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Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis (HCMBL).

Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis (HCMBL). Blood advances Kleinstern, G., Boddicker, N. J., O'Brien, D. R., Allmer, C., Rabe, K. G., Norman, A. D., Griffin, R., Yan, H., Ma, T., Call, T. G., Bruins, L., Brown, S., Bonolo de Campos, C., Hanson, C. A., Leis, J. F., Ding, W., Vachon, C. M., Kay, N. E., Oakes, C. C., Parker, A., Brander, D. M., Weinberg, J. B., Furman, R. R., Shanafelt, T. D., Cerhan, J. R., Parikh, S. A., Braggio, E., Slager, S. L. 2024

Abstract

HCMBL is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 HCMBL individuals using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results to that of our treatment-naïve CLL cohort(N=855) and employed Cox regression to estimate hazard ratios and 95% confidence intervals (CI) for associations with TTFT. Compared to CLL, the frequencies of any mutated genes were lower in HCMBL (70% versus 52%). At 10-years, 37% of HCMBL individuals with any mutated gene had progressed requiring treatment compared to 10% among HCMBL individuals with no mutations; this led to 5.4-fold shorter TTFT (95%CI:2.6-11.0) among HCMBL with any mutated gene versus none, independent of CLL-IPI. When considering individuals with low-risk of progression according to CLL-IPI, HCMBL individuals with any mutations had 4.3-fold shorter TTFT (95%CI:1.6-11.8) versus those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed HCMBL individuals who were high-risk for both prognostic factors with worse prognosis compared to low-risk CLL patients (i.e., 5-year progression rate of 32% versus 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify HCMBL individuals with more aggressive clinical course.

View details for DOI 10.1182/bloodadvances.2023012242

View details for PubMedID 38359367