Q: How do you define high-risk CLL today, and how durable of a response to initial treatment are you expecting for patients with high-risk disease?

Del(17p) and/or mutated TP53 have historically been considered high-risk categories, and they remain unique categories today. Currently, we have very little data with Bruton tyrosine kinase (BTK) inhibitors in the frontline setting among del(17p)/TP53-mutated patients. The largest study to date is the National Heart, Lung, and Blood Institute study, a phase 2 trial with a cohort of 51 patients with TP53 aberration.  The estimated 5-year progression-free survival among treatment-naïve patients in this cohort was approximately 74% with ibrutinib, as reported by Ahn et al. Now, that was likely a relatively healthy and selected population, so I am not certain that we can generalize those findings to the real world. Thus, I think that even with frontline ibrutinib, these traditionally high-risk patients remain at high risk. 

Likewise, we have recently seen some frontline data with venetoclax plus obinutuzumab, including a relatively small number of del(17p)/TP53-mutated patients, and there was still a higher risk of relapse during the 2-year follow-up. If you define a durable response as one that allows patients to live to their normal lifespans (and not require cellular therapy or allogeneic stem cell transplantation to get there), I am not convinced that we are at that point yet for the del(17p)/TP53-mutated population, particularly among younger patients. For older individuals who are not in the del(17p)/TP53-mutated group, we are starting to reach that point, except for those who transform or do not tolerate their treatment. I think that we should move toward combination BTK/BCL2 inhibitor therapy for these patients to hopefully reduce the risk of resistance and transformation. There has also been an effort recently to broaden the definition of high-risk beyond del(17p)/TP53, and that is certainly valid because young, unmutated patients will have steadily progressive disease and you need to get them through their lifespan. Complex karyotype is still a risk factor, but it is not as adverse as del(17p).  

I agree with Dr Brown that the frontline data with the novel agents are limited with respect to del(17p)/TP53-mutated patients, as the largest studies with the most mature data have included relapsed/refractory patients. If you extrapolate the data from the relapsed/refractory setting, I think that we can safely say that the outcomes for both frontline ibrutinib and venetoclax plus obinutuzumab are inferior in those with interruption of the TP53 gene. I also completely agree that these are the patients who should be directed toward BTK/BCL2 inhibitor combination therapy, with the caveat that there should be some sort of control or comparator group (eg, novel agent monotherapy ± anti-CD20 monoclonal antibodies) so that we can really understand whether these high-risk patients are benefiting from the BTK/BCL2 combination. Trials should enroll those specific high-risk subgroups to ensure sufficient power, otherwise you end up with small subsets of 5% to 10% with high-risk features. 

It is also important to study whether there is a benefit of stopping any therapy vs continuing therapy in high-risk patients. I am personally not convinced that it is the best idea to discontinue any of these treatment regimens that are being considered for patients with del(17p)/mutated TP53 in the setting of responding disease. But, at the same time, I am hesitant to advise that time-limited therapy is completely irrelevant in these situations. 

With regard to other risk factors, 11q deletion and IGHV mutational status have largely disappeared as indicators of poor risk in the novel treatment era; therefore, we are really left with del(17p)/mutated TP53 as the major risk group. Relying on complex karyotype as a risk factor can be problematic for a variety of reasons; it is difficult to assess and there is debate regarding the definition of complex, so it has the potential to be less helpful or less actionable on its own.

The definition of what is considered durable is changing. Historically, patients with del(17p)/mutated TP53 were very high risk and did not have durable responses to chemoimmunotherapy. If they did respond, the responses were not durable. We have a new ballgame with frontline ibrutinib, but data on frontline ibrutinib are limited in that only approximately 5% to 7% of frontline patients have del(17p)/mutated TP53, whereas you see higher rates due to clonal evolution in relapsed patients. Those individuals who were treated with chemoimmunotherapy and subsequently emerged with del(17p)/TP53 disease are considered very high risk, even on ibrutinib or venetoclax, but this population is shrinking. Nowadays, no one would ever give 3 or 4 rounds of chemotherapy to a patient with del(17p)/mutated TP53. So, today, the question is whether del(17p) is still considered high risk when ibrutinib is given as frontline therapy. My answer would be yes to some degree; however, any group that has responses that are as good as we are seeing today with ibrutinib really does not fit the classic definition of high risk. 

On the other hand, durability is, to a certain extent, in the eye of the beholder. In the absence of a curative regimen, I now consider younger (eg, 55 years at diagnosis), unmutated patients to be high risk from the perspective of them potentially requiring treatment for 25 years or more, depending on other influences on their longevity. Historically, we have considered older patients to be high risk, owing to a greatly diminished ability to tolerate chemotherapy. Now, with the small molecules, which are generally well tolerated, I would almost argue the opposite. With respect to venetoclax plus CD20 monoclonal antibody combination therapy, the question becomes: How much benefit is gained by adding the antibody? It is difficult to compare across trials because it seems as if you are getting better responses with every iteration of venetoclax-based regimens, from single-agent venetoclax to venetoclax plus rituximab to venetoclax plus obinutuzumab; however, every iteration of the venetoclax combination has been used in a less heavily pretreated population.