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Clinical Trial
. 2021 Jan 1;7(1):42-50.
doi: 10.1001/jamaoncol.2020.5774.

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial

Ehab Atallah  1 , Charles A Schiffer  2 , Jerald P Radich  3 , Kevin P Weinfurt  4 , Mei-Jie Zhang  5 , Javier Pinilla-Ibarz  6 , Vamsi Kota  7 , Richard A Larson  8 , Joseph O Moore  9 , Michael J Mauro  10 , Michael W N Deininger  11 , James E Thompson  12 , Vivian G Oehler  3 , Martha Wadleigh  13 , Neil P Shah  14 , Ellen K Ritchie  15 , Richard T Silver  15 , Jorge Cortes  7 , Li Lin  4 , Alexis Visotcky  5 , Arielle Baim  1 , Jill Harrell  3 , Bret Helton  3 , Mary Horowitz  1 , Kathryn E Flynn  1
Affiliations
Clinical Trial

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial

Ehab Atallah et al. JAMA Oncol. .

Abstract

Importance: Tyrosine 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 participants: The 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).

Results: Of 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 ≤ .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 relevance: In 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 confirmed in other studies.

Trial registration: ClinicalTrials.gov Identifier: NCT02269267.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Atallah reports receiving personal fees from Novartis, Bristol Myers Squibb, and Takeda and research support from Novartis and Takeda. Dr Radich reported receiving grants from the National Cancer Institute during the conduct of the study; and personal fees from Novartis, Bristol Myers Squibb, Takeda, Amgen, Cepheid, Bio-Rad, Adaptive, and SeaGen outside the submitted work. Dr Pinilla-Ibarz reported receiving grants from the National Institutes of Health during the conduct of the study; and personal fees from Janssen, AbbVie, AstraZeneca, Novartis, Pfizer, and Takeda outside the submitted work. Dr Kota reported receiving personal fees from Novartis and Pfizer outside the submitted work. Dr Larson reported receiving grants from the National Institutes of Health during the conduct of the study; and grants and personal fees from Novartis and Celgene; personal fees from Bristol Myers Squibb, Takeda, Amgen, CVS/Caremark, Epizyme, AstraZeneca, and Agios; and grants from Forty Seven, Rafael Pharmaceuticals, Astellas, Daiichi Sankyo, and Cellectis, outside the submitted work; in addition, Dr Larson had a patent to UptoDate Inc with royalties paid. Dr Mauro reported receiving personal fees and research funding from Novartis Oncology and Bristol Myers Squibb; personal fees from Takeda and Pfizer; and research funding from Sun Pharma/SPARC outside the submitted work. Dr Deininger reported receiving grants from the National Institutes of Health as a subcontract with the Medical College of Wisconsin during the conduct of the study; personal fees and research funding from Blueprint, Takeda, Novartis, and Incyte; personal fees from Medscape, Fusion Pharma, Sangamo, and DiserSol; and research funding from SPARC, Leukemia & Lymphoma Society, and Pfizer outside the submitted work. Dr Thompson reported receiving grants from Bristol Myers Squibb outside the submitted work. Dr Oehler reported receiving grants from the National Institutes of Health/National Cancer Institute during the conduct of the study; and personal fees from Bristol Myers Squibb, Takeda Pharmaceutical Company, and Pfizer Inc outside the submitted work. Dr Shah reported receiving grants from Bristol Myers Squibb during the conduct of the study. Dr Ritchie reported receiving research funding from Novartis and grants from Pfizer during the conduct of the study; and research funding from Celgene and grants from Jazz outside the submitted work. Dr Cortes reported receiving grants and personal fees from Novartis, Pfizer, and Takeda; and grants from Sun Pharma during the conduct of the study. Dr Horowitz reported receiving grants from the National Cancer Institute during the conduct of the study; and grants from Novartis, Bristol Myers Squibb, Pfizer, and Takeda outside the submitted work. Dr Flynn reported receiving grants from Jazz and Incyte outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Flow Diagram
MMR indicates major molecular response; PRO, patient-reported outcome; and TKI, tyrosine kinase inhibitor.
Figure 2.
Figure 2.. Probability of Molecular Relapse-Free Survival, Treatment-Free Remission (TFR), and Molecular Recurrence (MRec)
A, Kaplan-Meier plot for probability of molecular relapse-free survival and TFR. B, Probability of MRec, by BCR-ABL1 detectable by either real-time quantitative polymerase chain reaction (RQ-PCR) or droplet digital polymerase chain reaction (ddPCR) vs undetectable at baseline. C, Landmark analysis at 3 months: probability of MRec, by detectable or undetectable baseline PCR and 3-month PCR detectable or undetectable. MMR indicates major molecular response.
Figure 3.
Figure 3.. Mean Changes in Patient-Reported Outcomes After Tyrosine Kinase Inhibitor (TKI) Discontinuation and TKI Restart at 6 and 12 Months
Vertical lines indicate 95% CIs. PROMIS indicates Patient-Reported Outcomes Measurement Information System.
Figure 4.
Figure 4.. Fatigue After Tyrosine Kinase Inhibitor (TKI) Discontinuation and After Restarting a TKI
A, Trajectories (gray sold line) with 95% CIs (gray dotted lines) of model-estimated changes in Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue scores after TKI discontinuation (n = 172). B, Trajectories (gray sold line) with 95% CIs (gray dotted lines) of model-estimated changes in PROMIS fatigue scores after restarting a TKI (n = 57). The distributions of patient scores over time are shown as box plots (minimum excluding outliers, first quartile, median, third quartile, and maximum excluding outliers, with outliers shown as dots). Higher scores indicate greater severity of fatigue.
See this image and copyright information in PMC

Comment in

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