Effect of Prior Therapy With Nilotinib or Dasatinib on the Outcome After Allogeneic Stem Cell Transplantation for Patients With Chronic Myeloid Leukaemia

Chronic myeloid leukemia (CML) is a clonal disorder characterized by the chromosomal translocation t(9;22) which produces a fusion gene encoding the chimeric oncoprotein, BCR- ABL. This protein harbors a deregulated constitutive activated tyrosine kinase (TK) leading to leukemogenesis [1].

Imatinib mesylate, the first potent selective inhibitor of BCR-ABL TK [2] has become the frontline therapy for newly diagnosed CML patients [3]. It can induce haematologic and cytogenetic remission in all stages of CML, as well as in Ph positive acute lymphoblastic leukaemia (Ph+ ALL) with minimal toxicity [4, 5]. However, resistance and relapse during imatinib treatment are increasingly reported [6] and complete molecular remissions, as measured by polymerase chain reaction (PCR) are rare [7-9]. Loss of response to imatinib is frequently associated with mutations in the kinase domain of BCR-ABL which lead to impaired imatinib binding [10-12].

Nilotinib and Dasatinib are orally available kinase inhibitors that can overcome resistance to Imatinib [13 - 15]. Recent studies have demonstrated the efficacy and safety of both Nilotinib and Dasatinib in all stages of imatinib resistant CML. However, the long-term durability of these responses is uncertain yet, and substantial toxicity has been encountered [16]. Major adverse events observed during Nilotinib therapy were cytopenias, bone marrow suppression, gastrointestinal haemorrhage, diarrhea, cardiac dysfunction, liver toxicities and dermatitis [17-19] and during Dasatinib therapy grade 3/4 thrombocytopenia and neutropenia were reported in nearly half of the patients and non-hematologic toxicity consisted primarily of diarrhea, headache, fatigue, dyspnea and pleural effusion [20, 21].

Allogeneic stem cell transplantation (SCT) is now used mainly as salvage or curative therapy in patients with advanced CML who were previously treated with imatinib. While one study showed higher incidence of graft versus host disease (GVHD), venoocclusive disease (VOD) and transplant related mortality (TRM) [22], most studies have demonstrated that imatinib therapy prior to allogeneic SCT doesn't adversely affect transplantation outcome [23,24] . By contrast, previously used therapies for CML including busulfan and interferon alpha (if administrated less than 3 months before allogeneic SCT) have been reported to increase transplant related toxicities and mortality in CML patients undergoing allogeneic SCT [25, 26].

The impact of pre-transplant nilotinib or dasatinib therapy on transplant related complications, morbidity and outcome is mostly unknown and only two small case series have as yet been reported on this topic [27, 28]. However, allogeneic SCT will continue to be used as a salvage or curative therapy for CML especially in cases with resistance to kinase inhibitors or in patients at high risk of relapse, such as those in second chronic phase after blast crisis [29]. In the future 2nd generation TKIs may replace at least in part imatinib as frontline therapy for CML or will continue to be used in imatinib resistant patients. Nevertheless, in high risk patients allogeneic transplantation appears to remain the only curative treatment option.