Imatinib Mesylate For Chronic-Phase Chronic Myeloid Leukemia:Initial Treatment Versus After Failure Of IFN-α

BackgroundChronic myeloid leukemia (CML) is a malignant hematologic stem cell diseases with an incidence of about1-2cases per100000adults. The patients with CML will progress from chronic phase (CP) into accelerated phase (AP) and blastcrisis (BP).CML is characteried by leukemia cells carrying a Philadelphia chromosome (Ph1), forming by bcr-abl oncogene, which was a fusion of the abl from chromosome9q34and bcr on22q11.Imatinib mesylate (IM)is the first generation bcr-abl protein inhibitor, it has become the first-line treatment for CML. Before the IM era, interferon-a (IFN-a) was used for the treatment of patients with CML in CP (CML-CP). At present, due to the limitation of economic and other factors, there are still some of patients, who received IFN-a as first-line treatment. Some patients treated with IFN-a have finally received IM when they failure to response to or intolerance to IFN-a. However, there is limited information from China on the response to imatinib in the patients who are intolerant or refractory to IFN-a compared with newly diagnosed patients. In this study, we retrospectively analyzed the clinical outcome of patients with CML-CP after imatinib therapy, and compared the response to the treatment and safety in the patients after failure of IFN-a and patients receiving imatinib as initial therapy. Objective1. To compare and analyze efficacy of IM for the newly diagnosed CML patients and patients after failure to IFN-a.2. To compare primary and secondary cytogenetic resistance to IM between the newly diagnosed CML patients and the patients who failure to IFN-a therapy.3. To compare the different efficacy of IM therapy between the patients with CML in the early chronic phase (ECP) and the patients in the late chronic phase (LCP).4. To compare the toxicity of IM between the newly diagnosed CML patients and patients after failure of IFN-a therapy, including hematologic and non hematologic toxicity.MethodsA total of86CML patients in CP who received IM at400mg daily were subjected to analysis. The cytogenetic and molecular analyses were both performed every3months for the first6months and every6months thereafter. Cytogenetic response analysis was based on the G-banding in at least20cells in metaphase per sample. Molecular response analysis was based on transcript levels of Bcr-Abl determined by a standardized RQ-PCR method.Results1. At6months,83%(50/61) of newly diagnosed patients achieved partial cytogenetic response (PCyR), while37%of IFN-a failure group achieved PCyR (P<0.05). In addition,86.9%of newly diagnosed patients achieved complete cytogenetic response (CCyR) in24months, and67%of IFN-a group achieved CCyR in 24months. There was significant difference between two groups (P<0.001). The mean times achieved CCyR in newly diagnosed group and IFN-a failure group were6.0months and15.1months, respectively. Compared with newly diagnosed group, IFN-a failure group showed low rate of complete molecular remission (CMR)(70.4%vs40.0%, P=0.033).2. A total of28patients in two groups were cytogenetic resistance. There was14cases (22.9%) in the newly diagnosed group, including4cases (6.6%) with primary drug resistance. In IFN-a group,14cases (56.0%) were the primary drug resistance. There was significant difference between two groups (P=0.003).3.When the patients with CML in ECP were treated with IM,6/7,5/7,6/7,5/7cases in the newly diagnosed group got response with PCyR, CCyR, MMR and CMR, respectively by24months. Whereas,7/7,7/7,6/7, and5/7cases in the IFN-a group got response with PCyR, CCyR, MMR and CMR, respectively (P>0.05). However, the average time achieving CCyR were3.2months (2.9-5.1months) and12.1months (5.5-16.5months) for the newly diagnosed group and IFN-a group, respectively, there was a significant difference (P<0.05). Similarly, when the patients with CML in LCP were treated with IM, the average time achieving CCyR were6.3months (4.9-7.7months) in the newly diagnosed group and17.0months (5.9-28.8months) in IFN-a group, respectively (P<0.05).4. Hematologic and non hematologic toxicity after treatment with IM in two groups of patients were similar. However, the patients in IFN-a group showed more anemia and leukopenia with grade3-4(P<0.05).Conclusion1. Compared with newly diagnosed patients, CML patients after failure of IFN-a therapy have a high rate of primary cytogenetic resistance and much grade3-4hematologic toxicity.2. At6months, the patients in IFN-α group showed less PCyR.3. At24months, less patients in the newly diagnosed group achieved CCyR and CMR.4. The patients of IFN-a group in ECP and LCP needed a long time to achieve CCyR.5. This study suggested the patients with CML should receive the treatment of IM as early as possible. The CML patients after failure of IFN-α therapy may need the detection of mutation of bcr-abl and are suggested to use second generation tyrosine kinase inhibitors.