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221 High Early Death Rates, Treatment Resistance and Short Survival of Black Adolescent and Young Adults (AYAs) with Acute Myeloid Leukemia (AML) (Alliance)

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Clinical and Epidemiological: COVID and beyond
Hematology Disease Topics & Pathways:
AML, Translational Research, Clinically Relevant, Diseases, Disparities, Young Adults, Myeloid Malignancies, Study Population, Racial Inequities, Diversity, Equity, and Inclusion (DEI), Racism
Saturday, December 11, 2021: 3:00 PM

Karilyn Larkin, MD1, Deedra Nicolet2,3*, Ben Kelly, M.S.4*, Krzysztof Mrózek, MD, PhD5,6, Katherine E Miller, PhD7*, Saranga Wijeratne, M.S.8*, Stephanie LaHaye, PhD8*, Jessica Kohlschmidt, PhD6,9,10, James S. Blachly, MD11, Alice S. Mims, MD12, Christopher J. Walker, PhD1, Christopher C. Oakes, PhD1, Shelley Orwick, B.S.12*, Isaiah Boateng2*, Jill Buss, B.S.13*, Adrienne Heyrosa14*, Andrew J Carroll, PhD15, William Blum, MD16, Bayard L. Powell, MD17, Jonathan E Kolitz, MD18, Joseph O. Moore, MD19, Robert James Mayer, MD20, Richard A. Larson, MD21, Richard M. Stone, MD22, Electra D. Paskett, PhD23*, John C. Byrd, MD24, Elaine R. Mardis, PhD7* and Ann-Kathrin Eisfeld, MD25,26

1The Ohio State University Comprehensive Cancer Center, Columbus, OH
2Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH
3Alliance Statistics and Data Center, The Ohio State University, Columbus, OH
4Nationwide Children's Hospital and Ohio State University College of Medine, Columbus, OH
5The Ohio State University, Comprehensive Cancer Center, Columbus, OH
6The Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH
7The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
8The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH
9The Clara D. Bloomfield Center for Leukemia Outcomes Research, 4The Ohio State University Comprehensive Cancer Center, Hilliard, OH
10Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH
11Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
12Division of Hematology, The Ohio State University, Columbus, OH
13The Ohio State University, Columbus, OH
141Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH
15Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
16Department of Hematology and Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
17Wake Forest Baptist Health Comprehensive Cancer Center, Winston-Salem, NC
18Northwell Health Cancer Institute, Department of Medicine, Division of Hematology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY
19Duke University Medical Center, Durham, NC
20Dana-Farber Cancer Inst., Boston, MA
21Department of Medicine, Section of Hematology-Oncology, University of Chicago, Chicago, IL
22Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
23Division of Cancer Prevention and Control, The Ohio State University, Columbus, OH
24College of Medicine, University of Cincinnati, Cincinnati, OH
25Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
26The Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University, Columbus, OH

Background: AML is a highly aggressive hematologic malignancy. Patient (pt) outcomes are affected by disease-related factors including cytogenetic findings and gene mutations, as well as pt-related factors, such as age and race. Younger pts have superior survival: ~50% of pts diagnosed as AYAs (18-39 years) may be cured of their disease. However, the impact of race on the outcome and associated disease profiles in this pt population are unknown.

Methods: We compared survival and molecular profiles of 655 Non-Hispanic Black and Non-Hispanic White (hereafter referred to as Black, n=89 and White, n=566) AYA AML pts treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols based on standard intensity cytarabine/anthracycline induction therapy between 1986 and 2016. Three hundred ten pts were analyzed molecularly via targeted sequencing of 81 genes. Additionally, we performed integrated genomic profiling (whole-exome sequencing and transcriptome sequencing) and measured residual disease (MRD) in serial samples of 4 Black pts who relapsed with their disease.

Results: A comparison of clinical characteristics of AYA AML pts by race revealed almost identical age and sex distribution, and we found no significant differences between clinical features at diagnosis. With regard to genetic profiles, 42% of White pts were cytogenetically normal, whereas only 18% of Black pts had cytogenetically normal AML (CN-AML; p<0.001). The abnormal karyotypes in Black pts more often contained abnormalities associated with core-binding factor (CBF) AML (39% v 25%, p=0.01; Fig. 1A). White pts had more known pathogenic NPM1 variants (29% v 9%, p=0.01), whereas Black pts had a higher incidence of ZRSR2 pathogenic variants (9% v 0.4%, p=0.004) and tended to have pathogenic KRAS variants more often (12% v 5%, p=0.11; Fig. 1B).

Black AYA AML pts had worse outcomes including a higher early death rate (ED, defined as death within 30 days of diagnosis; 11% v 2%, p<0.001), a trend towards lower complete remission (CR) rate (73% v 82%, p=0.06) and a shorter overall survival (OS; median, 1.5 v 3.1 years [y], p=0.002). Notably, this survival disparity was almost exclusively driven by pts aged 18-29 y: Black pts had a higher ED rate (16% v 3%, p=0.002), a lower CR rate (66% v 83%, p=0.01) and shorter OS (median, 1.3 v 10.2 y, p<0.001) but not disease-free survival (DFS; p=0.16) than White pts aged 18-29 y. In contrast, there were no significant differences in these outcome metrics between Black and White pts aged 30-39 y (Fig. 2). Among all pts consolidated with intensive chemotherapy (n=566), multivariable analysis revealed Black race as an independent prognosticator of shorter DFS (p=0.04) and OS (p<0.001). These differences in OS were also significant when we included pts who received allogeneic transplantation in 1st CR (n=655; p<0.001). 18-29 y old Black pts with any non-CBF AML had very poor OS compared to White pts (5-y rates, 12% v 45%, p<0.001). CBF-AML pts aged 18-29 y tended to have an inferior OS compared with White pts (5-y rates, 41% v 44%, p=0.10).

To gain insights into the genetic features of Black AYA AML pts at different stages of the disease, we performed integrated genomic profiling on paired leukemic samples from diagnosis and relapse of 4 Black AYA pts. In all pts, the original dominant leukemic clone persisted and was dominant at relapse (Fig. 3). This suggests that the leukemic clone persists during treatment with conventional cytotoxic chemotherapy. This observation was further supported by MRD detection of NPM1 mutations in NPM1-mutated pts at time of morphologic CR.

Conclusion: Black AYA AML pts present with distinct molecular features, including very high frequencies of CBF AML, and low frequency of NPM1. Pts aged 18-29y account for the race-associated survival disparity, especially non-CBF pts who have dramatically poor survival. On the one hand, the lower CR rates combined with persistence of dominant clones at relapse suggest reduced response to induction chemotherapy, and suggests the need for different treatment intensities and/or modalities in this pt cohort. On the other hand, high early death rates are indicative of delay in diagnosis and care, including health inequities, calling for systematic changes particularly for this population.

Disclosures: Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Walker: Karyopharm Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Blum: Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria; AmerisourceBergen: Honoraria; Abbvie: Honoraria; Celyad Oncology: Research Funding; Nkarta: Research Funding; Forma Therapeutics: Research Funding; Xencor: Research Funding. Larson: Cellectis: Research Funding; Rafael Pharmaceuticals: Research Funding; Epizyme: Consultancy; Astellas: Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Stone: Onconova: Consultancy; Boston Pharmaceuticals: Consultancy; Innate: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Janssen: Consultancy; Arog: Consultancy, Research Funding; Aprea: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Macrogenics: Consultancy. Paskett: Pfizer: Research Funding; Merck: Research Funding. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Eisfeld: Karyopharm (spouse): Current Employment.

*signifies non-member of ASH