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Incidence and Risk Factors for All-Trans Retinoic Acid-Induced Differentiation Syndrome in Acute Promyelocytic Leukemia
J. Kor. Soc. Health-syst. Pharm. 2018;35:39-47
Published online February 28, 2018
© 2018 Korean Society of Health-System Pharmacists

Goun Junga, Ae-Ryoung Parka, Soon-Joo Kima, Shin-Yi Hwangboa, Hyen-O Lab,† and Sandy Jeong Rhiec,†

Department of Pharmacy, The Catholic University of Korea Seoul ST. Mary’s Hospital 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Koreaa College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do, 14662, Republic of Koreab Division of Life and Pharmaceutical Sciences & College of Pharmacy, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760 Republic of Koreac
Correspondence to: 나현오 Tel:02-2164-6598
공동교신 이정연 Tel:02-3277-3023
Received July 5, 2017; Revised August 10, 2017; Accepted December 28, 2017.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background : Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). All-trans retinoic acid (ATRA) triggers APL cells to differentiate into mature granulocytes. Differentiation syndrome (DS) otherwise known as retinoic acid syndrome is a complication associated with the treatment of APL with ATRA. DS is characterized by unexplained fever, weight gain, peripheral edema, dyspnea, pleuropericardial effusion, hypotension, and acute renal failure. Incidence of DS ranges from 2-27%, and detailed knowledge about DS is limited. The purpose of this study is to investigate the prevalence and risk factors of DS in APL patients.
Methods : This study was retrospectively conducted on patients diagnosed with APL that received initial oral administration of ATRA January 2012-June 2015. This study analyzed incidence, onset, clinical signs and symptoms, management, and risk factors of DS.
Results : Among 95 patients, 29 patients (30.5%) experienced DS, 12 with moderate form (12.6%) and 17 with severe form (17.9%). The first peak occurred during the first week of ATRA treatment. The most frequent clinical manifestations of DS were edema (82.8%), pleuropericardial effusion (75.9%), dyspnea (65.5%), and fever (62.1%). Intravenous dexamethasone was administered in 82.8% of patients with DS. ATRA was discontinued in 93.1% of patients with DS. The univariate analysis of prognostic factors identified the following characteristics as significantly associated with DS: blood urea nitrogen (BUN) ≥20 mg/dL and lactate dehyrogenase (LDH) ≥900 U/L. Upon multivariate analysis, abnormal levels of BUN remained independent prognostic factors for DS (OR 4.06; 95% CI 1.19-13.79; p=0.03).
Conclusion : In this study, high level of BUN is one of the risk factors that can predict the potential side effects of DS. We recommend the use of steroid to prevent DS for people taking ATRA with abnormal level of BUN.
Keywords : Acute promyelocytic leukemia (APL), All-trans retinoic acid (ATRA), Differentiation syndrome (DS)

February 2019, 36 (1)