Children with Juvenile Myelomonocytic Leukemia (JMML); A Single Center Experience
Authors: Satirer Özlem , Aytac Selin , Kuskonmaz Baris , Unal Sule , Gumruk Fatma , Niemeyer Charlotte , Cetin Mualla 
Published: October 2019

Abstract
Introduction
Juvenile myelomonocytic leukemia (JMML) is a unique, aggressive hematopoietic disorder of childhood caused by excessive proliferation of cells of monocytic and granulocytic lineages.
Childhood JMML is classified as a bridging disorder between myelodysplastic syndrome (MDS) and myeloproliferative diseases.More than 95% of JMML patients are diagnosed under the age of six years.
Children with JMML mostly present with hepatosplenomegaly, lymphadenopathy, bleeding, anemia, fever, recurrent infections, rash, failure to thrive and pulmonary disease.
Approximately 90% of patients carry either somatic or germline mutations of PTPN-11,K-RAS,N-RAS,CBL or NF-1 in their leukemic cells.
Aim
We want to describe the clinical and laboratory features in 55 cases of JMML seen at the Hacettepe University Pediatric Hematology Department during a 18 year period (January 2000-June 2018).
Patients & Methods
There were 38 males and 17 females aged between 1 months and 168 months (median 36 months).
On admission mean Hb, WBC and platelet was found to be 9.1±1.9 g/dl (range 5.7-14.6g/dl), 38.7±4.3 x10 3 µ/L (range 1.4 - 214 x10 3 µ/L) and 156 ± 7.8x 109 range (8-1598x109/L) , respectively.Results of cytogenetic analysis showed monosomy 7/7qdel in 16 cases.Somatic PTPN11 mutation was found in 23 children whereas somatic KRAS mutation in 7 and germline mutation in one case, somatic NRAS mutation in 3 cases and c-CBL mutation in 5 cases.
On admission 49% of patients had no blast cells on the peripheral blood smear.But 3 of 55 patients had 100% blast cells in peripheral blood smear.Monosomy 7 mutation was positive in all of these 3 patients and one of these case had an history of familial MDS and a positive GATA mutation, one other had NF-1 mutation.All three patients were died despite hematopoietic stem cell transplantation(HSCT).
On admission, 7 out of 55 patients had &gt;30% blast cells in bone marrow aspiration and 3 of them had %100 blast cells on the peripheral smear. The rest of this group except one who had a positive KRAS mutation and diagnosed as AML-M4 were treated with HSCT and 4/6 were stil alive.On the other hand, 7 out of 55 patients had 20-30% blast cells in bone marrow aspiration on admission and none of these patients had neither monosomy 7/7qdel nor trisomy 8 mutation.
c-CBL mutation was found to be positive in 5 case and all were still alive (two siblings with c-CBL and one other patient had a diagnosis of juvenile xanthogranulamatosis), and one patient with c-CBL mutation had a diagnosis of portal hypertension.On the other hand two siblings with monosomy 7 have a diagnosis of GATA mutation and both were died after HSCT.Almost 40% of this pediatric group (20/55) were died after a median follow up time 16 months (1-211 months).
Discussion
JMML is a clonal hematopoietic disorder of infancy and early childhood which results from oncogenic mutations in genes involved in the Ras pathway and allogeneic HSCT remains the only curative treatment more than 50% of patients.However, the timing of diagnosis and treatment is critical to outcome.Prompt HSCT is recommended for all children with NF1, somatic PTPN11 and KRAS mutations, and for most children with somatic NRAS mutations.'Watch and wait' strategy is usually for the group of patients with germline CBL mutations, specific somatic NRAS mutation, and in Noonan syndrome patients, cause spontaneous resolution has been reported in this group. Our results were compatible with the literature , however it seems that in our group despite allogeneic HSCT, relapse is the main treatment failure.

Disclosures
Niemeyer: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.