The mutational landscape in chronic myelomonocytic leukemia and its impact on allogeneic hematopoietic cell transplantation outcomes: a Center for Blood and Marrow Transplantation Research (CIBMTR) analysis
Mei, Matthew ; Pillai, Raju ; Kim, Soyoung ; Estrada-Merly, Noel ; Afkhami, Michelle ; Yang, Lixin ; Meng, Zhuo ; Abid, Muhammad Bilal ; Aljurf, Mahmoud ; Bacher, Ulrike ... show 10 more
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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
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UMass Chan Affiliations
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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.
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Mei M, Pillai R, Kim S, Estrada-Merly N, Afkhami M, Yang L, Meng Z, Abid MB, Aljurf M, Bacher U, Beitinjaneh A, Bredeson C, Cahn JY, Cerny J, Copelan E, Cutler C, DeFilipp Z, Diaz Perez MA, Farhadfar N, Freytes CO, Gadalla SM, Ganguly S, Gale RP, Gergis U, Grunwald MR, Hamilton BK, Hashmi S, Hildebrandt GC, Lazarus HM, Litzow M, Munker R, Murthy HS, Nathan S, Nishihori T, Patel SS, Rizzieri D, Seo S, Shah MV, Solh M, Verdonck LF, Vij R, Sobecks RM, Oran B, Scott BL, Saber W, Nakamura R. The mutational landscape in chronic myelomonocytic leukemia and its impact on allogeneic hematopoietic cell transplantation outcomes: a Center for Blood and Marrow Transplantation Research (CIBMTR) analysis. Haematologica. 2023 Jan 1;108(1):150-160. doi: 10.3324/haematol.2021.280203. PMID: 35443559; PMCID: PMC9827167.