Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor

Abstract

Background: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. Objectives: We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. Design: This is a prospective, multicenter study. Methods: We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). Results: A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type ( p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation ( p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS ( p = 0.015). Conclusion: Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

“…Similarly, patients treated more than 78 months with 2G-TKI were less likely to relapse after TKI discontinuation. These results were consistent with what Chen et al [3], Park et al [42] and Mahon et al [44] described before. They demonstrated that patients with a deeper and longer duration of MR prior to stopping TKI relapsed less.…”

“…However, our results are consistent with what Chen et al [18] observed in a large cohort of Asian patients treated with TKI, which supports that there are no differences among different regions and ethnic groups. The observed differences may be due to the fact that, according to our hypothesis, the transcript type by itself may not be sufficient to impact TFR, but it may have an effect with a longer duration of TKI treatment or a longer DMR [15,24,[38][39][40][41][42]. Pfirrmann et al [43] reported preliminary data from the EURO-Sky trial and proposed several models and prognostic factors related to MR 3.0 maintenance at 3 years after stopping TKI.…”

“…It is of note that the e14a2 transcript was included in one of the models together with the duration of TKI treatment, suggesting that e14a2 has an independent prognostic value in the setting of TFR. Park et al [42] reported that e14a2 together with longer DMR prior to TKI discontinuation were predictive indicators for successful TFR. In our study, we identified that e14a2 patients treated for more than 119 months with IM and also patients with e14a2 and sDMR longer than 108 months had a better TFR than e13a2 patients.…”

“…They demonstrated that patients with a deeper and longer duration of MR prior to stopping TKI relapsed less. Mahon et al [44] reported that patients with a median duration of IM therapy of at least 50 months had a higher sDMR rate than those with a shorter median treatment duration, while Park et al [42] suggested a DMR longer than 48 months for an undetectable e14a2 transcript type by droplet digital PCR and a better TFR. Some limitations of this study are inherent to its retrospective and multicenter nature.…”