Q: How are prognostic markers for CLL to be interpreted in the novel treatment era? 

Patients with del(17p) or TP53 mutation have been, and likely will continue to be, our highest-risk patients with CLL. This high-risk status is likely maintained today with any of our newer therapies. It is important to identify these patients up front, for triage away from chemoimmunotherapy and toward novel agent therapies. The CLL International Prognostic Index (CLL-IPI) codifies, to some extent, the important prognostic factors. I do not actually use the CLL-IPI specifically in most cases; however, the markers that were identified in its development certainly do match my view of the existing literature in terms of what remains important prognostically in patients today. The question has been raised as to how this changes in the era of novel agents. For example, if patients are starting ibrutinib-based therapy, how do we interpret the prognostic factors differently, considering that we still have much less information about this at this point? There is evidence that complex karyotype may be more important with the novel agents than we had realized in the prior chemoimmunotherapy era. Immunoglobulin heavy chain variable region (IGHV ) gene mutation status, so far, does not seem to be of the same significance in the novel agent era, but that may change with longer follow-up.

The most important aspects of prognostic testing are probably the patient population for which the particular prognostic markers were developed and what therapies were used. Some of the markers have important implications for some therapies, but not necessarily for others. For example, high-risk patients with CLL who have a del(11q), which is said to be a predictor of poor outcomes, can have durable responses when treated with the Bruton’s tyrosine kinase inhibitor ibrutinib. The factors that are likely the biggest drivers of prognosis with the novel agents and with the chemoimmunotherapy combinations are the following: TP53 interruption or del(17p), complex karyotype (ie, 3 or more abnormalities in the karyotype), and the IGHV mutation status.

IGHV mutation status is currently the key stratifying factor for either discussing or discarding the prospect of chemoimmunotherapy in the front-line setting when evaluating treatment options with patients. The cytogenetic markers are also helpful for assessing the risk of eventually relapsing after chemoimmunotherapy or treatment with the novel agents. A simplified version of my thinking on CLL risk factors is that we use the IGHV mutational status and cytogenetics to narrow down which patients are most likely to respond with a long remission to either chemoimmunotherapy or the novel agents. Ultimately, however, the role of chemoimmunotherapy will be challenged by ongoing, randomized clinical trials that compare novel agents with chemoimmunotherapy in the CLL front-line setting. Therefore, it is unclear whether the situation will remain as is or whether it will change within the next 1 to 3 years when these trials start reading out.