Practice of allogeneic hematopoietic stem cell transplantation for infantile autosomal recessive osteopetrosis
Authors: Burya A. E. , Kirgizov K. I. , Pristanskova E. A. , Melnikova M. B. , Palm V. V. , Mikhailova S. V. , Skorobogatova E. V. 
Published: June 2019

Generalized osteopetrosis is a rare hereditary disease characterized by impairment of skeleton bones formation, bone marrow dysfunction, neurologic deficiency and blindness. The main treatment for osteopetrosis is an allogeneic hematopoietic stem cell transplantation (allo-HSCT). To review and analyze experience of Department of bone marrow transplantation of RDKB (BMT RDKB) of allo-HSCT for patients with autosomal recessive generalized osteopetrosis; to evaluate tolerability and efficacy of the conditioning regiment administered. Between 2010 to 2018 years, 7 patients (2-male, 5-female) with autosomal recessive generalized osteopetrosis underwent allo-HSCT in tDepartment of bone marrow transplantation of RDKB. Median age at the moment of HSCT was 5,5 years (1–11 years). Before the transplantation myeloablative conditioning regimen was used: treosulfan, fludarabine and melphalan for 5 patients, treosulfan, fludarabine and thiotepa for 1 patient and treosulfan with fludarabine for 1 patient. In case of unrelated allo-HSCT antithymocyte globulin was added to the conditioning regimen. Bone marrow from matched (HLA- 10/10) unrelated donor was used for 4 patients, peripheral blood stem cells from matched unrelated donor was used for 1 patient, two grafts of unrelated umbilical cord blood (HLA 8/10 and 9/10) for 1 patient and peripheral blood stem cells from matched (HLA 10/10) from related donor – for 1 patient. For “graft-versus-host” disease (GVHD) prophylaxis either cyclosporine A/tacrolimus and methotrexate/ mofetil mycophenolate was used. White blood cell recovery had been achieved for 6 from 7 patients on +13 to +22 day (median +17 day). Quick autoreconstitution of hemopoesis was observed for the recipient of umbilical cord blood who got one myeloablative drug. The following early post transplantation complications were registered: oropharyngeal mucositis up to II degree in 6 patients, neutropenic enterocolitis up to II degree in 4 patients, up to III degree in 3 patients, sepsis in 3 patients. The GVHD symptoms occurred in 2 cases: skin form of II degree in one patient and skin form of II degree and intestinal form of IV degree in another patient. One patient with neurodegenerative form of osteopetrosis died with increase of hypertensive-hydrocephalus syndrome, cerebral edema with downward cerebellar herniation. During 5-6 months after allo-HSCT the 5 successfully transplanted patients experienced poor graft function but then reduction of extramedullary hemopoesis occurred and full engraftment was achieved. Hypercalcemia was reported in 2–5 months after allo-HSCT and was treated by administration of bisphosphonates. Visual impairment persisted after allo-HSCT. After 4–6 months after transplantation axis skeleton growth occurred for all 5 successfully transplanted patients, skull deformation reduced and no new zones of nerve’s compression were observed. No patients had any developmental delays after the treatment. Allo-HSCT is an effective systemic treatment of autosomal recessive generalized osteopetrosis. However because serious neurodegenerative condition cannot be reversed by allo-HSCT, such treatment may not be recommended for patients with heavy CNS impairment. Myeloablative conditioning regimen with two alkylating agents provides allogeneic reconstitution of hemopoesis. In post transplantation period, measures for hypercalcemia control are necessary. Early diagnostic of autosomal recessive generalized osteopetrosis can help to evaluate feasibility of allo-HSCT and to start treatment on time thus provide chance for long-term rehabilitation and prevention of serious disability. The study was approved by the Independent Ethics Committee of Russian Children's Clinical Hospital.