Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era

Simon Mantha, Debra A. Goldman, Sean M. Devlin, Ju Whei Lee, Diana Zannino, Marnie Collins, Dan Douer, Harry J. Iland, Mark R Litzow, Eytan M. Stein, Frederick R. Appelbaum, Richard A. Larson, Richard Stone, Bayard L. Powell, Susan Geyer, Kristina Laumann, Jacob M. Rowe, Harry Erba, Steven Coutre, Megan OthusJae H. Park, Peter H. Wiernik, Martin S. Tallman

Research output: Contribution to journalArticle

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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-trans retinoic 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 1 idarubicin 6 prednisone), ALLG APML4 (single arm of ATRA 1 idarubicin 1 arsenic trioxide 1 prednisone), CALGB C9710 (single arm of ATRA 1 cytarabine 1 daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin 1 cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA 1 cytarabine 1 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/mL vs <20 000/mL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD.

Original languageEnglish (US)
Pages (from-to)1763-1767
Number of pages5
JournalBlood
Volume129
Issue number13
DOIs
StatePublished - Mar 30 2017

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Acute Promyelocytic Leukemia
Tretinoin
Hemorrhage
Daunorubicin
Cytarabine
Idarubicin
Confidence Intervals
Prednisone
Leukocyte Count
Hazards
Blood
Therapeutics
Cells
Radiology
Oncology
Uncertainty
Multivariate Analysis
Clinical Trials
Imaging techniques
Incidence

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Mantha, S., Goldman, D. A., Devlin, S. M., Lee, J. W., Zannino, D., Collins, M., ... Tallman, M. S. (2017). Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood, 129(13), 1763-1767. https://doi.org/10.1182/blood-2016-10-747170

Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. / Mantha, Simon; Goldman, Debra A.; Devlin, Sean M.; Lee, Ju Whei; Zannino, Diana; Collins, Marnie; Douer, Dan; Iland, Harry J.; Litzow, Mark R; Stein, Eytan M.; Appelbaum, Frederick R.; Larson, Richard A.; Stone, Richard; Powell, Bayard L.; Geyer, Susan; Laumann, Kristina; Rowe, Jacob M.; Erba, Harry; Coutre, Steven; Othus, Megan; Park, Jae H.; Wiernik, Peter H.; Tallman, Martin S.

In: Blood, Vol. 129, No. 13, 30.03.2017, p. 1763-1767.

Research output: Contribution to journalArticle

Mantha, S, Goldman, DA, Devlin, SM, Lee, JW, Zannino, D, Collins, M, Douer, D, Iland, HJ, Litzow, MR, Stein, EM, Appelbaum, FR, Larson, RA, Stone, R, Powell, BL, Geyer, S, Laumann, K, Rowe, JM, Erba, H, Coutre, S, Othus, M, Park, JH, Wiernik, PH & Tallman, MS 2017, 'Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era', Blood, vol. 129, no. 13, pp. 1763-1767. https://doi.org/10.1182/blood-2016-10-747170
Mantha S, Goldman DA, Devlin SM, Lee JW, Zannino D, Collins M et al. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood. 2017 Mar 30;129(13):1763-1767. https://doi.org/10.1182/blood-2016-10-747170
Mantha, Simon ; Goldman, Debra A. ; Devlin, Sean M. ; Lee, Ju Whei ; Zannino, Diana ; Collins, Marnie ; Douer, Dan ; Iland, Harry J. ; Litzow, Mark R ; Stein, Eytan M. ; Appelbaum, Frederick R. ; Larson, Richard A. ; Stone, Richard ; Powell, Bayard L. ; Geyer, Susan ; Laumann, Kristina ; Rowe, Jacob M. ; Erba, Harry ; Coutre, Steven ; Othus, Megan ; Park, Jae H. ; Wiernik, Peter H. ; Tallman, Martin S. / Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. In: Blood. 2017 ; Vol. 129, No. 13. pp. 1763-1767.
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AU - Mantha, Simon

AU - Goldman, Debra A.

AU - Devlin, Sean M.

AU - Lee, Ju Whei

AU - Zannino, Diana

AU - Collins, Marnie

AU - Douer, Dan

AU - Iland, Harry J.

AU - Litzow, Mark R

AU - Stein, Eytan M.

AU - Appelbaum, Frederick R.

AU - Larson, Richard A.

AU - Stone, Richard

AU - Powell, Bayard L.

AU - Geyer, Susan

AU - Laumann, Kristina

AU - Rowe, Jacob M.

AU - Erba, Harry

AU - Coutre, Steven

AU - Othus, Megan

AU - Park, Jae H.

AU - Wiernik, Peter H.

AU - Tallman, Martin S.

PY - 2017/3/30

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N2 - 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-trans retinoic 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 1 idarubicin 6 prednisone), ALLG APML4 (single arm of ATRA 1 idarubicin 1 arsenic trioxide 1 prednisone), CALGB C9710 (single arm of ATRA 1 cytarabine 1 daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin 1 cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA 1 cytarabine 1 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/mL vs <20 000/mL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD.

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