MR4 sustained for 12 months is associated with stable deep molecular responses in chronic myeloid leukemia

Abstract

The majority of patients with newly diagnosed chronic myeloid leukemia (CML) will enjoy a life expectancy equivalent to that of unaffected individuals, but will remain on life-long treatment with a concomitant requirement for on-going hospital interactions for molecular monitoring and drug dispensing. In order to determine more accurately the frequency of monitoring required, we performed a ‘real-life’ retrospective single-center cohort study of 450 patients with CML in at least major molecular remission (MR3) to analyze the risk of loss of MR3 [defined as at least 2 consecutive real-time quantitative polymerase chain reaction (RT-qPCR) results >0.1% International Scale (IS)]. Patients who achieved sustained MR4 (sMR4, BCR-ABL1 RT-qPCR <0.01% IS for 12 months) had a probability of loss of MR3 at 1 and 5 years of 0 and 2.6% (95%CI: 1.2-5.4) respectively, compared to 4.4% (95%CI: 1.9-9.8) and 25.4% (95%CI: 16.7-36.7) respectively, in those who achieved sustained MR3 (sMR3) but not sMR4 (P<0.001). No patient who improved their response to a deep molecular level (at least MR4) lost MR3 if they were considered compliant, had no history of resistance and remained on standard dose tyrosine kinase inhibitor (TKI). MR4 maintained for at least one year represents a secure response threshold for patients with CML, after which no MR3 loss occurs if certain conditions are satisfied (standard TKI dose, full compliance, and lack of previous TKI resistance). This finding may justify reduction of the frequency of hospital interaction, with an associated positive impact on quality of life, survivorship, and economic burden to both patients and healthcare providers.

Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

“…Importantly, failure to sustain a MR4 was the only significant variable for loss of MMR in multivariate analysis. 59 We also found that sustained undetectable BCR-ABL1 (MR4.5) was associated with sustained MMR. 21 Conversely, MMR was lost in six of 22 (27%) patients with sustained detectable BCR-ABL1 and was associated with the acquisition of imatinib-resistant BCR-ABL1 kinase domain mutations in three of six patients.…”

“…A recent single-center review of 450 patients demonstrated that sustained MR4 for at least 12 months represented a secure response threshold. 59 This finding only applied to compliant patients with no history of previous TKI resistance who received standard-dose TKI. No such patient lost a MMR, whereas loss of MMR occurred in 25% of patients who had not achieved a MR4.…”

Assessment of quantitative polymerase chain reaction for BCR–ABL1 transcripts in chronic myeloid leukaemia: Are improved outcomes in patients with e14a2 transcripts an artefact of technology?

“…19 D'Adda et al reported that patients with the e13a2 transcript were less likely to achieve major molecular response (MMR; <0.1% IS) and hence had less chance of enrolling into trials of treatment discontinuation. 20 Furthermore, we and others reported in small patient cohorts that patients with the e13a2 transcript were more likely to experience an increase in BCR-ABL1 transcripts after treatment discontinuation and had lower rates of treatment-free remission 21,22 The differences in these outcome measurements between patients with e13a2 and e14a2 transcript types could be due to biological differences in the activity of the respective oncoproteins, or could alternatively, at least in part, be the result of technical factors, such as differential sensitivity of the BCR-ABL1 detection assay currently in use, to the two isotypes.…”

Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial

“…The stability of the molecular response has already been proposed as a variable influencing TFR success [ 17 ], but not enough data are currently available to establish a definite link. Although the stability of MR 4.5 is known to be associated with improved patient outcomes [ 34 , 35 ], to our knowledge, this is the first time it has been reported as a potential predictor of TFR success. However, it should be noted that the number of patients in some of the groups was very small.…”