Treatment Updates in Chronic Lymphocytic Leukemia - Episode 9

Approaching Therapy for Relapsed/Refractory CLL


Matthew S. Davids, MD: In the relapsed/refractory setting, we have a wide variety of options available to us now. Historically, we’ve used chemoimmunotherapy for the most part in the frontline setting, and the old teaching was dependent on the durability of response to initial chemoimmunotherapy. That would inform the choice of the next line of therapy. So, when patients got 4 or 5 years of benefit from their initial chemotherapy-based regimen, we would typically turn back to chemotherapy again in the second-line setting knowing that the response might be a little bit less durable, but still expecting the patient to do well.

However, I would say this has changed quite dramatically over the last couple of years with the advent of these novel agents, which are highly effective and very well tolerated for patients in the relapsed/refractory population. Certainly, the first step in this group, if they have not previously had deletion 17p, is to retest with FISH [fluorescence in situ hybridization]. If they’ve acquired deletion 17p, then they certainly need a novel agent-based approach, and I would not advocate using chemotherapy for those patients. It’s a little more complicated outside the setting of deletion 17p. I do think chemoimmunotherapy is still reasonable to consider for those patients.

If practitioners are going to make those recommendations, they should be aware of the data from the HELIOS study and Study 115, which looked at combinations of ibrutinib and idelalisib, respectively, with bendamustine and rituximab in the relapsed/refractory population. So, if you’re thinking about using an obinutuzumab and rituximab regimen for relapsed patients, you should think about it in combination with 1 of those 2 kinase inhibitors.

However, I would say I use chemotherapy quite rarely now in the relapsed population, and most of my patients will go on a novel-agent-only—based approach. For most patients right now, ibrutinib is the easiest drug to start with. It has the longest track record in terms of durability of response. And so, I think it’s a great option for many patients with relapsed/refractory disease.

However, there are some patients who have particular comorbidities that might make it challenging to receive ibrutinib, and those include patients with poorly controlled atrial fibrillation or other cardiac issues, particularly if they’re on anticoagulation or have other bleeding risks. For those patients, drugs like idelalisib or rituximab or venetoclax are potentially good options to consider. Right now, venetoclax is only approved for patients with relapsed deletion 17p disease. However, we saw some really exciting data at the ASH [American Society of Hematology] meeting from the MURANO study that looked at venetoclax and rituximab in the relapsed setting compared to bendamustine and rituximab. We saw dramatic improvements with the venetoclax-based regimen in terms of both progression-free and overall survival. This was just recently published in the New England Journal of Medicine, and I think it is likely to lead to a broader approval for venetoclax and rituximab in the relapsed/refractory population.

Michael Choi, MD: When a patient relapses and needs subsequent therapy, I do think it is important to reassess the same factors that we assessed when deciding their optimal first-line therapy. This does mean repeating molecular testing such as FISH and cytogenetics and in some cases, next-generation sequencing, as deletion 17p or P53 mutations may have emerged since the patient was last tested. This is critical if the patient is considering chemoimmunotherapy. Molecular testing or next-generation sequencing can be useful in the setting of progression after ibrutinib.

I do think it is important, at least for our field, to look more into mechanisms of resistance to other novel targeted agents like venetoclax. But as far as clinical utility in the standard of care, I do think testing for P53 mutations and FISH and cytogenetics are largely sufficient. The immunoglobulin gene mutation tends not to change over time, as that’s more a result of the cell of origin of that patient’s disease. And so, I do not find it necessary to redo that test.

Transcript Edited for Clarity