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Discontinuation of TKI Therapy
Source: Childhood Chronic Myeloid Leukemia Treatment (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: December 10, 2024 · Captured 2026-09-09.
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Context: Treatment of Childhood CML
Discontinuation of TKI treatment is an accepted strategy for adults with CML who meet strict criteria related to their duration of treatment and response to treatment. Guidelines for discontinuation of TKIs have been developed by both the ELN and the U.S.-based National Comprehensive Cancer Network (NCCN).[12,24] Key elements for both guidelines include the following:
TKI therapy for a minimum duration of 4 to 5 years for ELN and 3 years for NCCN.
A minimum duration of deep molecular response (DMR or MR4) (BCR::ABL1 protein transcript level ≤0.01% IS) of 2 years for both ELN and NCCN.
These guidelines specify close monitoring of BCR::ABL1 transcript levels after TKI discontinuation. Loss of MMR (or MR3) (BCR::ABL1 transcript level ≤0.1% IS) is generally used as the trigger for reinitiation of TKI therapy.
Loss of MMR is most likely to occur within the first 6 months of TKI discontinuation. Loss of MMR occurs much less frequently more than 1 year after TKI discontinuation. A meta-analysis included 3,105 adult patients who initiated a first attempt at TKI discontinuation. The study found that the probability of molecular recurrence was 35% after 0 to 6 months, 8% after 6 to 12 months, 3% after 12 to 18 months, and 3% after 18 to 24 months.[25] These results indicated that approximately 50% of adult patients maintained their molecular responses 2 years after TKI discontinuation. Relapses can occur when TKIs have been discontinued for more than 2 years, but these recurrences appear to be infrequent (<2%). Unfavorable outcomes were uncommon when relapses occurred. In addition, 90% of patients reacquired deep molecular remission after TKI reinitiation.
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There are limited data regarding TKI discontinuation in children with CML. This limited experience is explained, in part, by the low incidence of CML in children. In addition, few children with CML who are treated with TKIs meet the criteria for TKI discontinuation. For example, among patients enrolled on the International Chronic Myeloid Leukemia Pediatric Study (I-CML-Ped [NCT01281735]), only 9% of children with CML who were treated with TKIs met the criteria for TKI discontinuation.[26] Other reports have also supported this trend.[27,28] Although the small number of children studied is a limitation, it appears that the outcome for TKI discontinuation in children with CML is similar to that of adults. Two of the larger pediatric studies that discuss this topic are summarized below:
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The Japan Pediatric Leukemia and Lymphoma Study Group (JPLSG) reported on 22 children with CML who met their criteria for TKI discontinuation, which was similar to the NCCN's TKI discontinuation criteria.[28] The median age at CML diagnosis was 9 years, and the median age at TKI discontinuation was 16 years. The median duration of TKI therapy exceeded 8 years, and the median duration of MR4 before TKI discontinuation exceeded 4 years. Eleven of 22 children experienced loss of MMR at a median of 90 days after TKI discontinuation. All of these children subsequently regained MR4 after TKI resumption. The treatment-free remission rate at 12 months was 50%, and no relapses were observed beyond 4 months of TKI discontinuation.TKI withdrawal syndrome is observed in approximately 20% to 30% of adults when TKI therapy is discontinued.[29] The syndrome includes musculoskeletal pain that typically develops within 2 months of TKI discontinuation and continues for several months. The JPLSG study did not observe musculoskeletal pain in children after TKI discontinuation.
The International Registry of Childhood Chronic Myeloid Leukemia reported on 18 patients with CML who were younger than 18 years at diagnosis. These patients discontinued imatinib after meeting the criteria for TKI discontinuation (i.e., in chronic phase with a sustained DMR to imatinib [MR4; BCR::ABL1 transcript level ≤0.01% IS]) for at least 2 years.[26]Among the 18 children who stopped taking imatinib, 9 (50%) eventually resumed treatment.[26] Seven of these nine patients experienced loss of MMR (BCR::ABL1 transcript level ≤0.1% IS). Six of the seven patients regained MR4 within a median of approximately 5 months after TKI reinitiation. The remaining patient achieved MMR after TKI reinitiation. Two additional patients who had a one-log increase in BCR::ABL1 transcript levels, but did not meet the criteria for loss of MMR, were restarted on imatinib by their physicians. For the other nine patients who remained in treatment-free remission, the median follow-up period after imatinib discontinuation was 50 months. TKI withdrawal syndrome was not reported in any patients discontinuing imatinib.
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