Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia

Abstract

IMPORTANCETyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.OBJECTIVE To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML. DESIGN, SETTING, AND PARTICIPANTSThe Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020. INTERVENTION Discontinuation of TKIs.MAIN OUTCOMES AND MEASURES Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR). RESULTSOf 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P Յ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs. CONCLUSIONS AND RELEVANCEIn this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. 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 MRec; clinical application of this finding should be c...

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

“…The molecular recurrence rate for patients with detectable BCR-ABL1 by RQ-PCR, for undetectable BCR-ABL1 by RQ-PCR but detectable by dPCR, and for undetectable BCR-ABL1 by both dPCR and RQ-PCR were 50.0%, 64.3%, and 10.3%, respectively (P≤ 0.001). Accordingly, detection of BCR-ABL1 by RQ-PCR or dPCR at the time of TKI discontinuation predicted a higher risk of molecular recurrence (37).…”

“…The LAST study presented a TFR rate of 60.8% at 36 months. The median time to molecular recurrence was the same as that in STOP -2G TKI, both 4 months (37). In the RU-SKI study, 98 patients treated with first or second-generation TKI were included.…”

“…In recent years, digital PCR (dPCR) has emerged as one of the most promising tools. Some recent findings indicated that dPCR is more efficient than RQ-PCR for monitoring MRD in CML and contributes to selecting patients more compatible with TFR (37,(86)(87)(88). In the study by Nicolini et al, low levels of BCR-ABL1 were assessed by dPCR in 175 patients at the time of discontinuation of imatinib.…”

Making Treatment-Free Remission (TFR) Easier in Chronic Myeloid Leukemia: Fact-Checking and Practical Management Tools

“…The panel agreed that standard RT-qPCR is the technique of choice during TFR. ddPCR is a potential alternative to RT-qPCR [95,96] but not yet standard-Table 7 Frequency of molecular monitoring in case of stable and unstable MR4.5 maintained during the first 6 months after discontinuation. After month 6, patients with unstable MR4.5 must be monitored at closer intervals than those with a stable MR4.5.…”

Severe obesity in a patient on long-term treatment of chronic myeloid leukemia with imatinib: Body composition, associated disorders and outcome

“…Discontinuation of TKI in patients in complete response may improve their quality of life because of a better sleep pattern. More than 20% of patients with CML in complete response participating in The Life After Stopping Tyrosine Kinase Inhibitors (LAST) had a meaningful improvement in sleep disturbances after stopping this treatment [23].…”