Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection

Abstract

Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Although reduced intensity conditioning regimens seem to be related to better outcomes, a standard regimen for dyskeratosis congenita has never been defined. Here, we report a successful long-term outcome of an 8-year-old girl with dyskeratosis congenita who received 2 consecutive allogeneic hematopoietic stem cell transplants from different unrelated donors, because of rejection after the first one, both conditioned with fludarabine-based reduced intensity conditioning regimen. The second transplant was complicated by severe hemorrhagic cystitis and acute grade IV graft-versus-host disease in the early phase and mild chronic graft-versus-host disease and ureteral stenosis in the late phase. This experience confirms that dyskeratosis congenita is at high risk for transplant-related morbidity but that a fludarabine-based reduced intensity conditioning regimen is a safe and feasible option as a preparative regimen, as shown here in a second transplant after first graft rejection. To reduce the risk of graft-versushost disease, more effective prophylaxis schedules should be chosen in cases of unrelated donor, and haploidentical hematopoietic stem cell transplant with in vitro α/β+ and CD19+ depletion should be considered. Key words: Allogeneic hematopoietic stem cell transplant, Bone marrow failure, Reduced intensity conditioning regimen IntroductionDyskeratosis congenita (DC) is a rare heterogeneous inherited disorder, characterized by abnormal skin pigmentation, oral leukoplakia, nail dystrophy, and bone marrow failure. 1,2 Cancer predisposition with increased risk of squamous cell carcinoma and hepatolymphoid neoplasms and pulmonary fibrosis represent typical severe features of the disease. 3 About 60% to 70% of affected patients carry a mutation in telomerase genes (DKC1, TERC, TERT, NOP10, and NHP2), which are required to synthesize the tandem repeats of the TTAGGG sequencing or of the telosome/shelterin complex proteins (TINF2) acting at chromosome ends. 4 Their defect leads to telomere shortness and consequent chromosomal instability, with premature stem cell exhaustion, tissue failure, and high tissue sensitivity to toxic damage. 5 Moreover, high sensibility to oxidative stress has been demonstrated in DC-cultured cells. 6 Androgen therapy has been reported to improve bone marrow function 7 ; however, allogeneic hematopoietic stem cell transplant (HSCT) still represents the only curative option for DC-related bone marrow failure.Few reports on HSCT for DC have been published so far. Although overall survival has progressively improved over the years with ...