Strategies to Reduce the Use of Tyrosine Kinase Inhibitors in CML

February 2017, Vol 8, No 1

San Diego, CA—Although tyrosine kinase inhibitors (TKIs) including imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel), have dramatically improved outcomes in patients with chronic myeloid leukemia (CML), the costs of these drugs have spiraled out of control, causing some patients to stop treatment or cut their dosage because of financial toxicity. Data presented at the 2016 American Society of Hematology meeting show that it is possible for some patients with CML to reduce their TKI dose by 50% and maintain remission, perhaps even stop treatment altogether once deep and durable remission has been achieved after approximately 5 years of treatment.

Experts interviewed for this article agreed that the evidence is stronger for reducing the dose of TKI therapy than for stopping treatment altogether, because approximately 50% of patients who stop taking their drugs will have disease relapse.

Dose Reduction

The National Comprehensive Cancer Network guidelines for CML suggest continuing treatment indefinitely for patients who are in remission, but this may not be necessary for all patients; the side effects of TKIs can be difficult to tolerate and the cost of treatment is high.

In the British De-escalation and Stopping Therapy with Imatinib, Nilotinib, or Sprycel (DESTINY) study, investigators explored the effects of reducing the standard dose of TKI by 50% in 174 patients with a molecular response (MR) of MR4 (ie, undetectable disease or better), as well as MR3 (less-deep responses).

“As patients proceeded through de-escalation of therapy, we saw significant reductions in many side effects within the first 3 months of reduced dose therapy. After that, there was no further improvement in symptoms over time,” said study co-investigator Mhairi Copland, MBChB, PhD, FRCP, FRCPath, Institute of Cancer Sciences, University of Glasgow, United Kingdom.

Overall, 93% of patients showed no evidence of disease recurrence within 12 months of TKI dose de-escalation. Patients with molecular relapses (N = 12) were documented by month 12 of TKI dose de-escalation. The relapse rate was 18.4% in patients with MR3 at baseline (N = 49), and 2.4% in patients with MR4 at baseline (N = 125). The median time to relapse was 4.4 months in the sustained MR3 group versus 8.7 months in the sustained MR4 group.

When patients whose disease relapsed received TKI re-treatment at full doses, they attained MR3 by 4 months.

The dose de-escalation of TKI therapy reduced the costs of treatment by 46.7%. A 50% reduction in TKI saved £1,943,364 from an expected TKI cost of £4,156,969. The costs were reduced by 47% in the MR4 group and by 44.2% in the MR3 group.

TKI Withdrawal

Interim results of the EURO-SKI clinical trial showed that approximately 50% of 755 patients with CML who stopped TKI therapy had disease relapse by 15 months, and 78.3% had disease relapse within 6 months of stopping TKI therapy. These patients received TKIs for at least 3 years and had deep molecular remission (MR4) for at least 1 year before entering the study.

At 12 months, molecular recurrence-free survival was 55%; at 24 months, it was 50%; and at 36 months, it was 47%.

“Several studies have shown the feasibility of stopping TKI treatment, with consistent results over time. A sustained deep molecular remission over long-term TKI therapy seems to be necessary to attempt stopping therapy,” said lead investigator Francois-Xavier Mahon, MD, PhD, University of Bordeaux, France. “With decentralized but standardized PCR [polymerase chain reaction] monitoring, stopping TKI therapy in a large cohort of patients with CML appears feasible and safe.”

“Longer duration of imatinib therapy, optimally more than 5 years, prior to stopping therapy, correlates with a higher probability of relapse-free survival. Sex, age, and Sokal scores do not predict the probability of successfully stopping TKI,” he added.

Mikkael A. Sekeres, MD, MS, Director, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, OH, who was not involved in this study, said that he was more reassured by the dose de-escalation study than by the EURO-SKI study results.

“If I see more data reassuring me that the depth of remission is the same when relapsed patients [who stop their TKI] are restarted on therapy, then I will rethink the strategy of stopping TKI,” he said.

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