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Effects of Stopping Tyrosine Kinase Inhibitor Treatment for Chronic Myeloid Leukemia

Focus on Molecular Response and Patient-Reported Outcomes


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In a study (Life After Stopping TKIs; LAST) reported in JAMA Oncology, Atallah et al found that stopping tyrosine kinase inhibitor (TKI) therapy in patients with controlled chronic myeloid leukemia (CML) was associated with maintenance of major molecular response and achievement of treatment-free remission in the majority of patients. The team also recorded improvements in numerous patient-reported outcomes. Molecular recurrence was significantly more likely in patients with detectable BCR-ABL1 at the time of, or at 3 months after, stopping TKI treatment.

Study Details

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; had been treated with imatinib, dasatinib, nilotinib, or bosutinib for ≥ 3 years with continuous documented BCR-ABL < 0.01% by polymerase chain reaction (PCR) for at least 2 years; and had no previous TKI resistance. Patients were monitored for molecular recurrence by standard real-time quantitative polymerase chain reaction (RQ-PCR) on peripheral blood samples at regular intervals until 36 months. Molecular recurrence was defined as a single value > 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.

Among the 172 patients, median age was 60 years (range = 21–86 years); median time on TKI treatment prior to enrollment was 82.7 months (range = 36.1–199 months); and TKIs received prior to discontinuation were imatinib in 102 patients (59.3%), nilotinib in 39 (22.7%), dasatinib in 27 (15.7%), and bosutinib in 4 (2.3%).

Effects of Stopping TKIs 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 TKI treatment, 104 (60.8%) achieved treatment-free remission, 59 (34.5%) had molecular recurrence, and 67 (39.2%) restarted TKI 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 < 3 months in 16 (27.1%), at 3–6 months in 23 (39.0%), at 6–12 months in 9 (15.3%), at 12–24 months in 6 (10.2%), at 24–36 months in 3 (5.1%), and at > 36 months in 2 (3.4%). 

KEY POINTS

  • Treatment-free remission was achieved in 60.8% of patients after stopping TKI treatment.
  • Stopping TKI treatment was associated with improvement in patient-reported outcomes.

Molecular recurrence rates were 50.0% (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 10.3% (9 of 87) among those with undetectable BCR-ABL1 by both ddPCR and RQ-PCR (P < .001).

Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.99–6.50, 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. Detectable BCR-ABL1 by either method at 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 of TKI treatment, type of TKI, time to major molecular response, or lymphocyte count at discontinuation were found on multivariate analysis.

Among the 59 patients with molecular recurrence, 55 achieved BCR-ABL1 ≤ 0.01% after restarting TKI 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

Patient-reported outcomes were assessed using PROMIS (Patient-Reported Outcomes Measurement Information System) measures at regular intervals until 36 months. Overall, there was a statistically significant mean improvement in fatigue, depression, diarrhea, and sleep disturbance, and no mean change in pain interference after TKI discontinuation, with improvements being sustained over time. Restarting a TKI 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 at 12 months 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 TKI therapy:

  • Mean fatigue score 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
  • Mean pain interference scores worsened initially and then appeared to improve.

The investigators concluded, “In this study, TKI discontinuation was safe, and 60.8% of patients remained in treatment-free remission. Discontinuation of TKIs was associated with improvements in patient-reported outcomes. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of molecular recurrence; clinical application of this finding should be confirmed in other studies.”

Ehab Atallah, MD, of the Department of Medicine, Medical College of Wisconsin, Milwaukee, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by a grant from the National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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