Therapy-Related Myelodysplastic Syndromes with Isolated Del(5q): Comparative Analysis of Phenotype and Long-Term Survival

Background: Myelodysplastic syndromes (MDS) with chromosome 5q deletion [MDS-del(5q)] is a subcategory of MDS recognized by both the International Consensus (ICC) and World Health Organization (WHO) classification systems. Diagnostic criteria according to ICC-2022 include i) presence of del(5q) alone or with only one other additional cytogenetic abnormality, other than -7/del(7q), ii) absence of multi-hit TP53 mutation, iii) presence of ≥1 cytopenias, iv) presence of bone marrow myeloid dysplasia in ≥1 lineages, v) absence of ≥5% bone marrow blasts, and vi) absence of ≥2% circulating blasts (Arber et al. Blood 2022). We used WHO-2016 diagnostic criteria to identify Mayo Clinic patients with MDS-del(5q) and confirmed a study population that also met ICC-2022 criteria. The main objective of the current study was to describe the phenotype and long-term survival of patients with therapy-related MDS-del(5q) and compare the findings with a cohort of patients with primary MDS-del(5q), sourced from the same database.

Methods: The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from patients with MDS-del(5q) who were seen at the Mayo Clinic. Diagnosis of MDS-del(5q) was retrofitted to comply with ICC-2022 criteria, with the exception that patients with additional cytogenetic abnormalities were excluded from the current report (Arber et al. Blood 2022). Most patients were treated with lenalidomide, often given at the recommended dose of 10 mg/day x 21-28 days, with dose adjustements at physician discretion. Erythroid response criteria included transfusion independence for at least 8 weeks for transfusion dependent patients and an increase in hemoglobin by 1.5 g/dl lasting for at least 8 weeks, in transfusion independent patients. Transfusion dependency was assigned to those patients who had received at least 3 units of packed red cells in the 8 weeks prior to diagnosis. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA).

Results A total of 93 patients (median age 73 years; range 24-89; females 63%) were included in the current study, including primary (n=79) and therapy-related (n=14) MDS-del(5q). Cancer/treatment history for the latter group of patients included prostate cancer/radiotherapy (n=5), thyroid cancer/radiotherapy (n=2), breast cancer/radiotherapy (n=2), bladder cancer/chemotherapy (n=2), colon cancer/chemotherapy (n=1), lung cancer/chemotherapy (n=1), and non-Hodgkin's lymphoma/chemotherapy/radiotherapy (n=1). Median (range) time from radiotherapy/chemotherapy and recognition of MDS-del(5q) was 16 years (1.9-30). Comparison of presenting features for therapy-related vs primary MDS-del(5q) revealed the former to be associated with older age (median 77 vs 72 years; p=0.002), male gender (72% vs 30%; p=0.003), and lesser likelihood of transfusion-dependent anemia, at time of initial diagnosis (28% vs 68%; p=0.03). The two groups were otherwise similar in their leukocyte and platelet counts and mutational landscape, including prevalence of TP53 mutations (25% vs 13%, respectively).

All 79 patients with primary vs 10 of the 14 with therapy-related disease received lenalidomide therapy with erythroid response rates of 62% vs 80% (p=0.2) and complete/partial cytogenetic response rates of 13%/10% vs 0/0, respectively (p=0.05); the latter information was available in a subset of 64 patients. After a median follow up of 4.8 years, 38 (41%) deaths and 16 (17%) leukemic transformations were documented; the corresponding figures for therapy related/primary disease were 50%/39% and 14%/18%, respectively (p=0.4 and 0.7). Figure 1 depicts similar (p=0.6) survival data for therapy-related vs primary MDS-del(5q), with corresponding median survival (3-year survival) rates of 6.3 years (60%) vs 7.7 years (63%).

Conclusions: The current study describes the circumstances surrounding the development of therapy-related MDS-del(5q) and highlights differences in age and gender distribution, compared to primary MDS-del(5q). The two groups were otherwise similar in their response to lenalidomide therapy, overall survival, and leukemic transformation rates while their similarity in mutation distribution requires validation with higher number of informative cases.

Al-Kali:Astex: Other: research support to institution. Foran:AbbVie, Actinium, Aptose, Astex, H3Biosciences, Kura Oncology, Trillium, Xencor: Research Funding; Novartis, Servier, Pfizer, BMS, Taiho: Other: Formal Advisory Activities. Khera:Incyte: Consultancy; Optum: Honoraria. Shah:Astellas: Research Funding; Celgene: Research Funding; Marker Therapeutics: Research Funding.