Causes of Death in Patients with Myelodysplastic Syndrome and Spliceosome Mutations
Authors: Peddireddy Arjun S. , Kontoyiannis Panayiotis , Sasaki Koji , Chien Kelly S. , Senapati Jayastu , Montalban-Bravo Guillermo , DiNardo Courtney D. , Borthakur Gautam , Kanagal-Shamanna Rashmi , Bueso-Ramos Carlos E. , Pierce Sherry , Kantarjian Hagop M. , Garcia-Manero Guillermo , Urrutia Samuel 
Published: December 2024

BACKGROUND: Patients with myelodysplastic syndrome (MDS) and spliceosome mutations (SM) are found across the risk spectrum. Their causes of death (COD) include transformation to leukemia, pneumonia, sepsis, hemorrhage, or cardiovascular events. Our objective is to describe causes of death in this group as stratified by International Prognostic Scoring System-Molecular (IPSS-M) risk categories.

METHODS: We retrospectively analyzed the COD in a cohort of 137 deceased patients with MDS of varying risk levels (Very Low (VL), Low (L), Moderate-Low (ML), Moderate-High (MH), High (H), and Very-High (VH)) according to IPSS-M risk category at presentation to a single institution from 2017 to 2022. MDS-related death was defined as infection, bleeding, transformation to leukemia, or worsening cytopenia. Remaining COD such as cardiac, neurologic, and non-hematologic oncologic pathologies were classified as non-MDS-related. A Fisher's exact test was used for intergroup comparison, and Kaplan-Meier survival estimates were used for time to event analyses.

RESULTS: Among 137 deceased patients with SM MDS, 105 (77%) were male, and the median age of presentation was 72 years (range, 46-91 years). Median overall survival (mOS) was 21.2 months (range, 0.5-122.4 months). Thirty-one (22.6%) patients were IPSS-M VL, L or ML, defined as lower-risk MDS, and 106 (77.4%) were MH, H, or VH, defined as higher-risk MDS. SM mutations were distributed as follows: 42 (30.7%) patients with SRSF2, 36 (26.3%) with U2AF1, 35 (25.5%) with SF3B1, and 24 (17.5%) with ZRSR2. For the location of death, 66 (48.2%) patients died in the hospital, 47 (34.3%) died in their homes or home hospice, and 13 (9.5%) died in an institutional hospice.

In patients with IPSS-M VH, H or MH, the MDS-related COD accounted for 87 (82.1 %) deaths. Specifically, 29 (27.4%) died of MDS progression, 23 (21.7%) of leukemia transformation, 17 (16.0%) of pneumonia, and 9 (8.5%) of sepsis. Causes of non-MDS related death in this group included renal failure, accounting for 3 (2.8%) deaths, and lung cancer, also accounting for 3 (2.8%) deaths. The mOS for this group was 18.3 months.

In patients with IPSS-M VL, L, or ML, the MDS-related COD accounted for 20 (64.5%) deaths. Specifically, 5 (16.1%) died of MDS progression, 5 (16.1%) of pneumonia, 4 (12.9%) of sepsis, 2 (6.5%) of leukemia transformation, and 2 (6.5%) of CNS hemorrhage. For non-MDS-related COD in this group, 2 (6.5%) patients died of hepatic failure, 2 (6.5%) of COVID infections, and 1 (3.2%) of arrhythmia. The mOS for this group was 31.5 months. Overall, patients with higher-risk MDS were more likely to die of MDS-related COD (p = 0.005).

CONCLUSIONS: Most patients, regardless of risk status, will die of MDS-related COD. Despite lower rates of AML transformation in lower-risk MDS, mOS remains short for both groups. Strategies to affect the natural history of the disease and to reduce the risk of infection are necessary to prevent these outcomes. In this cohort, patients were more likely to die in the hospital than at institutional or home hospice. This finding highlights the complex medical management of MDS, a process that often requires intensive medical care. However, the proportion of patients who opted for home or hospice settings for end of life care reflects the importance of patient-centered end-of-life care and the need for expanding comprehensive support services.