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Precise and reliable predictive parameters to accurately identify chronic myeloid leukemia (CML) patients who can successfully discontinue their tyrosine kinase inhibitor (TKI) treatment are lacking. One promising parameter is depth of molecular response measured by BCR::ABL1 digital PCR (dPCR). The aim of this study was to validate a previously described prediction cutoff of 0.0023%IS and to assess the value of dPCR for treatment‐free remission (TFR) prediction in relation to other clinical parameters. A droplet‐based dPCR assay assessed BCR::ABL1 %IS prior to TKI discontinuation. The primary endpoint was molecular recurrence (MolR) by 36 months. A total of 186 patients from Canada, Germany, and the Netherlands were included. In patients with a first TKI discontinuation attempt (n = 163), a BCR::ABL1 dPCR < and ≥0.0023%IS had a MolR probability of 33% and 70%, respectively. Patients treated less than 6 years with a BCR::ABL1 dPCR <0.0023%IS had a MolR probability of 31%. After correction for treatment duration, both high dPCR value and the use of imatinib (vs. second‐generation TKI) were significantly associated with a higher risk of MolR (HR of 3.66, 95%CI 2.06–6.51, p <.001; and 2.85, 95%CI 1.25–6.46, p =.013, respectively). BCR::ABL1 dPCR was not associated with TFR outcome after second TKI discontinuation, however, with the limitation of a small number of patients analyzed (n = 23). In conclusion, BCR::ABL1 digital PCR based on the cutoff of 0.0023%IS is a valuable predictive tool to identify CML patients with a high probability of TFR success after first TKI discontinuation, including patients treated for less than 6 years. [ABSTRACT FROM AUTHOR]

Background: Typical chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by t(9; 22)(q34; q11) translocation. This chromosomal translocation forms the BCR::ABL1 fusion gene. The tyrosine kinase encoded by the BCR::ABL1 is considered to be the main pathogenic diver. BCR::ABL1 is not only a therapeutic target, but also a monitoring target. Monitoring of BCR::ABL1 reveals the progression of the disease and guides the next treatment. Now for CML, the target of treatment has been focused on treatment-free remission (TFR). Methods: We conducted a literature review of current developments of treatment-free remission and molecular monitoring methods. Results: More effective and sensitive CML monitoring methods such as digital droplet PCR (ddPCR) and next generation sequencing (NGS) have further studied the measurable residual disease (MRD) and clonal heterogeneity, which provides strong support for the exploration of TFR. We discussed some of the factors that may be related to TFR outcomes at the molecular level, along with some monitoring strategies. Conclusion: Currently, predictive indicators for treatment-free remission outcomes and recurrence are lacking in clinical practice. In future, treatment-free remission research should focus on combining the clinical indicators with molecular monitoring and biological markers to personalize patient conditions and guide clinicians to develop individualized treatment plans, so that more patients with CML can achieve safer and stabler treatment-free remission. [ABSTRACT FROM AUTHOR]

Objective Treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation at the first attempt is a therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML-CP). However, it remains unclear whether discontinuation of TKIs at a second or subsequent attempt can be performed safely.Patients and method Here, we report a 72-year-old man diagnosed with CML-CP. He achieved TFR successfully after TKI discontinuation at the third attempt. Before discontinuation, the patient received imatinib, nilotinib, and finally nilotinib. His neutrophil count at the third attempt was higher than after the second attempt. We also performed a retrospective investigation of 53 patients who discontinued TKIs on the first or subsequent attempts.Results Overall, 64 TKI discontinuations were documented (first, 53; second, ten; third, one). We found that a higher neutrophil count at the time of TKI discontinuation (>2439/μL; hazard ratio, 0.325; 95% confidence interval, 0.137–0.772; p = 0.011) was associated independently with lower rates of molecular relapse.Conclusion We report a case of a patient who successfully achieved third attempt TKI discontinuation and, an increased neutrophil percentage may reflect stronger antitumor immune responses in patients with CML-CP.

Treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation at the first attempt is a therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML-CP). However, it remains unclear whether discontinuation of TKIs at a second or subsequent attempt can be performed safely. Here, we report a 72-year-old man diagnosed with CML-CP. He achieved TFR successfully after TKI discontinuation at the third attempt. Before discontinuation, the patient received imatinib, nilotinib, and finally nilotinib. His neutrophil count at the third attempt was higher than after the second attempt. We also performed a retrospective investigation of 53 patients who discontinued TKIs on the first or subsequent attempts. Overall, 64 TKI discontinuations were documented (first, 53; second, ten; third, one). We found that a higher neutrophil count at the time of TKI discontinuation (>2439/μL; hazard ratio, 0.325; 95% confidence interval, 0.137–0.772; p = 0.011) was associated independently with lower rates of molecular relapse. We report a case of a patient who successfully achieved third attempt TKI discontinuation and, an increased neutrophil percentage may reflect stronger antitumor immune responses in patients with CML-CP. [ABSTRACT FROM AUTHOR]

Abstract Background Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP‐CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment‐free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence‐free survival (MRFS) after stop according to recommendations. Methods Over a 10‐year period, newly diagnosed CP‐CML patients and treated with first‐line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first‐line treatments. Results From January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41–62.19] at 2 years and 43.8% [31.45–56.15] at 5 years. Patients receiving frontline second‐generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others. Conclusion One third of CP‐CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second‐generation TKI frontline were associated with the highest MRFS.

