Pivotal Data Refine Treatment Strategies in Hodgkin Lymphoma and Follicular Lymphoma

Leo I. Gordon MD

Clinical updates in Hodgkin lymphoma and non-Hodgkin lymphoma (NHL) have continued to evolve the space, such as moving away from toxic regimens and more toward a personalized or chemotherapy-free approach, explained Leo I. Gordon, MD.

For example, in Hodgkin lymphoma, the randomized, phase III ECHELON-1 trial compared brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (A+AVD) with AVD plus bleomycin (ABVD) in 1334 patients with newly diagnosed, advanced Hodgkin lymphoma. Results showed that treatment with A+AVD led to a 23% reduction in the risk of progression, death, or initiation of new therapy, leading to the FDA approval in this patient population in March 2018.¹

However, the brentuximab vedotin regimen should not be a one-size-fits-all approach for patients, said Gordon, the Abby and John Friend Professor of Oncology Research, and professor of medicine (hematology and oncology), at Feinberg School of Medicine, Northwestern University. Checkpoint inhibition, he said, is continuing to be explored in various settings of the disease. In NHL, chemotherapy-free regimens continue to garner interest, specifically for patients with follicular lymphoma or low-grade lymphoma.

Results from the phase III RELEVANCE study showed that the combination of lenalidomide (Revlimid) and rituximab (Rituxan; R²) were found to have similar efficacy outcomes compared with rituximab plus chemotherapy in treatment-naïve patients with follicular lymphoma.² But beyond those data, investigators are looking into other frontline combination regimens, such as ibrutinib (Imbruvica), lenalidomide, and rituximab. A key challenge in the field, Gordon noted, is figuring out what to do for patients who relapse within 2 years of ending therapy.

OncLive: What are the key changes in Hodgkin lymphoma and NHL treatment?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Gordon discussed these recent updates in Hodgkin lymphoma and NHL and pointed to research on the horizon.Gordon: The [2 main] issues in Hodgkin lymphoma still remain: first, what to do with PET scans and how to improve results based on PET scans, [and second, answering] the question, “Where are we going in the future?”

In NHL, I reviewed data mostly on follicular lymphoma or low-grade lymphoma; I focused on initial therapy, new combinations, a trend toward moving away from chemoimmunotherapy. [There have been] data on the use of immunomodulatory (IMiD) agents, such as lenalidomide. The question of what to do in second-line therapy relates to the use of novel agents, chemoimmunotherapy, and the PI3K inhibitors, in which there is interest. Data [have been reported] on a new dual-PI3k inhibitor, copanlisib (Aliqopa).

Going back to Hodgkin lymphoma, could you discuss the impact of the FDA approval of the A+AVD regimen?

A burning question in low-grade lymphoma, especially follicular lymphoma, is what to do with patients who relapse within 24 months of initial therapy. That appears to be a fairly high-risk group, with [data suggesting] that those patients don’t do very well. The questions are, “What do we do upfront?” and “What do we do at the time of first relapse?”First of all, that has become the new control arm of an upcoming study that will compare brentuximab vedotin plus AVD with nivolumab (Opdivo), so we are introducing the checkpoint inhibitors in upfront treatment of [patients with] Hodgkin lymphoma. At our institution, we have not identified [A+AVD] as the [standard] frontline therapy yet. However, for the group of patients we think are at risk for pulmonary toxicity from bleomycin, it is a reasonable regimen. Whether [this regimen] should replace ABVD as the standard, I’m not certain yet. The North American subgroup analysis suggests that, once again, brentuximab vedotin offers better progression-free survival (PFS) compared with bleomycin.

Have new data with checkpoint inhibitors come out in this space?

