EHA 2012: Conference

2012 Jun 26, S Freeman

AMSTERDAM (EGMN) - Stopping imatinib in patients who have achieved stable remission of chronic myeloid leukemia for at least 2 years appears to be a safe therapeutic strategy, according to updated results of the Australasian Leukemia and Lymphoma CML-8 trial.

"Approximately 40% of patients who had been in a stable complete molecular response and stopped their treatment are in a complete molecular response with a median follow-up of 3 years," said consultant hematologist Dr. David Ross in an interview at the annual congress of the European Hematology Association.

As of April 2012, 18 of 40 patients remained in stable complete molecular remission (CMR) while off treatment. Although 22 patients had a molecular recurrence at some point after imatinib (Gleevec) withdrawal, they all responded to the reintroduction of imatinib, with most patients rapidly regaining CMR.

These data build on those already released from the STIM (Stop Imatinib) trial (Lancet Oncol. 2010;11:1029-35) and the STOP 2G-TKI study, which have also shown that imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) withdrawal is a feasible therapeutic strategy for some patients with chronic myeloid leukemia (CML).

The CML-8 trial involved 40 adult patients who had been treated with imatinib for at least 3 years and were in CMR for at least 2 years. CMR was defined as no detectable BCR-ABL mRNA as determined by real-time quantitative polymerase chain reaction (RT-PCR) analysis. The latter was checked every month during the first year after imatinib withdrawal, every 2 months in the second year, and then every 3 months for up to 5 years of total follow-up. The last patient entered the trial in 2011, so further data from the trial are likely in the future.

"We've not seen any relapses later than 2 years," said Dr. Ross, of SA Pathology and Flinders Medical Centre in Adelaide, Australia.

"If I were designing the study again now, I would only do the monthly testing for 6 months because all of the action is in the first 6 months," Dr. Ross said.

The median age of patients participating in the study was 60 years. The median duration of imatinib therapy prior to withdrawal was 5.8 years (range, 3-9 years).

Although it is much smaller, the CML-8 trial provides findings similar to those of the French STIM study, Dr. Ross said. "We have seen an almost identical rate of sustained molecular response," he observed.

"We've also seen that the strongest predictor [for relapse] is the Sokal score, which suggests that unfavorable disease biology at the very beginning is still, after all these years of treatment, the single most important predictor of relapse risk."

Univariate analysis showed a higher percentage of patients with a low to intermediate Sokal score remaining relapse free compared with those with a high Sokal score (49.3% vs. 14.3% of 35 patients, P = .002).

One year of prior interferon therapy was also found to be predictive of relapse-free survival, with patients who had taken interferon for 1 year faring significantly better than those who had taken it for less than 1 year (60% vs. 20% of 21 patients, P = .0042).

"Again, if you stayed on interferon for more than 12 months it means that you had a good response to interferon, so it's probably telling you the same thing in a different way," Dr. Ross suggested.

"I think the next step from this [CML-8 study] is to look at what is going to happen with the second-generation drugs," he added. "With the increasing use of nilotinib and dasatinib, the number of patients on imatinib is potentially going to diminish."

Another possible research question, Dr. Ross said, was to determine whether there is any value in pushing patients to achieve a CMR (that is, no detectable BCR-ABL) over achieving a major molecular response (MMR), in which BCR-ABL falls to less than 0.1%.

One trial that will look further at the issue of stopping tyrosine kinase inhibitors (TKIs) in CML is the EURO-SKI (European Stop Kinase Inhibitor) study. This multicenter, open-label, uncontrolled trial is being run by the European LeukemiaNet, and has just started to accrue patients.

"We hope to accrue 500 patients," said the trial's principal investigator Dr. Susanne Saussele in an interview. Dr. Saussele of the University Medical Centre Mannheim and the University of Heidelberg, both in Germany, noted, however, that the trial does not have the backing of pharmaceutical companies, so getting funding is proving to be a challenge for some countries. To date, the trial has only started in Germany and in Sweden.

The primary aim is to estimate the persistence of molecular remission in CML after stopping treatment with available TKIs. EURO-SKI will measure MMR 4 (BCR-ABL of 0.01% or less) and MMR (BCR-ABL of 0.1% or less). Patients will need to achieve MMR 4 for at least 1 year before they can stop TKI therapy, and will have reached the end point if they lose MMR and the BCR-ABL transcript level rises over the 0.1% threshold.

"We are using MMR, which is one log higher than MMR 4 used in the STIM study," Dr. Saussele said. "This is because the STIM study showed that a lot of patients are between MMR4 and MMR."

The estimated date for completion of the trial is June 2017, with the first data available from the trial expected in roughly 3 years' time.

The CML-8 study was conducted by the Australasian Leukemia and Lymphoma Group with funding from Novartis. Dr. Ross has received research funding and honoraria from Novartis. Dr. Saussele had no disclosures.

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