Matched Unrelated Allogeneic Stem Cell Transplantation for Patients with Congenital Amegakaryocytic Thrombocytopenia: Texas Children`s Hospital Experience
Authors: Bhar Saleh , Yassine Khaled , Martinez Caridad , Sasa Ghadir S. , Naik Swati , Mahoney Donald , Bertuch Alison A , Allen Carl , Ahmed Nabil , Hegde Meenakshi G. , Heslop Helen E. , Brenner Malcolm K. , Gottschalk Stephen , Krance Robert A. , Leung Kathryn S. 
Published: October 2019

Abstract
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by decreased or absent numbers of megakaryocytes and is not associated with congenital malformations. It is an autosomal recessive disorder with mutations in the thrombopoietin receptor c-MPL, presenting at birth with severe isolated thrombocytopenia. Given the increased risk of life threatening hemorrhage, close monitoring and supportive care with regular platelet transfusions is usually required. The severity of the MPL mutation may predict the clinical course of children with CAMT. Null mutations may rapidly progress to pancytopenia and aplastic anemia, while more modest functional loss of receptor function cause a transient increase in platelet count to > 50,000/µL during the first year of life with later progression to pancytopenia. Moreover, like other IBMFSs, CAMT has been referred to as a cancer predisposition syndrome. Allogeneic hematopoietic stem cell transplant (HSCT) offers the only curative option.
We present our institutional experience of three patients with CAMT who underwent matched unrelated HSCT early in the course of the disease when their presenting problem was isolated thrombocytopenia without pancytopenia, marrow failure or clonal evolution. We have used a fully ablative regimen with busulfan 1 mg/kg/dose for 16 doses (days -9, -8, -7, and -6), cyclophosphamide 50 mg/kg/dose for 4 doses (days -5, -4, -3, and -2) and alemtuzumab 3 mg/day (weight-based dosage) for 4 doses (days -5, -4, -3, and -2). Cyclosporine and mini methotrexate (on days +1, +3, +6 and +11) were given for GVHD prophylaxis.
The first two patients were siblings with persistent thrombocytopenia at birth, the first of whom had compound heterozygous mutations (c.256dupC and c.391+5 G>C) in the MPL gene. Both parents were carriers and the second sibling was diagnosed prenatally with the same mutations. No other phenotypic abnormalities were noted and testing for Fanconi anemia was negative. The siblings were transplanted with matched unrelated donors at 12 months and 14 months respectively.
Our third patient was diagnosed prenatally with germinal matrix hemorrhage and vetriculomegaly. He was noted to have thrombocytopenia after birth. He was treated initially for presumed neonatal alloimmune thrombocytopenia. Sequencing of the MPL gene revealed two compound heterozygous missense mutations (R257C and R102P). The patient was transplanted with a matched unrelated donor at the age of 11 months.
All patients tolerated the transplant with minimal toxicity, durable engraftment, and no acute or chronic GVHD. The first two siblings are approximately 4 years and 2 years post HSCT and the third patient is past day 100.
Previous reports of HSCT for CAMT that used matched unrelated donors recorded poor outcomes, with a high rate of graft failure. Although our current study is small in size, the results suggest that a HSCT following a fully ablative regimen containing alemtuzumab and performed early in the course of the disease may produce better outcomes, and will avoid the complications associated with marrow failure and clonal abnormalities.

Disclosures
Allen: Roche: Consultancy, Other: unpaid; NovImmune: Consultancy, Other: unpaid. Heslop:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement. Brenner:Celgene: Other: Collaborative Research Agreement; Cell Medica: Other: Licensing Agreement; Bluebird Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.