Page 155 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Safety analysis on DPYD genotype-guided dosing
continue treatment with the escalated dose.
The median follow-up period (similar to the entire treatment duration or when toxicity
was resolved) was 71 days (interquartile range [IQR]: 36─161 days). For wild-type patients median follow-up was 69 days (IQR 36─161 days) and for DPYD variant allele carriers 90 days (IQR 35─168 days).
(N=91)
5
Prospectively genotyped patients (N=1,181)
Historical cohort derived from literature (Meulendijks et al.)
DPYD wild-type patients (N=1,090)
DPYD variant allele carriers
Excluded (not treated, screen failure etc.) (N=72)
Excluded (not treated, screen failure etc.) (N=6)
Included DPYD wild- type patients
Included DPYD variant allele carriers (N=85) c.1236G>A N=51 c.2846A>T N=17 DPYD*2A N=16 c.1679T>G N=1
(N=1,018)
Figure 1. Consort diagram of included patients
Figure 1. Consort diagram of included patients.
Frequencies of severe toxicity for DPYD variant allele carriers who received genotype- guided dosing and wild-type patients who received standard dosing are depicted in Table 2. A total of 33 out of 85 (39%) DPYD variant allele carriers experienced severe (grade ≥3) fluoropyrimidine-related toxicity, which was significantly higher than the frequency in wild-type patients (23%, p=0.0013). The incidence of grade ≥4 toxicity was low but was comparable between both groups as well (four out of 85 (5%) for DPYD variant allele carriers vs 29 out of 1,018 3% for wild-type patients, p=0.49, Table 2).
The percentage of toxicity in DPYD variant allele carriers was mainly driven by the two most common variants, who also had higher toxicity frequencies. In total, 20 out of 51 c.1236G>A carriers experienced severe toxicity (39%) and eight out of 17 c.2846A>T carriers (47%). For DPYD*2A carriers, five out of 16 patients (31%) experienced severe toxicity. The single c.1679T>G carrier, who did receive reduced-dose treatment, tolerated the treatment well and did not experience severe treatment-related toxicity over the course of treatment (three cycles).
For 16 out of 85 DPYD variant allele carriers (19%) fluoropyrimidine-related toxicity resulted in hospitalization, compared to 140 out of 1,018 wild-type patients (14%, p=0.26). Median
Toxicity in DPYD variant allele carriers versus wild-type patients
DPYD variant allele carriers treated with full dose (N=333) c.1236G>A N=177 c.2846A>T N=85 DPYD*2A N=60 c.1679T>G N=11
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