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S. Claudiani et al.
AB
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).
require more frequent RTq-PCR testing if doses are reduced, patients admit to or are thought to be non-com- pliant or where there is previous evidence of resistance.
We found that patients who had achieved sMR3, who were known to be compliant and who were treated throughout their disease course with standard dose TKI had a low probability of loss of MR3. Furthermore, no patient satisfying these criteria and who achieved sMR4 experienced loss of MR3, and over time they gradually deepened their molecular responses. This leads us to sug- gest that the achievement of sMR4 in this group identifies patients at negligible risk of loss of molecular responses and that the frequency of molecular monitoring could be at 6-monthly intervals.
In contrast, the much higher rate of MR3 loss in the sMR3 only group (25.4% at 5 years) and the potential to subsequently lose CCyR, would favor continuation of molecular monitoring at a minimum frequency of 3- monthly in this group. Some of the patients who lost MR3 were on a reduced dose of their TKI and our observations are supported by the findings of the DESTINY study,23 in which approximately 30% of patients in sMR3 who reduced their TKI dose by 50% subsequently lost MR3. Although only one patient in the sMR3 group who was on standard dose TKI and thought to be compliant lost MR3, we are aware that we can never be certain of individual patient compliance, and would not recommend reduced vigilance in this group. We have previously reported a close association between compliance and major molecu- lar response.24 We think it unlikely that there would be an unexpected and clinically significant degree of non-com- pliance in patients in sMR4. In contrast, lack of compli- ance might be a contributing factor to the failure of patients in sMR3 to gain deeper responses. In fact, this lat- ter group are clearly responsive to TKI and the reasons for their failure to gain deeper responses are unclear.
It is possible that we have underestimated the probabil-
ity of loss of MR3 in the patients who achieved only sMR3 because this group may contain two distinct sub- populations: those who are destined to achieve sMR4 with longer follow up (and therefore have a better out- come) and those who do not have the biological potential to achieve deeper responses. We consider this unlikely because the median duration of follow up in patients who achieved sMR3 only was long (56.9 months), whereas the median time to sMR4 was 29.1 months (range: 3.3-172.1 months) from start of TKI therapy, such that sMR4 should have been observed had it been destined to occur.
We observed some differences between the patients who achieved sMR3 only and those who reached sMR4 in that the former group were more likely to express the e13a2 BCR-ABL1 transcript, more frequently demonstrat- ed resistance to their first-line TKI and were more likely to have required a higher dose of imatinib before the achievement of sMR3. Moreover, the time to sMR3 was longer in patients in whom this was the best response than in those who achieved sMR4. Although these factors may be useful in identifying a group of patients with a lower probability of achieving sMR4 after reaching sMR3, the fact remains that once sMR4 is reached, it is highly unlikely to be lost if the patient remains on standard doses of TKI. The only factor predictive for loss of MR3 in mul- tivariate analysis was the failure to achieve sMR4, leading us to conclude that sMR4 is a secure position for patients with CML.
The impact of the various levels of molecular response on patient outcome has been studied by others. For some time it was difficult to demonstrate an improvement in survival in patients who had achieved MR3 or better com- pared to those whose best response was CCyR.25-27 Most recently, data from the German CML Study IV showed that there were no progressions among patients achieving MR4.5, as compared to one, nine and 13 events in patients whose deepest responses were MR4, MR3 and CCyR,
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haematologica | 2019; 104(11)