Isolated Central Nervous System Relapse in Childhood Acute Promyelocytic Leukemia Katrin Scheinemann, MD, Sheila Weitzman, MB, FCP(SA), FRCP(C), Johann Hitzler, MD, John Doyle, MD, FRCP(C), and Oussama Abla, MD Summary: Central nervous system (CNS) involvement is rare in acute promyelocytic leukemia (APL). The majority of CNS relapses occur in patients with hyperleukocytosis at presenta- tion, and the optimal management of such patients is still controversial. We describe a 13-year-old boy with APL who developed an isolated CNS relapse after first-line treatment with all-trans retinoic acid and chemotherapy. A second remis- sion was achieved with a regimen consisting of intrathecal chemotherapy, intravenous high-dose cytarabine, and oral 6-mercaptopurine. All-trans retinoic acid was avoided owing to severe complications during initial therapy. The patient remains in molecular remission at 9 months after autologous stem cell transplant. Prognostic factors of CNS relapse in children with APL are needed to define the indications for CNS prophylaxis in this group of patients. Key Words: leukemia, children, CNS, relapse, promyelocytic (J Pediatr Hematol Oncol 2008;30:160–162) A cute promyelocytic leukemia (APL) is a rare type of leukemia accounting for approximately 10% of cases of acute myelogenous leukemia in children. 1 The leukemic blasts of APL typically harbor a chromosomal transloca- tion that involves the gene encoding for the retinoic acid receptor-a (RAR-a) on chromosome 17 and 1 of 5 different fusion partners. 2 In the most frequent APL variant, the t(15;17) translocation results in the formation of the promyelocytic leukemia (PML)/RAR-a fusion protein. 3 All-trans retinoic acid (ATRA), a ligand of RAR-a, has become the mainstay of APL treatment. Through binding to RAR-a, it allows the differentiation of APL blasts by relieving the leukemia-associated repression of gene transcription by PML/RAR-a. 4 With current therapy, including ATRA and anthracycline- based chemotherapy, 70% to 80% of children are alive and free of disease 5 years from diagnosis. 5 The outcome of the other 20% to 30% of patients is compromised, however, by early fatal bleeding or relapse of disease. Involvement of the central nervous system (CNS) at presentation is rare in children with APL, but increasing number of cases with CNS relapse have been reported since the introduction of ATRA therapy, with an incidence ranging from 1% to 3%. 6,7 We report a case of isolated CNS relapse in a child initially treated for APL with ATRA, daunorubicin, and cytarabine. We discuss the controversies regarding CNS- directed therapy and the management of CNS relapse in children with APL. CASE REPORT A 13-year-old boy presented with epistaxis, pallor, right arm pain, and weight loss. His initial white blood cell count (WBC) was 3.4  10 9 /L with 50% blasts. The platelet count was 19  10 9 /L and the hemoglobin value measured 63 g/L. His initial International Normalized Ratio was 1.3, partial thrombo- plastine time 23 seconds, fibrinogen 2.3 g/L, and D-dimer 4422. Examination of the bone marrow (BM) revealed 50% of blasts which were classic for APL by morphology and on flow cytometry were positive for CD33 and CD13 and negative for HLA-DR and CD34. The blasts were subsequently shown to harbor the t (15;17) by fluorescent in situ hybridization, and by reverse-transcriptase polymerase chain reaction (RT-PCR) to express PML/RAR-a fusion transcripts with the break point within the bcr3 region of the PML gene. FLT3-internal tandem duplication mutation was negative. On physical examination, there were no petechiae or ecchymoses; he had only 1 nosebleed at the transfer day. Neurologic examination was unremarkable. As is the usual practice, lumbar puncture was not performed at diagnosis owing to the high bleeding risk in APL. The patient began induction treatment using our standard of care therapy based on the Southwest Oncology Group protocol, with ATRA (45 mg/m 2 /d, days 1 to 30), daunorubicin (30 mg/m 2 /d, days 3 to 6), and cytarabine (200 mg/m 2 /d, days 3 to 9). On day 10 of induction, he developed a left basilic vein thrombosis and splenic infarction. ATRA was, therefore, held for 9 days and resumed later at a dose of 25 mg/m 2 /d. From day 4 of induction on, he complained of intermittent headaches. A cranial computed tomography scan performed 1 week later was normal. Owing to continuing headaches, an magnetic resonance imaging head was performed which was unremarkable. Ophthalmic examination showed bilateral mild papilledema and multiple retinal hemorrhages, prompting a presumptive diagnosis of pseudotumor cerebri. A lumbar puncture was not performed; therefore, his cerebrospinal fluid (CSF) opening pressure, at the time, is unknown. He was started on acetazolamide on day 25 of induction and ATRA was held for a further 3 days. The patient achieved complete molecular remission of his APL on day 45. Copyright r 2008 by Lippincott Williams & Wilkins Received for publication March 19, 2007; accepted August 16, 2007. From the Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. Reprints: Dr Oussama Abla, MD, Hospital for Sick Children, Division of Hematology/Oncology, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada (e-mail: oussama.abla@sickkids.ca). CLINICAL AND LABORATORY OBSERVATIONS 160 J Pediatr Hematol Oncol  Volume 30, Number 2, February 2008