UCSF Expert Highlights Progress in Lymphoma Landscape

Lawrence D. Kaplan, MD

Several treatment questions remain following data from recent clinical trials in Hodgkin lymphoma, mantle cell lymphoma (MCL), and follicular lymphoma (FL), explained Lawrence D. Kaplan, MD.

According to findings from the phase III ECHELON-1 trial, brentuximab vedotin (Adcetris) combined with doxorubicin, vinblastine, and dacarbazine (A+AVD) has shown significant activity in patients with advanced Hodgkin lymphoma.

The initial results of the global study indicated a 5.1% benefit with A+AVD in 2-year modified progression-free survival (mPFS) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A subgroup analysis of the North American population revealed an absolute difference of 10.6% in mPFS per independent review facility and an 11.7% difference in PFS per investigator review at 2 years.

As a result of these findings, the FDA approved the frontline combination of brentuximab vedotin and chemotherapy for adult patients with stage III/IV classical Hodgkin lymphoma in March 2018.

Although this is an advancement in the Hodgkin lymphoma space, Kaplan said skepticism surrounds brentuximab vedotin. Mainly, mPFS is not a standard endpoint for clinical trials and the antibody-drug conjugate has yet to show an overall survival (OS) benefit. There is also a considerable cost difference between A+AVD and ABVD.

Transitioning into MCL, Bruton tyrosine kinase inhibitors have become standard of care for the relapsed/refractory patient population. The first- and second-generation agents ibrutinib (Imbruvica) and acalabrutinib (Calquence) have shown promise, but the next steps for researchers are to expand on this progress. Ibrutinib is also being tested in combination with venetoclax in patients with MCL (NCT02471391).

In FL, combinations are also being explored, though the RELEVANCE trial failed to show superiority with lenalidomide (Revlimid) and rituximab (Rituxan) over chemotherapy.

OncLive: Can you expand on some of the latest data in these settings?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Kaplan, clinical professor of medicine, director, Adult Lymphoma Program, Division of Hematology-Oncology, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed recent updates and next steps in the expanding paradigm of Hodgkin lymphoma, MCL, and FL.Kaplan: For Hodgkin lymphoma, I discussed a trial in which patients either received standard ABVD or brentuximab vedotin plus AVD. The larger, international version of this trial was presented at the 2017 ASH Annual Meeting. It demonstrated a 5% increase in mPFS favoring the brentuximab vedotin arm. This study represents a subset of patients in North America, roughly half that of the bigger trial. It was a planned analysis, and it’s legitimate. The difference in mPFS here [in North America] was about 10%.

The study has been criticized though, and I would tend to agree. mPFS is not a standard endpoint; it’s never been validated. The study has not yet represented an OS benefit, and there is also a huge cost differential between these 2 treatments.

Can you speak to therapeutic developments in other lymphomas?

My practice at this time is to not use brentuximab vedotin. A big difference in the outcomes of this study were related to pulmonary toxicity; there were a bunch of deaths related to that in the ABVD arm. It’s now no longer necessary to do 6 cycles of this therapy, so that may explain the difference. At present, I don’t really suggest this regimen. The National Comprehensive Cancer Network has reviewed it and is also not quite on board.In terms of MCL, we’re looking at a combination of the 2 most active agents in the relapsed setting: ibrutinib and venetoclax. This has also been looked at in chronic lymphocytic leukemia. The major endpoint here is looking at MRD. It looks like this combination does improve MRD negativity. The question remains whether this will result in survival benefit.

In follicular lymphoma, the combination of rituximab and bendamustine has been a promising one. It’s been shown in phase II studies, and it was the subject of a 1000-patient international trial. Patients received either lenalidomide plus rituximab or lenalidomide and chemotherapy, which is the standard of care. It was a superiority trial, and the attempt was being made to indicate that rituximab was superior to chemotherapy. Those who designed the trial had high expectations, and as a result, the superiority idea should have been done differently. It looks like the outcomes were similar.

Lastly, I presented a new checkpoint inhibitor study. Instead of looking at T-cell checkpoints, we looked at macrophage checkpoints, such as CD47. It comes in the form of a “do not eat me” signal. This is a huge issue in terms of immune response and whether the cancer cells will be phagocytosed by a macrophage. The current study utilizes a novel agent targeting CD47. This was a phase I study, but it showed significant activity.

Ramchandren R, Advani R, Ansell S, et al. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. J Clin Oncol. 2018;36(suppl; abstr 7541). meetinglibrary.asco.org/ record/162378/abstract.