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Blood Res 2023; 58(S1):
Published online April 30, 2023
https://doi.org/10.5045/br.2023.2023035
© The Korean Society of Hematology
Treatment-free remission after discontinuation of imatinib, dasatinib, and nilotinib in patients with chronic myeloid leukemia
Correspondence to : Jae Joon Han, M.D., Ph.D.
Department of Hematology and Medical Oncology, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
E-mail: anemia@khu.ac.kr
*This study was supported by a grant from Kyung Hee University in 2018 (KHU-20182182).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy are expected to have long-term survival outcomes comparable to those of the general population. Many clinical trials have confirmed that some patients sustain molecular responses without continuing TKI therapy. Treatment-free remission (TFR) is a new goal in treating chronic CML. The safety and outcome of TFR were studied in clinical trials after discontinuing imatinib or the second-generation TKIs dasatinib or nilotinib. TFR was safe in approximately 50% of patients who achieved a deep molecular response to TKI therapy. Patients who relapsed after discontinuing TKI responded immediately to the reintroduction of TKI. The mechanism by which TFR increases the success rate still needs to be understood. The hypothesis that the modulation of immune function and targeting of leukemic stem cells could improve the TFR is under investigation. Despite the remaining questions, the TFR has become a routine consideration for clinicians in the practice of molecular remission in patients with CML.
Keywords Chronic myeloid leukemia, Dasatinib, Nilotinib, Imatinib, Treatment-free remission, Tyrosine kinase inhibitor
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Review Article
Blood Res 2023; 58(S1): S58-S65
Published online April 30, 2023 https://doi.org/10.5045/br.2023.2023035
Copyright © The Korean Society of Hematology.
Treatment-free remission after discontinuation of imatinib, dasatinib, and nilotinib in patients with chronic myeloid leukemia
Jae Joon Han
Department of Hematology and Medical Oncology, College of Medicine, Kyung Hee University, Seoul, Korea
Correspondence to:Jae Joon Han, M.D., Ph.D.
Department of Hematology and Medical Oncology, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
E-mail: anemia@khu.ac.kr
*This study was supported by a grant from Kyung Hee University in 2018 (KHU-20182182).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy are expected to have long-term survival outcomes comparable to those of the general population. Many clinical trials have confirmed that some patients sustain molecular responses without continuing TKI therapy. Treatment-free remission (TFR) is a new goal in treating chronic CML. The safety and outcome of TFR were studied in clinical trials after discontinuing imatinib or the second-generation TKIs dasatinib or nilotinib. TFR was safe in approximately 50% of patients who achieved a deep molecular response to TKI therapy. Patients who relapsed after discontinuing TKI responded immediately to the reintroduction of TKI. The mechanism by which TFR increases the success rate still needs to be understood. The hypothesis that the modulation of immune function and targeting of leukemic stem cells could improve the TFR is under investigation. Despite the remaining questions, the TFR has become a routine consideration for clinicians in the practice of molecular remission in patients with CML.
Keywords: Chronic myeloid leukemia, Dasatinib, Nilotinib, Imatinib, Treatment-free remission, Tyrosine kinase inhibitor
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Table 1 . Clinical outcomes of TKIs..
Study Ref. TKI Dose (mg) N Age at diagnosis 5-year MR4 (%) 10-year MR4 (%) 5-year MR4.5 (%) 10-year MR4.5 (%) 5-year survival (%) 10-year survival (%) CML-IV [8, 9] Imatinib 400–800 1,536 53 y 68 81 53 72 90 82 IRIS [6, 10] Imatinib 400 553 50 y NA NA NA NA 89 83.3 ENESTnd [12] Imatinib 400 283 46 y 42 56 35 45 92 88.3 Nilotinib 600 282 47 y 66 73 54 64 94 87.6 DASISION [11] Imatinib 400 260 49 y NA NA 33 NA 90 NA Dasatinib 100 259 46 y NA NA 42 NA 91 NA MR4, BCR::ABL1≤0.01%; MR4.5, BCR::ABL1≤0.0032%..
Abbreviations: NA, not available; Ref., reference; TKI, tyrosine kinase inhibitor; y, years..
