Combination Therapy Options Emerge in Treatment Landscape for Relapsed/Refractory CLL

William G. Wierda, MD, PhD

William G. Wierda, MD, PhD

Treatment options after relapse for patients with chronic lymphocytic leukemia (CLL) continue to evolve. In particular, recent data with small molecule combinations and fixed-duration treatments have shown strong activity in both the frontline and salvage settings.

“I think now is the time that we are working towards fixed-duration treatment, getting patients into a deep remission with non-chemotherapy-based treatment, with a small molecule-based treatment, and giving patients a treatment-free period,” said William G. Wierda, MD, PhD during the 23^rdAnnual International Congress on Hematologic Malignancies

Updated findings from the randomized phase III MURANO trial, presented during the 2018 ASH Annual Meeting, showed durable remissions in patients with relapsed/refractory CLL treated with venetoclax (Venclexta) plus rituximab (Rituxan) compared to bendamustine plus rituximab. Patients were treated with venetoclax for a fixed duration of 2 years and rituximab for 6 monthly cycles. The combination also led to prolonged progression-free survival (PFS).

Results from the phase II CLARITY trial, also presented at ASH, demonstrated that over 90% of patients with relapsed/refractory CLL achieved an objective response when treated with venetoclax in combination with ibrutinib. After 1 year, 54% of patients were in complete response (CR) or CR with incomplete marrow recovery.

In an interview withTargeted Oncology,Wierda, professor in the department of leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the emerging role of small molecule combinations and fixed-duration treatments in patients with relapsed/refractory CLL.

TARGETED ONCOLOGY:What are the current treatment options for patients with relapsed/refractory disease?

Wierda:Treatment options are changing these days, so for patients who have relapsed disease, their next treatment option depends on what they had prior to their progression. If we’re talking about frontline therapy or even a first or second salvage, the treatment options will be determined by what they have had previously and what they are refractory to. If patients have had prior chemoimmunotherapy, then we have a couple treatment options; we have ibrutinib monotherapy or venetoclax and rituximab as 2 treatment options. They’re different because the approach is different, and the treatment is different.

When patients go onto ibrutinib, they remain on treatment until the treatment is no longer effective or they have some toxicity. We know from the long-term follow-up data with ibrutinib monotherapy in the relapsed setting that the median PFS across all relapsed patients is about 51 months. They have very good, durable disease control with ibrutinib monotherapy, but they have to stay on treatment continuously and indefinitely. Also, we do see some side effects and toxicities from ibrutinib.

The other strategy is with venetoclax plus rituximab. There was a randomized trial looking at chemoimmunotherapy versus venetoclax plus rituximab, and that showed improved PFS for patients who received the venetoclax-based therapy. This is another option; it is an option that is different than ibrutinib monotherapy because we’re talking about fixed-duration treatment. Patients are on venetoclax for 2 years, then they stop. Rituximab is given in 6 monthly doses at the initiation of treatment. The data I presented are the follow-up from the MURANO trial which showed durable remissions, even in patients who had finished venetoclax and had come off treatment. Patients who are off treatment and achieved a deep remission by the end of treatment have excellent PFS in the absence of needing additional treatment.

That’s where we are with chemoimmunotherapy as first-line therapy. Things get a little more confusing and challenging when we are talking about treating first-line with ibrutinib, for example. We have data that Matthew S. Davids, MS, MMSc, spoke about with frontline ibrutinib-based therapy. That has changed, and is becoming, the standard of care in the frontline setting. In patients who have had ibrutinib monotherapy or with a CD20 antibody as their first treatment and are progressing, we have a couple of options. We have venetoclax-based therapy, and there’s data that shows a reasonable response rate with venetoclax-based treatment post-ibrutinib failure. There are other options including PI3K inhibitor-based therapy with a CD20 antibody, which has activity. There is a bit more toxicity associated with the PI3K-based therapy, so I would say that if patients have had ibrutinib prior, either in the frontline or as a subsequent treatment, venetoclax would be the next best option for salvage treatment. There are a lot of new strategies that are being developed. There are reversible BTK inhibitors, CAR T-cell therapy, and I covered some of those [in my talk].

