inhibitor-based regimens, although efficacy is expected to be limited in this setting with a shortened duration of response to each subsequent line of therapy. Allogeneic stem cell transplant remains an option for carefully selected patients who progress after autologous stem cell transplant and CAR T. Clinical trials involving combinations of novel agents in early lines of therapy are ongoing, and new compounds with unique mechanisms of action are in development. The results of ongoing clinical trials with novel agents will further change the treatment landscape for patients with MCL in the coming years.

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Glucocorticoids; Humans; Immunotherapy, Adoptive; Induction Chemotherapy; Lenalidomide; Lymphoma, Mantle-Cell; Proteasome Inhibitors; Protein Kinase Inhibitors; Receptors, Chimeric Antigen; Rituximab; Stem Cell Transplantation; Sulfonamides; Transplantation, Autologous; Transplantation, Homologous

Blastoid and pleomorphic mantle cell lymphoma (MCL) are among the worst prognostic, aggressive histology, high-risk variants of MCL, and, in this article, they are presented as blastoid MCL. Blastoid MCL have not been systematically studied, probably due to their rarity. De novo blastoid MCLs have superior outcomes compared with transformed MCL. Compared with classic MCL, extranodal involvement (mainly skin, central nervous system), frequent relapses, and inferior responses to conventional chemoimmunotherapy, BTK inhibitors and venetoclax are frequent in blastoid MCL. KTE-X19 induces excellent response in blastoid MCL. Combinations with novel agents are actively investigated. This article presents a comprehensive review on blastoid MCL in 2020.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunotherapy, Adoptive; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Receptors, Chimeric Antigen; Sulfonamides

Novel targeted therapeutics has significantly improved the outlook of patients with relapsed/refractory mantle cell lymphoma (R/R MCL). Despite significant efficacy, one of the major limitations of these targeted agents is presence of primary or acquired resistance to these novel drugs. Patients who fail primary therapy especially with ibrutinib have poor outcomes and may respond poorly to subsequent therapies. Hence, it is important to understand resistance mechanisms a priori to identify patients who are unlikely to respond, and to explore alternative therapeutic strategies. In this review, we will discuss the currently most active two drugs: ibrutinib and venetoclax, both of which have shown high response rates in R/R MCL. We review current understanding of genomic alterations associated with resistance, and discuss possible strategies to overcome these resistance mechanisms.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Patient Selection; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.

Topics: Adenine; Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Piperidines; Sulfonamides

Ibrutinib plus venetoclax, given with an ibrutinib lead-in, has shown encouraging clinical activity in early phase studies in mantle cell lymphoma (MCL). The ongoing phase 3 SYMPATICO study evaluates the safety and efficacy of concurrently administered, once-daily, all-oral ibrutinib plus venetoclax in patients with relapsed/refractory MCL. A safety run-in (SRI) cohort was conducted to inform whether an ibrutinib lead-in should be implemented for the randomized portion. Patients received concurrent ibrutinib 560 mg continuously plus venetoclax in a 5-week ramp-up to venetoclax 400 mg for up to 2 years. The primary endpoint was occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs). The SRI cohort enrolled 21 patients; six and 15 were in low- or increased-risk categories for TLS, respectively. During the 5-week venetoclax ramp-up, three patients had DLTs, and one patient at increased risk for TLS had a laboratory TLS; no additional TLS events occurred during follow-up. With a median follow-up of 31 months, the overall response rate was 81% (17/21); 62% (13/21) of patients had a complete response. SRI data informed that the randomized portion should proceed with concurrent ibrutinib plus venetoclax, with no ibrutinib lead-in. Ibrutinib plus venetoclax demonstrated promising efficacy; no new safety signals were observed.Trial registration: ClinicalTrials.gov, NCT03112174. Registered 13 April 2017, https://clinicaltrials.gov/ct2/show/NCT03112174 .

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Sulfonamides; Treatment Outcome

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

Topics: Adenine; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Female; Follow-Up Studies; Genes, p53; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm, Residual; Piperidines; Progression-Free Survival; Prospective Studies; Sulfonamides; Treatment Outcome

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.

Topics: Aged; Aged, 80 and over; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Neoplasm Proteins; Recurrence; Sulfonamides

Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800-1200 mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Female; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Male; Middle Aged; Progression-Free Survival; Sulfonamides; Treatment Outcome

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.. We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.. The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).. In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

Topics: Adenine; Administration, Oral; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Examination; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Historically Controlled Study; Humans; Intention to Treat Analysis; Lymph Nodes; Lymphoma, Mantle-Cell; Male; Middle Aged; Mutation; Neoplasm, Residual; Piperidines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Sulfonamides; Survival Rate

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Humans; Lymphoma, Mantle-Cell; Models, Theoretical; Molecular Targeted Therapy; Piperidines; Pyrazoles; Pyrimidines; Research Design; Sulfonamides; Treatment Outcome

