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4580 Dual Bclxl and BCL2 Inhibition with Navitoclax (NAV), Venetoclax (VEN), and Decitabine (DEC) for Advanced Myeloid Neoplasms (MN): Safety and Biological Activity in a Phase 1 Study

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, MDS, Combination therapy, Adult, Translational Research, MPN, Drug development, Clinical Research, CML, Chronic Myeloid Malignancies, CMML, Diseases, Treatment Considerations, Myeloid Malignancies, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Evan C. Chen, MD1, Yiwen Liu, MS2*, Hayden L. Bell, PhD3*, Ilene A. Galinsky, MSN, ANP-C1, Marlise R. Luskin, MD1, Eric S. Winer, MD1, Maximilian Stahl, MD4, Rahul Vedula, MD5, Virginia O. Volpe, MD1, Daniel J. DeAngelo, MD, PhD1, Karen Quillen, MD, MPH6, Jeremy Ryan, MS3*, Emma-Jayne Minihane, PhD3*, Matthew Hersch, BA3*, Rebecca Leonard1*, Donna S. Neuberg, ScD7, Richard M. Stone, MD8, Anthony G. Letai3, Andrew A. Lane, MD, PhD1 and Jacqueline S. Garcia, MD1

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Data Science, Dana-Farber Cancer Institute, Boston, MA
3Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Dana Farber Cancer Institute, Boston, MA
5Medical Oncology, Dana-Farber Cancer Institute, Stoneham, MA
6Beth Israel Deaconess Medical Center, Boston, MA
7Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
8Dana-Farber Cancer Institute, Boston, MA

Introduction: The combination of a DNA methyltransferase inhibitor (DNMTi) and the BCL2 inhibitor venetoclax (VEN) is effective for newly-diagnosed acute myeloid leukemia (AML). However, response rates of VEN/DNMTi are lower for other advanced myeloid neoplasms (MN). One resistance mechanism to VEN is increased cell dependence on the alternative anti-apoptotic protein BCLxL. We hypothesized that addition of the BCLxL/BCL2 inhibitor navitoclax (NAV) to VEN would increase apoptotic priming in advanced MNs and facilitate lower NAV dosing to reduce its platelet (PLT)-associated toxicity. We report results of a phase 1 study of NAV + VEN/decitabine (DEC) in advanced MNs.

Methods: This phase 1 study used a straight six-design. Eligible subjects were age ≥18 years, with PLT ≥25 x 109/L, and diagnosed with 1) secondary AML with treatment of prior MN or therapy-related AML (s/t-AML), 2) accelerated/blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) with ≥5% blasts, or 4) relapsed/refractory (R/R) MDS with ≥5% blasts. 1° objectives were to determine safety and recommended phase 2 dose (RP2D) of NAV + VEN/DEC. 2° objectives were to determine best overall response rate (ORR) and overall survival (OS).

Cycle (C) lengths were 28 days (D). DEC 20 mg/m2/day was administered IV D1-5 for all dose levels (DL). At DL0 (starting DL, open to all diagnoses), oral VEN 400mg/day and NAV 25mg/day were given D1-14. At DL1 (open to all diagnoses), NAV dose was increased to 50mg/day. At DL2 (BP-MF and AML only), VEN duration was increased to D21. For C1 only, NAV began D3 if PLT ≥10 x 109/L after VEN dose ramp-up D1-3. ORR was defined as complete remission (CR) or CR with incomplete hematologic recovery (CRi) for AML (ELN 2022); CR, CR uni/bilineage (CRuni/bi), or CR with partial hematologic recovery (CRh) for MDS (IWG 2023); CR or marrow response for MDS/MPN (IWG 2015); and acute leukemia response-complete (ALR-C) for AP/BP-MF (MPN-BP 2012). Hematologic dose-limiting toxicity (DLT) during C1 was defined as grade 4 neutropenia or thrombocytopenia >D42 in absence of disease, or PLT <10 x 109/L ≥7 days.

Results: Sixteen subjects were treated (4 s/t-AML, 3 AP/BP-MF, 4 chronic myelomonocytic leukemia [CMML], 1 MDS/MPN-unclassifiable [U], 4 R/R MDS). Median age was 72 years (range 50-80); 7 (44%) were female, and 3 (19%) were non-white. Four subjects previously received VEN; 1 had prior HSCT. The MDS/MPN-U subject withdrew after 3 NAV doses. Dose-escalation proceeded through DL0 (n=6), DL1 (n=7), and DL2 (n=1 only, due to discontinued NAV availability); dose-expansion occurred at DL1 (n=2). At DL1, 1 DLT occurred due to grade 4 ANC that resolved on D65. Frequent grade ≥3 TEAEs were neutropenia (69%), thrombocytopenia (63%), and febrile neutropenia (44%). One death occurred due to respiratory failure in a R/R MDS subject in C2.

