title: Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era.
abstract: Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-transretinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/μL vs <20 000/μL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD.
authors.affiliation: Department of Medicine, Hematology Service, and.
authors.forename: Simon
authors.initials: S
authors.lastname: Mantha
authors.affiliation: Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Goldman
authors.affiliation: Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Devlin
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Biostatistics Center, Boston, MA.
authors.forename: Ju-Whei
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Center, East Melbourne, Australia.
authors.forename: Diana
authors.initials: D
authors.lastname: Zannino
authors.affiliation: Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Center, East Melbourne, Australia.
authors.forename: Marnie
authors.initials: M
authors.lastname: Collins
authors.affiliation: Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Dan
authors.initials: D
authors.lastname: Douer
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Iland
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Eytan M
authors.initials: EM
authors.lastname: Stein
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.affiliation: Section on Hematology and Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC.
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, FL.
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN.
authors.forename: Kristina
authors.initials: K
authors.lastname: Laumann
authors.affiliation: Department of Hematology, Rambam Medical Center, Haifa, Israel.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Division of Hematology and Oncology, University of Alabama School of Medicine, Birmingham, AL.
authors.forename: Harry
authors.initials: H
authors.lastname: Erba
authors.affiliation: Division of Hematology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.affiliation: Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Cancer Research Foundation, Chappaqua, NY.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wiernik
authors.affiliation: Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
mesh_terms: D002986:Clinical Trials as Topic; D015331:Cohort Studies; D006470:Hemorrhage / Q000139:chemically induced* / Q000401:mortality; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects*; D015473:Leukemia, Promyelocytic, Acute / Q000150:complications* / Q000188:drug therapy; D007958:Leukocyte Count; D015999:Multivariate Analysis; D011379:Prognosis; D014212:Tretinoin / Q000627:therapeutic use
chemical_list: D014212:Tretinoin