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Sustained MR4 and molecular monitoring in CML
vival (OS).5-10 Indeed, the achievement of a major molecu- lar response (MMR, MR3) is often used as a surrogate end point in clinical trials,11 as failure to reach MR3 by 12 months is associated with lower rates of deeper molecular responses, PFS and OS.1, 11-13
Confirmed major molecular response (defined as MR3 on at least two consecutive occasions) has been described as a ‘safe haven’, in that patients who reach this level of response are highly unlikely to experience disease pro- gression.14-19 However, few studies have investigated the predictive value of a stable MR3 with respect to subse- quent loss of MR and the requirement for a change in ther- apy. Furthermore, there are no studies addressing the requirement for, and frequency of, molecular monitoring in patients who have achieved a stable MR3. We interro- gated our single center database to determine if we could identify a level of MR that is highly unlikely to be lost pro- vided the patient remains on treatment, a molecular threshold that would render frequent molecular monitor- ing unnecessary.
Methods
Patient selection
We included all patients diagnosed with CML in chronic phase, treated with TKI from January 2000 until December 2015, who achieved sustained MR3 (sMR3). We excluded patients treated with chemotherapy and/or stem cell transplantation before TKI. TKI were commenced at standard doses and may have been dose reduced subsequently to manage adverse events. Because some of the patients were treated prior to the availability of second-gener- ation TKI, doses of imatinib > 400 mg daily (HD) were prescribed for less than optimal responses in 15% of patients. Episode of non- compliance with treatment was recorded in our database when patients admitted to taking less than 100% of the prescribed ther- apy. The data cut-off was 31st October 2017. This retrospective observational study was approved by the research ethics commit- tee, and all patients gave written informed consent for their data to be stored and analyzed in our institutional database.
Response definitions
Standard definitions of response and resistance were used.3 Sustained MR3 (sMR3) and sustained MR4 (sMR4) were defined as BCR-ABL1 real-time quantitative polymerase chain reaction (RT-qPCR) of ≤0.1% and <0.01% (on International Scale, IS), respectively, maintained for at least one year. The BCR-ABL1 RT- qPCR was performed according to our previously established methodology.20 At least three consecutive assessments, at a fre- quency of 3-4 monthly, were required to define sustained response.
Single RT-qPCR results above MR3 or MR4 were considered fluctuations. The date of loss of MR3 and MR4 was the first of at least two consecutive RT-qPCR levels >0.1% and ≥0.01%, respec- tively.
A BCR-ABL1 RT-qPCR <1% was considered to be equivalent to complete cytogenetic response (CCyR).21 The date of loss of CCyR was the first of two consecutive RT-qPCR determinations ≥1% (IS).
Patient were monitored every three months throughout the entire follow up, according to current guidelines.3
Statistical analysis
Times to achievement of sMR3 and sMR4 were calculated from the date of starting TKI until the first day of RT-qPCR ≤0.1% and
<0.01% IS, respectively, maintained for at least one year. The probabilities of loss of MR3, MR4 and CCyR after the first year of sustained response were calculated using the Kaplan-Meier method, with patients being censored at last follow up on treat- ment. Potential prognostic factors for loss of MR3 were investi- gated using the log-rank test, with continuous variables split into groups using either quartiles or median values. Variables signifi- cant at the P<0.20 level were then included in a Cox proportional hazard regression analysis to find the best model.
Baseline characteristics were compared using the Mann- Whitney test for continuous variables, and Fisher Exact test for categorical variables.
Overall survival (OS) and the event-free survival (EFS) were esti- mated using the Kaplan-Meier method. For the analysis of survival from CML-related deaths (CML-OS), patients dying from any cause other than CML progression were censored at the date of death; all the other subjects were censored at the date of last fol- low up. Both OS and CML-OS were calculated from the date of diagnosis, whereas EFS was calculated from the first year in MR3. For EFS, progression to either accelerated or blast phases and death from any cause were considered as events.
P<0.05 was considered statistically significant. All analyses were performed with SPSS software (version 24; IBM, USA).
Results
Achievement of sustained MR3 and MR4
A total of 450 patients achieved sMR3 (Table 1) at a median time from start of TKI of 15.7 months (range: 2- 184 months). The median number of RT-qPCR assays in the first year of MR3 was five (range: 3-12), with a median interval between samples of two months (range: 0.5-4 months). The majority of patients, 336 of 450 (74.7%), were on first-line therapy at the time of achievement of sMR3, and most of the remainder, 96 of 114 (84.2%) had changed treatment because of resistance. Of the total cohort, 324 achieved sMR4 at a median of 11.4 months (range: 0-120 months) from sMR3 and 29.1 months (range: 3.3-172.1 months) from start of TKI therapy. The median number of RT-qPCR assays in the first year of MR4 was four (range: 3-11), with a median interval among samples of 2.8 months (range: 0.5-4). After the achievement of sMR3, the median interval between RT-PCR assays was 2.7 months (range: 0.5-9 months) and was identical in both groups. The 5-year probability of sMR4 after the achievement of sMR3 was 74% (95%CI: 69.3-78.2).
Online Supplementary Table S1 shows a comparison of clinical and CML-related characteristics between patients who achieved sMR3 only and those who reached sMR4. We observed a significant difference in the number of patients treated with high-dose imatinib and in the pro- portion of those with a history of resistance to first-line TKI (P=0.02 and P=0.0002, respectively), both more com- mon in the sMR3 only group.
Patients who achieved sMR4 reached sMR3 more rapid- ly (median 12.3 months, range: 1-135.2) than those whose best response was sMR3 only (median 24.5 months, range: 2.8-184.4; P<0.001). The median follow up of patients in sMR3 only was shorter (56.9 months, range: 12.3-155) than those in sMR4 (108.1 months, range: 14.6- 199.7).
Patients expressing the BCR-ABL1 e14a2 transcript achieved sMR3 more rapidly at 12.2 months (range: 1-130 months) than those expressing e13a2 at 21.4 months
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