Transplantation of Maternal Haploidentical TcRαβ-Depleted Stem Cells for Malignant Infantile Osteopetrosis – Optimal Timing and Rapid Hematological Recovery

BACKGROUND: Osteopetrosis (OP), characterized by improper bone resorption is in most cases caused by dysfunctional, hematopoietic stem cell (HSC) derived osteoclasts. A number of genetic mutations are described to underlie OP and disease phenotypes varies from benign to very severe, rapidly progressive forms of OP. In most cases hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Especially in infantile malignant OP early HSCT is critical in means to recover allogeneic osteoclast function to inhibit and prevent otherwise mutilating disease progression. The use of an alternative donor is required in the absence of an HLA-identical healthy sibling. While donor search is time consuming, umbilical cord blood transplantation is usually related to higher transplant related morbidity/mortality. We present a case of infantile malignant autosomal recessive OP that illustrates the advantage of the use of haploidentical maternal TcRαβ+ cells depleted graft as an attractive curative approach.

PATIENT: The boy, carrying a common mutation involving the TCIRG1 gene was diagnosed with OP at 3 months of age while showing signs of progressing anemia, hypogammaglobulemia, esotropia/exophthalmia with suspicion of blindness, impaired hearing and multiple skeletal malformations. Three weeks later conditioning regimen was initiated and consisted of ATG-F (30mg/kg), i.v. busulfan (TDM; AUC 90mg +/- 5mg/L*h) fludarabin (160mg/m2) and thiotepa (15mg/mg). Maternal G-CSF mobilized mononuclear cells were harvested from peripheral blood and TcRαβ+ cell were depleted from the graft (CliniMACS). The patient was transplanted with a single graft including 44.8x10⁶ CD34+ cells/kg, 48.6x10⁶ TcRγδ+ cells/kg and 0.0011x10⁶ of residual TcRαβ+ cells/kg, followed by post-transplantation in vivo CD20-depletion (Rituximab 375mg/m2). Platelets (>50x10⁹/L) and neutrophils (>0.5x10⁹/L) recovery was reached day +14, respectively day +15 post-HSCT. Immunosuppression consisted of Cyclosporine A and Methylprednisolon and was discontinued 4, respectively 6 weeks post-HSCT without any signs of GvHD. There was no significant transplant related morbidity. OP characteristics did not show obvious progression following HSCT and at one year post-transplant the patient is in a stable general condition with good quality of life. He has decreased but stable hearing performance, deeply impaired vision (already before HSCT), normalization of the phenotypic facial and skeletal characteristics, normal bone marrow function as well as normal physical and mental development. T-cell chimerism showed convertion from initially mixed chimerism (up to 40% of autologous cell) to 100% donor chimersim at 1 year post transplant.

CONCLUSION: We conclude that haploidentical HSCT with TcRαβ+ depleted graft is an encouraging approach in infantile malignant OP that enables 1) prompt HSCT with immediate available parental donor and 2) rapid and sustained hematological recovery.