Q: In your clinical judgment, when should therapy be initiated for patients diagnosed with CLL?

Amongst practitioners, I think that there may be some excitement to potentially begin novel agents earlier. I think that that is, in part, because of the activity of these agents and the fact that they are relatively easy to give. Toward that enthusiasm, I would also argue caution; there is no study to suggest that intervening early for any patient population with any modern therapy can improve outcomes. And so, I think that the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) recommendations for when to initiate therapy are the most appropriate and are the standard of care.

Q: In the font-line setting, how do you generally approach the selection of chemoimmunotherapy versus novel agents for patients with CLL?

The decision is guided by numerous clinical, prognostic, and patient-specific factors, which we discuss at length when considering the implications of age and fitness. However, to synopsize, comorbidity and age have been strong influential factors for the selection of chemoimmunotherapy (where either an intensive backbone with fludarabine/cyclophosphamide, or a less intensive backbone with bendamustine, or an even less intensive backbone with chlorambucil is used). Nonetheless, these treatments are used less often now with the emergence of the novel agents. We currently use the immunoglobulin heavy chain variable region (IGHV ) gene mutational status as a stratifying factor to determine whether patients would be candidates for chemoimmunotherapy. If they are mutated, we have long-term experience with fludarabine, cyclophosphamide, and rituximab (FCR), and we know that approximately 60% of patients remain in remission beyond 10 years if they have the lower-risk feature of mutated CLL. And for those patients, we still offer the FCR program, although, currently, we make efforts to reduce the number of administered chemoimmunotherapy cycles. Then, the cytogenetic markers are also helpful with assessing the risk of eventually relapsing after chemoimmunotherapy or on novel agents.

It is probably best to go one-by-one: 17p deletion (del[17p]) status is very important to know at the time when you have to make a choice about treatment because you do not want to use chemoimmunotherapy for any patient who has del(17p). If you put such patients on treatment with novel agents, those are patients who, in the front-line setting, but especially in the relapse setting, have higher risk of progressing, and one should be aware of that in order to have discussions about cellular therapy such as allogeneic hematopoietic stem cell transplantation or chimeric antigen receptor T-cell therapy. Another factor detected with the CLL fluorescence in situ hybridization cytogenetic panel is del(11q); patients with del(11q) are often younger male patients who are IGHV unmutated, and such individuals have shorter than average remission durations with chemoimmunotherapy, hence this, again, favors the use of novel agents over chemoimmunotherapy.

We recently published long-term findings in a population of both treatment-naïve and relapsed/refractory patients who received ibrutinib, which is the most commonly used novel agent for CLL, in Blood. Data on the efficacy and safety of ibrutinib were analyzed with a median follow-up of 5 years in 31 treatment-naïve patients and 101 patients with relapsed/refractory CLL/small lymphocytic lymphoma. Our 5-year experience with single-agent ibrutinib in patients with treatment-naïve and relapsed/refractory CLL showed that efficacy of long-term treatment with ibrutinib was sustained despite the presence of high-risk genomic features in a large proportion of our patient population.

First and foremost is determining whether there is P53 interruption or del(17p), and also whether there are 3 or more abnormalities in the karyotype (ie, complex karyotype)—and then also the IGHV mutational status—and these things are probably the biggest drivers for prognosis with the novel agents and with the chemoimmunotherapy combinations.

Our highest-risk patients continue to be those with del(17p) or TP53 mutation, and this is true probably even with any of our newer therapies. Thus, it is important to identify these patients up front, for triage away from chemoimmunotherapy and toward novel agent therapies. Other important factors continue to include the IGHV mutation status and certain patient-specific factors (eg, age, comorbidities, stage of disease). Stage is less important than it used to be, but it is still significant.