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S. Claudiani et al.
(range: 1-144 months; P=0.019) and were more likely to achieve sMR4, with 5-year probabilities of 81% (range: 74-86.5%) compared to 72.8% (95%CI: 64.8-79.6; P=0.009) for those with the e13a2 transcript (Online Supplementary Figure S1A and B).
Loss of sustained responses
Among the total cohort of 450 patients, the 1- and 5- year probabilities of loss of MR3 were 1.1% (95%CI: 0.5- 2.6) and 7.5% (95%CI: 5.2-10.7), respectively (Figure 1B), and of loss of CCyR 0.7% (95%CI: 0.2-2) and 5.9% (95%CI: 4-8.7), respectively. In univariate analysis, a his- tory of resistance to any TKI, time to sMR3 longer than 7.7 months (corresponding to the 1st quartile of the time of achievement of sMR3 in the whole patient cohort), and failure to reach sMR4 were significantly associated with loss of MR3. In multivariate analysis, only failure to reach sMR4 remained statistically significant (Table 2). Patients who achieved sMR3 after an increase in the dose of ima- tinib were more likely to lose MR3 than patients who achieved sMR3 after a change to a 2GTKI (Online Supplementary Table S2).
Of the 324 patients in sMR4, 29 (8.9%) lost MR4 at a median of 49.9 months (range: 2.5-111.4 months) after the first year in MR4, of whom 15 also lost MR3 at a median of 41.3 months (range: 15.3-112.7 months) after the first year in MR4 and 2.1 months (range: 0-23.3 months) from loss of MR4. At the time of MR4 loss and MR3 loss, no patient had remained on standard dose of TKI throughout their disease course. Seven were known to be non-compli- ant with therapy, 18 were on lower doses of TKI, and four had previously received TKI doses greater than standard doses for resistance (Figure 2). The probabilities of loss of MR3 at 1 and 5 years were 0 and 4.6% (95%CI: 2.5-8.2), and of loss of MR4 were 1.3% (95%CI: 0.5-3.5) and 8.7% (95%CI: 5.6-13.2), respectively (Figure 1A).
Of the 126 patients who achieved sMR3 only, 21 (16.7%) lost MR3 at a median of 21.5 months (range: 1-60 months) after the first year in MR3. The probabilities of loss of MR3 at 1 and 5 years were 4.4% (95%CI: 1.9-9.8) and 25.4% (95%CI: 16.7-36.7), respectively, which were higher than in the sMR4 cohort (P<0.001) (Figure 2B). At the time of MR3 loss, only one patient had remained on standard dose of TKI throughout their disease course. Five were known to be non-compliant with therapy, five were on lower doses of TKI, and ten had previously received TKI doses greater than standard doses for resistance (Figure 2).
Durability of response in patients achieving sMR4
Of the 324 patients in sMR4, 107 patients (23.7%) had remained on standard dose TKI after the achievement of sMR3 and sMR4. None of these patients lost MR3. In order to address the subsequent pattern of BCR-ABL1 RT- qPCR responses after their achievement of sMR3, we plot- ted a total of 3,305 consecutive results, with a median number of tests per patient of 29 (range: 6-93 tests) and a median interval between tests of three months (range: 1- 12 months). Most of the results (2,573, 77.8%) fell below the MR4 threshold, and demonstrated a continuing decline over time (Figure 3).
Events subsequent to the loss of MR3 and of MR4
In 36 patients who lost MR3, the median follow up since the loss was 24.5 months (range: 1.3-135.4 months).
Table 1. Study cohort characteristics (n=450). Variable
Gender Male
Female
Age at diagnosis (median, range)
<40
≥40 and <60 ≥60
Date of 1st line TKI start 2000-2006
2007-2011
2012-2014
2015
Transcript type
E14a2 E13a2 E14a2\e13a2 Others Unknown
Sokal score Low
Intermediate High Unknown
Previous interferon therapy
Yes
No
BCR-ABL1 mutation detected before the achievement of MR3
T315I
TKI 1st line Imatinib Dasatinib Nilotinib Bosutinib
TKI 1st line at MR3
Imatinib
Imatinib higher dose
-for resistance according to ELN Nilotinib
Dasatinib
Nilotinib Dasatinib Bosutinib Ponatinib
Bosutinib
N (%)
224 (49.7%) 226 (51.3%) 45 (19-86.4) 172 (38.2%) 200 (44.4%) 78 (17.3%)
252 (56.0%) 120 (26.7%) 74 (16.4%) 4 (0.9%)
222 (49.3%) 159 (35.4%) 50 (11.1%) 6 (1.3%) 13 (2.9 %)
135 (30%) 106 (23.5%) 109 (24.2%) 100 (22.2%)
90 (20%)
360 (80%) 24
3/24 (12.5%)
402 (89.3%) 21 (4.7%) 21 (4.7%) 6 (1.3%) 336 (100%) 226 (71.4%) 68 (16.1%) 54
21 (6.3 %) 16 (4.8%) 5 (1.5%) 96 (100%)
32 (33.3%) 54 (56.3%) 4 (4.2%) 6 (6.3%) 18 (100%) 1 (5.6%) 9 (50%) 7 (38.9%)
1 (5·6%)
Bosutinib
TKI ≥2nd line at MR3 for previous resistance to at least 1 TKI
TKI ≥2nd line at MR3 for previous intolerance Imatinib
Nilotinib
Dasatinib
n: number; TKI: tyrosine kinase inhibitor; ELN: European LeukemiaNet.
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