Characteristics of NRAS-mutated patients with chronic myelomonocytic leukemia in a national (ABCMML) and an international cohort (cBioPortal)

Chronic myelomonocytic leukemia (CMML) is a rare, genotypically and phenotypically heterogenous hematologic malignancy of elderly people with an intrinsic risk of progression and transformation into secondary acute myeloid leukemia (AML). With regard to the presence of myeloproliferation, CMML was originally subdivided into myeloproliferative disorder (MP-CMML; WBC count > 13 × 10⁹/L) versus myelodysplastic syndrome (MD-CMML; WBC count ≥ 13 × 10⁹/L) by the French-American-British (FAB) criteria [1, 2]. Since CMML is characterized by features of both myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), the World Health Organization (WHO) classification of 2002 assigned CMML to the mixed category (MDS/MPN) [3]. After the 2016 revision of the World Health Organization classification of myeloid neoplasms and acute leukemia [4], updated diagnostic criteria for CMML were reported recently by two groups [5, 6]. CMML patients may have highly variable outcomes, suggesting that several factors can determine the course of disease and the causes of death in these patients [7‐13].

Recently, we reported on the Austrian biodatabase for CMML (ABCMML). In the ABCMML, epidemiologic, hematologic, biochemical, clinical, immunophenotypic, cytogenetic, molecular and biologic data of patients with CMML have been collected from different Austrian centers for 40 years [14]. It has been shown to be a representative and useful real-life data source for biomedical research.

Due to the molecular heterogeneity of CMML, it is important to know the meaning of molecular characteristics in order to offer the patient the best possible management of their individual situation. Some studies have analyzed the impact of molecular aberrations on the clinical outcome and phenotype of disease, although findings in most studies were not validated by independent cohorts. However, a prognostic parameter should not enter clinical practice unless it has been demonstrated that it performs a useful role. External validation denotes evaluation of the performance of a prognostic parameter in a sample independent from that used to develop the model [15].

Big data containing a huge number of datasets from international large consortium efforts are now available for many cancer entities, including CMML. The cBioPortal platform is such a collection of big data aimed at building a platform in order to support clinical decisions for personalized cancer treatment [16]. Moreover, due to the large number of well-characterized patients, it is a perfect source of data for validation of findings in traditional, sometimes much smaller patient cohorts. In this study, we used data from CMML patients documented in cBioPortal to validate the features of NRAS-mutated CMML patients that have been analyzed in the ABCMML.

Patient data for this study were obtained from 2 sources as recently reported [17]

The clinical outcome of NRAS-mutated patients has been reported in a number of different cohorts. In a retrospective analysis of 213 CMML patients seen at the MD Anderson Cancer Center in Texas, 65 patients were analyzed with respect to the presence or absence of RAS point mutations (NRAS or KRAS). The presence of these mutations was not associated with differences in survival times in that study [8]. In a well-characterized cohort of 72 CMML patients from Cleveland, mutations in NRAS had no impact on OS [9]. A German CMML cohort of 81 patients was thoroughly molecularly analyzed by NGS [10]. Whereas TET2-mutated patients had better overall survival as compared to patients without this mutation, no other molecular parameter, including NRAS mutation, revealed any association with survival. In a French cohort of 312 CMML patients, the adverse impact of the NRAS mutation was borderline for OS (p = 0.06) and significant for AML-free survival (p = 0.02) [11]. Finally, in an Italian and Spanish CMML cohort of 214 patients, mutations in ASXL1, EZH2, NRAS, RUNX1, and SETBP1 significantly affected OS [12]. In multivariable COX regression analysis, all these mutations, except EZH2 mutations, retained an independent prognostic value for OS. Based on these findings, the authors developed a risk score including clinical features and genetic lesions which was validated in an independent cohort consisting of 260 patients diagnosed at the MLL Munich Leukemia Laboratory in Germany. Thus, looking at these data and findings in our study, it seems that the likelihood that NRAS mutations will become a significant prognostic factor is dependent on the size of the cohort, since in all four cohorts consisting of more than 200 patients, including the ABCMML, NRAS mutations had a significant adverse impact on OS in three of them and borderline significance (p = 0.06) in one cohort.

The correlation of phenotypic features with the mutational status in CMML patients has been described previously [19]. Molecular aberrancies in the RAS/MAPK signaling pathway have been shown to be associated with leukocytosis, myeloproliferation, and increased blast cells [20‐22]. In both cohorts in our study, it was consistently shown that NRAS mutations are associated with an increased white blood cell count and the presence of blast cells in peripheral blood, thus validating previous findings. A new finding is the fact that in both our cohorts, NRAS-mutated patients had lower platelet values, a feature that has been reported in CMML patients with mutations in RUNX1, TET2, and SRSF2 [19].

Limitations of this study include the fact that the proportion of patients with leukocytes > 13 G/L was significantly higher in the ABCMML cohort as compared to the cBioPortal cohort. The reason for this imbalance is not completely clear. Increased laboratory screening in recent years among asymptomatic persons may detect some diseases, including CMML, in an earlier phase than in the past. Therefore, older patient series may be enriched in patients with more advanced disease as compared to more recent series. In fact, we have seen a significant drop in the proportion of patients with MP-CMML from 66% to 48% since 2010 in the ABCMML cohort (unpublished data).

Another limitation are changes in the diagnostic criteria of CMML over time since its first description in 1982 of the ABCMML database, suggesting that this patient group is more heterogenous as compared to the cBioPortal group which contains patients who were included over a shorter period of time. Furthermore, it needs to be considered that a proportion of patients in ABCMML, in particular older patients, did not consent to BM puncture. However, we do not believe that this greatly affected diagnostic accuracy, since persistent peripheral blood monocytosis is the most important diagnostic feature, and a genoclinical model has recently been described that uses mutational data, peripheral blood values, and clinical variables to predict the MDS vs. CMML diagnosis with high accuracy in the absence of a BM biopsy result [23]. Moreover, somatic mutations associated with CMML were not only detected in CMML patients confirmed by BM biopsy but also in 57% of patients with nondiagnostic BM features. Interestingly, the OS of mutated patients with non-diagnostic BM was indistinguishable from mutated patients with diagnostic BM suggesting that that the mutational spectrum is a much more sensitive parameter for the detection of myeloid malignancies than BM morphology [24].

In recent years, health care management worldwide has changed from a disease-centered model to a patient-centered model [25]. The adoption of big data characterized by a large amount of digital data which are continually generated by people within clinical care and everyday life will enable the implementation of personalized and precise medicine based on personalized information. Furthermore, these data can be used for validation of findings from national cohorts, and thus make an important contribution to improving patient management.