Blood Res 2023; 58(S1):
Published online April 30, 2023
https://doi.org/10.5045/br.2023.2023035
© The Korean Society of Hematology
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
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.
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.
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
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..
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)..
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..
Table 4 . Predictive factors associated with treatment-free remission in multivariate analysis..
Study | N | Factors related to TFR rate | Hazard ratio | |
---|---|---|---|---|
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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