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Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim.

ABSTRACT: Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited disorder characterized at birth by thrombocytopenia with reduced megakaryocytes, which evolves into generalized bone marrow aplasia during childhood. Although CAMT is genetically heterogeneous, mutations of MPL, the gene encoding for the receptor of thrombopoietin (THPO), are the only known disease-causing alterations. We identified a family with three children affected with CAMT caused by a homozygous mutation (p.R119C) of the THPO gene. Functional studies showed that p.R119C affects not only ability of the cytokine to stimulate MPL but also its release, which is consistent with the relatively low serum THPO levels measured in patients. In all the three affected children, treatment with the THPO-mimetic romiplostim induced trilineage hematological responses, remission of bleeding and infections, and transfusion independence, which were maintained after up to 6.5 years of observation. Recognizing patients with THPO mutations among those with juvenile bone marrow failure is essential to provide them with appropriate substitutive therapy and prevent the use of invasive and unnecessary treatments, such as hematopoietic stem cell transplantation or immunosuppression.

SUBMITTER: Pecci A

PROVIDER: S-EPMC5760853 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim.

Pecci Alessandro A Ragab Iman I Bozzi Valeria V De Rocco Daniela D Barozzi Serena S Giangregorio Tania T Ali Heba H Melazzini Federica F Sallam Mohamed M Alfano Caterina C Pastore Annalisa A Balduini Carlo L CL Savoia Anna A

EMBO molecular medicine 20180101 1

Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited disorder characterized at birth by thrombocytopenia with reduced megakaryocytes, which evolves into generalized bone marrow aplasia during childhood. Although CAMT is genetically heterogeneous, mutations of <i>MPL</i>, the gene encoding for the receptor of thrombopoietin (THPO), are the only known disease-causing alterations. We identified a family with three children affected with CAMT caused by a homozygous mutation (p.R119C) o ...[more]

PMID: 29191945

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Project description:BackgroundTreatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12-16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109 /L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109 /L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP.ProcedurePatients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50-200 × 109 /L, maximum dose 10 µg/kg). Bone marrow examinations were not required.ResultsAt baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109 /L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109 /L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities.ConclusionsLong-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208-213. © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.

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Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim.

Publications

Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim.

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