Discontinuation of tyrosine kinase inhibitors (TKIs) is now a feasible therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML‐CP). Whereas approximately half of patients experience molecular relapse, after resuming with any TKI; the majority re‐achieve a deep molecular response (DMR). It is unclear whether such patients who re‐achieve a durable DMR can discontinue TKI safely again. Here, we retrospectively assessed first, second, and third attempts to stop TKIs in patients with CML‐CP. At the first attempt, 28 out of a total of 53 patients achieved sustained treatment‐free remission (TFR; 53.4%; 95% confidence interval [CI], 39.0%–65.9%). Subsequently, 10 of 25 patients attempted a second TKI discontinuation, and in all cases, this was after receiving second‐generation TKIs. Four of 10 patients successfully achieved TFR (37.5%; 95% CI, 9.9%–65.9%). All patients who relapsed at the second TKI discontinuation attempt were re‐administered TKIs, and soon achieved at least a major molecular remission. All six second relapse patients had a loss of MR4.5 at 3 months after TKI discontinuation. These findings suggest that second and third attempts to successfully stop TKI treatment are feasible in patients with CML‐CP. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP‐CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment‐free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence‐free survival (MRFS) after stop according to recommendations. Methods: Over a 10‐year period, newly diagnosed CP‐CML patients and treated with first‐line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first‐line treatments. Results: From January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41–62.19] at 2 years and 43.8% [31.45–56.15] at 5 years. Patients receiving frontline second‐generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others. Conclusion: One third of CP‐CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second‐generation TKI frontline were associated with the highest MRFS. [ABSTRACT FROM AUTHOR]

Summary: Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment‐free remission (TFR) success after TKI discontinuation, the optimal cut‐off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse‐free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut‐off period of time. The shortest cut‐off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut‐off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut‐off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%). [ABSTRACT FROM AUTHOR]

Background: Typical chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by t(9; 22)(q34; q11) translocation. This chromosomal translocation forms the BCR::ABL1 fusion gene. The tyrosine kinase encoded by the BCR::ABL1 is considered to be the main pathogenic diver. BCR::ABL1 is not only a therapeutic target, but also a monitoring target. Monitoring of BCR::ABL1 reveals the progression of the disease and guides the next treatment. Now for CML, the target of treatment has been focused on treatment-free remission (TFR)., Methods: We conducted a literature review of current developments of treatment-free remission and molecular monitoring methods., Results: More effective and sensitive CML monitoring methods such as digital droplet PCR (ddPCR) and next generation sequencing (NGS) have further studied the measurable residual disease (MRD) and clonal heterogeneity, which provides strong support for the exploration of TFR. We discussed some of the factors that may be related to TFR outcomes at the molecular level, along with some monitoring strategies., Conclusion: Currently, predictive indicators for treatment-free remission outcomes and recurrence are lacking in clinical practice. In future, treatment-free remission research should focus on combining the clinical indicators with molecular monitoring and biological markers to personalize patient conditions and guide clinicians to develop individualized treatment plans, so that more patients with CML can achieve safer and stabler treatment-free remission., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Some believe that tyrosine kinase inhibitor (TKI) therapy is as close to perfect as it gets in oncologic therapy. Patients diagnosed with chronic myeloid leukemia (CML) are treated with a daily oral therapy, through which most achieve remission. TKI therapy is not associated with classic chemotherapy side effects, and most patients are able to resume their normal activities of daily living. Moreover, recent data has demonstrated that CML does not affect the life expectancy of patients whose disease is well controlled with a TKI. However, TKI therapy is actually not that perfect. Patients need to stay on therapy forever. They have to remember to take their medications daily. TKIs are expensive, and the financial burden to patient and society cannot be overstated. Most patients' health-related quality of life is affected; common side effects include fatigue, muscle cramps, pain, edema, skin problems, and gastrointestinal symptoms. In addition, concerns about long-term side effects remain. Recently several studies have shown the feasibility and safety of discontinuation in a select group of patients. Herein, we will review the currently available data on stopping TKIs in CML. [ABSTRACT FROM AUTHOR]