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1434 Toxicity and Outcomes in Octo- and Nonagenarians with AML Treated with Venetoclax and Hypomethylating Agent Therapy

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Research, elderly, Clinical Research, Combination therapy, real-world evidence, Therapies, Adverse Events, Study Population, Human
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Ellen Madarang, PharmD1*, Jillian Lykon, PharmD1*, Wei Zhao, MD, MS2*, Mikkael A. Sekeres, MD1, Terrence Bradley, MD1, Namrata Sonia Chandhok, MD1, Justin Taylor, MD1, Tulay Koru-Sengul, PhD3*, Sunil G. Iyer, MD1*, Jacopo Nanni, MD4*, Cristina Papayannidis, MD, PhD5, Ryan M Miller, PhamD6*, Ashwin Kishtagari, MBBS7, Michael R. Savona, MD8, Jason Gilbert, MD9*, Daniel A. Pollyea, MD10, David A. Sallman, MD11, Najla Al Ali, MS11, Rami S. Komrokji, MD12 and Justin Watts, MD1

1University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL
2Division of Biostatistics, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL
3Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, FL
4Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
5IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy, Bologna, Italy
6Vanderbilt Ingram Cancer Center, Nashville, TN
7Division of Hematology & Oncology, Vanderbilt Ingram Cancer Center, Franklin, TN
8Vanderbilt University School of Medicine, Nashville, TN
9Division of Hematology, University of Colorado School of Medicine, Aurora, CO
10Anschutz Medical Campus, Division of Hematology, University of Colorado School of Medicine, Denver, CO
11Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
12Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Introduction

The venetoclax plus hypomethylating agent (VEN-HMA) combination has become the standard treatment for older or unfit patients (pts) with newly diagnosed AML since its approval in 2018. VEN-HMA is associated with significant cytopenias and infectious complications, potentially limiting its use in elderly (>80 years) adults. We explored the toxicity and efficacy of VEN-HMA in octo- and nonagenarians.

Methods

This is a multi-center retrospective analysis conducted at 5 institutions in the US and Europe. AML pts ≥80-years-old with or without prior HMA or chemotherapy who received at least 1 day of VEN-HMA between 3/2015 and 4/2022 were included. Dose adjustments for drug interactions with anti-fungals were recorded, and pharmacokinetically equivalent VEN doses are presented. All pts were included in the efficacy and safety analysis. Composite CR (cCR) was defined as CR+CRh+CRi. Baseline characteristics were analyzed by Chi-square/Fisher’s exact test. Kaplan-Meier method and multivariate Cox regression for OS as well as logistic regression for CR were used with pre-specified patient variables as predictors.

Results

Among 133 AML pts ≥80 years treated with VEN-HMA (75% with AZA, 25% with DEC), 88.7% were newly diagnosed, 11.3% relapsed/refractory (R/R), and 39.1% had prior MDS. Prior HMA was received in 46 pts (35%) and 8 pts (6%) had prior VEN. Median age was 82 years (range: 80-92) and 28.7% of pts had an ECOG PS ≥2. Most pts (52.6%) had ELN adverse risk AML, 36.1% had intermediate, 6% had favorable, and 5.3% were unknown. Molecularly, 22.6% of pts had a TP53 mutation, 22% NPM1, 15.8% IDH1/2, 9.8% FLT3-ITD and 6.8% FLT3-TKD.

Most pts (64%) received the standard dose and schedule of VEN (400 mg [79%] for 28 days [86%]) and HMA (AZA 75 mg/m2 for 7 days [95%], DEC 20 mg/m2 for 5 days [100%]) for the first cycle. Most pts subsequently underwent VEN dose or schedule reductions once response was achieved, with 80% of pts on a reduced schedule by time of analysis. The median final VEN dose and schedule was 400 mg (50-400 mg) for 21 days (4-28 days) with a median cycle length of 35 days (28-70 days). Most pts also had a dose reduction of HMA (51%), most commonly from 7 to 5 days of AZA (71%).

At time of analysis, 38 pts (29%) were still alive and in remission with 26 (20%) still on VEN-HMA. The 30-day and 60-day mortality rates were 8.3% and 15.2 %, respectively. Treatment emergent grade 3-4 anemia occurred in 50%, thrombocytopenia in 48%, neutropenia in 53%, and neutropenic fever in 45.7%.

The cCR rate for the entire population was 54.1% (72/133), with a CR rate of 40.6% (54/133). In patients who had a formal response assessment, the cCR rate was 63.7% (72/113) and CR rate was 47.8% (54/113). In univariate analysis, baseline characteristics associated with a lack of response included R/R disease or prior MDS (cCR for both 50% vs. 76.3% in newly diagnosed, p=0.015) and prior treatment with HMA (cCR 47.4% vs. 72.0% without prior HMA, p=0.01), while patients with an NPM1 or IDH1/2 mutation had higher response rates (cCR 76.9% for NPM1 and 64.7% for IDH1/2, p=0.033). In multivariate analysis (MVA), only prior MDS was associated with a lack of response (OR 0.27 [CI 0.09-0.80], p=0.018).

Median duration of follow-up was 7.5 months in all pts, 6.8 months in deceased pts and 17 months in those still alive. Median OS for all pts was 8.6 months (CI 7.0-11.5) (Figure 1). Median OS by ELN risk was: Favorable NE (4.2-NE), Intermediate 9.5 months (6.6-15.6, p=0.059), and Adverse 8.3 months (4.5-9.4, p=0.038). In patients who achieved a response (cCR), median OS was 13.9 months (CI 10.0-17.8) vs. 3.6 months (CI 0.9-6.6) in non-responders (p<0.001) (Figure 2). Pts who achieved a CR had a median OS of 15.6 months (CI 10.0-39.7) (p<0.001). Only TP53 mutations were associated with shorter OS (HR 2.06 [CI 1.14-3.70], p=0.016) in MVA of baseline characteristics.

Conclusion

AML pts ≥80 years old treated with VEN-HMA have high response rates, regardless of performance status and ELN risk. Pts with favorable ELN risk had good outcomes, while those with prior MDS or a TP53 mutation had worse outcomes consistent with clinical trials in younger patient populations. Elderly pts with AML can be treated successfully with VEN-HMA, with a subset (~40%) of responders having long survival. These patients may benefit from significant dose reductions, particularly after achieving response. Further studies of the optimal dose and schedule of VEN-HMA are needed in this age group.

Disclosures: Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bradley: Geron Corporation: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chandhok: Servier: Consultancy. Taylor: Karyopharm, Inc: Honoraria. Papayannidis: GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees. Kishtagari: CTI Biopharm: Speakers Bureau. Savona: Karyopharm Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Other: travel expenses; Taiho Pharmaceutical: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Incyte Corporation: Research Funding; TG Therapeutics: Consultancy, Other: Travel expenses, Research Funding; ALX Oncology: Research Funding; Astex Pharmaceuticals: Research Funding; Geron: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Other: travel expenses; Forma: Consultancy. Sallman: Syntrix Pharmaceuticals: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Nemucore: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lixte: Patents & Royalties: LB-100; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Komrokji: PharmaEssentia: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, 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; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH