Successful umbilical cord blood transplantation in a child with dyskeratosis congenita after a fludarabine‐based reduced‐intensity conditioning regimen

Dyskeratosis congenita (DC) is characterized by atrophy and reticular pigmentation of the skin, nail dystrophy and leukoplakia of mucosa membranes (Dokal, 2000). Other manifestations include hypotricosis, dysphagia, skeletal abnormalities, mental retardation and bone marrow failure (Dokal, 2000). Despite the fact that DC is considered mainly to be an X-linked recessive disorder, cases of both autosomal recessive and dominant transmission have been reported (Dokal, 2000). Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative approach for severe bone marrow failure experienced by patients with DC. However, results of allograft in these patients have been relatively poor, due to occurrence of both early and late complications, reflecting the increased sensitivity of endothelial cells to radiotherapy and alkylating agents (Berthou et al, 1991; Langston et al, 1996). As interstitial and obstructive lung disease, as well as liver toxicity, have been observed (Rocha et al, 1998), conditioning regimens avoiding radiotherapy and busulphan have been suggested. We report a patient with DC developing aplastic anaemia who was given cord blood transplantation (CBT) from a human leucocyte antigen (HLA)-identical sibling, using a fludarabine-based non-myeloablative conditioning regimen. A boy was diagnosed with DC at the age of 2 years. He was found to have skin reticular pigmentation, nail dystrophy, microcephaly, hyperhydrosis, hypotricosis and short stature. At that time, full blood cell count showed haemoglobin 3·1 g/dl, white blood cell count 3·0 × 109/l (absolute neutrophil count, ANC, 1·0 × 109/l) and a platelet count of 27 × 109/l. Bone marrow aspirate showed tri-linear hypoplasia and in vitro culture of committed progenitors documented reduced colony growth. Chromosomal analysis of both peripheral blood and marrow cells was normal and the diepoxybutane (DEB) test was negative. As anaemia and thrombocytopenia persisted, he was transplanted 5 years after diagnosis using the placental blood from his HLA-identical sister. The conditioning regimen consisted of 4 d (d −6 to d −3) fludarabine (30 mg/m2/d), cyclophosphamide (10 mg/kg/d) and rabbit antithymocyte globulin (ATG 3·75 mg/kg/d). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A. The number of nucleated cells infused was 3 × 107/kg. The post-transplant course was uneventful; ANC > 0·5 × 109/l was reached on d +18 and a self-sustained platelet count > 20 × 109/l on d +40. No symptoms or signs of either acute or chronic GVHD were observed. Complete donor chimaerism was documented on d +20, and 3, 6, 12 and 24 months after SCT. Thirty-six months after CBT, he is well, with normal blood count, normal immune function and a Lansky score of 100%. Effectiveness of allogeneic HSCT in patients with DC has been hampered by propensity to develop early and late complications. To the best of our knowledge, only seven out of 22 patients given an allograft have survived, fatal late events that occur years after transplantation have been reported (Berthou et al, 1991; Langston et al, 1996; Rocha et al, 1998; Ghavamzadeh et al, 1999) (Table I). Endothelial damage/activation syndrome (liver venous occlusive disease, thrombotic thrombocytopenic purpura) and pulmonary fibrosis have been reported to be common and often lethal events due to increased sensitivity of endothelial cells to both radiation and alkylating agents. Thus, it has been suggested that the preparative regimen should include neither radiotherapy nor busulphan (Rocha et al, 1998; Dokal, 2000). Fludarabine has been used successfully for allogeneic HSCT in patients not eligible for conventional conditioning, as regimens including this drug are well tolerated and have limited extra-medullary toxicity. We reasoned that a preparative regimen comprising fludarabine, low-dose cyclophosphamide and ATG should be sufficient to enable engraftment of donor stem cells without undue toxicity. As patients given a cord blood transplant have a low risk of developing GVHD (Rocha et al, 2000), we also speculated that use of this source of stem cells should spare our patient from the effects related to occurrence of immune-mediated complications, which represent a contributing factor for post-transplant endothelial damage (Rocha et al, 1998). Our case suggests that regimens including fludarabine may represent a safe and efficacious approach to cure aplastic anaemia in DC patients, in whom donor healthy stem cells should have a growth advantage. This work has been partly supported by grants from AIRC (Associazione Italiana Ricerca sul Cancro), CNR (Consiglio Nazionale delle Ricerche), MURST (Ministero dell'Università e della Ricerca Scientifica e Tecnologica) and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Policlinico S. Matteo to F.L.