Background: Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in young children that is classified as a myelodysplastic/myeloproliferative neoplasm and not only characterized by young age, hepatosplenomegaly, thrombocytopenia and monocytosis, but also by molecular aberrations in the RAS-RAF-MEK-ERK signaling pathway and GM-CSF-hypersensitivity. Most children with JMML experience an aggressive clinical course and the only curative treatment option for these children is stem cell transplantation (SCT). Osteogenesis imperfect (OI) is also an orphan inherited monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities. Current multidisciplinary management could only improve quality of life for patients, including physical therapy, drug treatment and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell or bone marrow transplantation, targeting the specific altered pathway rather than the symptoms, may develop new curative treatments. Here we report a 3-year-old boy who suffered from both JMML and OI, was successfully transplanted and kept presenting an encouraging outcome up to now. Aims:To investigate the possible efficacy and safety of Allogeneic Hematopoietic Stem Cell Transplantation in a boy both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta.

Methods:A 3-year-old boy presented with fatigue, fever, petechia and rash in Aug 2019, accompanying with loss of appetite, joint pain and severe hepatosplenomegaly. The boy had a special appearance of short stature and blue sclerae, meanwhile he suffered intermittent eczema and bone fracture twice since he was 2 years old. Similar characteristics were also positive in his grandmother, father and father's sister. The blood cell counts revealed anemia, thrombocytopenia and leukocytosis especially monocytosis. Bone marrow aspirate showed excessive proliferation of myelomonocytic cells and hypersensitivity to granulocyte-macrophage colony-stimulating factor in vitro. Somatic mutation of gene NF1, PTPN11 and COL1A1 were identified by Next Generation Sequencing.Therefore, the little boy was diagnosed with two rare diseases of Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta at the same time. After 4 courses of hypomethylating agents therapy, the boy underwent haploidentical allogeneic bone marrow stem cell transplantation combined with allogeneic single umbilical cord blood transplant in May 2020. The myeloablative conditioning regimen was composed of Decitabine (20mg/m2/day, days -13 to -9), Cyclophosphamide (25mg/kg/day, days -8 and -7), Busulfan(100mg/m2/day, days -6 to -3), Fludarabine (40mg/m2/day, days -6 to -2) and Cytarabine (100mg/m2/day, days -6 to -2). Post-Cyclophosphamide (50mg/kg/day, days +3 and +4), tacrolimus and mycophenolate mofetil were used for prophylaxis of graft-versus-host disease (GVHD).

Results:The number of infused TNCs from haplo-bone marrow and cord blood unit was 41.4×10^8/kg and 9.72×10^7/kg, respectively, while the number of infused CD34+ cells was 11.84×10^6/kg and 2.33×10^5/kg, respectively. The boy achieved sustained engraftment of both neutrophils and platelets at 16 days and 24 days, respectively, with complete haplo-donor chimerism of confirmed at 14 days. He developed grade III acute GVHD (skin, gut and liver) and recovered at 39 days after transplant. Clinical symptoms such as rash, joint pain and hepatosplenomegaly got complete remission, and the mutated genes like NF1, PTPN11 and COL1A1 all disappeared at 30 days. At the time of this report, the boy was alive with negative MRD and good quality of life with a follow-up of 3 months after HCT.

Conclusion:To our knowledge, this is the first report that a child both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta was cured by allogeneic hematopoietic stem cell transplantation.Our experience suggests that allogeneic bone marrow transplantation may be a novel safe and effective therapeutic strategy for OI patients.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.