{Reference Type}: Journal Article
{Title}: Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.
{Author}: Kleinstern G;Boddicker NJ;O'Brien DR;Allmer C;Rabe KG;Norman AD;Griffin R;Yan H;Ma T;Call TG;Bruins L;Brown S;Bonolo de Campos C;Hanson CA;Leis JF;Ding W;Vachon CM;Kay NE;Oakes CC;Parker AS;Brander DM;Weinberg JB;Furman RR;Shanafelt TD;Cerhan JR;Parikh SA;Braggio E;Slager SL;
{Journal}: Blood Adv
{Volume}: 8
{Issue}: 9
{Year}: 2024 May 14
{Factor}: 7.637
{DOI}: 10.1182/bloodadvances.2023012242
{Abstract}: <B>UNASSIGNED: </B>High-count monoclonal B-cell lymphocytosis (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 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 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 individuals with HCMBL with more aggressive clinical course.