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207 Survival Differences Among Patients (pts) with Acute Myeloid Leukemia (AML) Treated with Allogeneic Hematopoietic Cell Transplantation (HCT) Versus Non-HCT Therapies: A Large Real-Time Multi-Center Prospective Longitudinal Observational StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Clinical Allogeneic Transplantation: Results: To Transplant or Not to Transplant? That Is the Question
Hematology Disease Topics & Pathways:
Adult, Biological, AML, Diseases, bone marrow, Therapies, Elderly, Study Population, Clinically relevant, Myeloid Malignancies, transplantation
Saturday, December 1, 2018: 2:30 PM
Seaport Ballroom A (Manchester Grand Hyatt San Diego)

Mohamed L. Sorror, MD, MSc1,2, Barry E. Storer, PhD3,4*, Aaron T. Gerds, MD, MS5, Bruno C. Medeiros, MD6, Paul J Shami, MD7, John P. Galvin, MD, MS, MPH8, Kehinde U. Adekola, MBBS, MS9, Selina Luger, MD10, Maria R. Baer, MD11, David A. Rizzieri, MD12, Tanya M. Wildes, MD, MSCI13, Eunice S. Wang, MD14, Stefan Faderl, MD15, Jamie L. Koprivnikar, MD15, Mikkael A. Sekeres, MD, MS5, Sudipto Mukherjee, MD, PhD, MPH5, Julie Smith, MD16*, Mitchell Garrison, MD16*, Kiarash Kojouri, MD17*, Jennifer E. Nyland, PhD1*, Rachelle R. Moore, BS1*, Sophie L. Fleuret, BS1*, Ylinne Lynch, MD1,18*, Pamela S. Becker, MD1,19, Mary-Elizabeth M. Percival, MD, MS1,19, Brenda M. Sandmaier, MD1,2, Frederick R. Appelbaum, MD1,2 and Elihu H. Estey, MD1,19

1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
2Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
3Department of Biostatistics, University of Washington School of Public Health, Seattle, WA
4Clinical Statistics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
5Leukemia & Myeloid Disorders Program, Cleveland Clinic, Cleveland, OH
6Department of Medicine, Division of Hematology, Stanford University, Palo Alto, CA
7Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
8Feinberg School of Medicine, Northwestern University, Chicago, IL
9Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL
10Abramson Cancer Center at the University of Pennsylvania School of Medicine, Philadelphia, PA
11University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
12Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, NC
13Division of Oncology, Washington University School of Medicine, St Louis, MO
14Leukemia Service, Roswell Park Comprehensive Cancer Center, Buffalo, NY
15John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
16Confluence Health/Wenatchee Valley Hospital, Wenatchee, WA
17Skagit Valley Hospital Regional Cancer Care Center, Mount Vernon, WA
18Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA
19Division of Hematology, Department of Medicine, University of Washington, Seattle, WA

Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points.

Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter.

We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p<0.05) were used to develop multivariate models examining the association between HCT and mortality within 1) the general population as well as those with 2) intermediate vs 3) unfavorable ELN risk, and 4) vulnerable pts (age ≥60 years or HCT-CI scores ≥4). The latter group constituted the majority (76%). In these analyses, all pts were considered to be in the non-HCT group until receipt of HCT at which time they enter the HCT group. The contribution of deaths to the hazard ratio (HR) for HCT reflects the relative number and characteristics of pts remaining at risk in the two groups at the time a death occurs.

Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p<0.0001), age ≥70 years (p<0.0001), intermediate (p=0.03) and high ELN risk (p<0.0001), relapsed/refractory AML at enrollment (p=0.0005), relapse or refractory response to initial treatment after enrollment (p<0.0001), frailty per walk test (p=0.004), impaired QOL per FACT-G scores (p=0.02), increased depression per PHQ-9 (p=0.03), and dependent status per ADL scores <14 (p=0.05).

Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p<0.0001) ELN risk and in vulnerable pts (p<0.0001) (Table 3).

However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p>0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk.

Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in “genetic assignment” randomized studies (i.e. comorbidities and function).

New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT.

Disclosures: Gerds: Imago BioSciences: Research Funding; Gnentech: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Samus Therapeutics: Research Funding; Apexx Oncology: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. Shami: JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri: Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang: Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl: Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar: Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres: Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker: GlycoMimetics: Research Funding. Sandmaier: Kiadis Pharma: Consultancy; Bellicum: Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Bayer Healthcare: Honoraria; AnaptysBio: Equity Ownership; Oncoresponse: Equity Ownership.

*signifies non-member of ASH