Case 2: Treatment Options: Venetoclax +/- Rituximab

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Nitin Jain, MD:In terms of the therapy, Dr. Wierda, what therapy would you use in this patient who has failed ibrutinib, who has deletion 17p? What are your thoughts, at this time?

William Wierda, MD, PhD:The patient has had frontline ibrutinib and has high-risk features—particularly 17p deletion. And now, the patient is clearly progressing. I think that is reflective of the rise in the white count. The patient has a high white count, at this point, and clearly has progressive adenopathy and splenomegaly. So, we need a new treatment option for this patient. In this type of patient, I like to checkBTKmutation status and PLC gamma 2, just to confirm that those mutations are there. There probably are some additional BTK inhibitors, that are coming down the line, that don’t work by the same mechanism as ibrutinib and acalabrutinib. So, in the future, we may have additional treatment options for patients who have clinical progression on ibrutinib.

Right now, we have drugs that work by other mechanisms of action. Because of the presence of 17p deletion for this patient, chemotherapy is really not an option. That will potentially make things worse for the patient, giving the patient toxicity with no benefit. So, I don’t consider chemotherapy to be a reasonable option for this patient.

We have a drug that’s been recently approved. A small molecule inhibitor of BCL-2, formerly known as ABT-199, is now known as venetoclax (Venclexta). It’s currently approved in the United States for patients who have relapsed disease and 17p deletion. The approval was based on a phase II clinical trial that was reported on recently. Results of the trial showed the activity of venetoclax monotherapy in 107 relapsed patients with 17p deletion. The response rate, in that population, was about 80%. There were about 20% complete remissions among patients who were treated with venetoclax monotherapy, including patients who achieved an MRD—negative complete remission. To me, that speaks to the potency and efficacy of this monotherapy, even in a high-risk group. And, clearly, there’s activity by a TP53 independent mechanism of action.

Today, we have a treatment option for this patient who is progressing on ibrutinib. Venetoclax monotherapy, again, is approved, and I would put this patient on venetoclax as their next treatment.

I think there are a couple of clinical considerations in this scenario. The patient is progressing. He is on ibrutinib. We have seen patients who have explosive disease when you stop the ibrutinib. So, we need to be cautious in converting them or transitioning these types of patients, who are developing resistance, over to a new treatment. We have overlapped therapy, where we’re continuing the BTK inhibitor while we’re initiating venetoclax. That can be safely done. Other groups, and our group have also looked at accelerated escalation of venetoclax. One of the toxicities that we worry about with venetoclax has been fatal tumor lysis syndrome. That can be mitigated by initiating it at a low dose and escalating the dose over about 4 weeks of therapy. If you do it as it’s been recommended in the package insert, it’s safe. But that is a concern.

Nitin Jain, MD:So, maybe at that line there is tumor lysis syndrome, despite the fact that the patient has a white count of 153,000. Would you be worried about it? How would you manage this patient, in your practice, to start venetoclax?

William Wierda, MD, PhD:I would absolutely be worried about tumor lysis in this patient, who has a high white blood cell count. The factors that have been correlated with risk for tumor lysis are high white counts, particularly over 25,000, and lymph nodes. The bigger the lymph node cluster, or group, the higher the risk for tumor lysis. The other feature that we have to think about and take into consideration is kidney function. Patients who have compromised renal function will also have difficulty managing the electrolyte abnormalities that happen when we have a large number of cells undergoing apoptosis.

Nitin Jain, MD:Matt, at the ASH [American Society of Hematology] meeting, there was a presentation on the MURANO trial, where venetoclax was combined with rituximab. Maybe you can tell us about some of the highlights of this trial?

Matthew S. Davids, MD, MMSc:Sure. Dr Wierda just went through the data that led to the initial approval of venetoclax, which is actually an accelerated approval specifically for patients with relapsed CLL with deletion 17p. And so, the agency required a confirmatory study. The MURANO study is that registrational study in the relapsed/refractory CLL population. Part of the inspiration for the design of the MURANO trial came from a phase IB study where venetoclax was combined with rituximab. Strikingly higher rates of complete remission were seen, in the 50% range, with good tolerability. Even some patients who electively discontinued venetoclax in an MRD-undetectable state continued to remain in a good remission for a period of time.

So, that led to the development of the MURANO study, which was a randomized phase III trial of venetoclax with rituximab versus bendamustine with rituximab, which is a standard regimen for relapsed/refractory patients. The trial required 1 to 3 prior lines of therapy, a good performance status, and the patients were randomized (1:1) to the 2 arms. Patients with deletion 17p were included in this study, which is interesting because we just heard that we would not consider bendamustine and rituximab as a current standard-of-care option for these patients. I think this does highlight, again, the challenges with these large phase III international trials. When this trial was designed, that was still a regimen that was being used in some of the countries where this trial took place.

