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367 Phase II Study of Venetoclax Added to Cladribine (CLAD) and Low Dose AraC (LDAC) Alternating with 5-Azacytidine (AZA) in Older and Unfit Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Triplet Combinations of Novel Therapies
Hematology Disease Topics & Pathways:
Clinical Trials, Adults, AML, Non-Biological, Clinical Research, Chemotherapy, Clinically Relevant, Diseases, Therapies, Myeloid Malignancies, Study Population
Sunday, December 12, 2021: 9:30 AM

Patrick K Reville, MD, MPH1, Hagop Kantarjian, MD2, Gautam Borthakur, MD2, Naveen Pemmaraju, MD2, Courtney D. DiNardo, MD, MSCE2, Koji Sasaki, MD3, Naval Daver, MD4, Ghayas C. Issa, MD2, Maro Ohanian, DO2*, Guillermo Montalban-Bravo, MD2, Nicholas Short, MD5, Nitin Jain, MD3, Kapil N. Bhalla, MD2, Elias J. Jabbour6, Alessandra Ferrajoli, MD2, Koichi Takahashi, MD, PhD2, Caitlin R. Rausch, PharmD7*, Rashmi Malla, RN, BSN2*, Kelly Marek2*, Mark Brandt, BS2*, Uday R. Popat, MD8, Michael Andreeff, MD, PhD2, Guillermo Garcia-Manero, MD2, Marina Konopleva, MD, PhD2, Farhad Ravandi, MB Bs9 and Tapan M. Kadia, MD10

1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, MD Anderson Cancer Center, Houston, TX
4MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, HOUSTON, TX
6Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
7Department of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX
8Stem Cell Transplantation and Cellular Therapy, University of Texas M. D. Anderson Cancer Center, Houston, TX
9Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
10Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX

Background

The combination of venetoclax and 5-azacytidine (5-AZA) for older and unfit patients with newly diagnosed AML has led to significant improvements in remission rates and survival compared to 5-AZA alone. We previously reported encouraging results with a low-intensity backbone of CLAD/LDAC alternating with a hypomethylating agent (HMA) for older patients with AML observing better outcomes than historical experience with HMA alone. We hypothesized that the addition of venetoclax to the CLAD/LDAC alternating with HMA backbone may further improve outcomes for an expanded cohort of older patients with newly diagnosed AML.

Methods

This is a phase II study investigating the combination of venetoclax with CLAD/LDAC alternating with AZA in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL, CBF). The primary objective was composite complete response rate (CRc; CR+CRi); secondary endpoints were overall survival (OS), disease-free survival (DFS), overall response rate (ORR), and toxicity.

Induction was cladribine 5 mg/m2 IV over 30 minutes on D1-5 and araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV on D1-3 and araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 cycles. Venetoclax 400 mg was added on days 1-21 of each cycle with dose adjustments for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed.

Results

A total of 60 patients were treated on study with a median age was 68 years (IQR 64 - 73, range: 57 - 84); 22 (37%) patients were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. 14 (23%) patients had secondary AML (sAML). 36 (60%) had diploid cytogenetics with 12 (20%) patients having adverse cytogenetics at enrollment. By European Leukemia Network (ELN) risk, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. The most commonly mutated genes were NPM1 in 21 patients (33%), DNMT3A in 20 (32%), TET2 in 18 (30%), SRSF2 in 15 (25%), NRAS in 12 (20%), IDH2 in 11 (18%), RUNX1 in 11 (18%), and ASXL1 in 9 (15%). TP53 was mutated in 4 (7%) patients. Baseline characteristics are summarized in table 1.

Among 60 evaluable patients the CRc rate was 93%. Best response was CR in 48 (80%), CRi in 8 (13%), no response in 3 (5%), and death in 1 (2%) patient. Responses are summarized in Figure A. In responding patients with a bone marrow sample evaluable for assessment of measurable residual disease (MRD), 43/51 (84%) were negative for MRD at response assessment. Among patients with sAML, with adverse karyotype, or ELN adverse risk the CR/CRi rate was 86% (64%/21%), 83% (58%/25%), and 96% (81%/15%) respectively. 19 (34%) responders received a subsequent allogeneic stem cell transplantation. Early mortality was low with one patient (2%) dying within 4 weeks and four patients (7%) dying with in 8 weeks. Responses are summarized in table 2.

The most frequent grade 3/4 non-heme adverse events were febrile neutropenia (n=10), pneumonia (n=5), atrial fibrillation (n=2), and allergic reaction (n=2). One patient developed grade 4 tumor lysis syndrome.

With a median follow up of 20.4 months, the median duration of response (DOR) is not reached (95% CI: 18 - NE months). Estimated 12- and 24-month DOR are 69.2% (95% CI: 57.5 - 83.1%) and 60.5% (95% CI: 47.7 - 76.8%), respectively. Median OS is not yet reached (95% CI: 21 - NE months). Estimated 12- and 24-month OS are 71.5% (95% CI: 60.5 - 84.5%) and 60.4% (95% CI: 47.7 - 76.6%), respectively (figure B). The estimated 12-month OS for patients aged <70 years and ≥70 years was 75% and 73%, respectively. Median DFS is not yet reached (95% CI: 18.0 - NE months). Estimated 12- and 24-month DFS are 69.2% (95% CI: 57.5 - 83.1%) and 60.5% (95% CI: 47.7 - 76.6%), respectively (figure C).

Conclusion

CLAD/LDAC plus venetoclax alternating with AZA plus venetoclax is an effective, lower-intensity regimen that is well tolerated among older patients (≥ 60 years) with newly diagnosed AML, producing high response rates with durable MRD negative remissions. The rates of overall and disease-free survival are encouraging in this cohort of older AML patients with comparable efficacy in patients ≥70 as in patients <70 years old. Further study of this non-anthracycline containing backbone in younger patients unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies are warranted.

Disclosures: Kantarjian: AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; BMS: Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Precision Biosciences: Honoraria; NOVA Research: Honoraria. Borthakur: Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pemmaraju: Affymetrix: Consultancy, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; Aptitude Health: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; CareDx, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. DiNardo: Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Short: Novartis: Honoraria; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Honoraria. Jain: Incyte: Research Funding; Genentech: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board ; BeiGene: Other: Advisory Board, Research Funding. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Andreeff: Senti-Bio: Consultancy; Karyopharm: Research Funding; ONO Pharmaceuticals: Research Funding; Aptose: Consultancy; Medicxi: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Breast Cancer Research Foundation: Research Funding; Amgen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy; AstraZeneca: Research Funding; Oxford Biomedica UK: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy. Konopleva: AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Cellectis: Other: grant support; AstraZeneca: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ascentage: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Agios: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Ravandi: AstraZeneca: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding. Kadia: Novartis: Consultancy; Liberum: Consultancy; BMS: Other: Grant/research support; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Genfleet: Other; Jazz: Consultancy; Pfizer: Consultancy, Other; Agios: Consultancy; Astellas: Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; AbbVie: Consultancy, Other: Grant/research support; AstraZeneca: Other.

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