Venetoclax With Rituximab & Other Options After Relapse

Ian W. Flinn, MD, PhD:The patient’s initial response to therapy was fairly typical. He achieved a remission within 5 months. This was more of a clinical remission. We don’t know from a bone marrow biopsy whether the patient achieved a true complete remission, nothing being found in his bone marrow. But like most patients, this patient’s symptoms improved and his disease went away, too, clinically.

The only thing I think is a little bit atypical is that this patient had a little bit shorter duration, or remission, than I would have hoped or expected from the frontline use of ibrutinib. We know from the 7-year follow-up of the very initial studies that were done with ibrutinib that many patients, especially in the frontline, were enjoying much longer duration remission. And that’s some of the reasons why I would probably have ordered next-generation sequencing, to see if there’s something that we’re missing in terms of his information, duration of remission.

When someone uses frontline ibrutinib, the question comes up of what to use next. And in this patient, and in patients in general, I think there’s a lot of choices. You could go sort of backwards to chemotherapy; so bendamustine and rituximab [BR]. You could use a PI3 kinase inhibitor—we know that that’s a potential option for the patient—or you could use a venetoclax-based therapy. You know the different people would do different things. I think that the best data that we have, to date, is with venetoclax-based treatments.

The combination of venetoclax plus rituximab was tested in a large randomized trial that’s been published in theNew England Journal, and we’ve seen updates at the ASH [American Society of Hematology] meeting. This study showed, looked at the combination of bendamustine/rituximab versus venetoclax and rituximab in this relapsed patient population. So very akin to what our patient was, the choices for this patient, in that study, there was a substantial difference—you might say huge difference—in terms of progression-free survival for patients who were treated with venetoclax and rituximab versus the bendamustine and rituximab. And so I think it really establishes that as a go-to therapy for patients, for appropriate patients in the first-relapse setting.

At the ASH meeting, we’ve seen an update of the MURANO trial. The MURANO trial is this large randomized phase III trial comparing bendamustine/rituximab to venetoclax and rituximab in patients who’ve had previously 1 prior therapy for their chronic lymphocytic leukemia. This study showed that there was a huge advantage to using the venetoclax-based treatment compared to chemotherapy. In the earlier reports, we knew that there was a high MRD [minimal residual disease]—negativity rate with the venetoclax and rituximab combinations compared to the BR.

Now one of the things that’s been not clear, we’ve known from chemotherapy studies that patients who get MRD-negative, that this is basically a deeper remission, that this translates into an approved progression-free survival. The importance of this most recent update, which shows basically the same thing: If you become MRD-negative, that is associated with an improved progression-free survival, and that progression-free survival advantage has held up over time with longer follow-up.

What we don’t know, and hopefully trials will come to address is, is that whether we should be treating to MRD negativity, should we be doing an adaptive approach to how the length of remission, based on MRD negativity or the intensity of therapy, should it be changed. And that is a subject for further trials.

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