Haema 2012; 3(1): 45-56
by Ifigeneia Tzannou and Ioannis Baltadakis
Department of Hematology and Stem Cell Transplantation Unit, Evaggelismos General Hospital, Athens, Greece
Abstract
Allogeneic stem cell transplantation (allo-SCT) was the first modality proven to be cura- tive for chronic myeloid leukemia (CML) by eradication of the malignant Philadelphia-positive clone. Since the introduction of the first tyrosine kinase inhibitor (TKI), imatinib, and the outstanding results obtained by targeted therapy, allo-SCT is no longer a first-line treatment for the majority of CML cases. However, allo-SCT is currently a therapeutic option for the considerable proportion of patients (40%) who fail up front treatment with imatinib. The decision to proceed to allo-SCT depends on carefully weighting the expected benefits against the estimated risks of the procedure. The risk of transplantation is assessed by the European Group for Blood and Marrow Transplantation (ΕΒμτ) score which main- tains its validity nowadays,with an improvement of survival by 10-15% for all risk categories over the last decade. The ΕΒμτ risk scorecombined with the recently developed hematopoietic cell transplantation-specific comorbidity index (HCT-CI) could result in a more accurate prediction of the outcome of allo-SCT on individual patient basis, thereby facilitating better selection of suitable transplant candidates and allowing for customization of the procedure according to risk. The latter can be pursued by the choice of the appropriate conditioning regimen (myeloablative or reduced-intensity) in concert with the preemptive use of TKI and exploitation of the graft-versus-leukemia (GVL) effect by donor lymphocyte infusions (DLI) post transplant. For patients with advanced disease, improvement of the results of allo-SCT can been accomplished by pretransplant use of TKI in order to achieve a second chronic phase. Moreover, the outcomes of unrelated donor SCT, have become comparable to those of matched sibling transplants, due to selection of more compatible donors by DNA-based HLA typing techniques. According to current European Leukemia Net guidelines (2009), allo-SCT is mainly recommended for patients with advanced phase CML at presentation or with disease progression under imatinib treatment, as well as upon failure of therapy with second generation TKI (2G-TKI). However, the indications and the timing of allo-SCT in the era of TKI are subject to continuous revision in the light of emerging data from recent clinical studies. Patients with unfavorable outcomes with second-line TKI can be identified in advance, based on Sokal score at diagnosis, prior cytogenetic response (CgR) to imatinib, and occurrence of neutropenia during imatinib treatment (Hammersmith score), as well as by the absence of any CgRat 3 months of therapy with 2G-TKI. Furthermore, the level of molecular response at 3 months of treatment may define a subgroup of about 10% of patients, who are not going to respond to first- or second-line therapy with 2G-TKI. Therefore, in the immediate future, transplantation may be considered as a timely, second-line therapy for suitable patients according to the molecular response at the first 3 months of treatment with TKI. This approach will allow for a more rational design of the procedure, and may improve further the outcomes of allo-SCT in CML, which are largely dependent on disease phase and on the interval from diagnosis to transplant.