Tyrosine Kinase Inhibitor Discontinuation Can Improve CML Outcomes

By Marilynn Larkin

November 26, 2020

NEW YORK (Reuters Health) - In patients with chronic myeloid leukemia (CML), discontinuing tyrosine kinase inhibitor (TKI) therapy is safe and associated with better patient-reported outcomes, a nonrandomized trial reveals.

"Consider treatment discontinuation in CML patients who have achieved a sustained deep molecular response," Dr. Ehab Atallah of the Medical College of Wisconsin in Milwaukee told Reuters Health by email. "After treatment discontinuation, close monitoring with BCR-ABL PCR is necessary. PCR need to be monitored monthly for six months, every two months for 18 months then every three months thereafter."

"Patients with undetectable BCR-ABL1 at the time of discontinuation and at three months have a 96% of staying in major molecular response and not restarting therapy," he said.

As reported in JAMA Oncology, Dr. Atallah and colleagues enrolled 172 CML patients (median age, 60; 52% women) from 14 US centers from 2014-2016, with a minimum follow-up of three years. All participants had chronic disease and were well controlled with imatinib, dasatinib, milotinib or bosutinib.

Primary outcomes were patient-reported outcomes (PROSs) and molecular recurrence (MRec), defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) For samples with undetectable BCR-ABL1, droplet digital polymerase chain reaction (ddPCR) was performed by standard real-time quantitative polymerase chain reaction (RQ-PCR).

Of the 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved treatment-free remission (TFR).

Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at TKI discontinuation (hazard ratio, 3.60) and at three months (HR, 5.86) was independently associated with MRec. Further, on multivariable analysis, detectable BCR-ABL1 by either method at discontinuation was associated with a significantly higher risk of MRec (HR,10.11).

MRec was 50% for patients with detectable BCR-ABL1 by RQ-PCR at enrollment. For those with undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR, MRec was 64.3%; and for undetectable BCR-ABL1 by both ddPCR and RQ-PCR, MRec was 10.3%.

Of the 112 patients in TFR at 12 months, clinically meaningful improvements were seen in fatigue (80.4%), depression (34.8%), diarrhea (87.5%), sleep disturbance (21.4%), and pain interference (4.5%).

Notably, restarting a TKI resulted in worsening PROs.

Dr. Atallah noted, "ddPCR is not widely available at this point. I think it should be more widely available to help guide and inform treatment discontinuation decisions."

Dr. Theodore Braun of Oregon Health and Science University in Portland, coauthor of a related editorial, commented in an email to Reuters Health that the study "adds to an already large body of evidence that TKI discontinuation in patients with a deep molecular response is extremely safe."

However, he added, "This is the first study to demonstrate patient-reported outcomes after TKI discontinuation and demonstrates that patients do indeed have improved quality of life after discontinuation."

"Regarding biomarkers for successful discontinuation, all study participants had less than one leukemia cell in ten thousand normal cells," he said. "In this population, prior studies have shown that approximately 50% of such patients will not have disease relapse upon TKI discontinuation. Beyond this, there is no proven biomarker that predicts who will relapse and who will not. DdPCR may be able to do this, but it remains experimental at this time."

SOURCE: https://bit.ly/3nWzGGy and https://bit.ly/2J00hUo JAMA Oncology, online November 12, 2020.

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