BCR::ABL1 evaluation in bone marrow is no more predictive of TFR success than from peripheral blood

BackgroundDespite the excellent survival for chronic myeloid leukemia (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. ObjectivesWe 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. MethodsWith 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. ResultsThe median log10[BCR::ABL1IS] at 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 log10[BCR::ABL1IS], transcript levels were moderately correlated between PB and BM (Spearmans r=0.6). Using logistic regression, log10[BCR::ABL1IS] 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. ConclusionNo 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.