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Risk factors for post-HCT outcomes in CMML
ease process. Mutations in TP53 were less frequent in patients with CMML (<10%) than previously reported for MDS39 and were not strongly correlated with unfavorable outcomes, underscoring the biological differences between MDS and CMML. The difference may be related to the fact that CMML is infrequently a ”secondary dis- ease” (1 of 129 patients in the present series), whereas about 30% of MDS patients transplanted at our Center present with treatment-related or secondary disease.40 The data need to be interpreted with caution, in view of the limited sample size.
The present mutational data suggest a significant associ- ation of ATRX and WT1 with post-transplant relapse and overall mortality in patients with CMML. Although the numbers of cases with these mutations were limited, most mutations occurred in important functional protein domains, suggesting that the mutations would be of func- tional relevance.41 Somatic mutations in ATRX are also seen in up to 43% of patients with MDS with unexplained microcytosis42 and in a rare subtype of MDS associated with thalassemia (ATMDS).43 Previous studies in CMML have not included ATRX in their mutation panels,16,17 and additional investigations are warranted to confirm this association of ATRX mutations with CMML. WT1 muta- tions are common in patients with high-risk MDS and AML38 where they are associated with relapse.39,44 WT1 mutations in the present study occurred in or adjacent to loci that have been shown to be mutated in AML.44 Our CMML cohort was predominantly composed of high-risk patients as determined by CPSS and m-CPSS criteria, which, in turn, might be responsible for the prevalence of WT1 mutations and unfavorable transplant outcomes. Although there was a suggestive association of each indi- vidual mutation with relapse and survival, the biological impact of these mutations in a limited cohort of CMML patients must be assessed cautiously. Mutations co-occur with other mutations and rarely work as a single domi- nant factor. Cooperation with other mutations is likely.
Functional data in the right context (e.g., the exact identi- cal mutation at the endogenous locus in hematopoietic cells) are often lacking. The functional consequences of the frequent mutations in ATRX or WT1 will need to be tested in hematopoietic cells to confirm the proposed bio- logical impact of these mutations.
In conclusion, this analysis adds mutational risk factors to previously identified clinical risk factors for post-HCT outcome in patients with CMML, such as comorbidity, cytogenetic risk, and high-risk disease according to the CPSS and MDAPS. Molecular profiling identified distinct high-risk disease groups with high mutation burden, par- ticularly in epigenetic processes that characterized disease entities distinct from the conventional high-risk groups defined by cytogenetics. Of note, the data also show that these high-risk features are only incompletely overcome by HCT, and relapse and NRM rates remain high. This study confirms the clinical and molecular heterogeneity of CMML which significantly affects the outcome following HCT. New transplant strategies that target specific disease subgroups must be developed. Furthermore, early trans- plantation should be considered for patients with interme- diate-risk disease and lower HCT-CI. Vigilant surveillance and early enrollment in clinical trials for post-transplant relapse must be planned for patients with high-risk dis- ease as defined by complex cytogenetics and high muta- tion burden.
Acknowledgments
We thank all referring physicians for their continued support and all patients for participating in clinical studies. We are grate- ful to Gary Schoch for data collection and management, and Helen Crawford for help with manuscript preparation. This work was supported in part by P30 CA015704, P01 CA018029, a Cancer Center New Investigator Support Grant (RBS), a K12 CA076930 (JW), a CTI Biopharma Endowed Fellowship (JW), and an unrestricted grant from Histogenetics (HJD). DRC was supported by a stipend from Hallym University, South Korea.
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