Imatinib, a targeted inhibitor of the tyrosine kinase activity of the BCR-ABL oncoprotein, has demonstrated considerable efficacy in all phases of chronic myeloid leukemia (CML). 1 Recently, Palandri and colleagues reported on the long-term outcomes of patients with CML in accelerated phase2 (CML-AP) and blast crisis3 (CML-BC) treated with imatinib 600 mg/day. We have previously reported the results of phase II studies of imatinib for the treatment of CML-AP and CML-BC.4–6 This letter complements the reports by Palandri et al. by providing long-term follow-up results for these studies of advanced-stage CML patients treated with imatinib.
Initially, patients with CML-AP who enrolled in the STI571 0109 trial (phase II study of imatinib in patients with CML in accelerated phase) were treated with ima-tinib 400 mg daily (n=62). Following phase I data, which confirmed that higher doses were safe, the starting dosage was increased to 600 mg daily (n=119). Dose escalation (initially to 600 mg once daily and subsequently to 400 mg twice daily) was permitted for patients who relapsed. A total of 181 patients with a confirmed diagnosis of CML-AP were enrolled in the study.4 Analysis at 48 months indicated that 32 patients (18%) remained on imatinib therapy while 149 patients (82%) discontinued imatinib. Primary reasons for discontinuation included progression or lack of efficacy for 100 patients (67.1%), protocol violations or administrative reasons for 17 patients (11.4%), adverse events or toxicity for 13 patients (8.7%), bone marrow transplant for 5 patients (3.3%), and death for 14 patients (9.3%). Best observed responses included complete hematolog-ic response (CHR) in 40%, partial cytogenetic response (PCyR) in 7%, and complete cytogenetic response (CCyR) in 20% of patients. The median overall survival (OS) was 43 months for CML-AP patients treated with imatinib 600 mg/day. At 48 months, the estimated median time to progression (TTP) was 22.7 months and the estimated OS rate was 45% for patients treated with imatinib 600 mg/day. Seventy-four percent of patients with a major cytogenetic response (MCyR) at three months were alive at 48 months, compared with 41% without an MCyR (p=0.009) at three months. Safety data were unchanged since the prior report in 2002. As of November 2008, 42 patients (23%) remained on study follow-up with 16 patients (9%) continuing to receive the study drug.
A total of 229 patients with a confirmed diagnosis of CML-BC were enrolled in the STI571 0102 trial (phase II study of imatinib in patients with Ph+ CML in myeloid blast crisis) and treated with imatinib 400 or 600 mg/day.5 At 48 months, 3% of patients remained on imatinib therapy while 223 (97%) had discontinued imatinib therapy. The primary reasons for discontinuation included progression or lack of efficacy for 154 patients (69.0%), protocol violations or administrative reasons for 14 patients (6.3%), adverse events or toxicity for 19 patients (8.5%), bone marrow transplant for 10 patients (4.5%), and death for 26 patients (11.7%). Best observed hematologic response (HR) was achieved in 34% of patients, with 9% achieving a CHR. MCyR was achieved in 16% of patients and CCyR in 7% of patients. The estimated median TTP was 4.4 months and the estimated OS rate was seven months for patients treated with imatinib 600 mg/day. As of November 2008, 13 patients (6%) remained on study follow-up with 3 patients (1%) continuing to receive the study drug.
These results are consistent with the responses observed by Palandri et al. and the GIMEMA Working Party. Extended follow-up of these large, phase II trials demonstrate sustained imatinib efficacy among responding patients with either CML-AP or -BC as well as a favorable long-term safety profile supporting the use of imatinib in patients with advanced phases of CML. While these trials demonstrate significant survival improvements for patients with advanced CML receiving imatinib therapy compared with previous treatment options, the small number of patients remaining on therapy after four years illustrates the need for improved treatment options for patients with advanced phases of the disease.
- Funding: the clinical studies described in this manuscript (STI571 0102 and 0109) were sponsored by research funding from Novartis Pharmaceuticals Corporation.
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