A median of 2 cycles (range 1-not reached) was administered. ORR among evaluable subjects was 60% (9/15), including s/t-AML (ORR 2/4; both CR), AP/BP-MF (1/3; ALR-C), CMML (4/4; 1 CR and 3 marrow responses), and MDS (2/4; 1 CRh and 1 CRbi). To date, 5 subjects were bridged directly to HCT. At a median follow-up of 13 months (95% CI: 5.5-not reached), the 1-year OS was 35% (95% CI: 15%-83%) and median OS was 10 months (95% CI: 5.4-not reached).

BH3 profiling of pretreatment myeloblasts showed increased apoptotic priming in responding subjects (n=7; p=0.007) and BCLxL dependence (p=0.046) using the BH3 peptides BIM and HRK, respectively, compared to non-responders (n=6). Among 8 subjects with monoblasts (CD33+CD64+CD14+), all responders (n=4) had CMML and increased mitochondrial BCL2 and BCLxL dependence vs. non-responders (p=0.029). Based on this, single-cell RNA and chromatin profiling of 2 CMML subjects at 6 pre- and post-treatment timepoints was done, revealing transcriptomic and epigenomic signatures of a BCL2 and BCLxL-expressing, myeloid progenitor-like cell compartment that was eradicated on therapy. Finally, the immature platelet fraction was higher in subjects with baseline PLT <100 vs. ≥100 x 109/L (p=0.035), but this difference diminished upon adding NAV on C1D3, suggesting on-target BCLxL inhibition.

Conclusion: NAV + VEN/DEC is safe for high-risk MN with manageable cytopenias and evidence of BCL-xL on-target activity. Initial RP2D in MDS or MDS/MPN is NAV 50 mg D1-14. Continued study of BCLxL inhibition is recommended for high-risk MNs, especially CMML.

Disclosures: Chen: Rigel: Consultancy; AbbVie: Consultancy. Luskin: AbbVie: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria; KITE: Honoraria; Pfizer: Honoraria. Stahl: GSK: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Kymera: Membership on an entity's Board of Directors or advisory committees; Sierra Oncolgy: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. DeAngelo: MT Sinai MPN Consortium: Other: DSMB; Fibrogen: Other: DSMB; Daiichi-Sankyo: Other: DSMB; Glycomimetics: Research Funding; Abvie: Research Funding; Bristol-Meyers Squibb: Honoraria; Takeda: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Incyte: Consultancy; Jazz: Consultancy; Gilead: Consultancy; Curis: Consultancy; Blueprint: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy, Honoraria. Ryan: Zentalis: Consultancy. Neuberg: Madrigal Pharmaceutical: Current equity holder in publicly-traded company. Stone: Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; Syntrix Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; BerGenBio: Consultancy, Other: consulting fees; AROG Pharmaceuticals: Consultancy, Other: consulting fees; Aptevo Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consulting fees; Amgen: Consultancy, Other: consulting fees; Actinium Pharmaceuticals, Inc.,: Consultancy, Other: consulting fees; AbbVie: Consultancy, Other: consulting fees; Epizyme Inc: Consultancy, Other: consulting fees; Janssen: Consultancy, Other: consulting fees; Celularity: Consultancy, Other: consulting fees; Boston Scientific: Consultancy, Other: consulting fees; GSK: Consultancy, Other: consulting fees; Novartis: Consultancy, Other: consulting fees; Ligand Pharmaceuticals: Consultancy, Other: consulting fees; LAVA Therapeutics: Consultancy, Other: consulting fees; Kura Oncology: Consultancy, Other: consulting fees; DAVA Oncology: Consultancy, Other: consulting fees; Rigel Therapeutics, Inc.: Consultancy, Other: consulting fees; CTI BioPharma: Consultancy, Other: consulting fees; Hemavant Sciences: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Bristol Myers Squibb: Consultancy, Other: consulting fees; Syros Pharmaceuticals: Consultancy, Other: consulting fees; AvenCell: Consultancy, Other: consulting fees. Letai: Zentalis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Lane: Menarini Group: Other: Steering Committee, Research Funding; IDRx: Consultancy; AbbVie: Research Funding; Cimeio Therapeutics: Consultancy; Jnana Therapeutics: Consultancy; ProteinQure: Consultancy; Qiagen: Consultancy; Stelexis BioSciences: Consultancy; Medzown: Current equity holder in private company. Garcia: Taiho: Research Funding; Servier: Consultancy; Newave: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding.

*signifies non-member of ASH