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Imatinib dose reduction in CML
Figure 2. Courses of BCR-ABL (IS) in 68 patients with imatinib dose reduction. Results below the horizontal red line represent at least major molecular response (MMR). Sixty-one patients have never lost MMR (courses with black lines). Five patients with loss of MMR regained MMR while continuing with reduced imatinib dose at 400 mg/day (blue lines). Two patients with loss of MMR did not regain MMR while on the lower imatinib dose and were switched to nilotinib or imatinib at 600 mg/day, respectively (orange lines).
96%). With only one MMR loss occurring later than 12 months after dose reduction, the 3-year molecular RFS was 88% (95%CI: 77-94%) (Figure 3). However, MMR loss was only temporary in five of the seven patients; these patients regained MMR while still on the lower 400 mg imatinib dose. Only two patients with MMR loss were switched to more potent ABL-inhibition with nilo- tinib or 600 mg imatinib to regain MMR (Figure 2). It is worthy of note that, at the time of stopping high-dose treatment, 43 of 68 patients were at least in MR4, 33 of them even at least in MR4.5. Of the 43 patients, 10 lost MR4 at some point; none lost MMR.
Clinical variables and high-dose imatinib treatment durations prior to and after achieving major molecular response were associated with probabilities of relapse-free survival
Of the clinical variables evaluated at diagnosis, larger spleen size below costal margin (HR: 1.17, 95%CI: 1.03- 1.31; P=0.02), higher white blood cell count (WBC) (HR: 2.76, 95%CI: 1.69-4.73; P=0.0001), and a higher percent- age of eosinophils (HR: 1.21, 95%CI: 1.02-1.37; P=0.03) were significantly associated with probabilities of lower RFS (Table 1). Furthermore, the high-risk groups according to the Euro and the European Treatment and Outcome Study (EUTOS) scores, as well as the intermediate- and high-risk groups according to the EUTOS long-term sur- vival (ELTS) score, suggested significantly worse molecu- lar RFS than their corresponding low-risk groups.
The longer the total treatment time at 800 mg/day, the higher were the probabilities of RFS (HR: 0.95, 95%CI: 0.891-0.998; P=0.04). However, as in the EURO-SKI study, which analyzed TKI discontinuation, the main focus was to investigate treatment time after dividing this time inter-
val into the time of high-dose treatment before and after achievement of MR.27
Four of the 68 patients had already achieved MMR with 400 mg imatinib/ day prior to the high-dose treatment interval. The median time to achieving MMR was 5 months (range: 0-23 months) (Online Supplementary Table S1). The longer the time with treatment at 800 mg/day until achieving MMR, the lower were the probabilities of RFS (HR: 1.14, 95%CI: 1.02-1.27; P=0.02). Using the min- imum P-value approach, with the prerequisite that the smallest group contained at least 10% of the patients, a cutoff of 13 months was observed (Padjusted=0.007). This cut- off was confirmed with bootstrap resampling: in 1000 bootstrap samples, the cutoff of 13 months was most fre- quently chosen. For the 56 patients who had an MMR within 13 months while on treatment at 800 mg/day, the probability of molecular RFS 12 months after stopping high-dose treatment was 94% (95%CI: 84-98%), whereas it was 74% [95%CI: 39-91%; HR: 7.39 (95%CI: 1.62- 37.74)] for the 12 patients who had an MMR after more than 13 months of high-dose treatment (Figure 4A).
The median time from achievement of MMR until dose reduction to 400 mg was 23 months (range: 0-93 months) (Online Supplementary Table S1). The longer the time with MMR while on treatment at 800 mg/day, the higher were the probabilities of RFS (HR: 0.86, 95%CI: 0.72-0.96; P=0.0006). Using the minimum P-value approach, with the prerequisite that the smallest group contained at least 10% of the patients, a cutoff of 8.5 months was observed (Padjusted=0.011). This cutoff was confirmed with bootstrap resampling: in 1000 bootstrap samples, the cutoff of 8.5 months was most frequently chosen. For the 53 patients who were more than 9 months on high-dose treatment after achievement of MMR, the probability of molecular
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