Significance of cardiovascular comorbidity in patients with chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a rare, genotypically and phenotypically heterogenous hematologic malignancy of elderly people with an intrinsic risk to progress and transform into secondary acute myeloid leukemia (AML). With regard to the presence of myeloproliferation, CMML was originally subdivided into myeloproliferative disorder (MP-CMML; white blood cell [WBC] count >13 × 10⁹/L) versus myelodysplastic syndrome (MD-CMML; WBC count ≤13 × 10⁹/L) by the FAB criteria [1, 2]. Since CMML is characterized by features of both MDS and MPN, the World Health Organization (WHO) classification of 2002 assigned CMML to the mixed category, MDS/MPN [3]. CMML is further subclassified by the WHO into three groups based on blast equivalents (blasts plus promonocytes) in peripheral blood (PB) and bone marrow (BM) as follows: CMML‑0 if PB < 2% and BM < 5% blast equivalents; CMML‑1 if PB 2–4% or BM 5–9% blast equivalents; and CMML‑2 if PB 5–19% or BM 10–19% blast equivalents, and/or Auer rods are present [4]. CMML patients may have a highly variable outcome, suggesting that several factors can determine the course of disease and the cause of death in these patients [5‐9]. There are a number of established prognostic parameters that have been incorporated into several prognostic models [10‐21].

Cardiovascular disease is the leading cause of death in the general population [22]. Since CMML is a disease of elderly patients, cardiovascular disease may significantly impact the survival of these patients. The clinical significance of cardiovascular comorbidity in CMML is poorly investigated. Using the database of the Austrian Biodatabase for Chronic Myelomonocytic Leukemia (ABCMML), we analyzed 310 CMML patients with available information on cardiovascular comorbidity [23]. These information from our real-life database could be useful in the management of patients with CMML.

Cardiovascular morbidity is still the most common cause of mortality in people from European countries [22]. Since patients with CMML are often elderly and death in this cohort may be due to leukemia-related causes but also from non-leukemia-related causes, it is of interest to analyze whether cardiovascular comorbidity has an impact on survival in these patients. Our data show that this is obviously not the case, since the survival of patients with cardiovascular comorbidity was not different from patients with cardiovascular comorbidity. This was seen in all common subgroups of cardiovascular comorbidity such as coronary heart disease, atrial fibrillation, and hypertension. This finding is new and has, to the best of our knowledge, not been reported before.

Regarding other factors that may impact survival, the study cohort was comparable with CMML series reported by others. Among these established single prognostic parameters are leukocytosis > 13 G/L, anemia < 10 g/dL, thrombocytopenia < 100 G/L, and the presence of blast cells in peripheral blood. All these factors had a highly significant adverse impact on survival, indicating that the patient cohort we used in this study was comparable with CMML patient series published by others.

By comparing laboratory and molecular features between CMML patients with or without cardiovascular comorbidity, however, we found a lower number of circulating blasts in patients with as compared to patients without cardiovascular comorbidity. We also found in the molecular analysis a lower prevalence of EZH2 mutations in patients with cardiovascular comorbidity. Finally, time to transformation was significantly longer in these patients. We and others have shown that circulating blasts are an established adverse prognostic factor in patients with CMML [6, 23]. We have recently demonstrated that a composite molecular parameter including NRAS/CBL/EZH2, derived from its impact on spontaneous in vitro myeloid colony formation, was predictive for inferior survival as well as for an increased risk of transformation [26]. In the multivariable analysis reported by the Mayo group for their prognostic model, PB blasts but not BM blasts had a significant impact on leukemia-free survival [6]. This may provide an explanation for the shorter time to transformation which was observed in patients with cardiovascular comorbidity. Altogether, these data suggest that in our study, patients with cardiovascular comorbidity had less advanced CMML.

This finding is unexpected and provocative, and certainly needs to be explored by further studies. At the moment, it is unclear what this observation could mean and is just a matter of speculation. Due to the population-based nature of our study, we cannot exclude a selection bias favoring referral of patients with less comorbidity but more clinically aggressive disease by physicians in the community. In our study, a proportion of CMML patients was not primarily seen by an experienced center and therefore there is a possibility that patients with advanced CMML but not considered for treatment by their community physician because of severe comorbidities were not sent to a center of competence, resulting in a shift towards a higher proportion of more favorable patients in the cohort of patients with cardiovascular comorbidity. A second explanation could be more regular and better management of these CMML patients because of their comorbidities. Finally, a third and most exciting explanation could be that the medication which is taken by the patient for cardiovascular problems may have some unknown beneficial impact on the progression of CMML. Considering the role of inflammation in the progression of myeloid disorders, a higher consumption of anti-inflammatory drugs, particularly of acetylsalicylic acid, could mitigate chronic inflammation in these patients [27, 28]. Based on the available data in our dataset, it is not possible to prove or disprove this hypothesis. Therefore, these findings, which clearly need further attention, are hypothesis generating at best, and need to be validated by others before they are used as a basis for new potential treatment concepts.

There is some evidence in the literature supporting a link between TET2 mutations and cardiovascular disease. In 2014, independent epidemiological studies revealed that CHIP was associated with a substantial increase in the risk of all-cause mortality [29]. Unexpectedly, it was revealed that this increase in all-cause mortality could, at least in part, be attributed to a large increase in the frequency and death due to atherosclerotic cardiovascular conditions, such as coronary heart disease and ischemic stroke [30]. Specifically, it has been found that hematopoietic mutations in common driver genes, DNMT3A, TET2, and JAK2^V671F, can accelerate experimental atherosclerosis and/or heart failure by generating a pool of myeloid cells with an augmented proinflammatory profile [31]. In our study, we also looked for a potential difference in the proportion of mutations between patients with or without cardiovascular comorbidity. In our study, there was a trend toward a higher proportion of TET2 mutations in CMML patients with cardiovascular comorbidity.

We are aware of the limitations of our study. For example, most of the information used in this study was derived from retrospective real-world data that were not collected systematically or prospectively. Therefore, significant confounding by unknown parameters cannot be excluded, as discussed above. Moreover, not every parameter was available in all patients: data from patient records were obtained over many years and from many different centers, and the patients included in this study were a relatively heterogenous population regarding the blast cell counts. However, real-world data have recently been recognized as an important way to get insights into the routine management and natural history of rare diseases [32]. CMML is a rare disease and adequate patient numbers for a systematic and prospective study are not easy to collect within a limited timeframe. Moreover, the ABCMML provides information derived from molecular as well as from functional studies and therefore allows a more comprehensive view and deeper insight into the complex pathophysiology of this hematologic malignancy [23].