As treatment approaches for chronic lymphocytic leukemia (CLL) evolve, questions remain about the utility of older prognostic factors (ie, IGHV mutation, TP53 mutation, and CLL fluorescence in situ hybridization [FISH] panel) that were defined back in the era of chemotherapy. Advances in technology have also enabled the development of newer, more sensitive prognostic markers, such as measurable residual disease (MRD).

The 3 most common prognostic factors that are tested for in CLL are IGHV mutation, TP53 mutation, and CLL FISH panel, particularly 17p deletion (del[17p]). Studies have found that patients with CLL who have favorable risk factors (eg, mutated IGHV) are more likely to have favorable outcomes with chemotherapy than those with unmutated IGHV. The same is true for patients without del(17p)/TP53 mutation.

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Now that we are using targeted therapies in place of chemotherapy for CLL, there has been a reevaluation of these prognostic markers (ie, IGHV mutation, TP53 mutation, and CLL FISH panel) to determine if they are still relevant with today’s therapies. Recent work has found that the prognostic value of several of these markers depends on whether a patient is receiving continuous therapy with a BTK inhibitor vs a time-limited approach for 1 to 2 years. For example, both IGHV-mutated and -unmutated CLL respond well to continuous long-term BTK inhibitor therapy. However, data from the CLL14 study indicated that patients with mutated IGHV had better outcomes with the 1-year regimen of venetoclax and obinutuzumab than patients with unmutated IGHV. So, IGHV mutation status is relevant in the context of chemotherapy and appears to be relevant for time-limited targeted therapy as well, but it is not very relevant in the context of continuous BTK inhibitor therapy.

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Treatment-naive patients with TP53 aberrations do not have good outcomes with chemotherapy, but they do have very good outcomes with continuous BTK inhibitor therapy, similar to those of patients who do not have TP53 aberrations. In contrast, individuals with TP53 aberrations who receive time-limited therapies do not have similar outcomes to those of patients with wild-type TP53, although they do better than patients with TP53 aberrations who receive chemotherapy.

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Moreover, while there have been conflicting results about the prognostic value of complex karyotype in patients with CLL who are treated with targeted therapies, some recent data suggest that the cutoff to define a complex karyotype should potentially shift from 3 or more chromosomal abnormalities to 5 or more. Although testing for complex karyotype can potentially be helpful, it is not done routinely in the broader community today.

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Finally, MRD has prognostic relevance in CLL, especially in the context of time-limited approaches. Patients receiving chemotherapy who are MRD positive at the end of treatment relapse more quickly than those who are MRD negative, and the same is true for patients receiving time-limited targeted therapy. However, the same cannot be said for those receiving continuous daily BTK inhibitor therapy because these patients continue to have low levels of disease present. Nevertheless, they can keep their disease in check by continuing to take their BTK inhibitor.