Nonetheless, it included a pretty diverse population of CLL patients. The patients were treated with either 6 months of standard bendamustine/rituximab or a 2-year regimen of venetoclax; the first 6 months contained a combination with rituximab. Some of the progression-free survival results were really quite striking. We see that the median progression-free survival for the venetoclax/rituximab group has not been reached at a now close-to-2-year follow up. Whereas with bendamustine and rituximab, there was about a 17-month progression-free survival, which is actually pretty reasonable, considering that the trial included patients with deletion 17p.

Looking across the different subgroups in the MURANO study, the venetoclax/rituximab group had an advantage across all of the different groups, in particular in the deletion 17p patients. And so, that really highlights this as an option for patients with relapsed CLL with any of the different risk abnormalities. Now, this trial did not include patients who had progressed on ibrutinib, like our patient, in this case, so it’s not as informative for that particular population. Nonetheless, I would think that it would be largely applicable to that population.

In this larger phase III setting, with a lot of different centers included, the toxicity profile of venetoclax and rituximab looked quite favorable. There were slightly higher rates of neutropenia seen with venetoclax and rituximab versus with bendamustine and rituximab. But there was not a significant increase in infections. That’s really important. Dialing into some of the secondary endpoints in this study, we really saw dramatic improvements in the complete remission rate. At least, by the investigator-assessment, there was a 27% CR rate with the venetoclax regimen and there were MRD-negativity rates of 83% in the blood. This is something that was preserved over the study. There were high rates seen after 6 months. Looking at 12 months, 18 months, and even 24 months, these MRD-negative rates were quite high. Remember, though, that this is a 2-year regimen with venetoclax. So, one of the key questions with MURANO, going forward, is, at the end of the therapy, at 2 years, are these deep responses maintained? Or do we start to see patients progressing relatively soon after therapy finishes?

Nitin Jain, MD:If you look at the progression-free survival curve for the venetoclax arm in the MURANO trial, at the 2-year mark there is a drop in the curve for some patients. So, there are patients who are progressing possibly soon after stopping venetoclax or around the time of stopping venetoclax. Is that because they were MRD positive at that time? Is it because they had active disease? How does that possibly play into the appropriate duration of venetoclax, in your mind?

Matthew S. Davids, MD, MMSc:We haven’t seen the details, yet. That population is a relatively small group, in this study. But as we see future data cuts, I think this picture will become a little bit clearer. You’re probably right. These are probably patients who are not MRD negative at the end of treatment. Certainly, that could become a decision-making point in these patients, in terms of deciding whether to continue or stop therapy.

Nitin Jain, MD:So, for this patient—a patient who has deletion 17p, who has failed ibrutinib—I think treatment with venetoclax may be appropriate.

Nitin Jain, MD:One other drug that is approved in the relapsed setting is idelalisib. Idelalisib is a PI3-kinase delta inhibitor. The trial that led to the approval of idelalisib was a randomized controlled trial that randomized patients who had relapsed/refractory CLL. The patients were randomized to idelalisib plus rituximab versus rituximab alone. In that particular trial, there was a significantly improved progression-free survival in the idelalisib arm compared with the placebo plus rituximab arm. The 12-month overall survival was higher: 92% for the idelalisib/rituximab arm versus 80% for the placebo-plus-rituximab arm. So, that’s another option that is currently available. This regimen is approved, in the United States, for patients with relapsed CLL. And it could potentially be a consideration for patients in whom you may not want to use venetoclax. So, that’s another option for our patients who have failed ibrutinib.

William Wierda, MD, PhD:This is a relatively young patient who’s failed ibrutinib in the frontline setting. Now he is going on to salvage treatment. It’s probably important to have a discussion about allogeneic stem cell transplantation. In my mind, for a patient with a 17p deletion who has failed first-line ibrutinib and is now going on to salvage treatment with venetoclax, that’s probably something that we should be thinking about. We should at least be sending the patient for a transplant consult, to see what the transplant options are for that patient. The other issue is that clinical trials and investigational therapies are also important considerations. Certainly, we would love to have this type of patient referred to our center, to be put on a clinical trial. For example, we’re working on a CAR T-cell trial. This may be a great opportunity for patients who have very-high-risk disease, and I would put this patient into that category.

Transcript edited for clarity.