We are trading some toxicity, so patients getting brentuximab vedotin have more neutropenia and febrile neutropenia, and they require the use of a growth factor, which isn’t needed with ABVD. I’m concerned whether that will have long-term effects. I also have concerns about the every-2-week use of pegfilgrastim (Neulasta) for 6 cycles or 12 doses in young patients, so unless someone has a significant risk for pulmonary toxicity, we are still using ABVD as our standard.We are excited about the use of the checkpoint inhibitors. We did a study years ago on adjuvant [immunotherapy] in [patients with] diffuse large B-cell lymphoma (DLBCL) following autologous stem cell transplant with a checkpoint inhibitor; that was pidilizumab, which is no longer being used. Therefore, we have reasons to think, especially in Hodgkin lymphoma, that [these drugs] are going to be active.

We have an ongoing study led by Jane N. Winter, MD, [my colleague at Northwestern University], the principal investigator, with several institutions using pembrolizumab (Keytruda) as upfront treatment for [patient with] both early- and advanced-stage Hodgkin lymphoma, and Winter presented early results at the [10th International Symposiumon Hodgkin Lymphoma].

What other data were presented at the 2018 ASH Annual Meeting in Hodgkin lymphoma?

We are quite impressed with the response of a lead-in of 3 doses of pembrolizumab in patients with advanced Hodgkin lymphoma. We are seeing fairly dramatic improvement in PET scans, especially in those patients with bulky disease. That initial study is just being completed with approximately 30 patients in the phase II study, and we are planning a larger study to focus on patients with bulky disease. Barring any unforeseen toxicities, that’s going to be here to stay in upfront Hodgkin lymphoma. Not a lot of data are looking at the response rate in patients who previously have not been treated.When we see patients with DLBCL, we know from prior data that we can feel more comfortable about long-term success if patients stay in remission for 2 years, because when you look at the PFS curves, most of the relapses occur within the 2-year period. Once people reach 2 years, the curves are relatively flat; although certainly, some relapses occur. We weren’t so clear about that in Hodgkin lymphoma.

One study that didn’t get a lot of attention, but captured my interest, was a 2500-patient retrospective review. What they did was look at a statistical analysis of patients who achieved event-free survival (EFS) at 3 years and 5 years. It appears that for every subgroup, if they achieved EFS by 3 years and by 5 years, we could expect that their overall survival (OS) would be similar to the general population.

The risk of recurrence in the next 5 years is quite minimal. This gives us useful information for when patients with Hodgkin lymphoma ask, “When can I feel more comfortable about my visits—that it’s not as likely that I’m going to have a relapse?” Now we can [tell them]. That said, some patients do relapse 10 years later; exceptions exist to all of those rules, but in general, you can be a little more comfortable with that information.

In Hodgkin lymphoma, an important study was led and published by a dear, late friend and colleague [Oliver W.] Ollie Press, MD, PhD, in the Journal of Clinical Oncology in 2016. He looked at the role of PET scans in patients with advanced Hodgkin lymphoma and looked at PET2 scans. Patients who were PET2-negative continued with standard ABVD and those who were PET2-positive, which made up less than 20% of the group, were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP).

The data looked exciting, in that the eBEACOPP group did better than one might have expected [given that those patients had] early PET2-positive scans. The initial study was presented with 3 to 4 years of follow-up. The update looked at the same study, but it had almost 6 years of follow-up and the data hold pretty well. Two lessons emerged from that study. The first is that although the PET2-negative patients did well, that PET isn’t as predictive as we would like to think. Or, it may tell us that despite Deauville scores, the interpretation of a PET scan is somewhat more of an art than a science. And, it reminds us that we are not all artists. Our ability to interpret the PET scan leaves us short. We need to do a better job at a more formal, scientific interpretation of [these scans] by looking at metabolic tumor volume and using numbers to interpret it. Maybe that will be better because, right now, we’re just doing the subjective visual assessment of the PET scan. Perhaps that is the reason that PET is not as good as we thought it would be.

Moving onto follicular lymphoma, could you discuss the R² regimen?

