Late-onset differentiation syndrome in a child with acute promyelocytic leukemia

Abstract

All-trans retinoic acid (ATRA) improves the outcome of patients with acute promyelocytic leukemia (APL) [1, 2]. ATRA administration leads to complete remission in APL patients by inducing growth arrest and differentiation of the leukemic clone. Caution is needed during ATRA treatment because of the potential development of differentiation syndrome (DS), formerly known as retinoic acid syndrome. It is a cardiorespiratory syndrome characterized by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusions, acute renal failure, cardiac failure, and hypotension [3, 4]. Although this syndrome commonly develops during the first week after starting ATRA treatment [3, 4], late-onset DS has been observed in a substantial number of patients [4]. We report a child with APL who developed DS after 21 days on ATRA treatment. A 9-year-old boy was diagnosed as having APL with t(15;17)(q22;q11.12) and PML/RARa transcript. He was registered on the JPLSG (Japan Pediatric Leukemia/Lymphoma Study Group) AML-P05 protocol and ATRA was administered at 45 mg/m/day, PO. When his WBC count was over 5,000/lL, he received dexamethasone (DEX: 0.4 mg/kg/day, IV) for DS prevention (Fig. 1). Promyelocytes disappeared in his peripheral blood after starting daunorubicin and cytosine arabinoside. He became febrile on the 16th day and antibiotics were given with successful resolution of fever. On the 17th day, serum C-reactive protein (CRP) level increased to 1.6 mg/dL and he complained of chest pain. Chest X-ray, electrocardiogram, and echocardiography showed normal findings. On the 20th day, he again became febrile at 39 C and antibiotics were changed. On the 21st day, his urine output decreased from 549 to 248 mL in 8 h and he produced foamy sputum with fresh blood. He subsequently became dyspneic. Pulse oxymetry showed oxygen saturation at 85% and BP rapidly fell from 92/56 to 80/50 mmHg. Weight gain or peripheral edema was not observed, but serum creatinine level transiently increased from 0.26 to 0.32 mg/dL. Chest X-ray revealed bilateral patchy confluent opacities. Although echocardiography demonstrated no pericardial fluid, left ventricular ejection fraction (LVEF) decreased to 26%. At this point, serum CRP level was 5.6 mg/dL and brain natriuretic peptide was 757.4 pg/mL. Cultures of blood, urine, and sputum were negative. A probable diagnosis of DS was made. ATRA was discontinued and DEX (0.4 mg/kg/day, IV) was started. He was also treated with dobutamine and milrinone, leading to an increase of LVEF to 55% several hours later. His respiratory status promptly improved with resolution of pulmonary infiltrates. Myelocyte and metamyelocyte counts increased up to 200/lL from the 21st day through to the 24th day (Fig. 1). The pathogenesis of DS is not completely understood, although several mechanisms have been proposed. First, adhesion and aggregation of APL cells may be promoted by increased expression of CD11b, CD11c and CD54 (ICAM-1) during ATRA treatment [5]. Second, differentiated APL cells secrete serine proteases [6] and matrix metalloproteases [7], which can promote coagulopathy and cellular invasion, respectively. Third, ATRA-treated APL cells secrete inflammatory cytokines such as IL-8, IL-1b, G-CSF, and TNF-a [8] as well as CC chemokines such as monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1a, and MIP-1b [9]. H. Yoshida R. Matsumura E. Sato Y. Hashii H. Ohta (&) K. Ozono Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan e-mail: ohta@ped.med.osaka-u.ac.jp