A complex karyotype (CK) with mutations in TP53 or members of the RAS signaling pathway may be prognostic for outcomes after allogeneic hematopoietic cell transplantation (HCT) among patients with myelodysplastic syndromes or related diseases, according to a study published in Blood.1

The pathogenesis of myelodysplastic syndromes is driven by genetic alteration, but few studies have evaluated their role in outcomes after HCT. This study aimed to determine the effect of genetic alterations on HCT outcomes.

The multicenter study enrolled 797 patients from the Japan Marrow Donor Program who underwent HCT for myelodysplasia. The median interval between initial diagnosis and HCT was 9.4 months. During this time, 16% of patients progressed to secondary acute myeloid leukemia (sAML).

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Target-capture sequencing of 69 known driver genes and over 1100 single-nucleotide polymorphisms identified 1776 mutations and 927 abnormal copy segments, and 77.4% of patients had a genetic alteration.

Presence of a TP53 mutation was significantly associated with mutations in other driver genes and copy-number alterations including 17pLOH, del(5q), -7/del(7q), del(12p), and +21q. CK was present in 61% of samples with a TP53 mutation.

A higher number of genetic alterations was associated with decreased overall survival (hazard ratio [HR], 1.14/lesion; 95% CI, 1.11-1.17; P < 2.0 x 10-16) and increased risk of relapse (HR, 1.12/lesion; 95% CI, 1.08-1.17; P = 7.0 x 10-9).

The combination of TP53 mutations and CK was associated with a significantly short overall survival with a median of 4.8 months and a 100-day mortality rate of 38% (HR, 6.13; 95% CI, 4.51-8.32; P < 2.0 x 10-16). This was primarily due to early relapse, which occurred in 60% of patients (HR, 4.49; 95% CI, 3.21-6.28; P < .0001). These findings were not affected by disease subtype or conditioning regimen.

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Though RAS pathway mutations affected fewer patients (17%), their combination with CK was also associated with poor survival (HR, 1.84; 95% CI, 1.46-2.33; P = 2.6 x 10-7). This effect varied according to disease subtype; patients with myelodysplastic syndromes or myeloproliferative neoplasms demonstrated poorer outcomes.

Based on the results of this study, an alternative to HCT should be considered for patients with CK and mutations in TP53 or the RAS pathway.

Reference

  1. Yoshizato T, Nannya Y, Atsuta Y, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129:2347-58. doi: 10.1182/blood-2016-12-754796

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Hematologic Cancers