Disclosures: Atallah reports personal fees from Bristol Myers Squibb, Novartis and Takeda and research support from Novartis and Takeda. Flynn reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Braun reports no relevant financial disclosures. Druker reports personal fees or additional support from Aileron Therapeutics, Amgen, Aptose Biosciences, Blueprint Medicines, Celgene, Cepheid, Enliven Therapeutics, Gilead Sciences, GRAIL, ICON, Iterion Therapeutics, Novartis, Therapy Architects, VBL Therapeutics, Vincera Pharma and Vivid Biosciences, among others.
December 03, 2020
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TKI discontinuation safe for certain patients with chronic myeloid leukemia

Disclosures: Atallah reports personal fees from Bristol Myers Squibb, Novartis and Takeda and research support from Novartis and Takeda. Flynn reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Braun reports no relevant financial disclosures. Druker reports personal fees or additional support from Aileron Therapeutics, Amgen, Aptose Biosciences, Blueprint Medicines, Celgene, Cepheid, Enliven Therapeutics, Gilead Sciences, GRAIL, ICON, Iterion Therapeutics, Novartis, Therapy Architects, VBL Therapeutics, Vincera Pharma and Vivid Biosciences, among others.
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Discontinuation of tyrosine kinase inhibitors after 3 years of use appeared safe for adults with chronic myeloid leukemia who achieved a sustained deep molecular response, according to results of the LAST study published in JAMA Oncology.

Most patients (60.8%) in the cohort remained in treatment-free remission during the study period, and discontinuation of TKIs was associated with improvements in patient-reported outcomes, researchers reported.

Discontinuation of tyrosine kinase inhibitors after 3 years of use appeared safe for adults with chronic myeloid leukemia who achieved a sustained deep molecular response.

“Patients with CML have survival similar to the general population. However, seeing patients in the clinic and the many symptoms they have is what drove this research,” Ehab Atallah, MD, researcher in the department of medicine at Medical College of Wisconsin, told Healio. “At the same time we started this research, some preliminary data from France and Australia had demonstrated the safety of TKI discontinuation in a select group of patients.”

Although TKIs are associated with improvements in survival outcomes among patients with CML, the agents may lead to adverse events such as fatigue and diarrhea.

The prospective, single-group, nonrandomized LAST study evaluated molecular recurrence and patient-reported outcomes after discontinuation of TKI therapy among 172 patients (median age, 60 years; 51.7% women) with CML enrolled between December 2014 and December 2016 at 14 U.S. academic medical centers.

Patients had been treated for a minimum of 3 years with imatinib (Gleevec, Novartis; 59.3%), nilotinib (Tasigna, Novartis; 22.7%), dasatinib (Sprycel, Bristol Myers Squibb; 15.7%) or bosutinib (Bosulif, Pfizer; 2.3%).

Researchers monitored molecular recurrence — defined as loss of deep molecular response (BCR-ABL1 International Scale ratio > 0.1%) — by central laboratory testing and Patient-Reported Outcomes Measurement Information System computerized adaptive tests. They performed droplet digital polymerase chain reaction (PCR) on samples with undetectable BCR-ABL1 by standard real-time quantitative PCR.

Median follow-up was 41.6 months (range, 4.1-61.8).

Of the 171 patients evaluable for molecular analysis, 112 (65.5%) remained in deep molecular response, 104 (60.8%) experienced treatment-free remission, 59 (34.5%) experienced molecular recurrence and 67 (39.2%) restarted therapy.

Median time to molecular recurrence was 4 months (range, 1.5-41.3).

Common reasons for restarting therapy included molecular recurrence as determined by central (n = 54) or local (n = 4) laboratory tests, physician or patient decision (n = 6) and withdrawal syndrome (n =3).

Researchers observed an independent association between molecular response and undetectable BCR-ABL1 by both droplet digital and real-time quantitative PCR at the time of TKI discontinuation (HR = 3.6; 95% CI, 1.99-6.5) and at 3 months (HR = 5.86; 95% CI, 3.07-11.1).

Molecular recurrence rates were 50% for patients with detectable BCR-ABL1 by real-time quantitative PCR, 64.3% for those with undetectable BCR-ABL1 by real-time quantitative PCR but detectable by droplet digital PCR, and 10.3% for those with undetectable BCR-ABL1 by either PCR (P .001).

Researchers analyzed 1,883 patient-reported outcomes assessments and found significant improvements in fatigue, depression, diarrhea and sleep disturbance, but no change in pain interference, after discontinuation of TKIs.

Among the 112 patients in treatment-free remission at 1 year, most (80.4%) experienced clinically meaningful improvement in fatigue, as well as improvements in depression (34.8%), diarrhea (87.5%), sleep disturbance (21.4%) and pain interference (4.5%).

Restarting TKIs was associated with worsening patient-reported outcomes.

Kathryn E. Flynn, PhD
Kathryn E. Flynn

“One year after stopping their TKI, most patients reported less fatigue and less diarrhea. Many also reported fewer depressive symptoms and better sleep. This suggests that most patients will feel better after stopping TKIs,” Kathryn E. Flynn, PhD, professor of medicine at Medical College of Wisconsin, told Healio.

Atallah said patients with a sustained deep molecular response who discontinue TKIs should continue to be monitored.

Ehab Atallah, MD
Ehab Atallah

“After TKI discontinuation, close monitoring with real-time quantitative PCR for BCR-ABL1 is recommended monthly for 6 months, then every 2 months for 18 months, followed by every 3 months thereafter,” he said. “Future research should include better prediction of patients who can achieve a successful treatment-free remission. We will further analyze our samples to evaluate for any predictive factors.”

The intriguing findings from the LAST study suggest that patients with deeper responses are more likely to be able to successfully discontinue therapy, instructor of medicine Theodore P. Braun, MD, PhD, and researcher Brian J. Druker, MD, both of the division of hematology and medical oncology at Oregon Health & Science University, wrote in an accompanying editorial.

“Because droplet digital PCR is only available in a few centers and this was a relatively small study, additional validation studies will be necessary for these findings to be generalized,” they wrote. “If validated, a critical question is determining what about these patients allows them to achieve treatment-free remission.”

References:

Atallah E, et al. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.5774.
Braun TP and Druker BJ. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.5772.

For more information:

Ehab Atallah, MD, can be reached at Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226; email: eatallah@mcw.edu.

Kathryn E. Flynn, PhD, can be reached at Medical College of Wisconsin, 9200 W. Wisconsin Ave., Suite C5500, Milwaukee, WI 53226; email: kflynn@mcw.edu.