Dynamic Changes of Key Gene Mutations in the Disease Course of Patients with Chronic Myelomonocytic Leukemia
Authors: Yan Xin , Song Chunhua , Ge Zheng 
Published: December 2024

Background
Chronic myelomonocytic leukemia (CMML) is heterogeneous clonal hematopoietic neoplasms characterized by persistent monocytosis and hematopoietic dysplasia. Approximately 15~30% of CMML patients may have progressive disease (PD) and leukemic transformation (LT) (Exp Hematol Oncol,2022,11:32). However, the relationship between PD/LT and dynamic changes in genetic mutations is still uncovered. The study aimed to explore the critical dynamic changes of genetic mutations that may promote PD/LT in CMML patients and compare the differences between CMML and MDS patients.
Methods
A total of 21 CMML patients including 16 CMML-0, 3 CMML-1, 2 CMML-2 were enrolled in the cohort from 20 July, 2019 to 1 July 2024 at our institute. The patients in the cohort were sequenced with our reported targeted exome-seq for human leukemia driver genes (Blood Cancer J,2022;12:145), in which 15 patients had paired samples with two times sequencing. The 1st sequencing was at diagnosis and 2nd sequencing was at PD (4 patients), LT (4 patients) as well as non-PD/LT (7 patients). In addition, the 35 MDS patients were also enrolled in the cohort from 30 May, 2019 to 16 August, 2023 at our institute, they performed the paired targeted exome-seq for human leukemia driver genes at diagnosis and PD/LT.
The mutations were defined into four groups based on the dynamic changes of variant allele frequency (VAF). If a mutation was not detected at 1st sequencing while detected at 2nd sequencing, it was defined as a newly-acquired mutation. If the VAF of a mutation was increased by ≥10% in the 2nd sequencing versus the 1st sequencing, it was defined as a clonally-increased mutation. If the VAF of a mutation was decreased by ≥10% in the 2nd sequencing versus the 1st sequencing, it was defined as a clonally-decreased mutation. If the VAF of a mutation was changed ＜10% in the 2nd sequencing versus the 1st sequencing, it was defined as clone-stable mutations.
Results
In the cohort, 21 patients were analyzed with a median age of 72 (51~88) years, including 14 males and 7 females. The most frequently mutated genes that were detected at diagnosis were ASXL1(71%, n=15), TET2 (67%, n=14), SRSF2 (38%, n=8), NRAS (24%, n=5), and RUNX1(19%, n=4).
The most frequent newly-acquired / clonally-increased mutations during the disease course were RAS pathway(n=4,26.7%), ASXL1(n=4,26.7%), SETBP1(n=2,13.3%) mutations; Patients from the PD/LT cohorts had a higher median number of newly-acquired / clonally-increased mutations than the non-PD/LT cohort(3 vs.1, P=0.012); newly-acquired / clonally-increased RAS pathway mutations(50% vs.0%, P=0.029) were enriched in PD/LT cohorts than in the non-PD/LT cohorts.
Furthermore, to explore whether there is a difference in dynamic changes of genetic mutations between CMML and MDS patients, we compared their newly-acquired / clonally-increased mutations in the PD/LT cohorts. Results showed that newly-acquired / clonally-increased ASXL1(37.5% vs. 8.6%, P=0.033) and PTPN11 (37.5% vs. 8.6%, P=0.033) mutations were higher in CMML patients than in MDS patients. newly-acquired / clonally-increased RAS pathway mutations were frequent both in CMML (50%, n=4) and MDS (25.7%, n=8) patients, while newly-acquired / clonally-increased TP53 mutations were more frequent in MDS (25.7%, n=9) patients rather than in CMML (12.5%, n=1) patients.
Conclusion
The study clarified the dynamic changes of genetic mutations in CMML patients during the disease course. The PD/LT in CMML was associated with the increment of newly acquired and clonally-increased mutations. The newly acquired and clonally-increased mutations in RAS pathway may promote PD/LT in CMML patients. The newly acquired and clonally-increased TP53 mutation may promote PD/LT in MDS patients instead of CMML patients.