BCL-2 family proteins are frequently aberrantly expressed in mantle cell lymphoma (MCL). Recently, the BCL-2-specific inhibitor venetoclax has been approved by the US Food and Drug Administration for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In MCL, venetoclax has shown promising efficacy in early clinical trials; however, a significant subset of patients is resistant. By conducting a kinome-centered CRISPR-Cas9 knockout sensitizer screen, we identified casein kinase 2 (CK2) as a major regulator of venetoclax resistance in MCL. Interestingly, CK2 is over-expressed in MCL and high CK2 expression is associated with poor patient survival. Targeting of CK2, either by inducible short hairpin RNA (shRNA)-mediated knockdown of CK2 or by the CK2-inhibitor silmitasertib, did not affect cell viability by itself, but strongly synergized with venetoclax in both MCL cell lines and primary samples, also if combined with ibrutinib. Furthermore, targeting of CK2 reduced MCL-1 levels, which involved impaired MCL-1 translation by inhibition of eIF4F complex assembly, without affecting BCL-2 and BCL-XL expression. Combined, this results in enhanced BCL-2 dependence and, consequently, venetoclax sensitization. In cocultures, targeting of CK2 overcame stroma-mediated venetoclax resistance of MCL cells. Taken together, our findings indicate that targeting of CK2 sensitizes MCL cells to venetoclax through downregulation of MCL-1. These novel insights provide a strong rationale for combining venetoclax with CK2 inhibition as therapeutic strategy for MCL patients.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Casein Kinase II; Cell Line, Tumor; Down-Regulation; Humans; Lymphoma, Mantle-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced glutamine dependency and ibrutinib resistance. Consistent with this, GLS inhibition by its specific inhibitor telaglenastat suppressed MCL cell growth both in vitro and in vivo. Moreover, telaglenastat showed anti-MCL synergy when combined with ibrutinib or venetoclax in vitro, which was confirmed using an MCL patient-derived xenograft model. Our study provides the first evidence that targeting GLS with telaglenastat, alone or in combination with ibrutinib or venetoclax, is a promising strategy to overcome ibrutinib resistance in MCL.

Topics: Adult; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Inhibitors; Glutaminase; Glutamine; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local

Topics: Adult; Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Lymphoma, Mantle-Cell; Receptors, Chimeric Antigen

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Tumor Lysis Syndrome

Mantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogeneous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently used in patients who are untreated. Over the last several years, several targeted or small-molecule therapies have shown efficacy in the relapsed/refractory setting and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase 2 study of 38 patients with MCL who were untreated and ineligible to receive transplantation, in which the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multicenter, open-label, nonrandomized, single-arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness, or risk factors. Lenalidomide was dosed at 20 mg daily from days 1 to 21 of each 28-day cycle. The dose of venetoclax was determined using the time-to-event continual reassessment method. Rituximab was dosed at 375 mg/m2 weekly, starting on cycle 1, day 1 until cycle 2, day 1. No dose-limiting toxicities were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common adverse events were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86%, respectively. In total, 86% of patients achieved minimal residual disease undetectability via next-generation sequencing. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.clinicaltrials.gov as #NCT03523975.

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lenalidomide; Lymphoma, Mantle-Cell; Rituximab

Bruton's tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have demonstrated tremendous clinical benefits in mantle cell lymphoma (MCL) patients, but intrinsic or acquired resistance inevitably develops. In this study, we assessed the efficacy of the highly potent and selective MCL-1 inhibitor AZD5991 in various therapy-resistant MCL cell models. AZD5991 markedly induced apoptosis in these cells. In addition to liberating BAK from the antiapoptotic MCL-1/BAK complex for the subsequent apoptosis cascade, AZD5991 downregulated inhibitor of apoptosis proteins (IAPs) through a BAK-dependent mechanism to amplify the apoptotic signal. The combination of AZD5991 with venetoclax enhanced apoptosis and reduced mitochondrial oxygen consumption capacity in MCL cell lines irrespective of their BTKi or venetoclax sensitivity. This combination also dramatically inhibited tumor growth and prolonged mouse survival in two aggressive MCL patient-derived xenograft models. Mechanistically, the augmented cell lethality was accompanied by the synergistic suppression of IAPs. Supporting this notion, the IAP antagonist BV6 induced dramatic apoptosis in resistant MCL cells and sensitized the resistant MCL cells to venetoclax. Our study uncovered another unique route for MCL-1 inhibitor to trigger apoptosis, implying that the pro-apoptotic combination of IAP antagonists and apoptosis inducers could be further exploited for MCL patients with multiple therapeutic resistance.

