1. Fuerst, Mark L.

Article Content

ORLANDO, Florida-Patients with chronic myeloid leukemia (CML) can safely stop taking imatinib if they achieve a deep molecular response of at least two years' duration, according to a study with a median follow-up of more than five years, as reported at the American Society of Hematology Annual Meeting (Abstract 345).

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

Previous studies have shown that imatinib can be safely discontinued if patients achieve a sustained deep molecular response. A second deep molecular response was achieved in most of the patients after treatment resumption, and no CML progression events were reported, said Gabriel Etienne, MD, PhD, of Institut Bergonie in France.


The rates of molecular recurrence ranged from 19 to 67 percent, depending on the definition of molecular recurrence and the baseline characteristics of the study populations.


"Several key issues remain to be determined, including occurrence of late molecular relapse and identification of predictive factors of molecular relapse," Etienne said.



Etienne provided an update of the French 1 Stop Imatinib (STIM1) study with a median follow-up of 65 months after imatinib discontinuation. In this multicenter study, imatinib of more than three years' duration was prospectively discontinued in 100 CML patients, median age of 59, who were in deep molecular response with undetectable minimal residual disease (MRD) sustained for at least two years.


Importantly, he said, the molecular relapse was defined as positivity of BCR-ABL transcript in quantitative real-time polymerase chain reaction (PCR) confirmed by a second analysis point.


Study Details

He and his colleagues performed quantitative PCR tests for BCR-ABL transcripts from peripheral blood every month during the first year and every two months thereafter. In cases of molecular relapse, the treating physician was recommended to reintroduce tyrosine kinase inhibitor (TKI) treatment.


The majority of the patients had low to intermediate Sokal risk scores. Half of the patients were previously treated with interferon.


In the imatinib de novo patients, the time from imatinib onset to sustained cumulative molecular response (CMR) was 18.5 months and the CMR duration before imatinib discontinuation was 35 months. In those treated with prior interferon, time to sustained CMR was 15.5 months and CMR duration was 38 months.


Sixty-one patients relapsed; 17 of these lost major molecular response at the time of relapse. Four patients died after molecular recurrence of CML-unrelated causes. Of the relapsing patients, 80 percent achieved a molecular response within one to three months and 15 percent within four to seven months. The median time to molecular recurrence was 2.5 months.


TKI therapy was restarted in 57 out of the 61 relapsed patients, and 55 patients achieved a second CMR within a median time of 4.2 months, Etienne reported. "None of the molecular-relapse patients have CML event progression."


In patients who achieved the first six months without recurrence, the probability of molecular relapse was 10 percent at 24 months.


Some 39 patients remained free from molecular recurrence at a median of 67 months follow-up. One patient died of a CML-unrelated cause (myocardial infarction) nine months after imatinib discontinuation.


"At the last available molecular evaluation, 37 out of the 39 patients were in CMR," Etienne said. More than 40 percent of the patients maintained a stable CMR, while the others have intermittent positive BCR-ABL transcript detection without molecular relapse.


The probability of molecular relapse-free survival at six months was 43 percent; at 24 months it was 38 percent; and at 84 months it was 38 percent.


Related Factors

In order to identify factors associated with molecular relapse, the researchers analyzed several baseline patient characteristics, including gender, age at diagnosis and at imatinib cessation, Sokal risk score, previous treatment with interferon, time from the start of imatinib therapy to first undetectable minimal residual disease, duration of undetectable MRD before imatinib discontinuation, and imatinib duration.


Using multivariate analysis, Sokal risk score was the only variable associated with a significant probability of molecular relapse, Etienne said. "Those with a low Sokal risk score had a significantly reduced risk of molecular relapse."


Summing Up

Summing up, Etienne said: "With a longer follow-up after imatinib discontinuation, we report no CML event progression. Most if not all relapsing patients have achieved a second deep molecular response after TKI resumption. Molecular recurrence was very rare after six months, and no molecular recurrence was reported after two years."


He said imatinib discontinuation is safe, provided that a deep sustained molecular response has been achieved before discontinuation, and that patients are closely monitored after treatment cessation.


"Sokal risk score continues to be a strong, significant factor associated with molecular relapse, suggesting that eradication of the leukemic clone may depend on the intrinsic feature of the disease."


He noted that the statistical analysis of predictive factors was limited because half of the patients were previously treated with interferon.



In an interview, the moderator of the session where the results were reported, Guiseppe Saglio, MD, Professor of Hematology at the University of Turin in Italy, said: "With long-term follow-up, no late relapses were observed. However, the kinetics of the recurrent molecular clones is not good. With recurrences early on, we see the onset of clones that were resistant to therapy."


Saglio noted that only five to 10 percent of recurrences occurred at later times, and generally no more than 12 months since discontinuation of imatinib.


"The kinetics of clones is different depending on the time of relapse," he said. "We see clones with rapid growth as well as those with slow growth. It will be important to understand this difference in relapses. This will tell us the way to block recurrences and provide patients who discontinue TKIs with therapy that is successful."


In the question-and-answer session, Etienne noted that the researchers will continue to monitor these patients because "we don't know whether there will be very, very late relapses."