Childhood MPNs Jong Jin Seo, MD, PhD. Division of PHO, Asan Medical Center Univ. of Ulsan College of Medicine Seoul, Korea
Aim • To introduce the key differences of childhood Ph- MPNs compared to adult disease with regard to clinical presentation, diagnosis, D/D, management and prognosis • To facilitate smooth transition to adult hematologist
Contents • Introduction • Differences in molecular incidences • Differences in clinical manifestations • Suggested diagnostic algorithm • Suggested management • Prospects
Ph- MPNs in Children • Uncommon with approx. 100 fold lower incidence literature on childhood MPNs, very limited • PV and ET occur in older children, but most pediatric PMF occur in infants and young children • Clinical and hematological findings, considered similar to those in adults • Diagnostic criteria and treatment approaches, usually adopted adult recommendations • However, several recent studies revealed significant differences btw adult and pediatric Ph- MPNs
Age-specific incidence of MPNs in Korea, 2011 J Korean Med Sci 2016 31:1579-85
Distribution of driver mutations in pediatric and adult MPN cohort • Driver gene mutations were lower (34%) than adult patients • Substantial childhood MPNs were negative for driver gene mutation, carried mutation in other genes, and higher percentage of patients had no detectable mutation Karow A. Leukemia 2015 29:2407-9
Diagnostic challenge • Due to lower incidence/paucity of driver mutations and lack of clonal marker • Frequently rely on clinical and laboratory factors • Exclusion of secondary disorders
Childhood PV • Only small case series and case reports in teenagers and young adults • Exact incidence, unknown • Prevalence of JAK2V617F mutation, much lower, about 30-40% of sporadic pediatric PV • Less symptomatic than adult; only about half of pediatric PV present with symptoms related with polycythemia • The lower rate of thrombosis (about 5 %) in children, attributed to much better vascular integrity of children • Positive physical findings, less common in children
Absolute erythrocytosis in childhood
Revised WHO Dx criteria for PV WHO Dx criteria may not be wholly applicable in children as • 2 major Dx criteria is difficult to be fulfilled in many pediatric patients due to lower prevalence of JAK2 mutations 1 major & 2 minor criteria need to be met to make a formal Dx
Proposed diagnostic algorithm for childhood PV
Differential diagnosis • Search for rare mutations of EPO-R in patients with JAK2 - erythrocytosis with normal or slightly reduced EPO levels • To differentiate ”Primary Familial and Congenital Polycythemia (PFCP)”, the frequently misdiagnosed disorder as PV
Proposed therapeutic algorithm of polycythemic children Giona L. Blood 2012 119:2219-2227
Pediatric ET • Approximately 1/1,000,000 children • Low prevalence of driver mutations • Majority of children with ET are asymptomatic • More benign course compared to adults • Decreased risk of thrombosis or bleeding • Familial screening for children with a familial history of thrombosis, recommended to differentiate JAK2 - ET from hereditary or familial forms of thrombocytosis due to mutations of TPO or MPL other than W515
Proposed diagnostic algorithm for childhood ET
Proposed Tx stratification for pediatric ET Kucine N. Haematologica 2014 99: 620-628
Proposed therapeutic algorithm of thrombocytopenic children Giona L. Blood 2012 119:2219-2227
Pediatric PMF • Quite rare in children; less than 100 reports • Epidemiologic data are lacking • The only MPN observed in infants and young children • Underlying genetics of childhood PMF, undetermined • Wide spectrum in clinical presentation • Appears to be a unique entity compared to adult PMF
Pediatric PMF
• Largest study of 19 childhood PMF • Median age; 14 mo (range 0-17 yrs) • No child developed malignant transformation • 5 out of 19 (26%) had spontaneous resolution • JAK2V617F and MPL515L mutations, negative • Less frequent constitutional symptom in contrast to adult patients, other than fever and fatigue • Heterogeneous phenotype ranging from spontaneous resolution to rapidly progressive, sometimes fatal, disease curable only by HSCT • Distinct clinical, hematologic, BM, and molecular features from adult patients
Pediatric PMF
• 14 pediatric patients diagnosed as PMF according to WHO 2008 criteria • No patient had spontaneous remission • 6 patients (43%) transformed to AML • Median survival from time of Dx was 28 mo • 7 patients (50%) had type 2 mutations of CALR • No patient had mutations in other candidate genes • No differences in age, gender, blood cell counts, % of circulating blast, OS, and leukemia transformation btw patients with and without CALR mutation • CALR mutations screening could be used as molecular marker for diagnosis of pediatric PMF
Treatment of childhood MPNs (1) • Conservative initial approach is justified due to the significant lower rate of thrombosis • Phlebotomy to maintain hematocrit less than 45% • Antiplatelet therapy with low dose aspirin; risk of Reye syndrome in children less than 12 yrs old • Cytoreductive therapy should be cautious and used as a last resort considering the low vascular risk • Selection of a cytoreductive agent is best made after discussion with child and parents • Cytoreductive therapy, either with HU or IFN- α , indicated for patients with past Hx of thrombosis or PLT >1.5 million/mm 3
Treatment of childhood MPNs (2) • Safety and efficacy of HU are unclear in children, and risk of long-term leukemogenicity has not been proven • IFN- α can achieve a durable complete molecular response of JAK2 mutant allele in some, but high rate of AE and inconvenience of frequent IV administration limits its usage • Pegylated IFN- α , considered as the first line therapy in children by some due to less AE and better efficacy, but safety and efficacy are unclear in patients <18 yrs • Anagrelide to maintain PLT <600,000/mm 3 • Ruxolitinib? • Insufficient data to recommend a specific agent, and choice should be individually tailored
Prospects • With the apparent differences in clinical course and genetic drivers from adults with MPN, further researches on the pathogenesis and outcomes are clearly needed • Identification of as yet unknown driver events through NGS technology may provide new therapeutic targets of MPN • International collaborative study is essential for this rare disease in childhood
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