Development of T-cell Acute Lymphoblastic Leukemia in a Patient in Very Long Lasting Complete Remission of Juvenile Myelomonocytic Leukemia Alexei A. Maschan, PhD, MD,* Lili A. Khachatrian, MD,* Galina G. Solopova, MD,* Elena Yu Ossipova, PhD,* Luidmila V. Baidun, MD,w Svetlana V. Dmitrieva, MD,* Mikhail A. Maschan, MD,*w and Igor B. Resnikz Summary: Juvenile myelomonocytic leukemia (JMML) occurs with an incidence of 1.2 per million children a year, and represents 18% to 30% of all myelodysplastic (MDS) and myeloproliferative (MPS) disorders in the age group below 15, being by far the most common MDS/MPS in children younger than 4 years. The only therapeutic approach which results in a definitive cure of patients with JMML is myeloablative chemo-therapy/radio-therapy, fol- lowed by allogeneic hematopoietic cell transplantation. Few cases of transformation of JMML in acute lymphoblastic leukemia have been reported. We describe a child with JMML diagnosed at the age of 4 months in whom complete remission was achieved with 13-cis retinoic acid and cytosine-arabinoside and was sustained for 7 years with no maintenance therapy. Ninety-eight months after the diagnosis of JMML was established, overt T-cell leukemia developed. Treatment with acute lymphoblastic leukemia (ALL)- directed chemotherapy induced complete restoration of normal hemopoiesis, but testicular involvement persisted. The patient died after transplantation with unrelated cord blood. This case suggests that JMML is a true stem cell disorder and that stem cell transplantation should be considered, even in patients with a very favorable clinical course. Key Words: JMML, children, T-ALL, transformation (J Pediatr Hematol Oncol 2011;33:e32–e34) J uvenile myelomonocytic leukemia (JMML) occurs with an incidence of 1.2 per million children a year, and represents 18% to 30% of all myelodysplastic and myeloproliferative disorders in the age group below 15, being by far the most common myelodysplastic/myelopro- liferative (MDS/MPS) in children younger than 4 years. 1–3 JMLL is believed to be derived from very early hemato- poietic progenitors, most likely primitive multipotent stem cells. The clinical course of JMML is poorly predictable, but almost invariably fatal. Complications associated with cytopenias are the main cause of death in patients with JMML, although a substantial minority of patients progress to a frank acute myeloid leukemic phase. The only therapeutic approach which results in a definitive cure of patients with JMML is myeloablative chemotherapy/radiotherapy, followed by allogeneic hema- topoietic cell transplantation. 4,5 The graft-versus-leukemia effect has been shown to play a major role in eradication of malignant clones. 6,7 Conventional AML-directed che- motherapy is not able to cure or even prolong meaningfully survival of patients, although clinical and hematologic improvement and even complete remissions (CR) are not rare. 8 Differentiation therapy with 13-cis retinoic acid (RA) alone or combined with low doses of cytosine-arabinoside (AraC) is reportedly able to produce significant hematolo- gic improvement and prolong survival in a subset of young patients with JMML. 9 Other than progression to a myeloid blast crisis, a few cases of transformation in B-lineage lymphoblastic leuke- mia and 1 case of T-lineage non-Hodgkin lymphoma have been described in patients with JMML, further suggesting the stem cell origin of the disease. 10–14 Herein we describe the first case of overt T-lympho- blastic leukemia arising in a patient after CR of JMML, which was achieved after treatment with 13-cis RA+AraC and lasted 7 years with no maintenance therapy. CASE DESCRIPTION K.K. was a 4-month-old Caucasian male who was admitted to the local hospital with fever, a poor appetite, failure-to-thrive, and intermittent vomiting. On admission, purulent bilateral conjunctivitis and hepatosplenomegaly (+6cm below the costal margin) were noted. The complete blood counts (CBC) showed mild anemia [hemoglobin (Hb), 9.4 g/dL], hyperleukocytosis, (22  10 9 /l-46 10 9 /L), a left shift, (15% immature myeloid cells), monocytosis, (>2000/mm 3 ), and profound thrombocytopenia, and erythronormoblastosis (2:1000). A bone marrow aspirate was hypercellular, with 4.2% undifferentiated blasts, 54% cells of neutrophil lineage, 9.2% erythroid cells, and 2.6% monocytes. There were only scarce megakaryocytes with normal morphology. Antibiotics and prednisolone (1.5 mg/kg body weight/d) were administered and the patient was referred to our hospital. The examination on admission was remarkable for several multiple dense bluish nodular elements 1.5 cm in diameter affecting the skin of the anterior abdominal wall, generalized painless lymph node enlargement up to 1.5 cm, a few old petechiae, and marked hepatosplenomegaly. There were neither “cafe´ -au-lait” spots typical of neurofibromatosis type I nor features suggesting Noonan syndrome. The CBC was as follows: Hb 10.2 g/dL; white cell blood count (WBC) 18.7 10 9 /L (blasts, 4%; myelocytes, 4%; meta- myelocytes, 6%; bands, 5%; segmenteds, 40%; monocytes, 5%; Copyright r 2011 by Lippincott Williams & Wilkins Received for publication June 17, 2009; accepted July 25, 2010. From the *Federal Research Center for Pediatric Hematology, Oncology, and Immunology; wRussian Children’s Hospital, Le- ninskii prospect, Moscow, Russian Federation; and zDepartment of Bone Marrow Transplantation, Cancer Immunotherapy and Immunobiology Research Center, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Reprints: Alexei A. Maschan, PhD, Federal Research Center for Pediatric Hematology, Oncology and Immunology, 117 Leninskii prospect, 117997 Moscow, Russian Federation (e-mail: amaschan @mail.ru). CLINICAL AND LABORATORY OBSERVATIONS e32 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 33, Number 1, January 2011