Haploidentical non‐myeloablative stem cell transplantation as Salvage for graft failure in a patient with juvenile myelomonocytic leukemia

To the Editor: A 2-year-old male, with del(7q) juvenile myelomonocytic leukemia (JMML) was treated with an unrelated umbilical cord blood transplantation (UCBT) after intravenous busulfan, fludarabine, and thymoglobulin conditioning regimen, but had primary graft failure with autologous recovery at 31 days post-transplant. First regimen was intravenous busulfan (19 mg/ kg), fludarabine (160 mg/kg), and rabbit thymoglobulin (10.5 mg/ kg). Nine months later he underwent a second UCBT following intravenous busulfan (20 mg/kg), cyclophosphamide (120 mg/ kg), and melphalan (140 mg/m). No neutrophil recovery was seen until 60 days post-transplant, and bone marrow biopsy showed hipocellular marrow, confirming engraftment failure. The patient then underwent a haploidentical transplant, receiving peripheral blood stem cells collected from his mother. The conditioning regimen consisted of fludarabine (30 mg/m/day, from day 5 to 2), cyclophosphamide (500 mg/m/day, from day 5 to 2) and alemtuzumab (3 mg/day from day 4 to day 0). Total number of infused CD34þ cells was 30.90 10/kg. The patient had neutrophil engraftment on day 14 post-infusion with no major toxicities. Cytomegalovirus reactivation was the only infection observed. Donor chimerism of 100% was observed on day 30 post-transplantation. The patient developed grade II acute graft-versus-hostdisease (GVHD) of the skin on day 30, which was responsive to oral prednisone. On day 95, cyclosporine was switched to tacrolimus due to microangiopathic anemia. At 7 months post-transplant, the patient developed progressive increase of alkaline phosphatase and bilirubin. Severe vanishing bile duct syndrome secondary to chronic hepatic GVHD was diagnosed by liver biopsy. The patient was started on prednisone and mycophenolate mofetil with partial response. Daclizumab was added to the regimen and resulted in normalization of hepatic function. The patient is now 22 months after transplantation and in complete remission. He is still on immunosuppressive therapy (prednisone, tacrolimus, and sirolimus), doses being tapered. He is now 5 years old, shows a satisfactory cognitive development, started going to school, and has no sign of chronic GVHD. He is still hypogammaglobulemic and intravenous immunoglobulin is replaced monthly. The boy has a short stature due to premature closure of epyphisis. Graft failure is a life-threatening complication of hematopoietic stem cell transplantation (HSCT) [1] and is more frequent following UCBT [2]. When graft failure occurs, a second transplant from the most available source is a therapeutic option [3]. Haploidentical related donor is a possible approach, since most patients have a potential donor readily available. However, the toxicity of the conditioning regimen, the increased immunosuppression necessary to overcome HLA disparity and the need for graft T-cell depletion can increase the chance of disease relapse and infections [4,5]. The use of non-myeloablative regimens may decrease the toxicity of haploidentical transplants. One report described the feasibility and efficacy of non-myeloablative regimens using fludarabine and alemtuzumab [6]. The study was conducted in adults, and we adapted the regimen for our patient. An adjusted dose of alemtuzumab was used based on previous reports with this drug in children [7]. Our case illustrates that non-myeloablative haploidentical transplant without ex vivo T-cell depletion is a possibly useful strategy in primary graft failure after UCBT.