Elsevier

The Lancet Oncology

Volume 11, Issue 11, November 2010, Pages 1029-1035
The Lancet Oncology

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Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial

https://doi.org/10.1016/S1470-2045(10)70233-3Get rights and content

Summary

Background

Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib.

Methods

In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR–ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985.

Findings

100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1–30), and 69 patients had at least 12 months follow-up (median 24 months, range 13–30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29–52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR–ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge.

Interpretation

Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors.

Funding

French Ministry of Health (Programme Hospitalier de Recherche 2006 grants), Institut National du Cancer (INCA).

Introduction

Imatinib (Novartis, East Hanover, NJ, USA) is the standard of care for patients with chronic myeloid leukaemia (CML), and induces durable responses and prolongs event-free survival and progression-free survival.1, 2, 3 In the International Randomised Study of Interferon versus STI571 (IRIS) protocol,4, 5 the estimated overall survival of patients who received imatinib as initial therapy was 89% at 5 years and 85% at 8 years (93% when deaths only related to CML were considered). However, current practice has been for patients to continue treatment indefinitely, and the ability of imatinib to eradicate the CML clone is uncertain.

Patients with CML are monitored by quantitative RT-PCR to detect the leukaemic BCR–ABL transcript.6 The major molecular response, which is defined as a 3-log reduction of leukaemic cells, and the depth of molecular response increase with time.7, 8 The proportion of patients who respond to imatinib treatment increases with time, leading to undetectable residual disease on quantitative RT-PCR, which is designated a complete molecular remission (CMR).9

Conscious of patient safety, we believe that achievement of CMR for at least 2 years is a reasonable starting point for investigations into possible discontinuation of imatinib. In a pilot study10 of patients achieving CMR who stopped imatinib, a molecular relapse of 50% (95% CI 21–79) was reported. However, all patients had previously been treated with interferon α. In the Stop Imatinib (STIM) study, which also included newly diagnosed patients who had not previously been treated with interferon α, we aimed to assess persistence of CMR after discontinuation of imatinib, and establish the factors that could be associated with CMR persistence.

Section snippets

Patients

Patients who were 18 years and older, with a confirmed diagnosis of CML in chronic or accelerated phase, treated with ongoing imatinib at any dose for at least 3 years, and in sustained CMR for at least 2 years, were eligible for inclusion at one of 19 participating institutions in France. For all the patients at diagnosis, the Philadelphia chromosome was found in 100% of bone-marrow cells. Previous treatment with autologous transplantation or interferon α, and previous or present treatment

Results

From July 9, 2007, to Dec 17, 2009, 100 patients with CML and a median age of 63 years (range 29–80) were recruited to the STIM trial. 48 patients were men and 52 were women. 51 patients were previously treated with interferon α. After imatinib was discontinued, a molecular relapse occurred in 54 patients after a median follow-up of 17 months (range 1–30). 46 patients remained free of molecular relapse at a median follow-up of 14 months (range 1–25). The overall probability of maintenance of

Discussion

In our interim analysis of the STIM trial, 39% of patients remained in CMR after discontinuation of imatinib, without evidence of CML recurrence; at 12 months, the probability of persistent CMR at 12 months was 41% (95% CI 29–52). Imatinib is capable of long-term disease control in patients with CML, but up to now treatment has needed to be continued for an indefinite time (panel). In this trial, patients who had a molecular relapse after discontinuation retained sensitivity to the drug,

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