CLL: Combination Therapies and Future Outlook

Matthew S. Davids, MD, MMSc:For low-risk patients with CLL, particularly if they’re older, I do think that there still will be a role for monotherapy with novel agents. Because we now have 5-year data from the relapsed/refractory settings suggesting that patients with low-risk CLL can have very durable benefits to ibrutinib alone. However, most patients with CLL are going to have either some high-risk marker or some comorbidity that’s going to make it challenging to stay on ibrutinib long-term, or they might be younger. And we don’t know what the true long-term results are of ibrutinib-based therapies.

So, I think that there is certainly a growing role for combination-based approaches in CLL. I think this helps us to reduce the amount of time the patients need to be on the novel agents, and this will hopefully help to reduce the resistance that we’ve seen arising to ibrutinib. We know that patients on ibrutinib monotherapy can develop specific mutations inBTK, which make them resistant to the drug. And we’re hopeful that by targeting multiple mechanisms at the same time, we’ll be able to avoid these types of resistance mutations. I think this is how chemotherapy regimens were originally developed to become combinations. And I think we’re going to need the same approach with novel agents.

I think the advantage that we have now is that we have a lot of good science to inform what the optimal designs are of these trials, which mechanisms to combine. And I think in general, they should be better tolerated combinations than what we saw with chemotherapy.

We don’t know what the optimal combinations are at this point. We have many effective tools in our armamentarium. We have chemotherapy, we have ibrutinib-based therapies, venetoclax and the other novel agents, and then we have CD20 antibodies.

So, many of the studies that were presented at the ASH meeting this year were including novel agents only or novel agents with antibodies. But one of the studies that we’ve been working on is actually combining ibrutinib with chemotherapy, and that’s iFCR, or ibrutinib plus FCR. And the idea with our study is to try to get into very deep remissions that are achieving MRD undetectability for patients. We think that by building on some of the benefits of FCR, we may be able to develop a curative regimen for more CLL patients. There are some risks with FCR, but we find in general that the younger patients do tend to tolerate it well as long as they’re properly supported with antibiotics and growth factor throughout treatment.

With the IFCR regimen, we are targeting younger, fit CLL patients. So, everyone on the study was 65 years or younger at the time of treatment. And we did allow initially some patients with deletion 17p on to the study. However, in general, their responses were not as deep as the other patients. So, moving forward, we’ve been recruiting patients who do not haveTP53dysfunction, but we do allow patients on who have both mutated and unmutatedIGHV, and we’ve actually seen good results for both groups. In particular, the unmutatedIGHVgroup, which typically does not have a durable response to FCR alone, we’re seeing very high rates of MRD undetectability by adding the ibrutinib. And so, we’re optimistic that that might be a particular group that might benefit from this combination.

So, in addition to the iFCR study at the ASH meeting, there were also some exciting data presented on iFCG, which the “G” is Gazyva or obinutuzumab. And that was presented by Nitin Jain and colleagues. And I think what’s interesting about their study is that even after 3 cycles of chemoimmunotherapy, they were seeing very deep responses and moving patients on to chemotherapy-free maintenance therapies. And I think if we can reduce the number of cycles of chemoimmunotherapy, I think that’s beneficial in terms of the toxicity profile. So, I think both of these regimens—iFCR and iFCG—look very promising for our patients.

Although the past few years have been very exciting for CLL with the approval of several different novel agents as monotherapies, I think the next few years are going to be equally exciting. We now have all these tools in our armamentarium, and we can combine them together to achieve time-limited MRD undetectability with patients who are now going to benefit for many, many years from a chemotherapy-free approach. I think it’s a very exciting time for our CLL patients.

Transcript edited for clarity.

• A 76-year-old male presented with symptoms of low-grade fever, (101.1^oF) chills, and weight loss. The patient feels severely fatigued and required extensive rest. He was recently hospitalized for pneumonia.
• PMH: Hypertension controlled on candesartan, diabetes managed with metformin
• PE: Pallor and is weak-appearing, vital signs WNL, enlarged mobile lymph nodes bilaterally (~2.0 cm), anterior cervical chain, no hepatosplenomegaly
• PS, ECOG 2
• Laboratory findings:
  • WBC; 18.5 X 10⁹/L, 65% lymphocytes
  • Lymphocytes; 86.2 X 10⁹/L
  • Hb; 12.2 g/dL
  • Platelets; 305 X 10⁹/L
  • ANC; 120/mm³
• Flow cytometry; CD5+, CD19+, CD23+, CD38-low,
• Cytogenetics, IgVH mutation status, unknown
• β2M, 2.6 mg/L
• BM biopsy; 50% lymphocytes
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with ibrutinib and achieved a complete response to therapy after 2 months