When Is it Safe for Patients with Chronic Myeloid Leukemia to Stop Tyrosine Kinase Inhibitor Treatment?

With the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, dasinitib, or nilotinib, patients with chronic myeloid leukemia (CML) experience longer survival and higher response rates than with previously available treatments. For certain patients who achieve a durable molecular response (MR) with TKI treatment, it may be possible to stop TKI treatment and maintain relapse-free survival, according to results from the EURO Stop TKI (EURO-SKI) study presented at the European Hematology Association’s 21st Congress.

“A high percentage of patients [with CML and treated with TKIs] reach deep molecular responses,” investigator Johan Richter, MD, PhD, from Lund University in Sweden, noted during his presentation of the results. “There is a reasonable expectancy not only to further improve survival, but to cure the disease. … An important step toward finding a cure for CML is to increase the rate of patients in durable molecular remission after TKI withdrawal.”

In EURO-SKI, investigators analyzed outcomes of 760 adult patients (median age at diagnosis = 52.0 years; range = 11.2-85.5 years) with chronic-phase CML who stopped TKI treatment to define prognostic markers of durable molecular response after withdrawal.

All patients received TKI treatment for at least three years and were in MR4 (defined by at least 4-log reduction in BCR-ABL transcripts) for at least one year (confirmed by 3 consecutive PCR results during the last 12 months prior to study inclusion). Patients who had disease progression after prior TKI treatment were excluded. One patient decided not to stop therapy after inclusion.

Before discontinuing TKIs, patients were screened for at least six weeks; if MR4 was confirmed, TKI therapy was stopped and patients were followed every four weeks for six months, followed by every six weeks until two years post-withdrawal, then every three months.

The majority of patients were treated with imatinib as their first-line TKI (94%), followed by nilotinib (4%) and dasatinib (2%). One-hundred and fifteen patients switched to alternate TKIs as their second therapy due to intolerance, prior to discontinuation in MR4: 57 to dasatinib, 47 to nilotinib, and seven to imatinib.

The median time from diagnosis to stopping TKI treatment was 7.7 years (range = 3.1-22.6 years); median duration of TKI treatment was similar, at 7.6 years (range = 3.0-14.2 years).

MR4 was reached by a median of 21 months (range = 3.0-140.0 months) and, prior to stopping TKIs, patients were in MR4 for a median of 4.7 years (range = 1.0-13.3 years). The median patient age at the time of withdrawal was 60.3 years (range = 19.5-89.9 years).

After a median follow-up of 10 months (range = 1-36 months), 717 patients had evaluable molecular data. Of these, 381 patients were still in major molecular remission (MMR; BCR-ABL1 ≤0.1% according to the International Scale), 331 patients lost MMR, and four died in remission. The molecular relapse-free survival after stopping TKI treatment (the study’s primary endpoint) was:

  • 62% (95% CI 58-65%) at 6 months
  • 56% (95% CI 52-59%) at 12 months
  • 51% (95% CI 47-55%) at 24 months

Dr. Richter and colleagues also looked at 448 patients treated with first-line imatinib to identify prognostic factors of MMR at six months after discontinuing imatinib, finding no significant correlation between sex, age, or risk score and post-TKI success. They did, however, find that treatment duration and MR4 duration increased the likelihood of MMR at six months.

The odds ratio for treatment duration was 1.16 (95% CI 1.08-1.25), “meaning that one additional year of imatinib treatment increases the odds to stay in MMR by 16 percent,” Dr. Richter said. “We also identified a cutoff suitable for stopping imatinib therapy, which is around six years,” Dr. Richter said. Molecular relapse-free survival at six months was 65.5 percent for imatinib treatment >5.8 years and 42.6 percent for treatment ≤5.8 years (p<0.001).

Stopping TKI treatment, he added, would eliminate the associated toxicities (including “financial toxicity”) and improve patients’ quality of life. These associations would need to be analyzed in further detail.

Additional follow-up is needed to reach definitive conclusions about the long-term responses and risk of recurrence after stopping TKI therapy.


Reference

Richter J, Mahon FX, Guilhot J, et al. Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial. Abstract #S145. Presented at the EHA 21st Congress, June 10, 2016; Copenhagen, Denmark.

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