Embracing Newer Therapies in High-Risk CLL

Ian W. Flinn, MD, PhD:So now that we’re seeing ibrutinib and other BTK [Bruton tyrosine kinase] inhibitors used as frontline therapy, the question comes up: What do you do with patients after that? We’ve seen a lot of very good data from the venetoclax combinations. Most prominently, the MURANO data show that the combination of venetoclax plus rituximab is superior to chemoimmunotherapy, this time with bendamustine-rituximab. There was a superior progression-free survival and overall survival in patients who were treated with that combination.

So that’s what I tend to do. I tend to use venetoclax combinations after frontline therapy with ibrutinib. There are many venetoclax combinations that are being studied. We’ve seen data with venetoclax and with rituximab. There are also venetoclax and obinutuzumab data that have been published in that setting, and I think that’s also a very important combination.

I think the most important take-home message for community oncologists who are treating high-risk patients is to embrace some of the newer therapies and to get away from the therapies of the past with chemoimmunotherapy. We know from these studies that I’ve just mentioned that targeted therapy with a BTK inhibitor improves outcomes for patients in these high-risk populations.

I think another thing to suggest to the community oncologist is that if things aren’t going the way that you think they should in the high-risk patient, then you’re going to want to send them to a Center of Excellence where they see a lot of these patients. I think it’s also reasonable, if someone is refractory to ibrutinib, if they are progressing on ibrutinib, to seek a second opinion or a consultation at that time. Many times, there’s an underlying reason. Is that reason because they have aCys481mutation, where using 1 of the new alternative BTK inhibitors might be of help? There are a variety of reasons why patients might become refractory to ibrutinib. Trying to figure that out is important.

The treatment landscape for CLL [chronic lymphocytic leukemia] is evolving rapidly. Today we’re using ibrutinib as frontline therapy for patients with chronic lymphocytic leukemia. But I’m not sure that’s what we will be doing tomorrow. We know that 1 of the disadvantages of placing patients on ibrutinib is that they tend to remain on this therapy indefinitely. That’s difficult for many of our patients to swallow. Taking a pill forever, even if it does make them feel much better, even if it does put them into remission, is a challenge.

We now have seen several studies with combination data, generally in combinations with venetoclax, where patients can be treated for a limited time with a combination regimen and then come off treatment.

Most prominently, we’ve seen data from the combination of venetoclax with obinutuzumab, which were recently published inBlood, showing a 100% overall response rate in the frontline setting with MRD [minimal residual disease] negativity of 75% in the bone marrow, or 75% in the blood, that is maintained over time. This is an exciting combination, and we’ll see data from CLL14, which is being conducted by the German CLL Study Group, shortly. This is a randomized phase III trial that has compared the combination that was published in the phase I population with a phase III setting, comparing it to obinutuzumab with chlorambucil. From press releases, we know that this was positive. And frankly, it’s hard to imagine why it wouldn’t be positive. But the more specific information about the depth of the remission will come out. So that’s a combination that will likely change the frontline setting.

Another combination that’s being studied is the combination of venetoclax with ibrutinib. In early studies and early results, this combination has shown a very high complete remission rate and a high MRD-negative rate.

There are also studies looking at all 3 drugs: obinutuzumab, venetoclax, and ibrutinib. Time will only tell whether that 3-drug regimen is or isn’t more important than the 2-drug regimens. And frankly, which 2-drug regimen is the best is not clear. You can imagine that using 2 of these oral agents might be fairly expensive and difficult. Therefore, you might face some challenges from patients and their physicians in implementing this as frontline therapy.

Transcript edited for clarity.

Case:A 62-Year—Old Male WithIgVH-Unmutated CLL

• A 62-year-old male presented to PCP with complaints of extreme fatigue and night sweats
• PE: Enlarged mobile lymph nodes bilaterally (~1.5 cm), no palpable spleen or liver
• Laboratory findings:
  • WBC; 100 X 10⁹/L
  • Lymphocytes; 82 X 10⁹/L
  • Hb; 11.2 g/dL
  • Platelets; 190 X 10⁹/L
  • ANC; 1,950/mm³
  • LDH 150 U/L
• Cytogenetic; del(11q),IgVH-unmutated
• β2M, 2.9 mg/L
• Referred to community oncology who diagnosed patient with chronic lymphocytic leukemia
• Patient was started on ibrutinib + rituximab (IR)
• Rai Stage I