Topics: Adult; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; Inhibitor of Apoptosis Proteins; Lymphoma, Mantle-Cell; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

Topics: Adenine; Adult; Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrimidines; Sulfonamides

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Drug Resistance, Neoplasm; Fatal Outcome; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Piperidines; Splenic Rupture; Sulfonamides; Treatment Failure; Withholding Treatment

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunophenotyping; Lymphoma, Mantle-Cell; Male; Middle Aged; Phenotype; Piperidines; Sulfonamides

Apoptosis-regulating BCL-2 family members, which can promote malignant transformation and resistance to therapy, have become prime therapeutic targets, as illustrated by the striking efficacy in certain lymphoid malignancies of the BCL-2-specific inhibitor venetoclax. In other lymphoid malignancies, however, such as the aggressive mantle cell lymphoma (MCL), cell survival might rely instead or also on BCL-2 relative MCL-1. We have explored MCL-1 as a target for killing MCL cells by both genetic and pharmacologic approaches. In several MCL cell lines, MCL-1 knockout with an inducible CRISPR/Cas9 system triggered spontaneous apoptosis. Accordingly, most MCL cell lines proved sensitive to the specific MCL-1 inhibitor S63845, and MCL-1 inhibition also proved efficacious in an MCL xenograft model. Furthermore, its killing efficacy rose on combination with venetoclax, the BCL-X

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Humans; Lymphoma, Mantle-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Pyrimidines; Sulfonamides; Thiophenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We herein report the case of a 73-year-old male patient who was diagnosed with leukemic non-nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second-line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single-agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2-4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression-free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab-intolerant patient with an ibrutinib-resistant MCL. This case suggests that obinutuzumab- and venetoclax-based combination therapy might be salvage therapy in patients with ibrutinib-resistant MCL.

Topics: Adenine; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Remission Induction; Salvage Therapy; Sulfonamides

Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Topics: Adenine; Adult; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukocytes, Mononuclear; Lymphoma, Mantle-Cell; Piperidines; Pyrimidines; Sulfonamides

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Humans; Lymphoma, Mantle-Cell; Male; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Survival Rate; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Lymphoma, Mantle-Cell; Protein Kinase Inhibitors; Recurrence; Retreatment; Sulfonamides; Treatment Outcome

Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.

Topics: Activating Transcription Factor 3; Adenine; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Chromatin; Chromosomal Proteins, Non-Histone; Circulating Tumor DNA; Cohort Studies; DNA Helicases; Drug Resistance, Neoplasm; Genome, Human; Humans; Lymphoma, Mantle-Cell; Models, Biological; Mutation; Nuclear Proteins; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Sulfonamides; Transcription Factors; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Synergism; Humans; Hydrazines; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Niacinamide; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Triazoles; Tumor Cells, Cultured

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it.. We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of. We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality. Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Lymphoma, Mantle-Cell; Mice; Mice, Inbred NOD; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Thiophenes; Xenograft Model Antitumor Assays

Mantle cell lymphoma (MCL) is typically an aggressive and rare form of non-Hodgkin lymphoma (NHL) with a poor prognosis despite recent advances in immunochemotherapy and targeted therapeutics against NHL. New therapeutic agents are needed for MCL. In this study, we generated a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated QS1189, and confirmed its anti-cancer effects towards MCL and other lymphomas. QS1189 was highly selective for CDK7 and showed potent anticancer effects in MCL compared to other targeted therapeutic agents, such as ibrutinib and venetoclax. Consistent with a conventional CDK7 inhibitor, QS1189 treatment significantly decreased phosphorylation of the carboxyl-terminal domain of RNA polymerase II and transcription-associated genes. QS1189 induced cell cycle arrest at the G2/M phase and apoptosis. Interestingly, QS1189 overcame the acquired resistance to venetoclax, which is mediated by Bcl-xL. Similarly, QS1189 showed potent tumour cell growth inhibition of various lymphomas. Thus, CDK7 might be a suitable therapeutic target for inhibiting lymphoma, and QS1189 is a promising therapeutic option for various lymphomas and cells with acquired resistance to targeted therapy.

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lymphoma, Mantle-Cell; Phosphorylation; Piperidines; Pyrazoles; Pyrimidines; RNA Polymerase II; Sulfonamides; Triazoles

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Cluster Analysis; F-Box Proteins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Mantle-Cell; NF-kappa B; Proteasome Endopeptidase Complex; Protein-Tyrosine Kinases; Proteolysis; Proto-Oncogene Proteins c-bcl-2; Receptors, Antigen, B-Cell; Signal Transduction; Sulfonamides

The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD50 < 10 nM). Mcl-1 and Bcl-xL both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x(L) up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; CD40 Antigens; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; NF-kappa B; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; RNA, Messenger; RNA, Neoplasm; Sulfonamides; Tumor Microenvironment

Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl-2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2high MCL cells to acadesine. This effect was validated in vivo, where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients.

Topics: Actins; Aminoimidazole Carboxamide; Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Chemokine CXCL12; Chemotaxis; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Mantle-Cell; Mice; Mice, SCID; Microfilament Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Phosphoproteins; Proto-Oncogene Proteins c-bcl-2; Ribonucleosides; Sulfonamides