Decitabine: Risk of Differentiation Syndrome

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Decitabine is a hypomethylating agent1 that selectively inhibits DNA methylation and is indicated for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) in Malaysia.2

Differentiation syndrome, also known as retinoic acid syndrome, is a potentially fatal complication of induction therapy with differentiating agents such as all-trans retinoic acid (ATRA) or arsenic trioxide [ATO] in patients with acute promyelocytic leukaemia (APL).3-5 The onset of clinical manifestations of differentiation syndrome has been reported in a range of 0 to 46 days after starting differentiation therapy.5 Differentiation syndrome usually consists of unexplained fever, hypotension, respiratory distress with pulmonary infiltrates, pleural effusions, pericardial effusions, acute renal failure, and/or hyperleukocytosis.4-6 If a definitive diagnosis could not be made, any other medical conditions that could explain the clinical manifestations, such as pulmonary haemorrhage, pneumonia, congestive heart failure, renal failure, and septic shock, should be ruled out.5


Background of the Safety Issue

In January 2021, the National Pharmaceutical Regulatory Agency (NPRA) had learned from the European Medicines Agency (EMA) on the risk of differentiation syndrome following the use of decitabine.3

Based on two (2) case reports published in the literature, spontaneous reports, and a plausible mechanism of action, EMA concluded that the causal association between decitabine and the differentiation syndrome to be at least a reasonable possibility.3 As a DNA-hypomethylating agent, decitabine may induce differentiation and apoptosis of leukaemic cells, and differentiation syndrome typically occurs when leukaemic blasts are massively present.3,5 EMA has requested the product registration holders of the products involved to update package insert with the risk of differentiation syndrome.3


Adverse Drug Reaction (ADR) Reports7

NPRA has received 10 reports with 16 adverse events suspected to be related to decitabine. Among these reports, there were two (2) reports of fever, but no events of differentiation syndrome were reported.


Advice for Health Care Professionals:

  • Be alert on the risk of differentiation syndrome associated with the use of decitabine.
  • Advise patients to be cautious whilst on decitabine therapy, and to inform healthcare professionals if any signs and symptoms of differentiation syndrome occur.
  • When the first sign or symptom of differentiation syndrome appears, consider
    • discontinuation of decitabine treatment until the symptoms have resolved;
    • initiation of treatment with high-dose intravenous corticosteroids;
    • haemodynamic monitoring, and to resume treatment cautiously.
  • Please report all suspected adverse events associated with decitabine-containing products to the NPRA.


NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (34)] has been issued for registration holders of decitabine-containing products to update the local package inserts with this new safety information.



  1. Jabbour E, Issa J-P, Garcia-Manero G, Kantarjian H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341–51.
  2. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). DACOGEN (decitabine) 50 mg Powder for Concentrate for Solution for Infusion [Internet]. Revision date: March 2021 [Cited on 27 October 2021]. Available from (access restricted).
  3. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s). Decitabine. 2021 Jan [cited 27 Oct 2021]. Available from:
  4. European Medicines Agency (EMA). Summary of Product Characteristics. DACOGEN [Internet]. Revision date: 2021 July [Cited 2021 Oct 27]. Available from:
  5. Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059.
  6. Laufer CB, Roberts O. Differentiation syndrome in acute myeloid leukemia after treatment with azacitidine. Eur J Haematol. 2015 Nov;95(5):484–5.
  7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. [Cited 2021 Oct 27]. Available from (access restricted).



This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.




National Pharmaceutical Regulatory Agency (NPRA)

Lot 36, Jalan Universiti (Jalan Prof Diraja Ungku Aziz), 46200 Petaling Jaya, Selangor, Malaysia.

  • Phone: +603-7883 5400




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