Imatinib Meslate In Accelerated And Blastphase

Although it is unlikely that patients, nowadays, will enter blastic or accelerated phase without having received prior treatment with imatinib, it is worthwhile to review the results of imatinib therapy in ima-tinib-naive patients for historical interest, as well as to gain some understanding of the role of bcr/abl in the growth and proliferation of CML cells during transformation to the blast phase.

The clinical development of imatinib mesylate followed the traditional development of cytotoxic agents in leukemia with the finding of the maximally tolerated dose in a phase I study5 and then subsequent phase II evaluations in subsets of CML patients. Two separate trials evaluated the efficacy of imatinib in CML patients in accelerated phase and in blastic phase, with further subset analysis of patients in either myeloid or lymphoid blast transformation.6-10

The accelerated-phase study, reported by Talpaz et al.,6 included 181 confirmed patients with accelerated phase as defined by a set of criteria that had been demonstrated retrospectively to correlate with survival rates compared to chronic-phase patients, and that were different than that of blastic-phase patients. These criteria included the presence of 15-30% blasts, or 30% blasts and promyelocytes, or 20% basophils in the blood or marrow, or a platelet count less than 100 X 103 /L unrelated to anticancer therapy. Patients were treated with 400 or 600 mg of imatinib daily. Overall, 69% of the patients achieved a sustained hematologic response, 34% complete, and the rest either achieved a blast percentage in the marrow under 5% with incomplete peripheral blood recovery (marrow response) or a return to a second chronic phase (no criteria for accelerated disease as defined above). The rate of complete cytogenetic response was 17%, and the 1-year progression-free and overall survival was 59 and 74%, respectively. Patients treated with 600 mg compared to 400 mg realized greater benefit with a higher overall cytogenetic responses (28% vs 16%) and better progression-free and overall 1-year survival rates (67 and 78% vs 44 and 65%), with no significant increases in toxicity.

Although the definition of accelerated phase of CML by hematologic criteria, as outlined above, was used in the initial studies of imatinib, subsequent patients have been labeled accelerated phase purely on the basis of clonal evolution, i.e, the development of chromosomal abnormalities in addition to a single t(9;22). In an analysis by O'Dwyer et al., the results of treatment with imatinib at a dose of 600 mg was evaluated based on the criteria used for defining accelerated phase.11 Patients with accelerated disease based on hematologic criteria without clonal evolution had a significantly worse response rate and time to treatment failure compared to patients with clonal evolution as the sole criterion for defining accelerated disease. Patients with clonal evolution alone had a major cytogenetic response rate of 73% and a treatment failure rate at 1 year of 0% compared to a major cytoge-netic response rate of 31% and a 1-year treatment failure rate of 28% in patients with hematologic criteria alone for accelerated disease. Patients with both hema-tologic and clonal evidence of accelerated disease did the worst of all three groups, with cytogenetic response rates of 12.5%, a 1-year treatment failure rate of 67%, and a median time to treatment failure of 8 months. This experience suggests that patients with clonal evolution alone, without other evidence of accelerated disease, have a similar response rate to that of patients with chronic-phase disease, provided they receive doses of 600 mg or higher of imatinib.

The myeloid blast-phase study reported by Sawyers et al.9 included 229 evaluable patients with more than 30% blasts in the blood or marrow, with a myeloid phe-notype demonstrated by immunophenotypic and cyto-chemical evaluation. As in the accelerated-phase study, patients were treated with either 400 or 600 mg of ima-tinib. Overall, 31% of the patients achieved a sustained hematologic response. Hematologic responses were complete in only 8% of the patients, with the majority being classified as a return to chronic phase. Major and complete cytogenetic responses were observed in 16 and 7%, respectively. Patients previously untreated for the blast phase of disease fared better, experiencing an overall and complete hematologic response (CHR) rate of 36 and 9%, compared to 21 and 6%, respectively, for patients who had received prior induction chemotherapy for blast-phase disease. Major cytogenetic responses were observed in 16% of the patients, in whom 7% were complete. The median survival for all patients was 6.9 months, with 32% of the patients still alive at 1 year. The impact of the dose of imatinib was significant, with overall hematologic responses of 34% for patients treated with 600 mg compared to 9% for patients receiving 400 mg of imatinib. Cytogenetic responses were also significantly better with the higher doses of imatinib (18% vs 6%).

Transformation of CML to a lymphoid blast phase is less common than myeloid transformation, and patients in this category treated with imatinib have been grouped together with patients with Ph+ acute lymphoblastic leukemia. In both phase I and phase II studies, imatinib demonstrated efficacy in lymphoid blast-phase patients similar to responses seen in patients with myeloid blast phase.10 Overall, 25% of the patients in lymphoid blast phase achieved a sustained hematologic response to imatinib, but responses were generally of short duration, with a median time to progression of 2.2 months. Similar to patients with Ph+ ALL, imatinib alone has limited efficacy in lymphoid blast phase, and further development is based on the incorporation of imatinib into chemotherapy-based regimens.12

In addition to the inability of imatinib alone to control established lymphoid blast disease, imatinib has been shown, in some instances, to fail to prevent the onset of lymphoid transformation in patients in chronic phase. Sudden onset of blast-phase disease, especially lymphoid transformation, has been observed in patients prior to the development of ima-tinib, including patients who had a complete cytoge-netic response on treatment with interferon alpha or postallogeneic transplantation.13 Recent observations have demonstrated a similar phenomenon in patients in cytogenetic remission on imatinib.14 In addition, complete response to imatinib does not protect against the development of meningeal involvement by lym-phoid blast cells. In several patients, meningeal relapse occurred despite control of marrow disease.15 Imatinib levels in these patients were demonstrated to be approximately 2 logs lower in the cerebrospinal fluid compared to plasma.16

The results of these trials in patients with advanced phases of CML have demonstrated that imatinib, a relatively specific tyrosine kinase inhibitor of bcr/abl, was effective in inducing sustained responses, which compared favorably to results with more intensive chemotherapy-based regimens. Importantly, ima-tinib's biologic activity in these patients with advanced disease demonstrated that signal transduc-tion mediated by the BCR/ABL protein was still a relevant target for therapeutic inhibition, but that mech anisms of resistance, genetic reexpression or mutation of BCR/ABL, and/or clonal evolution, leads to eventual loss of clinical activity and progression of disease.1718 Efforts to overcome resistance have included dose escalation of imatinib19 and the addition of other chemotherapeutic or molecularly directed agents to imatinib.2021 Other efforts currently underway are the development of newer tyrosine kinase inhibitors with activity in the mutated forms of BCR/ABL.22

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