Ehab Atallah, MD
Kathryn Flynn, PhD
In the prospective LAST study reported in JAMA Oncology, Ehab Atallah, MD, and Kathryn Flynn, PhD, of the Medical College of Wisconsin, Milwaukee, and colleagues, found that stopping tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia (CML) was associated with the maintenance of major molecular response and achievement of treatment-free remission in the majority of patients and with an improvement in numerous patient-reported outcomes.1 Molecular recurrence was significantly more likely in patients with detectable BCR-ABL1 at the time of or at 3 months after stopping tyrosine kinase inhibitor treatment.
In the study, 172 adult patients from 14 U.S. centers were enrolled between December 2014 and December 2016 and had a minimum follow-up of 3 years. All patients had chronic-phase CML and either the BCR-ABL1 b3a2 (e14a2) or b2a2 (e13a2) variants that result in the p210 BCR-ABL protein; had been treated with imatinib, dasatinib, nilotinib, or bosutinib for at least 3 years with continuous documented BCR-ABL less than 0.01% by polymerase chain reaction (PCR) for at least 2 years; and had no previous tyrosine kinase inhibitor resistance.
Patients were monitored for molecular recurrence by standard real-time quantitative PCR (RQ-PCR) on peripheral blood samples monthly for the first 6 months, every 2 months until 24 months, and then every 3 months until 36 months. Molecular recurrence was defined as a single value of at least 0.1% BCR-ABL1 based on the International Scale ratio. Droplet digital PCR (ddPCR) was performed on samples with undetectable BCR-ABL1 on RQ-PCR. In patients who restarted tyrosine kinase inhibitor therapy, RQ-PCR was performed approximately every 3 months until the BCR-ABL1 International Scale ratio was less than 0.01% on two consecutive measurements.
Effects of Stopping Tyrosine Kinase Inhibitors on Molecular Response
Median follow-up was 41.6 months (range = 4.1–61.8 months). Among 171 patients evaluable for molecular analysis, 112 (65.5%) remained in major molecular response after stopping tyrosine kinase inhibitor treatment, 104 (60.8%) achieved treatment-free remission, 59 (34.5%) had molecular recurrence, and 67 (39.2%) restarted tyrosine kinase inhibitor therapy.
Among the 59 patients with molecular recurrence, median time to recurrence was 4 months (range = 1.5–41.3 months), with recurrence observed at up to 3 months in 16 (27.1%), at 3 to 6 months in 23 (39.0%), 6 to 12 months in 9 (15.3%), 12 to 24 months in 6 (10.2%), 24 to 36 months in 3 (5.1%), and more than 36 months in 2 (3.4%).
Molecular recurrence rates were 50% (14 of 28) among patients with detectable BCR-ABL1 by RQ-PCR, 64% (36 of 56) among those with BCR-ABL1 undetectable by RQ-PCR but detectable by ddPCR, and 10% (9 of 87) among those with undetectable BCR-ABL1 by both ddPCR and RQ-PCR (P < .001). Rates were 4.0% (3 of 75) for patients with undetectable BCR-ABL1 by either method at both baseline and 3 months, 31.0% (9 of 29) for those with BCR-ABL1 detectable at baseline and undetectable at 3 months, 44.4% (4 of 9) for those with BCR-ABL1 undetectable at baseline and detectable at 3 months, and 73.8% (31 of 42) for those with BCR-ABL1 detectable at both baseline and 3 months.
Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of tyrosine kinase inhibitor discontinuation (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 3.07–11.1, P < .001) and at 3 months (HR = 5.86, 95% CI = 3.07–11.1, P < .001) were independently associated with reduced risk of molecular recurrence, and detectable BCR-ABL1 by either method at treatment discontinuation was associated with a significantly higher risk (HR = 10.11, 95% CI = 3.35–30.49, P < .001). No associations of molecular recurrence with age, sex, Sokal risk score, duration and type of tyrosine kinase inhibitor treatment, time to major molecular response, or lymphocyte count at treatment discontinuation were found on multivariate analysis.
Among the 59 patients with molecular recurrence, 55 achieved BCR-ABL1 ≤ 0.01% after restarting tyrosine kinase inhibitor treatment, 2 were lost to follow-up, 1 did not restart treatment, and 1 died prior to achieving BCR-ABL1 ≤ 0.01%.
Patient-reported outcomes were assessed using Patient-Reported Outcomes Measurement Information System criteria monthly for the first 6 months, at 8 and 12 months, and then every 6 months until 36 months. In patients restarting a tyrosine kinase inhibitor, assessment occurred approximately every 3 months for 1 year and every 6 months thereafter.
Overall, there was a statistically significant mean improvement in fatigue, depression, diarrhea, and sleep disturbance and no mean change in pain interference after tyrosine kinase inhibitor discontinuation, with improvements being sustained over time. Restarting a tyrosine kinase inhibitor was associated with a mean worsening of patient-reported outcomes.
Among the 112 patients in treatment-free remission at 12 months, clinically meaningful improvements were observed in 90 (80.4%) for fatigue, 39 (34.8%) for depression, 98 (87.5%) for diarrhea, 24 (21.4%) for sleep disturbance, and 5 (4.5%) for pain interference.
Among patients who restarted tyrosine kinase inhibitor therapy, mean fatigue scores worsened, peaking at approximately 10 months and then improved; minimal changes in mean depression score were observed; mean diarrhea scores worsened, peaking at approximately 12 months and then improved; mean sleep disturbance scores initially worsened and then appeared to improve over time; and mean pain interference scores worsened initially and then appeared to improve.
The investigators concluded: “In this study, [tyrosine kinase inhibitor] discontinuation was safe and 60.8% of patients remained in [treatment-free remission]. Discontinuation of [tyrosine kinase inhibitors] was associated with improvements in [patient-reported outcomes]. These findings should assist patients and physicians in their decision-making regarding discontinuation of [tyrosine kinase inhibitors]. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of [tyrosine kinase inhibitor] discontinuation was associated with higher risk of [molecular recurrence]; clinical application of this finding should be confirmed in other studies.”
DISCLOSURE: The study was supported by a grant from the National Cancer Institute. Dr. Atallah has served as a consultant or advisor to AbbVie/Genentech, Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Pfizer, Syndax, and Takeda; has participated in a speakers bureau for AbbVie, Celgene, Jazz, and Novartis; and has received institutional research funding from Takeda. Dr. Flynn has received research support from Jazz and Incyte outside the submitted work.
1. Atallah E, Schiffer CA, Radich JP, et al: Assessment of outcomes after stopping tyrosine kinase inhibitors among patients with chronic myeloid leukemia. JAMA Oncol. November 12, 2020 (early release online).