Imatinib Withdrawal in CML Patients After Molecular Remission

Abstract & Commentary

By Andrew Artz, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Artz reports no financial relationships relevant to this field of study.

Synopsis: Imatinib results in significant and durable responses for CML. The safety of discontinuation has not been rigorously tested. In a prospective study, imatinib was discontinued among CML patients in a complete molecular remission (CMR) for 2 years or more. Among 69 patients with at least one year of follow-up, 61% relapsed by molecular analysis, almost all by 6 months. After imatinib reintroduction, all 42 relapsing patients responded, of which 26 (62%) entered CMR again. High Sokal score at baseline, female sex, and shorter period of CMR predicted for relapse on imatinib discontinuation. Around 40% of patients with CML in prolonged CMR on imatinib do not relapse at least one year after stopping the drug.

Source: Mahon F, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: The prospective, multicenter STOP Imatinib (STIM) trial. Lancet Oncology. 2010;11:1029-1035.

Imatinib mesylate, gleevec, an oral inhibitor of BCR/ABL tyrosine-kinase activity, results in frequent and durable remissions, as documented in the seminal international randomized study of interferon vs STI571 (IRIS) trial.1 Follow-up data indicate 85% estimated survival at 8 years. Although cytogenetic remission remains an important milestone indicating a low likelihood of future progression, molecular monitoring of BCR/ABL transcripts enables determination of deeper responses. A 3-log reduction, as assessed by RT-PCR for BCR/ABL, indicates a major molecular response (MMR), and undetectable disease by quantitative RT-PCR is considered a complete molecular remission (CMR).2 At present, indefinite therapy is recommended. In a study of 12 patients who achieved CMR for 2 years, imatinib discontinuation resulted in molecular relapse in 50%.3 The authors now embarked on a larger trial to determine whether some CML patients in CMR on imatinib may safely discontinue therapy.

In this multi-institutional trial, patients 18 years and older with CML in chronic or accelerated phase on imatinib therapy for 3 years, and in sustained CMR for at least 2 years, were eligible. The authors report on 69 patients with at least 1 year of follow-up. After imatinib discontinuation, molecular relapse was established in 42 patients (60.8%). Almost all relapses occurred within 6 months, with two relapses occurring at 7 months and 19 months, respectively. Two patients with molecular relapse had a declining transcript levels by the second molecular analysis and eventually re-entered CMR without imatinib therapy.

Prognostic factors for relapse included women (70% vs. 46%), shorter CMR prior to discontinuation, and higher Sokal risk score in multivariable analysis. Specifically, molecular relapse occurred in 17 of 35 in the low-risk Sokal group, 15 of 23 in the intermediate-risk Sokal group, and 7 of 8 patients in the high-risk Sokal group. Treatment of molecular relapse by imatinib 400 mg daily enabled 16 (38%) to have reductions and 26 (62%) to achieve CMR. No hematologic progression or mutant BCR/ABL phenotype has occurred, although follow-up is limited.

Commentary

The advent of tyrosine-kinase inhibitors (TKIs) has turned CML from a slowly lethal condition into a highly treatable illness. Specifically, imatinib mesylate results in high response rates, and a fraction of patients achieve a major molecular remission if not CMR. Traditionally, an allogeneic hematopoietic transplant was considered the only curative treatment. The question emerges whether a high level of sustained CMR, induced by imatinib, has eradicated the malignant clone or reduced the disease adequately to discontinue therapy. In a pilot study of 12 patients, around 50% of patients with CML in CMR experienced a molecular relapse after stopping imatinib.

In this prospective French study, the authors report interim data from 69 patients in CMR for 2 years or greater and with 1 year of follow-up after imatinib discontinuation. The authors found 39% at year 1 remained in CMR after imatinib discontinuation. Of the 61% (n = 42) who developed a molecular relapse after stopping imatinib, all but 2 relapsed by 6 months. Risk factors for relapse after imatinib discontinuation included higher Sokal risk group (7 of 8 in the high-risk Sokal group at baseline relapsed), female sex, and shorter CMR duration at the time of discontinuation. Importantly, the strategy did not induce resistance, as all patients responded to imatinib reintroduction, with 26 of 42 re-entering CMR and 16 showing decreased BCR-ABL levels.

These data, although provocative, are clearly too early to change the recommended approach of indefinite therapy. The follow-up for such patients is short. We must also recognize the eligible population of those entering CMR after imatinib is quite small. Still, there are patients right now for whom imatinib interruption may be advisable or necessary, such as pregnancy, drug cost, non-adherence, or temporary inability to tolerate pills (e.g., surgery). These data provide reassurance that at least for those in CMR, especially if after a prolonged period of CMR, discontinuation for a short period of time may not be harmful. The fact that relapses tended to occur early suggests that at the time of discontinuation, early and aggressive monitoring would be needed.

The advent of second-generation TKIs, such as dasatinib and nilotinib, as front-line therapy, and the associated higher molecular responses, raise the possibility of a much larger population entering CMR, and might even promote more rapid uptake of such drugs in preference to imatinib as initial treatment. For example, nilotinib and dasatinib induce a 1-year molecular response rate of 43%-46% compared to 22%-28% for imatinib.4,5 The notion of a clinical trial assessing if discontinuation identifies patients that might benefit from second-generation TKIs or closer long-term monitoring is intuitively appealing. Further, CML subsets may be characterized for whom initial TKI therapy is curative without an allogeneic hematopoietic transplant.

In summary, 61% of CML patients in complete molecular remission on imatinib relapsed after drug discontinuation with 1 year of follow-up. Higher Sokal risk group at diagnosis, shorter period in molecular remission, and female sex were associated with a greater relapse risk. Longer follow-up will establish the viability of TKI discontinuation for CML.

References

1. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 355:2408-17, 2006

2. Colombat M, Fort MP, Chollet C, et al. Molecular remission in chronic myeloid leukemia patients with sustained complete cytogenetic remission after imatinib mesylate treatment. Haematologica. 2006;91:162-168.

3. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109:58-60.

4. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.

5. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270.