BLAST: A Globally Applicable and Molecularly Versatile Survival Model for Chronic Myelomonocytic Leukemia
Abstract
We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to "BLAST": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being "favorable" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, "unfavorable". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.
Article Details
Authors (35)
Ayalew Tefferi
4Mayo Clinic, Scottsdale, United States
Saubia Fathima
1Mayo Clinic, Hematology, Rochester, United States
Maymona Abdelmagid
4Mayo Clinic, Scottsdale, United States
Ali Alsugair
1Mayo Clinic, Hematology, Rochester, United States
Fnu Aperna
2Advent Health, Orlando, United States
Mahsa Rezasoltani
1Mayo Clinic, Hematology, Rochester, United States
Muhammad Yousuf
Anuya Natu
1Mayo Clinic, Division of Hematology, Rochester, United States
Clifford M Csizmar
Mayo Clinic, Rochester, Minnesota, United States
Mark Gurney
3Mayo Clinic, Rochester, United States
Terra L Lasho
Mayo Clinic, Rochester, Minnesota, United States
Christy M. Finke
Mayo Clinic, Rochester, Minnesota, United States
Rashmi Kanagal-Shamanna
Danielle Hammond
1The University of Texas MD Anderson Cancer Center, Houston, TX
Kelly Sharon Chien
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Alexandre Bazinet
1The University of Texas MD Anderson Cancer Center, Houston, United States
Courtney D. DiNardo
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Tapan M. Kadia
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Abhishek A. Mangaonkar
26Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
Naval G. Daver
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Animesh D Pardanani
Mayo Clinic, Rochester, Minnesota, United States
Gautam Borthakur
5MD Anderson Cancer Center, Houston, United States
Cinthya J Zepeda-Mendoza
Mayo Clinic, Rochester, Minnesota, United States
Kaaren K Reichard
Mayo Clinic, Rochester, Minnesota, United States
Rong He
Sanam Loghavi
Francesco Passamonti
University of Milan, Milan
Farhad Ravandi
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Koji Sasaki
1The University of Texas MD Anderson Cancer Center, Houston, TX
Dirk Larson
Guillermo Garcia-Manero
Francesco Onida
22ASST Fatebenefratelli-Sacco, University Milan, Milan, Italy
Naseema Gangat
4Mayo Clinic, Scottsdale, United States
Guillermo Montalban-Bravo
Mrinal M. Patnaik
Division of Hematology, Department of Internal Medicine, Mayo Clinic