Detection Rate of Integrated Molecular and Cytogenetic Biomarker Testing for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries and typically occurs in elderly individuals. There will be an estimated 21,250 newly diagnosed cases in the United States this year and 4,320 deaths. Due to the highly variable clinical course of this disease, prognostication and risk stratification methods are necessary for guiding decisions on clinical management. Integrated prognostic models incorporating laboratory testing for multiple molecular, cytogenetic, and other biomarkers have recently been proposed by major clinical guidelines to classify patients into risk subgroups. The current NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia describe such an integrated prognostic model known as the Rossi model that includes TP53, NOTCH1, SF3B1, and BIRC3 mutations along with the cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) to classify CLL patients into 4 distinct prognostic subgroups: high-risk (TP53 and/or BIRC3 abnormalities), intermediate-risk (NOTCH1 and/or SF3B1 mutations and/or deletion 11q), low-risk (trisomy 12 and wild-type for all genetic lesions), and very low-risk (deletion 13q only). The 10-year survival rates for these subgroups are 29%, 37%, 57%, and 69%, respectively. To assess the clinical value of an integrated biomarker testing approach, we analyzed results of 651 consecutive cases submitted to our clinical diagnostic laboratory for testing on our integrated panel of molecular and cytogenetic biomarkers for CLL. Our panel includes detection of genomic alterations by FISH (deletion 6q, 13q, 11q, 17p, trisomy 12, IGH rearrangement, and IGH/CCND1 translocation) and detection of sequence variants in BIRC3, BTK, MYD88, NOTCH1, PCLG2, SF3B1, and TP53 by next-generation sequencing (NGS). In total, 472 cases had positive findings by either FISH (90%) or NGS (46%) for a detection rate of 72.5%. Using the Rossi integrated prognostic model, 17.5% of cases fell into the high-risk subgroup, 20% of cases fell into the intermediate-risk subgroup, 43.5% of cases fell into the low-risk subgroup, and 19% of cases fell into the very low-risk subgroup. Importantly, among cases with positive FISH findings, 40.1% of cases also had positive molecular findings. In approximately 84% of cases belonging to the low-risk cytogenetic subgroups by FISH assessment alone, the incorporation of molecular findings resulted in reclassification into a higher-risk subgroup. Among the FISH-negative cases, 17% were classified as high-risk or intermediate-risk based on the molecular findings. Together, these findings support the clinical value of an integrative biomarker testing approach that includes both molecular and cytogenetic biomarkers to stratify CLL patients into risk subgroups to help guide decisions on clinical management.