Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia

Abstract

Key Points• Risk assessment is crucial in patients with CMML because survival may range from a few months to several years.• Integrating clinical features, morphology, and genetic lesions significantly improves risk stratification in CMML.Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics.In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation.Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] 5 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR 5 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

How I investigate chronic myelomonocytic leukemia

“…SF3B1 and U2AF1 mutations recur in MD‐CMML variant, whilst mutations affecting the RAS pathway, RUNX1, and EZH2 are more common in the MP‐CMML variant . Of these, ASXL1 mutations are of particular importance as they have been correlated with adverse prognosis and a poor overall survival . Such mutational profile may have clinical repercussions in the near future, as target molecules targeting the RAS signaling pathway and the spicing machinery are under investigation …”

When clinical heterogeneity exceeds genetic heterogeneity: thinking outside the genomic box in chronic myelomonocytic leukemia

“…4,6,24 A recent study identified RUNX1, NRAS, and SETBP1 as additional somatic gene mutations with prognostic relevance. 30 Combinations of mutations appear to have specificity for monocytosis and are highly enriched in CMML. For example, comutation of TET2 and SRSF2 was associated with monocytosis in .90% of cases in on series.…”

CMML: Clinical and molecular aspects

“…If ASXL1 RUNX1 and SETBP1 mutations appear detrimental in most series [3,15,[55][56][57], the prognosis of TET2, SRSF2 and RAS/CBL mutations seems more controversial, perhaps because of interactions with other gene mutation status [58], clinical variables such as myeloproliferative features, or with treatment. Finally, rare mutations such as those in EZH2 or DNMT3A are probably of poor prognosis [59,60], but only very large series will allow to incorporate them into molecular stratifications.…”

“…The GFM score can thus be used in centers relying on Sanger sequencing. Recently, the CPSS was integrated with molecular data to derive CPSS-mol that accounts for the poor prognosis of ASXL1, RUNX1, NRAS and SETBP1 mutations, and thus requires access to NGS for practicality [57]. Two other scores integrating clinical and molecular features, one from the Mayo clinic and the other from an international consortium have also been proposed [62,63].…”