Novel DDX41 variants in Thai patients with myeloid neoplasms.

Germline DDX41 mutations were recently reported to cause MDS/AML and donor-derived leukemia after transplantation. While previously described in Western countries, DDX41 variants have not been reported in a Southeast Asian population. We performed targeted sequencing of blood or bone marrow samples from 109 Thai patients with myeloid malignancies. Among the 109 patients (75 MDS, 8 MPN, 11 MDS/MPN and 15 AML), the most frequent mutations were in ASXL1 (17.4%), TET2 (16.5%) and SRSF2 (12.8%), respectively. DDX41 variants were detectable in six (5.5%) cases. Four patients exhibited three presumable germline DDX41 mutations: p.S21fs (n = 2), p.F235fs (n = 1), and p.R339H (n = 1). While p.S21fs was previously reported in myeloid neoplasm, the latter two variants have not been described. Two of these cases harbored concomitant probable germline/somatic DDX41 mutations (p.S21fs/p.R525H and p.R339H/p.K494T), while the other two patients carried only somatic mutations (p.R525H and p.F438L). The p.K494T and p.F438L variants have not been previously reported. In patients with DDX41 alterations, the diagnoses were MDS with excess blasts (4), secondary AML (1) and low-risk MDS (1). In conclusion, we identified DDX41 variants in Thai patients with myeloid malignancies in which these variants could be used to assess predisposition to MDS in Southeast Asia.

Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable-like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.

A Randomized Multicenter Trial Comparing Low-Dose Prednisolone Versus Observation for Prevention of Recurrences in Adult Immune Thrombocytopenia.

Adult immune thrombocytopenia (ITP) commonly relapses after stopping treatments. This may be preventable by low-dose steroids. In this multicenter study, adult patients with ITP who had been responding to corticosteroids were randomized with the 2 strata of newly diagnosed and relapsed ITP to prednisolone 7.5 mg/d or observation for 6 months. Relapses were defined by a platelet count below 30 × 109/L and/or clinical bleeding. There were 75 patients evaluable for the efficacy and 77 for safety. The recurrent ITP comprised 57.3%. During the median follow-up of 42 weeks, there were 20.5% (8/39) and 25% (9/36) of recurrences in the prednisolone and control groups ( P = .643), with the hazard ratio (HR) of 0.75 ( P = .549). The significant factor that could predict recurrences was relapsed ITP with the HR of 2.79 (95% confidence interval, 1.02-7.64, P = .037). Prednisolone showed a trend toward a benefit in the relapsed subgroup ( P = .070). Adverse events were not different ( P = .540) and mostly mild. In conclusion, prednisolone maintenance could not prolong relapse-free survival. Relapsed patients deserve further investigations for preventive measures.