Trends of incidence and survival of patients with chronic myelomonocytic leukemia between 1999 and 2014: A comparison between Swiss and American population-based cancer registries

BackgroundChronic myelomonocytic leukemia (CMML) is a rare hematopoietic malignancy. Treatment with hypomethylating agents (HMA) was introduced between 2004 and 2006 but its impact on population-based survival remains controversial. The aim of this study was to investigate epidemiological characteristics and survival before and after introduction of HMA treatment.MethodsWe performed a population-based analysis of CMML cases reported to the Cantonal Cancer Registries in Switzerland (SWISS) and the Surveillance, Epidemiology, and End Results (SEER) Program from the United States for 1999–2006 (before HMA) and 2007–2014 (after HMA). Time trends were compared for these two time periods.Results423 and 4144 new CMML cases were reported to the SWISS and SEER registries, respectively. We observed an increasing proportion of older patients ≥75 years in the SWISS (50.3%–62.3%) compared to a decreasing one in the SEER population (59.1%–55.1%). Age standardized incidence-rates were similar and remained stable in both countries (0.32–0.38 per 100’000 py). Relative survival (RS) improved significantly in the SEER (3 years 27%–37%; 5 years 19%–23%; p < 0.001 for both) but remained stable in the SWISS population (3 years 48% to 40%; 5 years 34% to 26%; n.s. for both).ConclusionsWith the exception of opposing age-trends, epidemiologic characteristics are similar in both countries and comparable to other population-based registries. RS remains poor and different time trends of population-based survival cannot be faithfully explained by HMA but most likely by changes in diagnostic accuracy within prognostically distinct age-groups.     

Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia

TET2 enzymatically converts 5-methyl-cytosine to 5-hydroxymethyl-cytosine, possibly leading to loss of DNA methylation. TET2 mutations are common in myeloid leukemia and were proposed to contribute to leukemogenesis through DNA methylation. To expand on this concept, we studied chronic myelomonocytic leukemia (CMML) samples. TET2 missense or nonsense mutations were detected in 53% (16/30) of patients. In contrast, only 1/30 patient had a mutation in IDH1 or IDH2, and none of them had a mutation in DNMT3A in the sites most frequently mutated in leukemia. Using bisulfite pyrosequencing, global methylation measured by the LINE-1 assay and DNA methylation levels of 10 promoter CpG islands frequently abnormal in myeloid leukemia were not different between TET2 mutants and wild-type CMML cases. This was also true for 9 out of 11 gene promoters reported by others as differentially methylated by TET2 mutations. We found that two non-CpG island promoters, AIM2 and SP140, were hypermethylated in patients with mutant TET2. These were the only two gene promoters (out of 14,475 genes) previously found to be hypermethylated in TET2 mutant cases. However, total 5-methyl-cytosine levels in TET2 mutant cases were significantly higher than TET2 wild-type cases (median = 14.0% and 9.8%, respectively) (p = 0.016). Thus, TET2 mutations affect global methylation in CMML but most of the changes are likely to be outside gene promoters.