Retrospective Evaluation of 90 Children with Essential Thrombocytemia: The AIEOP Experience
Authors: Putti Maria Caterina , Giona Fiorina , Consarino Caterina , Fiori Gian Mario , Giordano Paola , Ladogana Saverio , Jankovic Momcilo , Micalizzi Concetta , Pession Andrea , Pierani Paolo , Ramenghi Ugo , Scapin Margherita , Teofili Luciana , Tucci Fabio , Tettoni Katia , Zanazzo Andrea Giulio , Randi Maria Luigia 
Published: October 2019

Abstract
While Essential Thrombocytemia (ET) is a typical chronic myeloproliferative disease (MPD) in adults of median/advanced age, it is rarely seen in children. Literature is scarce on this issue and mostly focused on case reports. Current diagnostic criteria in adults are those of WHO2008; new biological markers show a growing clinical relevance. In contrast, we suggested from individual Institutions’ experience that these criteria are questionable for children. Therapeutic options in pediatric age are far from established, as demonstrated by the heterogeneous treatments reported in the literature. We thus analyzed a large series of thrombocytemic children, diagnosed and followed in the Units of Italian Association of Pediatric Hematology and Oncology (AIEOP), to evaluate their clinical and biological features in comparison with adult counterparts. 90 children with sporadic ET were reported. Children with familiar history of MPD were excluded. Diagnosis was performed initially according to the PVSG criteria and since 2001 to the WHO criteria. All patients underwent bone marrow aspirate; biopsy was performed only in one third of children. Main clinical data, age at diagnosis, length of follow up (f-up), possible treatment and complications were recorded for all cases. Since 2002, most patients were analyzed for significant biological features, either retrospectively or at diagnosis. V617FJAK2mutation was analyzed by allele specific PCR on DNA extracted from granulocytes. Erythroid colonies (EEC) were obtained with and without addition of erythropoietin. Clonality was studied on female patients according to HUMARA method. The mutations of thrombopoietin (TPO) and its receptor (c-MPL) genes were performed by sequencing methods. Prevalence of females (62 girls and 28 boys) was seen as in adult ET. Median age at diagnosis was 6.75 years (range 1 mo-17 yrs); median f-up was 5 years (range 2–11 yrs). Platelets counts at diagnosis were 611–4020 × 109/l (median 1260); haemoglobin was normal, leukocytosis was frequent. Splenomegaly was present in 21% of cases. In 57 patients thrombocytemia was a casual finding. Headache was the most frequent complaint(25%). 10 patients presented minor symptoms. Major problems were seen at diagnosis in 2 infants (deep venous thrombosis with Budd-Chiari syndrome) and during f-up in 2 more children (deep venous thrombosis and splenic infarction with venous thrombosis); no major hemorrhagic events were recorded. One girl had autoimmune peripheral neuropathy. Treatment was heterogeneous and often modified during f-up: 28 children did not receive any treatment; 29 cases used low dose ASA alone or in association. Cytoreduction was obtained by hydroxyurea (29 cases), interferon alfa (17cases) and anagrelide (26 cases), aiming at platelets level 400–600 × 109/l. Treatment was stopped for toxicity in 1 case of IFN and 3 cases of Anagrelide. The V617F JAK2 mutation, present in about 50% of adult ET, was found in 16 out of 65 children (24%). Of 28 informative female patients, 17 (60%) had clonal myelopoiesis. Spontaneous EEC grew in 15 out of 32 cases (47%). We could not find any mutation of TPO or cMPL genes in sporadic patients. In conclusion, this represents the largest reported series of pediatric ET. Differences from adult cases are shown: most cases have little or no clinical symptoms; the incidence of thrombotic events is low. The primitive proliferative nature of these cases is not always confirmed: V617FJAK2 mutation is less frequent than in adults and its correlation with the clinical severity is not firm. This heterogeneity requires the definition of specific criteria for diagnosis and treatment of ET in children.
Main features of pediatric ET
Features Symptoms Treatment patients 90 None 52 (55%) None 28 M/F 28/62 Budd Chiari 2 ASA 29 Age at Dx 6.75 y (1m–17y) Deep Venous Thrombosis 2 Anagrelide 26 Follow-up 5 y (2–11) Haedache 22 (25%) a-IFN 17 Plts × 109/L 1260 (611–4020) Paresthesia 3 OHU 29 WBC × 109/L 11.75 Nosebleed 2 JAK2 V617F 16/65 (24%) Abdominal pain 4 EEC pos 17/28 (60%) Splenomegaly 19 (21%) Monoclonality 15/32 (47%) Peripheral neuropathy 1 MPL/TPO mutation none