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.

Figure 1.

Probabilities of loss of responses after achieving sustained molecular response (MR)-3 (sMR3) and sMR4. (A) Probability of loss of MR3 and MR4 after the first year in MR4 (vertical line indicates time of sMR4, i.e. time at which MR4 was sustained for 12 months). (B) Probability of loss of MR3 for all 450 patients (vertical line indicates time of sMR3, i.e. time at which MR3 was sustained for 12 months) (blue curve); probability of loss of MR3 for patients who achieved sMR3 only (n=126) and those who achieved sMR4 (n=324) (green curves). (C) Probability of loss of complete cytogenetic response (CCyR) for patients who achieved sMR3 only (n=126) and those who achieved sMR4 (n=324). n: number; CI: Confidence Interval.

Figure 2.

Patient outcomes. Flow diagram showing outcomes of 450 patients after the achievement of sustained molecular response (MR)-3 (sMR3). The boxes in the lower part of the image contain information about the tyrosine kinase inhibitor (TKI) dose at the time of response loss. LD: lower TKI dose (compared to the standard recommended doses for first or subsequent lines); SD: standard TKI dose; HD: higher TKI dose; sMR4: sustained MR4; pts: patients.

Figure 3.

A total of 3,305 consecutive real-time quantitative polymerase chain reaction (RT-qPCR) results in patients achieving sustained molecular response (MR)-4 (sMR4) and on standard dose tyrosine kinase inhibitor (TKI) (n=107). The starting point is the date of achievement of sMR3. The red line depicts the linear trend-line of BCR-ABL1/ABL1 RT-qPCR values (expressed in % on International Scale, IS) over time. n: number.

Figure 4.

Overall survival (OS) (A) and event-free survival (EFS) (B) for the entire patient cohort (n=450). (A) The green line depicts the chronic myeloid leukemia (CML)-OS, whereas the blue line shows the OS. (B) EFS was calculated from the first year in sustained molecular response (MR)-3 (sMR3) (red vertical line indicates time of sMR3, i.e. time at which MR3 was sustained for 12 months).