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TKI dose de-escalation feasible in CML with stable MMR

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TKI de-escalation has important implications

The interim DESTINY trial findings indicate the feasibility of a dose reduction approach to minimize adverse events associated with TKI treatment and to improve quality of life, Elisabetta Abruzzese, MD, wrote in an editorial.

De-escalation also appears to provide important cost savings, she noted (Lancet Haematol. 2017 Jul;4:e304-5).

“For patients who are unable to stop therapy, adjustment of the treatment doses without jeopardizing the clinical outcome has important clinical implications. Combination of reduced dosage TKIs with newer (ABL001) or older approaches (immunomodulation) might represent a future answer to that,” she said.

Dr. Abruzzese is with Tor Vergata University, Rome. She reported receiving personal fees from Ariad/Incyte, and serving on the advisory board or as a consultant for Novartis, Pfizer, Ariad/Incyte, and Bristol-Myers Squibb.



Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.

The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).

Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.

The median time to recovery was 77 days.

The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.

Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.

During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.

Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.

Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.

“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”

This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.

Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.

The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.

Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.

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