Background: Despite the excellent survival for chronic myeloid leukaemia (CML) patients treated with tyrosine kinase inhibitors (TKI), most CML patients report poorer quality of life due to TKI side-effects. In the DESTINY trial ( NCT01804985 ), CML patients halved their TKI dose for 12 months prior to TKI cessation, with 24 months of follow-up off therapy. Enrolled patients (n=174) were in stable deep molecular remission (DMR; BCR::ABL1IS <0.01%) or major molecular response (MMR; BCR::ABL1IS <0.1%), assessed in peripheral blood (PB) following more than 3 years of TKI treatment. Molecular recurrence-free survival (MRFS) at 3-years was 72% (DMR) and 36% (MMR), indicating PB BCR::ABL1IS burden at TKI de-escalation/cessation is predictive for recurrence. As shown previously, BCR::ABL1 kinetics during dose de-escalation are predictive for molecular recurrence after TKI stop. However, it has not been determined if BCR::ABL1 RT-qPCR in bone marrow (BM) improves risk prediction compared to PB. Objectives: We compared the predictive value of BCR::ABL1IS measurements at the time of dose de-escalation between PB and BM with respect to molecular recurrence, including assessing if the inclusion of a BM measurement at time of dose de-escalation improved the predictive power of BCR::ABL1 kinetics during de-escalation. Methods: With written informed consent, PB and BM samples were collected and BCR::ABL1IS was measured using RT-qPCR. Of 107 patients evaluated, 42 had molecular recurrence and 65 maintained TFR. To describe BCR::ABL1 kinetics during dose de-escalation, we applied linear regression. Estimated individual intercept and slope parameters were used within a logistic regression model to check for their predictive value for molecular recurrence. Results: The median log10BCR::ABL1[IS] at the time of dose de-escalation was higher in patients who experienced recurrence in both BM and PB (BM: -2.69 for recurrence vs. -4 for TFR; PB: -2.78 for recurrence vs. -2.98 for TFR). Based on samples with detectable log10BCR::ABL1[IS], transcript levels were moderately correlated between PB and BM (Spearman r=0.6). Using logistic regression, log10BCR::ABL1[IS] values from either BM or PB taken at time of de-escalation were similarly predictive of TFR success at 36 months post de-escalation (BM: OR=1.8; PB: OR=2.6). Moreover, using intercept and slope as characteristics of the treatment kinetics during dose de-escalation jointly as independent, PB-based predictors (ORintercept=13.8, ORslope=1.5) led to a similar conclusion and allowed for classification of patients into three risk groups: low, high, unclear. We identified 54 patients (50%) with low risk, 20 patients (19%) with high risk, and 33 patients (31%) with unclear risk. Considering TFR success, patients in the low-risk group show 87% MRFS 24 months after TKI stop, whereas all high-risk patients had molecular recurrence within 16 months of trial entry. Conclusion: No difference in the predictive power of a single measurement taken prior to dose de-escalation using either PB or BM samples could be shown. However, predictive power was enhanced by determination of slope and intercept of sequential PB BCR::ABL1 samples obtained during TKI de-escalation. Overall, BM evaluation prior to treatment cessation was not more predictive than PB of TFR success, however using BCR::ABL1 kinetics in PB during TKI de-escalation enabled classification of patients for risk of molecular recurrence.
Patterson et al. (Wed,) studied this question.