Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.
Summary Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off‐label venetoclax in combination with low‐dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD‐) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD‐ after 1–2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax‐based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD.
Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 , leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P 3 3-phosphatase (PTEN), PtdIns(3,4,5)P 3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P 2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4-and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function. (Blood. 2015;125(18):2815-2824
Key Points Simultaneous inhibition of Cdk9 and PI3K in human AML cells liberates Bak from both Mcl-1 and Bcl-xL, inducing Bak-dependent apoptosis. Dual inhibitors of Cdk9 and PI3K, such as PIK-75, have broad activity against malignant cells including human AML cells.
Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB <10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data. Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.
Introduction: Molecular MRD monitoring in NPM1 mutant (mut) AML is now standard of care in many countries as prospective clinical trials have demonstrated that suboptimal reduction and/or rising levels of NPM1mut transcript are associated with disease relapse (Ivey, NEJM 2016; Balsat, JCO 2017). Higher levels of NPM1mut MRD positivity are associated with poorer outcomes after allogeneic hematopoietic stem transplantation (allo-HSCT) (Dillon, EHA 2019). Data regarding the effectiveness of pre-emptive MRD intervention is scant. A reduction in NPM1mut MRD was reported in 17/33 (52%) receiving azacitidine (Platzbecker, Lancet Oncol 2018). Among patients with NPM1mut molecular relapse in the NCRI AML17 trial, 16/27 (59%) achieved MRD negativity with 1-2 cycles of FLAG-Ida salvage chemotherapy (manuscript in preparation). As the BCL-2 inhibitor venetoclax in combination with low-dose cytarabine (LDAC) or hypomethylating agents (HMA) are known to be highly active in NPM1mut AML (Wei, JCO 2019; Strickland, EHA 2018), we hypothesized that venetoclax-based regimens could represent an effective low intensity option for patients with persistent or rising NPM1mut MRD. Methods: Consecutive patients with NPM1mut AML from 4 sites treated with venetoclax-LDAC/HMA for MRD eradication were included if previously received at least 1 cycle of intensive chemotherapy and achieved complete remission. cDNA was analyzed on bone marrow aspirate ± peripheral blood samples using a NPM1 mutant specific RT-qPCR (Ivey, NEJM 2016) according to Europe Against Cancer guidelines (Gabert, Leukemia 2003). Results are expressed as MRD level relative to the diagnostic sample (%) with both samples normalized to a control gene (ABL). Results: A total of 10 patients were treated with venetoclax (600 mg PO daily D1-14) in combination with LDAC (20 mg/m2 SC twice daily D1-10; n=8), or venetoclax (400 mg PO daily D1-14) azacitidine (75 mg/m2 SC daily D1-7; n=2) as summarized in Table 1. If concurrent posaconazole was used, the dose of venetoclax was adjusted to 100 mg PO daily. The median age of the cohort was 61.2 years (range 31-81). All patients had intermediate risk cytogenetics, including 8 with normal karyotype at diagnosis. Concurrent mutations in addition to NPM1 are shown in Table 1. The number of consolidation cycles received prior to venetoclax ranged from 0-4 and typically included high-dose cytarabine. Three patients had failed other MRD-directed therapies prior to treatment with venetoclax. Six patients (Cases #1-6) received venetoclax-LDAC/HMA for NPM1mut molecular relapse after complete molecular remission (CRMRD-), or progression after molecular persistence at low copy number (CRMRD+). Five of six (83%) achieved CRMRD- after only 1-2 cycles, with ongoing CRMRD- after a median of 134 days (range 59-447). One patient had failed to respond to FLAG-Ida but achieved CRMRD- after just 1 cycle of venetoclax-LDAC (Figure 1A). Three patients proceeded to subsequent allo-HSCT, including 2 in CRMRD- (Figures 1B and C). Follow up post-HSCT is ongoing (<60 days). Four patients (Cases #7-10) were treated for molecular persistence after completion of induction and 0-3 cycles of consolidation chemotherapy. All 4 patients responded, including 3 (75%) who achieved CRMRD-. Case #7 (Figure 1D) had received prior gemtuzumab ozogamicin and azacitidine without molecular response but then achieved CRMRD- after receiving venetoclax-azacitidine, which was sustained for >23 months without an allo-HSCT. Venetoclax in combination with LDAC/HMA was well tolerated. Febrile neutropenia occurred in 2 patients (20%) and one patient had grade 4 sepsis. Grade 4 neutropenia occurred in 70% (median duration 10 days) and grade 4 thrombocytopenia in 40% (median duration 16 days). Conclusion: In the setting of molecular NPM1mut MRD relapse or persistence, venetoclax in combination with LDAC/HMA was highly effective, with MRD reductions in 100% and complete molecular remission in 80%. Future clinical exploration is warranted to validate the role of venetoclax as a pre-emptive approach to suppress persistent or rising NPM1mut MRD. Disclosures Dillon: Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ivey:Novartis: Honoraria. Vassili:Amgen: Honoraria. Taussig:Celgene: Research Funding. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau. Raj:Jazz: Honoraria, Speakers Bureau; Daiichi Sankyo: Honoraria; Pfizer: Honoraria; MSD: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Speakers Bureau; Mallinckrodt: Honoraria, Speakers Bureau. Fong:Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy. Grigg:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Knapper:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero: Membership on an entity's Board of Directors or advisory committees. Wei:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax as a MRD-directed therapy in AML, which is not an approved indication.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.