Long-Term Outcome of Children with Acute Myeloid Leukemia in First Remission Given Allogeneic HSCT from a Matched Family Donor After a Conditioning Regimen Comprising Busulfan, Cyclophosphamide and Melphalan

Background. More than 80% of children with de novo acute myeloid leukemia (AML) achieve complete remission (CR) after aggressive induction chemotherapy. However, post-remission treatment plays a crucial role in the final outcome of these patients. In this regards, possible post-remission treatments include high dose chemotherapy, as well as autologous or allogeneic hematopoietic stem cell transplantation (HSCT). In the last years, several groups have compared allogeneic HSCT with chemotherapy or autologous HSCT in adults as well and children with AML in first remission. These studies have demonstrated that allogeneic HSCT is superior to the other forms of post-remission therapy in children with AML not carrying favourable cytogenetic characteristics. We herein report the long-term results of a prospective multicenter study aimed at evaluating the safety and efficacy of an original combination of 3 alkylating agents, busulfan (BU), cyclophosphamide (CY) and melphalan (L-PAM) as conditioning regimen for patients affected by de novo AML other than the FAB M3 subtype and given allogeneic HSCT from a matched family donor in first haematological CR. Patients and methods. Seventy consecutive patients (40 males and 30 females), affected by de novo AML in first CR, received an allogeneic HSCT from a HLA-matched family donor after a conditioning regimen combining BU (4 mg/Kg/day for 4 days), CY (60 mg/Kg/day for 2 days) and L-PAM (140 mg/m2). BU dosage was adjusted after the pharmacokinetic study performed following the first administration, in order to maintain a concentration to the steady state (Css) comprised between 600 and 900 ng/mL. Transplants were performed in one of the transplant centers of the Italian Association for Pediatric Hematology / Oncology (AIEOP) between 1992 and 2002. Median patient age at HSCT was 7 years (0.5 – 17). Two patients had FAB M0 AML, 25 M1, 17 M2, 12 M4, 21 M5, 1 M6 and 2 M7 AML. Children with M3 AML were excluded from the study. Five patients with CBF anomalies, either isolated or associated with loss of sex chromosome, were considered to have favourable cytogenetics. The median interval between diagnosis and HSCT was 3.9 months (2.9 - 9). All patients were given bone marrow stem cells. GVHD prophylaxis consisted of cyclosporine-A (Cs-A) alone in 89% of patients, the remaining children receiving a combination of Cs-A with short-term methotrexate. Results. Median follow-up for surviving patients is 9 years (range, 6 – 16 years). The conditioning regimen was well tolerated, and no patient died for causes directly attributable to the myeloablative treatment. All patient engrafted, the median time to reach neutrophil and platelet recovery being 13 (7 - 28) and 21 (13 – 115) days, respectively. The cumulative incidence (CI) of grade II-IV acute GVHD was 58% (48 – 71), while that of grade III-IV acute GVHD was 14% (8 – 25). Chronic GVHD incidence was 27% (18 – 39). Ten-years survival probability was 77% (67 - 87), while 10-years disease-free survival (DFS) was 76% (65 - 86). The cumulative incidence of relapse was 17% (10 – 29), while the cumulative incidence of transplant-related mortality was 7% (3 – 17). Results improved over time, DFS being 59% (41 – 78) for patients transplanted before 1997 and 86% (75 – 96) for those transplanted after 1997. No other variables influenced the probability of both survival and DFS. Conclusions. Our study, conducted on a significant number of children affected by AML in first CR and with a very long follow-up demonstrate that allogeneic HSCT from a matched family donor can cure a large proportion of patients. The combination of dose-adjusted BU, CY and L-PAM was safe and well tolerated, with an incidence of TRM of only 7% and no death directly attributable to the conditioning regimen. Furthermore, the combination of 3 alkylating agents showed a good anti-leukemic activity, the probability of leukaemia recurrence being only 17%.