New Criterion for Restarting Therapy in CML

Roxanne Nelson

January 08, 2014

Life-long therapy with tyrosine kinase inhibitors (TKIs) is still the consensus treatment for patients with chronic myeloid leukemia (CML), but researchers are examining the feasibility of discontinuing therapy in select individuals. The latest study on this approach, known as the A-STIM (According to Stop Imatinib) trial, suggests that patients should be evaluated for loss of major molecular response (MMR). This could be used as a criterion for resuming therapy.

The study was published online December 9, 2013, in the Journal of Clinical Oncology.

The researchers assessed MMR persistence in CML patients who had stopped imatinib (Gleevec), and found that roughly one third lost MMR after a median of 4 months off therapy. The cumulative incidence of MMR loss at 12 and 24 months was estimated at 35% and 36%, respectively.

There were no late molecular relapses observed in the remaining patients, even after follow-up of more than 4 years.

"MMR loss could be used as a practical criterion for future discontinuation studies," write the researchers, led by Philippe Rousselot, MD, PhD, from Hôpital Mignot in Le Chesnay, France. In fact, they note that this criterion has been chosen for a trial already in progress — the Europe Stop TKI trial.

Change of Criterion

The same group of researchers used complete molecular response (CMR) as the evaluation criterion in their previous study — the Stop Imatinib (STIM) study. That study involved stopping the drug in 100 CML patients who had been on imatinib for at least 2 years and who had achieved CMR during treatment. After stopping imatinib, 41% of patients maintained CMR for 1 year and 38% maintained CMR for up to 2 years.

In the STIM study, molecular relapse was defined as "positivity of BCR-ABL transcripts with quantitative reverse-transcriptase polymerase chain reaction with a ratio of BCR-ABL to ABL ≥ 10–5." But Dr. Rousselot and colleagues point out that during the molecular follow-up of the patients in the pilot and STIM studies, they observed occasional positivity of BCR-ABL transcript levels, which suggests that the definition of molecular relapse could be revised.

With that in mind, for the A-STIM trial, they evaluated whether the loss of MMR (defined as ≥0.1% BCR-ABL IS) was a safe and clinically relevant measure for defining molecular relapse in this population.

The cohort consisted of 80 patients with chronic-phase CML who had stopped treatment with imatinib after prolonged CMR. The median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months), and the median duration of CMR was 41 months (range, 24 to 96 months).

After the discontinuation of imatinib, the median follow-up was 31 months, during which 29 patients (36%) lost MMR. The median time off therapy for these patients was 4 months, and only 4 patients (14%) lost MMR after 6 months.

The researchers also used CMR to analyze molecular relapse, and the corresponding rate was 56% (45 patients) after a median of 4 months off therapy. Of this group, 8 patients (18%) lost CMR after 6 months, 2 of which were late molecular relapses at months 35 and 40.

Of the 51 patients who remained in MMR, 28 (55%) had BCR-ABL transcript positivity, which corresponded to either occasional positive assessments of BCR-ABL transcripts below the MMR threshold in 12 patients (24%) or to less than 2 consecutive positive values below the MMR threshold in 16 patients (31%).

Second CMR

Thirty-one patients in the cohort restarted treatment (mainly imatinib) after the loss of MMR. In all patients who were retreated, MMR was regained at a median follow-up of 17 months, 23 patients regained CMR, and 8 patients are in MMR while receiving treatment. The cumulative incidence of a second CMR was 84% at 24 months, and there was no loss of hematologic response during the time off treatment.

Several of the authors report relationships with industry, as noted in the paper.

J Clin Oncol. Published on December 9, 2013. Abstract

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