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Table 2 . TKI discontinuation studies..
Study TKI N Eligibility criteria Molecular recurrence-free survival Depth of MR Minimum Tx. (y) Minimum MR (y) STIM1 [20, 21] Imatinib 100 MR5.0 3 2 38% at 5 years STIM2 [26, 27] Imatinib 200 MR4.5 2 2 50% at 2 years A-STIM [28] Imatinib 80 MR5.0 3 2 64% at 2 years TWISTER [22] Imatinib 40 MR4.5 3 2 45% at 42 months KID study [25] Imatinib 90 MR4.5 3 2 58.5% at 2 years TRAD [32] Imatinib 108 MR4.5 3 2 56.8% at 12 months DASFREE [29] Dasatinib 84 MR4.5 2 1 46% at 2 years D-STOP [30] Dasatinib 54 MR4.0 2 2 62.9% at 12 months DADI [31] Dasatinib 63 MR4.0 1 1 49% at 6 months NILST [33] Nilotinib 90 MR4.5 2 2 58.9% at 1 year ENSESTfreedom [34-37] Nilotinib 190 MR4.5 2 2 48.2% at 5 years ENESTop [38] Nilotinib 126 MR4.5 3 1 42.9% at 5 years STOP 2G-TKI [39] Dasatinib/nilotinib 60 MR4.5 3 2 53.6% at 4 years EURO-SKI [40] Any TKI 755 MR4.0 3 1 49% at 2 years Summary 2,040 ≥MR4.0 1–3 1–2 38–64% MR4, BCR::ABL1≤0.01%; MR4.5, BCR::ABL1≤0.0032%; MR5.0, BCR::ABL1≤0.001%..
Abbreviations: INF-α, interferon-α; MR, molecular response; TKI, tyrosine kinase inhibitor; Tx., treatment; y, year(s)..
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Table 3 . Criteria for TKI discontinuation in guidelines with modifications..
Criteria European LeukemiaNet 2020 NCCN V1. 2023 I. Mandatory Disease status Chronic phase only Same Patient communication Motivated patient Same BCR::ABL1 test High-quality quantitative PCR using the international scale with a rapid turnaround of test results Same Monitoring Monthly for the first 6 months, every 2 months for 7–12, and every 3 months thereafter Same II. Stop allowed Line of therapy First-line, second-line if intolerance was the reason for the change NS Type of transcript Typical e13a2 or e14a2 Quantifiable Duration of TKI >5 years (>4 yr for 2G TKI) >3 years Duration of DMR >2 years Same III. Stop recommended for consideration Duration of TKI >5 years >6 years Duration of DMR >3 years if MR4 same >2 years if MR4.5 NS MR4, BCR::ABL1≤0.01%; MR4.5, BCR::ABL1≤0.0032%..
Abbreviations: 2G TKI, second-generation tyrosine kinase inhibitors; DMR, deep molecular response; NCCN, National Comprehensive Cancer Network; NS, not specified..
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Table 4 . Predictive factors associated with treatment-free remission in multivariate analysis..
Study N Factors related to TFR rate Hazard ratio P STIM1 [21] 88 vs. 11 Sokal risk score (low+intermediate vs. high) 2.22 0.024 100 Imatinib duration (<58.8 mo vs. ≥58.8 mo) 0.540 0.024 DASFREE [29] 64 vs. 20 Age (<65 yr vs. ≥65 yr) 0.044 0.0012 42 vs. 42 Dasatinib duration (<median vs. ≥median) 7.761 0.0051 37 vs. 47 Prior therapy line (1st vs. 2nd+3rd) 8.804 0.0138 ENESTop [39] 126 Time since 1st MR4.5 until TFR entry for every month increase 1.033 0.032 EURO-SKI [40] 405 MR4 duration while under TKI 1.18 0.0007 405 Duration of TKI treatment before MR4 1.12 0.08 MR4, BCR::ABL1≤0.01%; MR4.5, BCR::ABL1≤0.0032%..
Abbreviations: MR, molecular response; TFR, treatment-free remission; TKI, tyrosine kinase inhibitor..
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