Safety Data for TKI Cessation Emerges for Chronic Myeloid Leukemia

Recent studies found that for certain patients with CML, it is possible to safely reduce or stop TKI treatment.
BY SILAS INMAN @silasinman
PUBLISHED: DECEMBER 06, 2016
It is safe to stop or dose-reduce tyrosine-kinase inhibitors (TKIs), without risking poorer long-term outcomes for patients with chronic myeloid leukemia (CML) who have obtained a major molecular response (MMR), according to findings from two studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting.

In the EURO-SKI trial, the 18-month molecular recurrence-free survival (mRFS) rate was 52 percent following TKI discontinuation. At 36 months, 47 percent of patients remained free of molecular recurrence. Treatment duration effectively predicted which patients would relapse, with better mRFS seen in those treated for longer than 5.8 years.

"This trial, which is close to true life, demonstrated that half of patients are still off treatment without molecular recurrence with a median follow-up of 15 months," commented lead investigator Francois-Xavier Mahon, M.D., Ph.D., University of Bordeaux, Bordeaux, France.

In a second study, labeled DESTINY, the TKI dose was cut in half for 12 months followed by treatment cessation. During the reduced dose phase, only 6.9 percent of patients relapsed. The depth of response at baseline was predictive of relapse, with more recurrence seen in those with MR3 versus MR4.

"Many patients are uncomfortable stopping therapy completely but are much more comfortable reducing the dose of therapy," said the senior author of the DESTINY study Mhairi Copland, M.B. Ch.B., Ph.D., F.R.C.P., FRCPath, Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, United Kingdom. "The ability to reduce the dose safely really does make this an option for much more patients."

The EURO-SKI trial enrolled 821 patients with chronic phase CML across 11 European countries. Patients were monitored during a screening phase for up to six weeks, to ensure a molecular response prior to stopping treatment. In the first year, follow up and molecular testing by RQ-PCR was conducted every four weeks for the first six months followed by every six weeks. After the first year, testing was conducted every three months.

Overall, molecular data were assessable for 755 patients, 373 of which experienced a molecular recurrence, which was defined as the loss of MMR (BCR-ABL greater than 0.1 percent). Most recurrences were in the first six months (78.3 percent). There were four deaths among those who experienced remission.

Treatment and MR4 duration prior to stopping therapy significantly correlated with MMR status at six months. Each additional year of treatment increased the chances of staying in MMR at cessation by 16 percent. Those treated with imatinib for more than 5.8 years had a six-month mRFS rate of 65.5 percent compared with 42.6 percent for those with a treatment duration up to 5.8 years.

"Longer duration of imatinib-therapy prior to TKI-stop correlates to a higher probability of relapse-free survival," Mahon said. "Gender, age or any of the other variables in EUTOS or Sokal-scores do not predict the probability of successful TKI-stop."



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