Author:
Mei Matthew,Pillai Raju,Kim Soyoung,Estrada-Merly Noel,Afkhami Michelle,Yang Lixin,Meng Zhuo,Abid Muhammad Bilal,Aljurf Mahmoud,Bacher Ulrike,Beitinjaneh Amer,Bredeson Christopher,Cahn Jean-Yves,Cerny Jan,Copelan Edward,Cutler Corey,DeFilipp Zachariah,Diaz Perez Miguel Angel,Farhadfar Nosha,Freytes César O.,Gadalla Shahinaz M.,Ganguly Siddhartha,Gale Robert Peter,Gergis Usama,Grunwald Michael R.,Hamilton Betty K.,Hashmi Shahrukh,Hildebrandt Gerhard C.,Lazarus Hillard M.,Litzow Mark,Munker Reinhold,Murthy Hemant S.,Nathan Sunita,Nishihori Taiga,Patel Sagar S.,Rizzieri David,Seo Sachiko,Shah Mithun Vinod,Solh Melhem,Verdonck Leo F.,Vij Ravi,Sobecks Ronald M.,Oran Betul,Scott Bart L.,Saber Wael,Nakamura Ryotaro
Abstract
Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell’s C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.
Publisher
Ferrata Storti Foundation (Haematologica)