Novel Agents, Combos Transforming Treatment in MCL and CLL

James N. Gerson, MD

The introduction of the novel targeted agents ibrutinib (Imbruvica), acalabrutinib (Calquence), and venetoclax (Venclexta), among others, is rapidly changing the relapsed/refractory space of mantle cell lymphoma (MCL) and the upfront setting of chronic lymphocytic leukemia (CLL), said James N. Gerson, MD.

Moreover, combination strategies are now being looked at for treatment-naïve patients. In MCL, several innovative studies are ongoing, such as the SHINE trial (NCT01776840), which is looking at ibrutinib in combination with bendamustine and rituximab (Rituxan; BR) in patients with newly diagnosed disease, said Gerson. The data, if found to be positive, could have an immense impact on MCL treatment.

In CLL, the utilization of these novel agents has led to an evolving role of upfront chemotherapy for several patients.

"It is a very rare patient that I would consider chemotherapy for," said Gerson. "Perhaps, for a young patient with a mutated IgHV, I might still consider chemotherapy, but essentially everyone else should be treated with one of these targeted agents.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Gerson, an assistant professor of clinical medicine, Perelman School of Medicine, University of Pennsylvania, discussed exciting updates in MCL and CLL and other potentially practice-changing trials on the horizon.

OncLive: What agents in MCL are moving through the pipeline?

Gerson: The majority of recent updates in MCL have been in the relapsed/refractory space. There has been a flurry of approvals for a disease that hasn't had much of anything for a long time.

The first of these was ibrutinib, which was approved in the relapsed/refractory setting a couple of years ago. Acalabrutinib is the newcomer to the stage, and there have been some recent publications and data on that. Venetoclax has also been an agent of interest that has been brought over from CLL to MCL.

We are continuing to look at moving these agents in combination for the relapsed/refractory setting and the upfront setting, with the hope of improving upon outcomes that are fairly poor across the board. Potentially, [we can] take away chemotherapy completely in the upfront setting.

What trials do you find particularly intriguing?

We are waiting for a lot of data. The SHINE trial is looking at the combination of ibrutinib with BR versus BR alone; it is accrued but we are awaiting data.

There are also early data on a chemotherapy-free regimen of ibrutinib and rituximab in the upfront setting. There were recent presentations on that, but nothing has been published yet.

One publication from The New England Journal of Medicine looked at the combination of ibrutinib and venetoclax. Most patients were in the relapsed/refractory setting, but there were a couple [of patients treated] upfront. Those data are very compelling as well.

Potentially more exciting than any of those is CAR T-cell therapy in MCL. There is an extreme paucity of data right now, but an early initial presentation at the 2019 ASCO Annual Meeting from the TRANSCEND NHL 001 trial showed that of 9 patients treated [with CAR T cells], 7 of them were in complete remission. Stay tuned for CAR T-cell therapy. It is still too early to say but, it is most likely coming [to practice].

What strategies are utilized to alleviate toxicity for older patients with MCL?

Most elderly patients who are not transplant candidates are being treated with bendamustine-based therapies, the most common being BR. A recently published phase III trial comparing VR-CAP (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin, and prednisone) to R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone) for a transplant-ineligible population showed a significant improvement in the VR-CAP arm.

That is something I am utilizing [frequently] in my clinic. Certainly though, there are elderly patients who cannot receive an anthracycline. For those patients, BR is what you turn to.

There is a small number of patients who you might treat with single-agent rituximab if they are elderly, have limited volume of disease, or are asymptomatic. For most elderly patients, you wouldn't use an anthracycline or take them to a consolidative transplant.

Could you expand on the “watch-and-wait” approach for MCL and what benefit it has?

The classic, “textbook” treatment of MCL is immediate induction therapy. If a patient is young, we consider a consolidative transplant.

However, in practice, we find there is a large number of patients who are asymptomatic at the time of diagnosis, have relatively small burden of disease, and have beneficial prognostic markers, such as low Ki67 or unmutated p53. Many reports show that some of those patients can be safely observed initially. The vast majority of them will need treatment eventually—unlike in follicular lymphoma where there is a real spontaneous remission rate—but you can watch them for a significant amount of time, as long as a couple of years.

Moreover, there are interesting data that haven’t been presented yet, but that I have been a part of, which is looking at the outcome of these patients once you decide to treat them. Potentially, those patients do not need to be treated the same as a typical patient with MCL. Stay tuned for that because it is not yet published, but it too is coming.

Shifting to CLL, what updates are occurring in that space?

The most exciting change in CLL is the abandonment of chemotherapy in the upfront setting in lieu of targeted therapies, which is actually the same list of agents that I mentioned for MCL: ibrutinib, venetoclax, and often times acalabrutinib, although those data are very preliminary.

As of a couple of years ago, we thought there was equivalency between ibrutinib and standard chemotherapy such as fludarabine, cyclophosphamide, and rituximab (FCR), and BR. As of the 2018 ASH Annual Meeting, we think that for the majority of patients, ibrutinib is preferred to any chemotherapy with the exception being patients with unmutated IgHV.

The most recent update is the approval of obinutuzumab (Gazyva) combined with venetoclax for the upfront management of CLL. It is quite advanced because unlike ibrutinib, [obinutuzumab and venetoclax] is a 1-year, short-course duration of therapy, whereas ibrutinib is essentially indefinite treatment.

We don't have as much long-term data with the venetoclax/obinutuzumab combination as we do with ibrutinib. That is reason for pause, because not every patient is going to want to take something that is less established in the field. That said, it is a great option for patients who are not looking to be on therapy indefinitely. One year of therapy is often a lot easier to swallow than being on something potentially for the rest of your life.

The other big change in the relapsed/refractory setting is we are getting another slew of agents, such as the PI3K inhibitors. A third [PI3K inhibitor] is now FDA approved and is providing more options for patients than ever before.

What factors do you consider when you’re deciding which treatment to use?

There is a small number of patients [for whom I would use chemotherapy for]—for example, a young patient with an unmutated IgHV who wants to be done with therapy in 4 to 6 months.

There are data out of Germany, showing that you can actually use minimal residual disease (MRD) to guide the number of chemotherapy cycles you give. You might be able to get away with 3 or 4 cycles of FCR, for example, for a young patient.

That said, for every other type of CLL, those patients ought to be considered for ibrutinib or the combination of venetoclax and obinutuzumab. The question of which of those to use is up to the patient. There are no comparative data, and quite possibly there never will be; it is unknown whether one is more effective than the other. Some patients will want to do the combination of venetoclax and obinutuzumab because it is 1 year of therapy verses therapy indefinitely. Other patients will say there are much more data on ibrutinib; it is well-established, and they know what to expect 5 years from now. For those reasons, they may choose the more tried-and-trusted approach.