The spectrum of treatment options for patients with CMML is continuously expanding. Early reports suggested that etoposide could give good results in CMML, with true complete responses in some cases and improvement rather than worsening of cytopenia [22
]. In a randomized phase III trial in patients with proliferative CMML, HU was more effective and achieved a faster response than cytotoxic chemotherapy with VP16 [23
]. Interestingly, this study remains the only randomized trial in a pure CMML patient population which demonstrated a survival benefit. Allogeneic stem cell transplantation, which is the only curative therapy, is rarely feasible because of age and/or comorbidities. While unresponsiveness to aggressive chemotherapy is a characteristic for most CMML patients, there may be subgroups that might benefit from more intensive chemotherapy. It is important to note that the approval of hypomethylating agents such as AZA and decitabine (DEC) was originally based on myelodysplastic syndrome studies which included only few patients with CMML. In a phase III clinical multicenter trial of 358 MDS patients including only 11 patients with dysplastic CMML, the median overall survival was 24.5 months in the AZA group as compared to 15.0 months in the conventional care group, leading to the FDA approval of AZA for this subtype of CMML [24
]. The approval of DEC for CMML was also based on a phase III clinical trial of 170 patients with MDS, 14 of them with CMML [25
]. The ORR was significantly higher in the DEC group versus supportive care (17% vs. 0%, p
< 0.001), but the median OS was not significantly different between the two arms. Additional phase II studies confirmed the efficacy of hypomethylating agents in all subtypes of CMML and, therefore, these agents are commonly considered as standard of care for higher risk CMML [26
]. In the largest retrospective study with a pure CMML cohort, patients were treated with AZA (n
= 56) and DEC (n
= 65) [34
]. The ORRs were 41% according to the IWG MDS/MPN response criteria (AZA-56%, DEC-58%), with CR rates of < 20% for both agents. No significant differences in response rates were seen between MP-CMML and MD-CMML. Similar findings were reported in a smaller prospective phase II Italian study, with 43 CMML patients receiving DEC [33
]. The ORR after six cycles was 47.6%, with seven CRs (16.6%), eight marrow responses (19%), one partial response (2.4%), and four hematological improvements (9.5%). After a median follow-up of 51.5 months, median OS was 17 months, with responders having a significantly longer survival than nonresponders. A recent European multicenter randomized phase III trial evaluating DEC ± HU versus HU in advanced MP-CMML did not show significant differences in outcome [35
]. Thus, despite these numerous studies, the impact of treatment on the outcome of CMML patients is not well defined. In this retrospective observational study, we show that the outcome of patients improved after the year 2000 and that patients receiving AZA had a better survival that patients not receiving this treatment. Our results are in line with a recent multicenter retrospective study including 949 unselected consecutive CMML patients which investigated whether HMA provides a benefit in subgroups of CMML patients [36
]. Adjusted median OS for patients treated with HU versus HMA was 15.6 months as compared to 20.7 months (p
= 0.0002). In patients with MP-CMML, median OS was 12.6 months as compared to 17.6 months (p
= 0.0027) for patients treated with HU versus HMA. HMA were not associated with an OS advantage for patients classified as having lower-risk disease (i.e., MD-CMML with < 10% blasts, CMML‑0, or lower-risk CPSS). Considering all the caveats of a retrospective nonrandomized trial, these data suggest HMA as the preferred treatment for patients with higher-risk CMML and those with MP-CMML. Regarding prognosis, a similar observation has been made by the Duesseldorf MDS registry, which reported a change in the prognosis of patients with myelodysplastic syndromes during the past 30 years, with an improvement of survival in patients diagnosed after 2002 (30 vs. 23 months, p
< 0.0001) [38
A sometimes impressive but greatly variable response to HMA provides the rationale for searching for biomarkers that predict response. Differentially methylated regions of DNA have been shown to separate DEC responders from nonresponders by Meldi [39
]. Other predictors for response to HMA treatment were reported by Duchmann et al. [40
]. In a retrospective analysis of 174 CMML patients treated with HMA multivariate analysis showed that mutations in ASXL1
predicted lower ORR, and RUNX1
mutations and CBL
mutations predicted inferior OS. The combination of TET2
mutation and ASXL1
wildtype predicted higher CR and better OS. In this study, we also looked at the predictive value of some parameters, including blood picture abnormalities as well as molecular features.
When looking at subgroups, the following patient cohorts had a significant survival benefit in association with AZA therapy: patients with Hb > 10 g/dL, patients with monocytosis > 10 G/L, and patients with mutations in RASopathy genes.
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. Thus, not every parameter was available in all patients. In addition, data from patient records were obtained over many years and from many different centers. Moreover, the patients included in this study were a relatively heterogenous population regarding the blast cell count, and there was a lack of molecular data in a significant number of patients. 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 [41
]. CMML is a rare disease and adequate patient numbers for a systematic and prospective study are not easy to collect within a limited timeframe.
In conclusion, the results of our population-based study show an improved survival of CMML patients with the introduction of AZA treatment. Patients without significant anemia and myelomonocytosis due to hyperactivation of the RAS pathway seem to benefit most from this treatment.