Page 174 - Haematologica April 2020

M. Kroll et al.
Figure 1. Flow chart showing patient numbers in individual high-dose methotrexate courses including drop outs during high dose methotrexate consolidation.
was performed later in the course of consolidation, i.e. in the third (n=3) or the fourth course (n=1). The remaining 19 of the 51 patients were treated with a 0.5 g/m2 MTX dose throughout the whole consolidation phase.
Next we analyzed toxicities after the first and the forth HD-MTX course of all the DS-ALL patients who complet- ed consolidation (n=95) (Figure 2C-D). DS-ALL patients showed a significant decrease in the rate of grade 3/4 stomatitis after the last course as compared to the initial course (stomatitis, in the first course n=27 of 93 [29.0%], in the fourth course n=9 of 91 [9.9%], P=0.002). In con- trast, the number of patients with grade 3/4 leukopenia significantly increased (30 of 94 [31.9%] vs. 45 of 89 [50.6%], P=0.01). Similarly, NDS-ALL patients showed a decrease in grade 3/4 stomatitis and an increase in grade 3/4 leukopenia during the course of consolidation therapy (stomatitis, 53 of 942 [5.6%] vs. 9 of 923 [1.0%], P<0.001; leukopenia, 250 of 952 [26.3%] vs. 477 of 935 [51.0%], P<0.001).
Impact of MTX dose reduction on cumulative incidence of relapses
The 5-year-cumulative incidence risk of relapse (5y-CIR) was compared between DS-ALL patients who received a dose of 0.5 g/m2 in the first HD-MTX course with those who received 5 g/m2 (Figure 3A). No significant differ- ences in 5y-CIR were observed (0.5 g/m2 subgroup n=5 of 50, 5y-CIR±SE=0.09±0.04 vs. 5 g/m2 subgroup n=7 of 41, 5y-CIR=0.10±0.05, P=0.51). Next we compared the 5y- CIR of DS-ALL patients who received a 0.5 g/m2 MTX dose in the first course and increased dosages in subse- quent courses with those of patients who were treated with a MTX dose of 0.5 g/m2 throughout the whole con- solidation phase. No significant CIR difference between both groups was observed (0.5 g/m2 and escalated, 5y-CIR= 0.14±0.07 vs. 0.5 g/m2 and continued, 5y-CIR=0.00±0.00, P=0.42) (Figure 3B).
Association of MTX plasma levels and toxicity
To investigate whether differences in MTX plasma lev- els might explain the high rates of severe toxicities
observed in DS-ALL we analyzed MTX plasma levels of all patients at 42 and 48 hours after the start of the initial MTX infusion (Figure 4A-B). At 42 hours median MTX plasma levels in DS-ALL were 0.21 μmol/L (range 0.05– 3.40 μmol/L) for 0.5 g/m2 MTX and 0.90 μmol/L (0.17– 4.60) for 5 g/m2 MTX (P<0.001). At 48 hours DS-ALL median plasma levels were 0.16 μmol/L (0.01–1.80) and 0.43 μmol/L (0.22–3.60), respectively (P<0.001). For NDS- ALL patients who received a 5 g/m2 MTX dose median MTX plasma levels were 0.50 μmol/L (0.04–21.60) at 42 hours and 0.31 μmol/L (0.00–10.99) at 48 hours after the start of the first MTX infusion. Thus, at both time points DS-ALL patients showed significantly higher MTX plas- ma levels after 5 g/m2 MTX compared to NDS-ALL who received the same dose. DS-ALL patients treated with 0.5 g/m2 MTX had significantly lower MTX plasma levels compared to DS-ALL treated with 5 g/m2 MTX and NDS- ALL treated with 5 g/m2 at both time points (P<0.001 for each comparison). To further analyze whether MTX plas- ma levels may have an impact on toxicity within the DS- ALL cohort we analyzed the occurrence of grade 3/4 toxi- cities according to MTX plasma level quartiles at 42 and 48 hours (Figure 4C-D). At 42 hours DS-ALL patients with MTX plasma levels within the highest quartile (≥0.905 μmol/L, n=23) suffered from grade 3/4 leukopenia, throm- bocytopenia and stomatitis significantly more often com- pared to patients within the lowest quartile (≤0.200 μmol/L, n=24) (leukopenia, highest quartile n=7 of 22 [31.8%] vs. lowest quartile n=1 of 22 [4.6%], P=0.046; thrombocytopenia, 7 of 22 [31.8%] vs. 0 of 22 [0%], P=0.009; stomatitis, 9 of 21 [42.9%] vs. 0 of 22 [0%], P=0.001). DS-ALL patients with MTX levels within the highest quartile at 48 hours (≥0.470 μmol/L, n=22) showed significantly higher rates of grade 3/4 thrombocy- topenia and stomatitis compared to the lowest quartile (≤0.160 μmol/L, n=25) (thrombocytopenia, 9 of 21 [42.9%] vs. 1 of 25 [4.0%], P=0.003; stomatitis, 10 of 20 [50.0%] vs. 2 of 25 [8.0%], P=0.002).
SLC19A1 polymorphism rs1051266
The chromosome 21-encoded and ubiquitously
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