Discontinuation of Imatinib in Patients with CML and Sustained Complete Molecular Response (CMR) for Over 2 Years in the Japanese Population – An Interim Analysis of KEIO STIM Study,

The introduction of imatinib mesylate in the treatment of chronic myeloid leukemia (CML) has dramatically changed its treatment outcome. The drug alone can induce durable hematologic, cytogenetic and molecular response, leading to a marked improvement of progression free survival (PFS). One of the next directions of treatment is to explore the possibility of long-term discontinuation of tyrosine kinase inhibitors (TKIs), and to identify the factors associated with sustained complete molecular response (CMR) after discontinuation. The French STIM study is the first large prospective trial to show that imatinib can be safely discontinued in a subset of patients who have maintained CMR for at least 2 years. We have performed a similar prospective study to confirm this result in the Japanese population.

To evaluate whether CMR will be sustained after stopping imatinib therapy, and to identify the clinical characteristics that could be associated with persistent CMR after drug discontinuation in the Japanese population.

Adult patients with CML, treated at Keio University Hospital, with sustained CMR (defined as negative quantitative and qualitative PCR of bcr-abl in the bone marrow) for over 2 years were enrolled in the study. After the discontinuation, patients were monitored monthly for the first 6 months and every 2 months thereafter, by peripheral blood quantitative PCR (TMA method; Amp-CML). Treatment with imatinib or one of the other TKIs was initiated if the Amp-CML value exceeded 100 copies.

30 patients have been enrolled in the study at the time of the analysis. 20 patients (66.6%) were male. The median age of the patients was 54 (range 28 –77) years old. 11 patients (36.7%) had a previous history of interferon treatment. 20% of the patients were negative for CMV serology. The Sokal risk score was low in 19 (63.3%), intermediate in 7 (23.3%) and high in 2 (6.7%) patients. The median time on imatinib treatment was 92 (range 32–114) months and the median duration of CMR was 55.5 months, ranging from 24 to 94 months. The median daily dose of imatinib taken at the time of discontinuation was 400 mg (range 200–400).

The median follow-up of the patients at the time of this analysis was 5 months (range 1–6). Imatinib or one of the second generation TKIs were restarted in 11 patients (36.7%) (4 at month 2, 6 at month 3 and 1 at month 5; 3 were on imatinib, and 8 on dasatinib), leading to an estimated 6 months drug-free survival rate of 55.8%. All patients responded to either TKI. 5 patients have at least one positive PCR but the value have not exceeded 100 copies over time and have not been retreated by TKIs, leading to an estimated 6 months PCR-negative survival of 37.8%. According to the criteria of the French STIM study (positive and rising PCR value in two consecutive observation), an estimated 6 months relapse-free survival in our patient population was 46.8%. In comparing patients with sustained drug-free, relapse-free, or PCR-negative survival with those who did not, univariate or multivariate analysis did not show any significant difference for age, previous interferon treatment, duration of imatinib treatment, duration of CMR, sex, cytomegalovirus serology, peripheral blood NK or T cell subpopulation, or Sokal risk score. Although clinical side effects such as facial puffiness or muscle cramping markedly decreased with the discontinuation of imatinib, QOL analysis using SF-36 before and 2 months after the discontinuation did not show any significant improvement.

Sustained CMR was achieved in a substantial proportion of patients who had been in CMR for over 2 years after the discontinuation of imatinib. All patients restarted on TKI treatment remained sensitive to treatment. There was no significant factor identified as a predisposing condition for sustained CMR in our patient population. However, our results are comparable to that of the previous French STIM study in terms of relapse-free survival, suggesting that there is no ethnic difference in the effect of stopping imatinib. This study is the first to evaluate the effect of imatinib discontinuation in the Asian population, and thus provides an important insight into the effect of imatinib and drug-free survival of CML patients in sustained CMR. Longer observation period and increased number of patients is necessary to draw a concrete conclusion, and to identify the factors relative to persistence of CMR.

Okamoto:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharma: Honoraria, Research Funding.