Reattempt of tyrosine kinase inhibitor discontinuation after maintenance therapy with ponatinib in patients with chronic myeloid leukemia in the chronic phase: Result of JALSG CML RE-STOP219 study.

Abstract Objective: In the management of chronic myeloid leukemia (CML), treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation is increasingly acknowledged as a key therapeutic goal, reflecting both clinical efficacy and patient quality-of-life considerations. However, patients who relapsed after TKI discontinuation require lifelong TKI therapy. Evidence for a second attempt at TKI discontinuation remains limited, with less promising outcomes reported. Here, we present the results of the JALSG CML RE-STOP219 trial. The present trial is a single-arm, open-label study, the objective of which is to evaluate the possibility of achieving TFR after maintenance therapy with ponatinib (Trial ID: jRCTs041190117). Patients and Methods: The target population consists of patients who have failed to discontinue TKI therapy. The criteria of age 18 years or older, chronic-phase CML, no history of hematopoietic stem cell transplantation, presence of detectable BCR::ABL1 fusion gene by conventional PCR, were mandatory. Eligibility criteria include patients enrolled in clinical trials related to TKI discontinuation or patients who have undergone TKI discontinuation under strict conditions in real-world practice (at least 3 years of TKI treatment history and at least 2 years of MR4.5 maintenance period). Patients were enrolled after regaining MR4.5 following TKI resumption. Those with prior ponatinib use or those with uncontrolled comorbidities were excluded. Following enrolment, the TKIs in use were switched to ponatinib (15 mg/day) and continued for a period of 12 months. Patients who maintained MR4.5 during this period discontinued and progressed to TFR phase, followed by 24 months of observation. The primary endpoint was defined as the TFR rate at 12 months (the proportion of patients maintaining MMR without requiring retreatment). In case of MMR loss, ponatinib or the previously used TKI was resumed, and followed up until MMR re-achieve or a period of six months. Results: Of the 50 patients enrolled, one withdrew consent prior to starting treatment. The remaining 49 received ponatinib maintenance therapy. Eight patients discontinued ponatinib (due to adverse events n=5, physician decision n=2, or patient preference n=1). Ultimately, 41 patients underwent a second TKI discontinuation. No cases of MR4.5 loss were observed during the ponatinib maintenance period. Among patients who attempted ponatinib discontinuation, 73.2% were male, with a median age of 46 years (range 11–72) at initial diagnosis. Risk classification at initial diagnosis revealed that 48.5% of patients were categorized as low-risk by Sokal score, while intermediate and high-risk accounted for 33.3% and 18.2%, respectively. The TKIs that were discontinued first were dasatinib (39.0%), nilotinib (36.6%), imatinib (14.6%) and bosutinib (9.8%). The molecular response depth at the time of initial TKI discontinuation was MR4.5 in 97.6% of cases. TKI re-initiation was triggered by loss of MMR in 82.9% of cases, loss of MR4.0 in 14.6% of cases, and loss of MR4.5 in 2.4% of cases, respectively. Patients were registered at a median age of 54 years (range 27–75). The TFR rate at 12 months was 36.6% (90% confidence interval: 24.1–50.6). TKI withdrawal syndrome was reported in three cases (all grade 1). Univariate analysis identified several favorable factors associated with successful TFR: (1) initial TKI discontinuation with imatinib; (2) longer treatment duration prior to initial TKI discontinuation; and (3) longer TFR duration during the initial TKI discontinuation. All patients who lost MMR regained it within three months of TKI resumption. There were no cases of disease progression or death during the observation period. Conclusion: This study suggests that a second TKI discontinuation following ponatinib maintenance therapy may confer the benefit of successful TFR in certain patients. Notably, patients who initially discontinued imatinib showed a higher TFR rate. Additionally, long-term treatment history and longer TFR duration during the initial TKI discontinuation correlated with a higher TFR rate. However, some patients experienced serious adverse events, such as cardiovascular complications, underscoring the need for careful benefit-risk assessment in clinical practice.