Expert Explains Latest Advances in Hodgkin Lymphoma, MCL

Chaitra S. Ujjani, MD

Novel regimens recently added to the paradigms of Hodgkin lymphoma and mantle cell lymphoma (MCL) have led to a more personalized therapeutic approach in clinical practice, explained Chaitra S. Ujjani, MD.

For example, brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (AVD) demonstrated superior progression-free survival (PFS) compared with standard ABVD chemotherapy (AVD plus bleomycin) in patients with Hodgkin lymphoma, according to phase III findings from the ECHELON-1 study.

In the large international trial, the brentuximab vedotin regimen reduced the risk of progression, death, or initiation of new therapy by 23% compared with ABVD. The primary endpoint was modified PFS (mPFS), which Ujjani says takes more factors into consideration than standard PFS. Two-year mPFS rate was 82.1% for brentuximab vedotin versus 77.25% for standard chemotherapy (HR, 0.77; 95% CI, 0.60-0.98; P = .035).

As a result of the findings, the FDA approved the CD30-targeted antibody-drug conjugate in March 2018 for use in combination with chemotherapy as a frontline treatment for adult patients with stage III/IV classical Hodgkin lymphoma.

Moreover, in mantle cell lymphoma (MCL), the promising activity with BTK inhibitors in relapsed/refractory patients has led researchers to explore them in the frontline setting. For example, the phase II ENRICH trial (NCT01880567) is analyzing ibrutinib (Imbruvica) with rituximab (Rituxan) maintenance therapy in elderly patients with newly diagnosed MCL.

Ibrutinib and acalabrutinib (Calquence) are both FDA approved for patients who have had at least 1 prior line of therapy.

Ujjani, a hematologist/oncologist at Seattle Cancer Care Alliance, said researchers are hopeful that acalabrutinib will improve upon the efficacy and toxicity challenges seen with ibrutinib, but that both BTK inhibitors fit in the treatment paradigm.

OncLive^®: Please provide an overview of the ECHELON-1 study.

In an interview at the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Ujjani discussed the latest progress in both Hodgkin lymphoma and MCL.Ujjani: This is a frontline classical Hodgkin lymphoma study for advanced-stage patients. In this study, they looked at standard ABVD chemotherapy compared with AVD plus brentuximab. We know that in patients with previously untreated Hodgkin lymphoma, up to 40% of them will be refractory or will relapse to their initial therapy. Therefore, better induction regimens are necessary.

Brentuximab vedotin is a well-known antibody-drug conjugate to CD30, and it's already FDA approved for Hodgkin lymphoma in a number of other situations. Now, it's being looked at in the frontline setting. When rituximab came onto the scene, it totally changed the future of B-cell lymphoma. We thought we could do the same thing with brentuximab vedotin and add it to standard chemotherapy. They added it initially in a phase I study. While the combination was effective, there were some issues with toxicity. They revamped it, and now we have this combination with AVD.

The highlights of this study are that there were more than 1300 patients randomized. The prior endpoint was modified PFS. This is a little different from normal PFS, which we see in a lot of clinical trials. Normally, PFS flags patients who have progressed or died. In this study, mPFS means those who died, those who progressed, as well as those who had an end-of-treatment PET/CT scan that was deemed not sufficient by the treating oncologist. Those patients were flagged and referred to another line of treatment. In this study, they compared the 2 arms. They found the response rates were similar. But, there was a difference in PFS. The 2-year mPFS was 82% in the brentuximab arm versus 77% in the ABVD arm.

Are there any unanswered questions with brentuximab vedotin?

This led to the approval of brentuximab. The other thing to take away is that there are some toxicities to manage; neuropathy can be an issue. This can be managed with dose adjustment. Febrile neutropenia also frequently comes up.There are a few different things that still need to be explored. A group [of researchers] at Dana-Farber Cancer Institute published a study of brentuximab vedotin in combination with bendamustine for relapsed patients. They had achieved complete remission under that regimen, allowing them to be eligible for a stem cell transplant. That's an interesting combination.

What is the rationale to combine brentuximab vedotin with nivolumab?

How has immunotherapy in general impacted the Hodgkin lymphoma field?

Moving onto MCL, what are some key updates in that treatment paradigm?

There's also been interest in brentuximab vedotin with nivolumab (Opdivo). This is an immunotherapy agent that is approved in Hodgkin lymphoma. The early-phase studies look very promising in the relapsed setting, and it's being looked at in the frontline setting as well.They obviously have 2 very different mechanisms of action. The rationale in combining them was that you could give 2 different types of targeted therapies together and possibly improve outcomes. You could also avoid chemotherapy. The goal is to achieve more personalized treatments.First, nivolumab is a very effective agent. The responses we saw for the patients [treated with nivolumab] who relapsed on brentuximab vedotin were very impressive. It speaks to the biology of the disease and how it's a little different from non-Hodgkin lymphoma (NHL).For MCL, we're hopefully switching to a space similar to chronic lymphocytic leukemia (CLL) where we're seeing more targeted therapies. A few years ago, the BTK inhibitor ibrutinib was approved. Response rates have been in the mid-60% range. The drug has been associated with some unique adverse events (AEs). Now, we're looking at ways to improve this.

What are some next steps to take in the treatment of patients with MCL?

Are there any other exciting agents coming through the pipeline?

How do you determine whether to choose acalabrutinib or ibrutinib for a relapsed/refractory patient with MCL?

One of the ways is developing second-generation BTK inhibitors that are hopefully more effective and tolerable. Acalabrutinib is a second-generation BTK inhibitor that has been improved. Response rates have been very promising; we're just waiting to see how durable these responses are. The drug also appears to be a little better tolerated. We still see a little bit of bleeding, but nothing significant.Looking at other biologics is another way to go. BCL-2 plays a role in the pathogenesis of CLL, so we can see if a BCL-2 inhibitor would work in this setting. Venetoclax (Venclexta) is an example; patients with MCL seem to benefit from it. We combined it with ibrutinib and saw impressive response rates. It was a phase II study, but still very encouraging.There are MCL1 inhibitors that are in early stages. There are more BTK inhibitors in the works, too. We don't know if these will play a role in MCL. Obviously, chimeric antigen receptor (CAR) T-cell therapy has also been exciting. We'll see whether this can be applied to MCL. It's probably too soon to say. We're still trying to determine how old a patient should be to safely receive CAR T cells. We have a pretty good hand on how to manage AEs. Once we get a better idea of who can handle this therapy, we will better understand where this fits into treatment.Thus far, we don't really know which one is better. Ibrutinib is given once a day, while acalabrutinib is given twice a day. Patient compliance is something you have to take into consideration. The AE profile of the drug is also something to think about. In terms of bleeding risk, if someone has a high risk of bleeding, perhaps we would avoid ibrutinib. It depends on the individual.

Connors J, Jurczak W, Straus D J, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 ECHELON-1 study. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 6.