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Letters to the Editor
Thirty-two of the 37 patients (86.5%) required inter- ruption of maintenance therapy, and the median duration of interruption for all patients was 47 days (range, 0– 148 days). In patients with a 6-MP initial dose <10 mg/m2, the days of interruption during whole maintenance therapy was significantly shorter than in patients with a 6-MP ini- tial dose of 10 mg/m2 or more (P=0.042) (Online Supplementary Figure S3). When limited to the interruption within the first 8 weeks of maintenance therapy,8 the effect of the initial dose was more remarkable (Figure 1C).
In terms of toxicities, 36 of the 37 patients were observed to have grade 3 or worse neutropenia. Grade 4 leukopenia and grade 4 neutropenia were observed in 16 (43.2%) and 32 (86.4%) patients, respectively, and the median observation times of leukopenia and neutropenia were 33 days (range, 19–662 days) and 37 days (range, 9–
139 days), respectively, from start of the maintenance therapy (Figure 1D). We, thus, confirmed that the dose- limiting toxicity of 6-MP in patients with NUDT15 bi- allelic variant was neutropenia. Moreover, during the consolidation therapy (most of the protocol adopted early consolidation with 6-MP, so called "IB"), severe myelosuppression was observed in 21 of these patients (Online Supplementary Table S3). Conversely, grade 3 or worse liver enzyme elevation was observed in only 10 patients.
The median duration of follow-up was 1,398 days (range, 84–5,357 days) from the start of maintenance therapy. One patient relapsed during maintenance thera- py and five patients relapsed at 772 to 2,659 days from the start of maintenance therapy. Three of these six patients died at 499 to 720 days after relapse. The causes
AB
CD
Figure 1. Tolerability and efficacy for patients with NUDT15 bi-allelic variants. (A) Major haplotypes of NUDT15. (B) Average 6-mercaptopurine (6-MP) dose in each NUDT15 bi-allelic variant. (C) The association between initial 6-MP dose and therapy interruption for 56 days for start of therapy in maintenance therapy in patients with NUDT15 bi-allelic variant. Black circles and white circles show starting dose for patients with bi-allelic variant of exon 3 and others, respectively. (D) Toxicity during maintenance therapy.
haematologica | 2021; 106(7)
2027