Prognostic factors for transformation into secondary
Prognostic factors for transformation into secondary AML and survival include peripheral blood cell counts, serum lactate dehydrogenase, percentage of bone marrow blasts, specific cytogenetic abnormalities as well as somatic mutations in myeloid driver NPS-2143 (e.g. ASXL1) [8,9]. By next-generation sequencing (NGS), molecular mutations are detectable in >90% of CMML patients. The somatic mutation patterns in patients with CMML are heterogeneous and include markers, which are also encountered in other myeloid malignancies such as SRSF2, CBL, EZH2, JAK2V617 F, KRAS/NRAS, RUNX1, and TET2 .
At present, the only curative treatment remains intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo HSCT). Due to the toxicity of this approach, including infections, severe graft versus host disease, and other organ toxicities, allo HSCT remains reserved for a minority of fit and mostly younger patients . Treatment recommendations for CMML patients are mainly extrapolated from experiences gained in MDS and MPN patients, as randomized trials are scarce and difficult to perform in this rare disease. Palliative treatment options include supportive care with transfusions and erythropoiesis stimulating agents (ESA) as well as cytoreductive treatment with hydroxyurea . Other experimental therapies, such as the JAK inhibitor ruxolitinib, are currently under investigation . In the presence of excess of blasts > 5% or other poor prognostic factors, treatment with hypomethylating agents (HMA), such as 5-azacitidine (AZA) or decitabine (DEC), are used for CMML patients. The recommendation of HMA treatment is based on results of three clinical MDS trials, which cumulatively comprise about 20 CMML patients that were finally randomized to HMA therapy [, , ]. In the United States (US) AZA and DEC were approved by the Food and Drug Administration (FDA) for the treatment of all subtypes of MDS, including CMML in 2004 and 2006, respectively . DEC is not approved for treatment of MDS or CMML in Europe or Switzerland. So far, only one small phase 1 study has been published that specifically investigated DEC in CMML patients . Additional efficacy data derives from aggregated evidence of several phase 2 studies [19,20] as well as retrospective analyses in cohorts and population-based cancer registries [, , , ]. Overall, responses to HMA range from 35 to 70% in CMML patients with improvement of survival of 6 months in responders 24]. Both HMA have similar response rates, with higher complete responses reported for DEC compared to AZA (58% vs 20%) in retrospectives studies [23,24]. However, it remains controversial, whether introduction of HMA treatment improved survival of CMML patients on a population-based level.
Discussion Our time trend analysis identified a disproportional increase of estimated annual cases in Switzerland (46.6%) compared to the US population (7.1%), based on a similar population growth of 14% in both countries. Median age at diagnosis, sex distribution and incidences from the SWISS and SEER populations are generally comparable to other reports from population-based registries, as summarized in Supplementary table 4. The demographic composition of both populations (age and sex) were comparable, with the exception of opposite time-trends of median age at diagnosis. We found an increasing median age at diagnosis in the SWISS in contrast to a decreasing in the SEER population. CMML is generally diagnosed at higher age [, , , , ]. The higher frequency of younger patients <75 yrs of age observed in the SWISS population in 1999–2006 is, therefore, unusual and may explain the better OS and RS in Switzerland in the first time period. In contrast, an increasing proportion of patients <75 yrs of age were observed in the SEER population in 2007–2014, which could have influenced the improvement of OS and RS in the US in the second time period. Based on the unusual predominance of CMML patients <75 yrs of age in the SWISS population in the first time period, we conclude that a better case ascertainment and classification of CMML in the elderly population has contributed to the increase of annual cases and incidence in Switzerland for the second time period. On the contrary, more patients <75 yrs were diagnosed in SEER in the second time period, suggesting an increased diagnostic awareness in younger CMML patients in the US over time. The ASRs remained comparable and stable for both populations, reflecting that differences in annual cases and CIR are mainly caused by population size, demographic composition (age and sex), or diagnostic accuracy, and not by new etiological factors.