Prior Treatment with Dasatinib Followed by Stem Cell Transplantation In Patients with CML In Advanced Phases with BCR-ABL Mutation.

The prognosis for patients with chronic myeloid leukemia (CML) in advanced phases remains dismal, especially for those who develop ABL mutation. Administration of second-generation tyrosine kinase inhibitors (TKI) might provide an effective approach for patients with BCL-ABL mutation, but it only offers short-tem benefit in most cases. Allogeneic stem cell transplantation (allo-SCT) seems the only curative therapy for advanced CML, and limited data exist on the effectiveness of allo-SCT following prior treatment with new TKI dasatinib.

To evaluate the efficacy of this combination therapy, patients with advanced disease harboring BCL-ABL mutation were enrolled between May 2009 and May 2010, and given dasatinib for a predetermined period, and then referred to myeloablative allo-SCT. All the patients were conditioned with busulfan/cyclophosphamide based regimens. ATG was used for those who received HLA-haploidentical transplantation. Cyclosporin, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prophylaxis.

(1) Five patients with accelerated phase (n=1) and blast crisis (n=4) were enrolled. The median age was 37 years (range, 11–42 years). All the patients had a history of chronic phase (CP) before enrollment. Three patients progressed to advanced phases on imatinib. The other two patients didn't receive any TKIs during the CP. When progressing to blast crisis, imatinib was administered but showed no response. BCR-ABL mutations were detected at the beginning of enrollment. The mutations were F359C, D296G, E459G, Y253H, Y253F. (2) After enrollment, patients were treated with dasatinib for 1–3months (median, 2 months). At the time of transplant, all patients achieved complete hematological response and returned to CP, and two patients achieved partial cytogenetic response. Dasatinib was well-tolerated expect one patient who developed pleural effusion. (3) Donors were HLA-haploidentical related in two cases,HLA-identical related in one case, and HLA-identical unrelated in two cases, respectively. All patients engrafted successfully, with a median time to neutrophil (>500/ul) and platelet (>30000/ul) recovery of 15 and 17 days respectively. Two patients experienced grade III-IV acute GVHD). Chronic GVHD (cGVHD) was observed in three patients, including two with extensive cGVHD. The relapse rate after transplantation was 0. Only one patient died from pulmonary fungal infection while in complete molecular remission. After a median follow-up of 6.5 months, four patients were alive with complete cytogenetic remission, including three in complete molecular remission.

Dasatinib given before allo-HSCT do not negatively affect transplant engraftment and response rate. Myeloablative transplantation for imatinib-resistant CML may have a satisfactory outcome when combined with dasatinib, which could provide a good quality of remission prior to transplantation and a curable opportunity after transplantation.

No relevant conflicts of interest to declare.