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Blood, 22 January 2009, Vol. 113, No. 4, pp. 775-783.
Prepublished online as a Blood First Edition Paper on October 22, 2008; DOI 10.1182/blood-2008-07-168617.


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Submitted July 16, 2008
Accepted September 18, 2008

Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-transretinoic acid and anthracycline chemotherapy: characteristics, outcome and prognostic factors

Pau Montesinos, Juan M. Bergua, Edo Vellenga, Chelo Rayon, Ricardo Parody, Javier de la Serna, Angel Leon, Jordi Esteve, Gustavo Milone, Guillermo Deben, Concha Rivas, Marcos Gonzalez, Mar Tormo, Joaquin Diaz-Mediavilla, Jose D Gonzalez, Silvia Negri, Elena Amutio, Salut Brunet, Bob Lowenberg, and Miguel A Sanz*

Department of Medicine of the Universitat Autonoma de Barcelona, Hospital Universitario La Fe, Valencia, Spain
Hospital San Pedro de Alcantar, Caceres, Spain
University Hospital, Groningen, Netherlands
Hospital Central de Asturias, Oviedo, Spain
Hospital Universitario Virgen del Rocio, Sevilla, Spain
Hospital 12 de Octubre, Madrid, Spain
Hospital General, Jerez de la Frontera, Spain
Hospital Clinic, Barcelona, Spain
Fundaleu, Buenos Aires, Argentina
Hospital Juan Canalejo, La Coruna, Spain
Hospital General, Alicante, Spain
Hospital Universitario, Salamanca, Spain
Hospital Clinico Universitario, Valencia, Spain
Hospital Clinico San Carlos, Madrid, Spain
Hospital Insular, Las Palmas, Spain
Hospital Carlos Haya, Malaga, Spain
Hospital Cruces, Baracaldo, Spain
Hospital Sant Pau, Barcelona, Spain
Erasmus University Medical Center, Rotterdam, Netherlands
Hospital Universitario La Fe, Valencia, Spain

* Corresponding author; email: msanz{at}uv.es.

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Detailed knowledge about the differentiation syndrome has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of DS in 739 APL patients treated with ATRA plus idarubicin in two consecutive trials (PETHEMA LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. Multivariate analysis identified presenting WBC count of > 5 109/L and abnormal serum creatinine level correlating with an increased risk of development of severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced seven-year relapse-free survival in the LPA96 trial (60% vs 85%, P = 0.003), but this difference was not apparent in the LPA99 trial (86% vs 88%).


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