Fast track — ArticlesDiscontinuation 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
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.
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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,
References (24)
- et al.
International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib
Blood
(2009) - et al.
Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than two years
Blood
(2007) - et al.
Discontinuation of imatinib therapy after achieving a molecular response
Blood
(2004) - et al.
Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission
Leuk Res
(2004) - et al.
Serial measurement of BCR–ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy
Blood
(2006) - et al.
Is it possible to discontinue imatinib mesylate therapy in chronic myeloid leukemia patients with undetectable BCR/ABL? A case report and a review of the literature
Leuk Res
(2009) - et al.
In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib
Blood
(2010) - et al.
Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia
N Engl J Med
(2001) - et al.
Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia
N Engl J Med
(2002) - et al.
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia
N Engl J Med
(2003)
Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia
N Engl J Med
Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia
N Engl J Med
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