TARGETED ONCOLOGY:What were some of the key points from your talk?

Wierda:The key point in regard to the MURANO data and the long-term follow-up from the MURANO data is that there are patients who achieve a deep remission by the end of the 2-year treatment, and that remission and PFS are maintained after they come off the venetoclax-based therapy. In the relapsed setting, fixed-duration treatment is a potential strategy for managing disease as opposed to putting patients on treatment that is indefinite and continuous.

The next point I think is important is that we are seeing a lot of very impressive, interesting, and exciting data around the small molecule inhibitor combinations, such as ibrutinib plus venetoclax or ibrutinib plus venetoclax plus a CD20 antibody. We are seeing deep remissions in a high proportion of patients with those combination strategies both in the frontline setting and in the salvage setting. Those early data are exciting and may become the next standard of care.

Then I think CAR T does present some opportunity for improvement in outcomes, particularly in patients who are refractory to standard treatments. There is still work that we need to do with that strategy to make it more tolerable and effective.

TARGETED ONCOLOGY: What data have been reported for the combination of ibrutinib and venetoclax?

Wierda:For the ibrutinib/venetoclax data, there are several trials that were reported at ASH on that combination. MD Anderson has a clinical trial with 2 cohorts, a relapsed cohort and a frontline cohort. The UK group has a trial called the CLARITY trial; they predominantly reported data on relapsed patients receiving ibrutinib plus venetoclax. The Ohio State Comprehensive Cancer Center has a trial that they have done with ibrutinib and venetoclax plus a CD20 antibody. All of those trials, both in the frontline setting and the relapsed setting, have seen very high complete remission rates. We are seeing a very high proportion of minimal residual disease-negativity as a very well tolerated treatment with no toxicity or safety concerns with the combination above what we expect to see with either of the drugs as monotherapy.

TARGETED ONCOLOGY:Could you also discuss the early data seen so far with CAR T cells in CLL?

Wierda:The very early data where CAR T cells were studied in patients with CLL, not in combination with any other treatment, had a lower complete remission rate than had been reported for, as example, acute lymphoblastic leukemia (ALL). The ALL complete remission rate is about 80%. In CLL, it’s about 30% with CAR T cells, looking just at CAR T cells. There was a lot of data that the University of Pennsylvania group produced in terms of looking at the CAR T product and the CAR T potency of that product for patients with CLL, and what they found was there was a higher potency in the product when they collected the T cells from patients when patients were on ibrutinib. Ibrutinib has some immune modulating effects; patients who are pheresed and have their T cells collected at the time they are on ibrutinib potentially have a better product, and also those CAR T cells work better in the presence of ibrutinib in patients who are receiving CAR T cells. The current strategy and the early data that was presented at ASH is looking at ibrutinib in combination with a CAR T. There is a suggestion that there is better activity, better tolerability even, with that combination, but we need to treat more patients.

TARGETED ONCOLOGY:What is the main take home message?

Wierda:The take home message is that the response rates and the depth of remission are better now than they ever were in terms of frontline therapy and in terms of relapsed treatment. I think now is the time that we are working towards fixed-duration treatment, getting patients into a deep remission with non-chemotherapy-based treatment, so with a small molecule-based treatment, and giving patients a treatment-free period.

We will have a better idea of what relapse looks like and what refractory disease looks like as we treat more patients on these studies when they relapse, so that’s an area we are certainly interested in studying, [like] ibrutinib-refractory disease or BTK inhibitor-refractory disease. There are a lot of drugs right now and strategies that are novel and new that we are interested in developing that may be the next advance in CLL. We have had a lot of advances in CLL, and I think right now, more than ever, there is opportunity for additional advances, so we need to boost our referral and make sure that our colleagues in the community know we are working on clinical trials and new drug development. If they have patients who are refractory to standard treatments, we would like to see those patients.