Molecular Lesions in Low-Risk Myelodysplastic Neoplasms Disrupt Prognostic Model for Leukemia

The inclusion of molecular lesion data in prognostic models for predicting overall survival (OS) for patients with low-risk myelodysplastic neoplasms (LR-MDS) causes bone marrow (BM) blast percentage and other traditional OS prognostic parameters to lose clinical significance, according to a retrospective study in the British Journal of Haematology.1

“As we move towards an era of molecular diagnosis, the interaction of the molecular profile together with some of the classic parameters is a topic of interest,” the authors wrote.

The study, which evaluated 227 patients with LR-MDS in Spain, found that the presence of molecular data led to a change in risk stratification for 30% of patients. Slightly more than 1 in 5 patients progressed to acute myeloid leukemia (AML).The change was most notable in patients classified as Intermediate-1 according to the International Prognostic Scoring System (IPSS) and in the Intermediate groups as defined by the revised IPSS.

Genes with prognostic ability for OS included the RUNX1 mutation (HR, 1.7; 95% CI, 1.1-2.9; P = .05). MDS with an SF3B1 mutation were associated with a significantly lower mortality risk compared with patients who did not have the mutation (HR, 0.23; 95% CI, 0.1-0.5; P < .001). Patients with symptomatic anemia and transfusion dependency (TD) (HR, 2.5; 95% CI, 1.6-3.9; P < .001) had lower median OS.

Conventional parameters for risk stratification prognosis for patients with low-risk myelodysplastic neoplasms drop their clinical significance once molecular lesions are included in prognostic scores. | Image Credit: © ibreakstock-stock.adobe.com

Probability of progression to AML was statistically significant for the RUNX1 and TP53 mutations with BM blasts (5%-9% vs < 5%) and platelets < 50 × 109/L.

BM blast percentage (< 5% vs 5%-9%) and thrombocytopenia (< 50 × 109/L) did not have an impact on survival. All patients had less than 9% BM blasts.

The results repeated following a multivariate Cox regression analysis for patients with less than 5% BM blasts, the threshold for LR-MDS according the World Health Organization 2022 and International Consensus Classification (ICC) classifications. Patients without the RUNX1 mutation and those with anemia and TD had lower median OS. At the same time, mortality risk for patients with the SB3B1 was significantly lower.

The median OS for the cohort was 44 months, and the patients’ median age, 72 years.

Mutations were detected in 93% of the patients. There were 548 mutations overall, with a per-patient median of 2 mutations. Nearly half the patients had 3 or more mutations. Patients with molecular data were analyzed for survival and probability of progression to AML.The most common mutated genes were TET2, SF3B1, ASXL1, SRSF2, RUNX1, TP53 and DNMT3A.

Nearly half the patients had blood transfusion and erythropoietic-stimulating agents at the time of diagnosis. Azacitidine was administered to 15% of patients after erythropoietic-stimulating agents failed, and 10% of patients, those with 5q abnormality, received lenalidomide. During follow-up, 4% of patients received allogeneic stem cell transplant (ASCT) and ASCT receptors were stopped for survival analysis at the time of the transplant.

The study did not include patients with the following characteristics: cytogenetic features other than normal karyotype, -Y, del(11q), del(5q), del(20q), del(12p), +8 or double including del(5q); proliferative chronic myelomonocytic leukemia (white blood cell count > 13 × 109/L, CMML-MP FAB subtype) with an Intermediate-2 or High score according to the CMML-specific prognostic scoring system (CPSS).

Recent studies show that the typical 20% blast threshold to define AML is arbitrary; MDS cases with excess blast 2 (10%-9% blasts) and AML share biological characteristics.Yet, patients with 19% blasts are routinely deemed ineligible for AML studies, and patients with 21% blasts are excluded from MDS studies. Patients with de novo AML who have secondary-type AML mutations appear to have similar poor prognosis as with clinically defined secondary AML.2

“These results do not necessarily mean that the blast count does not have a primary role in the initial study of patients with MDS. On the contrary, bone marrow examination continues to be a cornerstone in the diagnosis of MDS,” the authors wrote. “Given the complexity and subjectivity in the morphologic assessment of dysplasia and blast count in MDS, particularly in low blast cases and considering the wide clinical heterogeneity of this group of patients with low-risk disease, molecular annotation is a fundamental tool for a better stratification.”

References

1. García-Culebras M, Alcalde P, Márquez-Malaver FJ, et al. Incorporation mutational profile might reduce the importance of blast count in prognostication of low-risk myelodysplastic syndromes. Br J Haem. 2024;205(5):1765-1772. doi:10.1111/bjh.19714

2. Estey E, Hasserjian RP, Döhner H. Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal. Blood. 2022;139(3):323-332. doi:10.1182/blood.2021011304