Risk for Disease Progression Changes Over Time in CLL, Depending on Somatic Mutations

Risk for disease progression among patients with chronic lymphocytic leukemia (CLL) over time differed between those with mutated or unmutated disease, showing that gene somatic hypermutation plays a role throughout the disease course, according to study results published in Leukemia.

CLL is characterized by substantial clinical heterogeneity for its genetic abnormalities and its level of differentiation as evidenced by the status of the IGVH (immunoglobulin heavy variable) rearrangement — which is associated with better responses to certain treatments and prolonged survival.

“Therefore, this has spurred intense activity towards identifying biomarkers that might assist in accurate risk stratification, including both overall disease evolution (prognostic biomarkers) and response to treatment (predictive biomarkers),” the researchers wrote.

“Precise prognostication represents an even more urgent need within early stage patients, who reach up to 85% of all CLL at the time of diagnosis,” they added. “For these patients, determination of who will require treatment and when is of vital importance for both treatment and lifestyle decisions, thus relevant to both the patient and his/her (caregiver) but also the attending physician and health care at large.”

Evidence has suggested that determining the somatic hypermutation status of IGHV genes are essential for treatment decision-making. However, such molecular biomarkers and potential prognosis are assessed under the assumption that risk stratification is stable over the disease course.

“Risk assessment in CLL has so far been attempted assuming stable predictability of each considered prognosticator over the disease course, whereas the possibility that the impact of each marker may change over time has been overlooked,” the researchers wrote. “This may hinder revealing the true impact of any given biomarker which is especially relevant considering that CLL represents a dynamic setting where changes in both the tumor and the host occur over time. Thus, conceivably, the impact of any individual biomarker at a specific time point during the disease course may differ from that defined at the time of the initial evaluation.”

The researchers explored a different course of action that has been applied in myelodysplastic syndromes. The approach aimed to determine the prognostic power of whether particular biomarkers may depend on the length of time from diagnosis by assessing the over-time risk for CLL progression in 1,900 early-stage patients, who were stratified by mutated (1,224 patients) or unmutated (676 patients) CLL.

“Our analysis focused on how the risk for CLL progression evolved over time, between the two (somatic hypermutation) categories in both the entire cohort as well as within subgroups of patients defined by a specific genomic background,” the researchers explained. “…Based on these time-specific risk values, we suggest a new method to statistically evaluate the differences between the (mutated) CLL and (unmutated) CLL patients regarding risk evolution for CLL progression. In addition, we propose a novel tool to visualize the risk evolution differences between (mutated) CLL and (unmutated) CLL patients.

Disease evolution among patients with mutated CLL appeared stable, gradually decreasing the over-time risk for CLL; whereas, those with unmutated CLL demonstrated an influenced risk by elapsed time and genomic background. In particular, risk evolution decreased for those carrying del(13q) or del(11q) and NOTCH1 mutations, remained stable for those with SF3B1 mutations, and increases for patients with TP53 aberrations or trisomy 12 after the fifth year from diagnosis.

“In conclusion, the different patterns of risk evolution for disease progression observed between (mutated) CLL and (unmutated) CLL support the notion that the (somatic hypermutation) status represents more than a simple prognostic/predictive classification marker, and that segregation of CLL patients based on (somatic hypermutation) might aid to detect important time effects on risk evolution within specific genomic subgroups of CLL patients,” the researchers wrote.

“Moreover, our results strongly imply that each genomic abnormality may be linked to a differential risk for disease progression over time while its prognostic impact may be modulated with the time elapsing from the initial diagnosis,” they added.