In the PET2-positive group, although the data look better, a higher risk of secondary malignancies still exists. There is some caution, and using eBEACOPP isn’t the final answer. We need to look at better ways of treating these [patients]. Maybe [we should try] earlier use of the checkpoint inhibitors, assuming we don’t see some late toxicities. That might be a way to go.Certainly, some data show that a chemotherapy-free approach in patients with follicular lymphoma is perhaps equal to chemotherapy with rituximab plus either bendamustine or CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]. What people are beginning to look at are ways to improve that. Loretta J. Nastoupil, MD, of The University of Texas MD Anderson Cancer Center, presented a small study of lenalidomide, rituximab, and ibrutinib in patients with follicular lymphoma and marginal zone lymphoma.

Data are early, but the overall response rate (ORR) and complete response (CR) rates are quite impressive; the ORR was approximately 90% and the CR was close to that, at around 80%. This was a little bit surprising because ibrutinib in follicular lymphoma was a bit of a disappointment, based on some of the early studies that we saw. Maybe something is there, and synergy exists in a small number of patients.

Data were presented looking at the combination of obinutuzumab (Gazyva) and lenalidomide as upfront treatment in patients with follicular lymphoma. These patients did a maintenance course of therapy for 1 year with lenalidomide, and with obinutuzumab for another year. It was a long treatment, but it’s not different than what people do in follicular lymphoma after chemotherapy. We saw some very good responses and reasonable toxicity; with IMiDs, questions come up about secondary malignancies. That is something we are watching and nothing seems to stand out yet as a major concern, but that is also an important [area to study].

In the relapsed setting, patients have many options. John Leonard, MD, of Weill Cornell Medicine, presented the AUGMENT study. This was a randomized trial comparing R² with rituximab alone, and the results showed some clear improvement in PFS and, so far, OS in patients who get R² versus rituximab alone. Surprisingly, no increase in secondary malignancies occurred in the R² group; in fact, they were slightly less in that group. [R² has associated] toxicities, such as skin rashes, flare reactions, and neutropenia. The question in that study is, “Is rituximab alone enough?”

Will chimeric antigen receptor (CAR) T cell therapy potentially be explored?

The PI3K inhibitors have gained a lot of attention; we have idelalisib (Zydelig) and duvelisib (Copiktra), oral agents with reasonable response rates. None of the new agents have asCAR T-cell therapy definitely has a role in this patient population; the early data with tisagenlecleucel (Kymriah) suggest very exciting response rates in patients with follicular lymphoma. We are interested in looking at CAR T-cell therapy in not only patients with either relapsed or [heavily] relapsed follicular lymphoma, but also in those who relapsed less than 24 months after chemotherapy or after initial therapy. We have to do better at managing the toxicities. We have to do better at managing the cost.

At our institution, Reem Karmali, MD, MS, has proposed radioimmunotherapy are better than the data with the cost, but that is down the road. That said, the [PI3K inhibitors] are out there and are active studies using CAR T cells in patients with early relapsed follicular with some concerning toxicities, such as diarrhea, hepatitis, and pneumonitis. The CHRONOS-1 study looked at copanlisib in lymphoma. Certainly, people around the country are going to do that. We have a study coming up with the use of ibritumomab tiuxetan (Zevalin) with pembrolizumab in those patients with relapsed follicular lymphoma.

Preclinical laboratory studies are examining the effects of radiation and the combined synergistic effects of radiation and checkpoint inhibitors. We have reason to think that enhancement of radiation’s effects and of checkpoint inhibitors’ effects exists, based on how the immune system is modulated; myeloid-derived suppressor cells and T-regulatory cells might be affected by that combination. The creation of a favorable environment is an exciting area of research.

References

1. Connors JM, Jurczak W, Straus DJ., 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 Hodgkin lymphoma. Blood 2017;130(6). bloodjournal.org/content/130/Suppl_1/6.
2. Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol. 2018;36(suppl 15; abstr 7500). doi: 10.1200/JCO.2018.36.15_suppl.7500.