A Prospective Trial of Minimal Intensity Conditioning with Fludarabine and Anti-CD52 Antibody Alone in Dyskeratosis Congenita

Background: Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome classically presenting with a clinical triad of skin pigment abnormalities, nail dystrophy, and oral leukoplakia. Progressive BMF occurs in approximately 80% of patients by 30 years of age and is the primary cause of death, followed by pulmonary failure and malignancies. HCT for DC is limited by a high incidence of treatment-related mortality, due to the exacerbation of underlying multi-organ disease by alkylating agents and radiation in the conditioning regimen. DC is caused by lesions in telomere biology genes, which compromise cellular replicative capacity. Because of this intrinsic cellular defect, we hypothesize that DC patients will show acceptable rates of engraftment with a minimally cytotoxic conditioning regimen that excludes alkylating agents and radiation. Vuong et al. (Acta Hematologica, 2010) have previously reported successful engraftment in a single DC patient using fludarabine and antithymocyte globulin conditioning. Based on this rationale and experience, we initiated a prospective HCT trial with immunosuppression-only conditioning, which would be predicted to improve outcomes and reduce secondary malignancies in DC patients. 

Methods: Patients up to age 30 years old with a well-matched bone marrow donor are conditioned with anti-CD52 and fludarabine, and receive cyclosporine A and mycophenolate mofetil as graft versus host disease (GVHD) prophylaxis. Primary outcome measures include neutrophil engraftment at day +30 and survival at day +100, and secondary outcome measures include rates of graft failure, infections, GVHD, secondary malignancies, and acute and long-term toxicities.

Results: 3 patients with DC underwent unrelated donor HCT with one-year follow-up. 18 month-old identical twins with TINF2 mutations and transfusion-dependent BMF received HCT from a fully HLA-matched donor, and were platelet–independent and neutrophil engrafted by day +28. Myeloid chimerism was consistently fully donor. Lymphoid chimerism was <10% donor on day +100, and increased to 88-95% donor by one year post-transplant. The third patient was an 18 year-old female with DC due to CTC1 mutations and transfusion-dependent BMF, who underwent single allele (HLA B) mismatched HCT. She was platelet-independent and neutrophil-engrafted by day +21. Myeloid and lymphoid chimerism were fully donor in the post-transplant period. Currently one year post-HCT, all three patients are transfusion-independent and off immunosuppression without significant toxicities.

Conclusions: Early data suggest the feasibility of an immunosuppression-only conditioning regimen for allogeneic HCT in patients with DC. Ongoing studies will determine the general applicability of this regimen in a disease as heterogeneous as DC, and longer-term follow-up will reveal the impact on late effects.