Childhood MPNs Jong Jin Seo, MD, PhD. Division of PHO, Asan Medical - - PowerPoint PPT Presentation

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

Karow A. Leukemia 2015 29:2407-9

• 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

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
• f 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/mm3

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

• f 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/mm3
• 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