Clinical and Biological Features, Treatment and Long-Term Outcome of 65 Children with Ph- Myeloprolipherative Disorders (MPD).

Introduction: MPD rarely occur in children and published data of pediatric patients (pts) are limited. In adults, current diagnostic criteria are those of the WHO2008 and the therapeutic options are supported by controlled studies. From our experience, we suggested that the biological markers show a clinical relevance in Ph- MPD children and may influence their management. Patients and methods: We retrospectively analyzed 65 pts aged 20 years (yrs) at diagnosis (dx) with Ph-negative MPD, observed between December 1981 and March 2009. Dx was performed according to the PVSG or WHO criteria. Since 2002, 52/65 pts were studied for JAK2 mutations, polycytemia rubra vera-1 (PRV-1) RNA expression, thrombopoietin (TPO) and its receptor (c-MPL) mutations, erythropoietin receptor (EPO-r) gene mutations, spontaneous endogenous erythroid colony (EECs) growth, clonality on female pts. Results: Thirty-nine females and 26 males with a median age at dx of 14 yrs were classified as follow: 34 (52%) essential thrombocythemia (ET), 16 (24.5%) familial thrombocythemia (FT), 11 (17%) polycythemia vera (PV), 3 (4.5%) familial polycythemia (FP) and 1 idiopathic myelofibrosis (IM). Clinical and biological data, treatment and outcome are reported. Pts with familial disease were younger than those with the sporadic form (p<.05). Hematocrit (Hct) values were higher in ET than in FT pts (p .0047). Fifty pts underwent a bone marrow aspirate and biopsy (15 FT and FP children were excluded). No chromosome abnormalities were found. Overt fibrosis was present in 1 pt. Symptoms at dx were recorded in 21/64 pts (33%) and splenomegaly was present in 13/64 (20%), more frequently in sporadic disease pts. The JAK2V617F mutation was found in 47.5% of ET and 27% of PV. Clonal myelopoiesis was present in 7/11 (63.5%) ET and 2/3 PV females. None of the FT and FP pts showed JAK2V617F mutations or clonality. EECs grew in 58% of ET, in 42% of FT and in 40% of PV. PRV-1 RNA overexpression was found in 29/44 pts (66%). No EECs growth or EPO-r gene mutation was found in FP pts. The median EPO level was 5 mU/ml (1.1–16.4) in polycythemic pts. MPLS505A mutations were detected in15/16 FT pts and a novel HIF2A mutation in 1 FP pt. Treatment was modified during follow-up (f-up): 15 children did not undergo any treatment and 16 pts received more than one cytoreductive drugs. Phlebothomies were carried out in 9 polycythemic pts. Overall, 26 pts were treated with different cytoreductive drugs (hydroxyurea, interferone-alpha, anagrelide and pipobroman). Because of the persistently higher platelet (PLT) count, ET children needed more cytoreductive drugs than FT pts (p .0006). Anti-platelet agents were used in 40 pts and stopped in 30. No hemorrhagic events were recorded; 3 pts (5%) developed thromboses. Eight pts had 11 pregnancies (4 abortions: 2 spontaneous). Five pts showed progressive splenomegaly, 2 (1 PV and 1 ET, untreated) of them developed IM. Two pts developed a cancer. All pts are alive after a median f-up of 10 yrs. Conclusions: This represents the largest reported series of pediatric MPD. A broad familial work-up combined to molecular analyses allowed us to characterize the MPD disorders in our pediatric population, to plan suitable treatments and to better manage their disease. ET (34 pts) FT (16 pts) PV (11 pts) FP (3 pts) IM (1 pt) -------------------------------------------------------------------------------- M/F 10/24 7/9 8/3 1/2 F Age at Dx (yrs) 15.53 (5.24–19.75) 11.91 (0.22–17.45) 16.47 (3.68–18.8) 11.18 (11.18–14.16) 19 WBC x 109/L 9,88 (5,62–22,22) 8,43 (5,17–16,06) 6,73 (4,86–28,67) 6,76 (5,4–6,77) 13,35 Hct % 41.65 (29–53) 36.15 (32.3–42) 53.9 (50–72.5) 53.20 (42.4–54.5) 31 PLT x 109/L 1109 (633–2800) 990,5 (611–2950) 217 (166–945) 207 (202–271) 995 Symptoms 12/33 (36%) 4/16 (25%) 5/11 (45%) 0/3 no Splenomegaly 8/34 (23.5%) 2/15 (13%) 3/11 (27%) 0/3 no Anti-platelet agents 27/34 (79.4%) 9/16 (56%) 4/11 (36%) 0/3 no Cytoreductive drugs 23/34 (68%) 2/16 (12.5%) 1/11 (9%) 0/3 no EECs pos 11/19 (58%) 5/12 (42%) 4/10 (40%) 0/3 no PRV-1 RNA overexpr 14/19 (74%) 6/12 (50%) 6/10 (60%) 3/3 (100%) yes JAK2 V617F mut 10/21 (47.5%) 0/13 3/11 (27%) 0/3 no Monoclonality 7/11 (63.5%) 0/7 2/3 (66%) 0/2 yes MPLS505A mut 0/15 15/16 (94%) – – – Thromboses 1/34 (3%) 2/16 (12.5%) 0/11 0/3 no Pregnancies 9 2 – – – F-up (yrs) 10.02 (0.37–27.28) 11.02 (0.86–26.96) 9 (0.25–17.14) 2 (2–9) 12