Introduction: Because Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are rare in pediatric and young adults (PAYA), the genomic landscape, clinical features, management, and prognosis for younger patients remain obscure. MPN are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells. While both polycythemia vera (PV ) and essential thrombocytosis (ET) present as indolent, chronic diseases, ~25% of older adults will progress to myelofibrosis (MF) and acute myeloid leukemia (AML) with abysmal outcomes. To help inform management of younger patients, we sought to elucidate molecular features, clinical findings, and outcomes in this unique population.
Methods: The Hopkins MPN cohort enrolled 630 patients with ET, PV or MF between 2005-2015, all of whom had quantitative JAK2V617F, CALR, and MPL genotyping. Eighty-two (13%) patients were diagnosed at <30 years (PAYA), whereas 548 were diagnosed at >31 years (Adult). We compared clinical features, complications, and survival in both groups.
Epidemiology: The mean age of diagnosis was 25 years (range 1 week - 30 years) in PAYA versus (v.) XX years in Adults. Diagnosis at presentation in PAYA included: ET (n=53; 65%), PV (n=29; 35%), and, MF (n=4; 5%), contrasting with the Adult cohort, which included a great percentage with PV (42%) and MF (15%). Females comprised the majority in both cohorts (72% v. 59% in PAYA and Adults, respectively).
Genomic landscape: The relative distribution of JAK2, CALR or MPL mutations were identical in both cohorts, with 50% of ET and MF positive for JAK2V617F, and 100% of PV patients positive for either JAK2V617F or JAK2 exon 12 mutations. CALR mutations comprised 11/38 (29%) ET and 5/12 (42%) MF in PAYA patients with similar frequencies in Adults. Only 1 PAYA patient had an MPL mutation. JAK2V617F allele burden increased with advancing age, although at a significantly lower rate in PAYA compared to the Adult cohort. Family history of MPN was similar in both cohorts (~9%). One PAYA patient had congenital ET (diagnosed at 1 week old); his mother, father and uncle also had ET.
Complications: The most frequent complications were venous thromboses, followed by arterial events and migraines. The most common sites for venous thromboses included: abdominal (splenic, mesenteric, hepatic vein, portal vein, n=11 ), pulmonary emboli (n=X), leg (n=5), and cerebral sinus thrombosis (n=4). Arterial events included MI (n=4), TIA (n=2), and stroke (n=1). Three PAYA patients received orthotopic liver transplants for Budd Chiari Syndrome.
Progression: Median follow-up was longer for PAYA compared to Adults (12 v. 8 years). MPN progressed in 21/82 (26%) of PAYA as follows: 1) PV to MF (n=6, median age 51 years, median time to progression 23 years), 2) ET to MF (n=4, median age 50 years, median time to progression 27 years), 3) ET to PV (n=10, median age 33 years, median time to progression 8 years). One PAYA patient developed AML 28 years after PV diagnosis and 2 years after progressing to MF. Time to transformation for all phases was longer, although age at transformation was lower, in PAYA compared to Adults.
Survival: Deaths occurred in fewer (n=8; 9.7%) PAYA v. Adult patients (n=167; 30%). Overall median survival was longer in PAYA (32 v. 12 years), yet the median age of death in PAYA was lower (58.5 v. 72 years) compared to the Adult cohort. Cause of death in PAYA was attributed to post transplant complications (n-2), pulmonary hypertension (n=1), AML (n=1) and bone marrow failure (n=4).
Conclusions: While JAK2V617F is a common acquired somatic mutation in HSC associated with aging and male sex, it also occurs in the PAYA population, and paradoxically, affects more females than males. Younger age at diagnosis is associated with lower risk disease (ET or PV v. MF) and a longer latency before progression to MF or AML, suggesting that older age, rather than disease duration, is a primary risk factor for progression.The genomic landscape of driver lesions was similar in PAYA and Adult cohorts. Despite presentation with lower risk disease, PAYA patients had a high rate of progression to MF. The high frequency of thromboses suggests that management of PAYA patients should include measures to prevent this complication, while the prolonged overall survival in PAYA underscores the need to control systemic symptoms while avoiding exposure to therapies that increase the risk of leukemia.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.