Although it is not essential to have prognostic data for patients who are not ready for treatment, I like to have this information for newly diagnosed patients regardless of whether they are in need of treatment because it gives me a better overall picture of their disease status and it informs how closely I need to monitor them. Currently, 17p deletion (del[17p]), TP53 mutation status, and IGHV mutation status are the 3 markers that are most important when considering patients who require initial treatment. Fluorescent in situ hybridization (FISH) identifies del(17p), as well as del(11q), trisomy 12, and del(13q). The latter 3 markers are informative but do not greatly impact how we treat patients. Loss of TP53 function, through del(17p) or through mutations in the TP53 gene on del(17p), is associated with high-risk disease. FISH is sensitive for del(17p) mutations involving the TP53 gene, and next-generation sequencing is also increasingly used. The identification of IGHV mutation status is valuable in that it is associated with a more favorable prognosis and the potential for cure with a chemoimmunotherapy regimen such as fludarabine, cyclophosphamide, and rituximab (FCR) in patients who can tolerate it. Those with del(17p) or mutated TP53 should not receive chemoimmunotherapy. I prefer to use Bruton tyrosine kinase inhibitor therapy for those with del(17p)/TP53 mutation because this regimen is continuous, and I believe that it is important to have continuous suppression of the malignant clone. 

My concern with fixed-dose regimens, such as venetoclax-based regimens, for patients with TP53 aberration is that there is a higher risk in the untreated/unmaintained setting. For individuals who do not have these features, my preference is for fixed-duration treatment with venetoclax plus obinutuzumab. However, there is recent work with combinations of targeted therapy, and I think that we will eventually transition into an era where fixed-duration combinations of targeted therapies become the standard of care for most patients achieving minimal residual disease negativity, allowing patients to come off treatment with the expectation of a long treatment-free interval. 

For individuals with mutated IGHV, we know that approximately 50% of those who receive chemoimmunotherapy with FCR have a progression-free survival of longer than 10 years, so that is still an option for younger and fitter patients who can tolerate FCR. There are also emerging prognostic factors that correlate with outcome. ZAP-70, CD38 expression, thymidine kinase, and β2 microglobulin have all been associated with higher-risk disease; however, we do not currently use any of these to direct treatment. In addition, other mutated genes such as NOTCH1, SF3B1, and XPO1 have been identified as having prognostic value, but they are infrequent in chronic lymphocytic leukemia and are not useful for directing treatment.