Options After Second Relapse and Unmet Needs in CLL

Ian W. Flinn, MD, PhD:So if the patient develops relapse after having ibrutinib and after having venetoclax plus rituximab, I think the next line of therapy in my mind is a PI3 kinase inhibitor. I doubt that you’re going to get much benefit from, again, going to bendamustine/rituximab, or something along those lines. So I think a PI3 kinase inhibitor, duvelisib or idelalisib, would be my next line of therapy. We know from some studies that you can get patients into remission with this. I think, unfortunately, that the remission durations are probably not what we want them to be. But in third-line therapy, hopefully the venetoclax and rituximab will allow this patient to have a durable remission.

There are a number of other studies and other therapies that are under investigation. For instance, combinations with venetoclax and ibrutinib or other BTK inhibitors, you know, 2- or 3-drug regimens. Can you salvage patients with that? We know that there are other investigational therapies, such as CAR [chimeric antigen receptor] T cells, that are being investigated, and they may also be appropriate for the patient, the right age, and comorbidities.

The combination of ibrutinib/rituximab or ibrutinib and venetoclax or venetoclax and an anti-CD20 is attractive because sometimes we see synergy between these therapies. We saw data this year at the American Society of Hematology meeting looking at the combination of obinutuzumab, venetoclax, and ibrutinib. And this was very exciting data that showed very high complete remission rates, high MRD [minimal residual disease]—negativity rates with this combination. I think really what’s not clear to me is which of the combination is ultimately going to win out? Do we need 3 agents in the frontline setting? If it’s not, and it’s 2, which 2 should that be?

You know, of course, venetoclax and ibrutinib have very high single-agent activity in patients with CLL [chronic lymphocytic leukemia]. We’re eventually going to see data coming out from the German CLL study group looking at the combination of obinutuzumab and venetoclax. We know from a press release that there was substantial improvement in progression-free survival when compared to obinutuzumab and chlorambucil and very high MRD negativities based on a phase I trial that’s previously reported with that combination.

So, I mean, I think it’s really an exciting time in CLL. We’re seeing unprecedented high MRD-negativity rates, high progression-free survivals. But there’s a lot of work still to be done about what is the best combination, especially in the frontline setting. Is it 2 drugs? Is it 3 drugs? If it’s 2 drugs, which 2 drugs should be, how we should sequence things. I think a lot of those questions remain unanswered.

I think this patient, in many ways, is a typical patient that we’re going to be seeing going forward. And I think we know that there’s a shift away from cytotoxic chemotherapy to these more small molecule—based therapy, like ibrutinib. And the logical succession is then to go on to venetoclax-based treatment.

The big question in going forward, I think, is going to be what to do with patients after they progress after venetoclax and rituximab. There are many therapies that are being investigated at this point. Today I think the standard of care would be to use a kinase inhibitor, such as duvelisib, in this patient population. But I think we need to do more. There are many different approaches that are being tested, immunotherapeutic approaches, most classically CAR T cells. But also other therapies that are in investigation, such as bispecific antibodies, which are a little bit more an off-the-shelf approach than putting people through a CAR T-cell therapy.

But that information is very immature at this time, and ultimately what’s going to be the win-out is hard to know.

Transcript edited for clarity.

A 71-Year-Old Man With CLL

• A 71-year—old man presented with symptoms of persistent fatigue and weight loss
• PMH: Left axillary lymph node, 1.5 cm X 1.5 cm
• PE: Left axillary lymph node, 1.5 cm X 1.5 cm
• Laboratory findings:
  • WBC, 133,000; 85% lymphocytes (ALC, 68,000 cells/mL)
  • Hb; 11.4 g/dL
  • Platelets; 111 X 10⁹/L
  • ANC; 174/mm³
• Molecular testing:
  • Flow cytometry; CD19++, CD5+, CD20+, CD23++, CD38+
  • IgVHmutated
  • FISH, +12
• β2M, 3.0 mg/L
• Diagnosis; chronic lymphocytic leukemia
• BM biopsy; CLL in 88% of cells
• The patient was treated with ibrutinib and achieved a complete remission within 5 months
• 13 months later, the patient reported extreme fatigue; now with 3.0 X 3.0-cm lymph node
• Laboratory findings:
  • Repeat FISH: remained +12
  • WBC, 225 X 10⁹/L
  • HB, 9.6 g/dL
  • Platelets, 103 X 10⁹/L