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Impact of genetic alterations in stem-cell transplantation for myelodysplasia and secondary acute myeloid leukemia

Tetsuichi Yoshizato, Yasuhito Nannya, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Hiromichi Suzuki, Yasunobu Nagata, Yusuke Sato, Nobuyuki Kakiuchi, Keitaro Matsuo, Makoto Onizuka, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Hiroo Ueno, Masahiro M. Nakagawa, Bartlomiej Przychodzen, Claudia Haferlach, Wolfgang Kern, Kosuke Aoki, Hidehiro Itonaga, Yoshinobu Kanda, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Torsten Haferlach, Yasushi Miyazaki, Keizo Horibe, Masashi Sanada, Satoru Miyano, Hideki Makishima and Seishi Ogawa

Key points

  • TP53 and RAS-pathway mutations predict very poor survivals, when seen with complex karyotype and MDS/MPN, respectively.

  • For patients with mutated TP53 or complex karyotype alone, long-term survival could be obtained with stem-cell transplantation.

Abstract

Genetic alterations, including mutations and copy number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem-cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy number alterations, whose effects on transplantation outcomes were investigated. We identified 1,776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival, while clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected post-transplant survivals independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with complex karyotype were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without complex karyotype. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms. Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with complex karyotype and myelodysplastic/myeloproliferative neoplasms, respectively. However, for patients with mutated TP53 or complex karyotype alone, long-term survivals could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.

  • Submitted December 28, 2016.
  • Accepted February 8, 2017.