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Reply to Goel et al. ‘TP53 mutation allele-burden and disease outcome in MDS/AML’

Leukemia volume 31, pages 767–768 (2017)Cite this article

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Molecular annotation of somatic mutations has brought forth a paradigm shift in the prognostic discrimination and management of patients with myelodysplastic syndromes (MDS) and related diseases while shedding light on significant genetic heterogeneity. We have recently reported and validated that the variant allele frequency (VAF) of TP53 mutations is a powerful predictor of outcome in a large cohort of patients with MDS and secondary acute myeloid leukemia (sAML), which further refines prognosis over binary mutation analysis and clinical prognostic models.1 As these findings not only bring forth an additional layer of prognostic complexity but also provide critical prospective questions that need to be addressed, we anticipate and welcome further discussion of this concept and read with interest the correspondence to our manuscript.2

In a small cohort (n=14), the authors did not show a difference in survival based on a TP53 VAF cutoff of 20%. Although an additional cohort (n=36) did not show a survival difference at this cutoff, a trend for inferior outcomes was observed (P=0.09) and long term survivors were only observed in patients with a TP53 VAF<20%. Methodologically, the selection of VAF cohorts in which to analyze outcomes needs to be rigorously defined and ideally will be prospectively validated in order to best guide the management of these patients. In our study, a VAF of >40% was chosen a priori as this represented the dominant clone in all mutant cases, which was then compared with patients with a VAF <20%. Importantly, we could refine prognostication across VAF cohorts (P=0.0002). Nazha and colleagues from the Cleveland Clinic recently reported on the impact of TP53 VAF and outcomes in a similar size TP53 mutant cohort (n=74), and were also able to show allele burden to have a powerful impact on survival.3 With nearly identical VAF cutoffs, the median OS was 12.4 months for VAF <25%, 8.5 months for VAF 25–50% and 3.4 months for VAF >50%. We utilized a recursive partitioning algorithm to stratify for survival in our combined TP53-mutant cohort of 77 patients and identified a VAF cutoff of 20% to best stratify for survival with a median OS of 23 months for patients with a VAF of <20% versus 6 months with a higher VAF (P=0.0036). However, we fully recognize that this could be dependent on multiple factors, including therapeutic interventions and comorbidities, and aim to investigate this further in a prospective clinical study.

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References

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Authors and Affiliations

  1. Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    D A Sallman, R Komrokji, A List & E Padron

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  1. D A Sallman
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  2. R Komrokji
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Correspondence to E Padron.

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Sallman, D., Komrokji, R., List, A. et al. Reply to Goel et al. ‘TP53 mutation allele-burden and disease outcome in MDS/AML’. Leukemia 31, 767–768 (2017). https://doi.org/10.1038/leu.2016.257

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