Emerging data help refine treatment strategies for Hodgkin's lymphoma and follicular lymphoma

Leo I. Gordon MD

As the treatment paradigms for Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL) continue to evolve, the field is starting to move away from the use of chemo-immunotherapy and evolving toward innovative combinations and less toxic treatments, explained Leo I. Gordon.

In Hodgkin's lymphoma, for example, the randomized phase III trial ECHELON-1 compared brentuximab vedotin (Adcetris) with doxorubicin, vinblastine and dacarbazine (A + AVD) to AVD and bleomycin (ABVD) in 1334 patients with a new diagnosis of advanced Hodgkin lymphoma. The results showed that treatment with A + AVD resulted in a 23% reduction in the risk of progression, death or initiation of a new treatment, which led to the approval of the FDA in this patient population in March 2018.¹

However, the dosing regimen of brentuximab vedotin should not be a unique approach for patients, said Gordon, research professor in oncology Abby and John Friend, and professor of medicine (hematology and oncology) at the Feinberg School of Medicine University of North West. Inhibition of checkpoints, he said, continues to be explored in a variety of disease settings. In the NHL, chemotherapy-free regimens continue to be of interest, particularly for patients with follicular lymphoma or low-grade lymphoma.

The results of the Phase III RELEVANCE study have shown that lenalidomide (Revlimid) and rituximab (Rituxan;²) had similar efficacy results to those of rituximab and chemotherapy in treatment-naive patients with follicular lymphoma.² But beyond these data, researchers are looking at other first-line regimens, such as ibrutinib (Imbruvica), lenalidomide, and rituximab. Gordon noted that one of the key challenges on the ground was determining what to do for patients who relapse within two years of completing treatment.

In an interview with Targeted oncologyGordon discussed these recent updates on Hodgkin lymphoma and NHL and highlighted future research.

TARGETED ONCOLOGY: What are the main changes in the treatment of Hodgkin lymphoma and NHL?

Gordon: the [2 main] Hodgkin lymphoma problems remain: first, what to do with PET exams and how to improve the results based on these exams, [and second, answering] the question: "Where are we going in the future?"

In NHL, I looked at data primarily on follicular lymphoma or low grade lymphoma; I focused on the initial treatment, the new combinations, a tendency to discontinue chemoimmunotherapy. [There have been] data on the use of immunomodulatory agents (IMiD), such as lenalidomide. The question of what to do in second-line therapy concerns the use of new agents, chemo-immunotherapy and PI3K inhibitors, which are of interest. The data [have been reported] copanlisib (Aliqopa), a new dual PI3k inhibitor.

A burning issue in low grade lymphoma, especially follicular lymphoma, is what to do with patients who relapse within 24 months of initial treatment. This seems to be a fairly high risk group, with [data suggesting] that these patients are not doing very well. The questions are: "What do we do at the start?" And "what do we do at the time of the first relapse?"

TARGETED ONCOLOGY: Going back to Hodgkin's lymphoma, could you discuss the impact of the FDA's approval of the A + AVD diet?

Gordon: First, it became the new control arm of an upcoming study comparing brentuximab vedotin and DAV with nivolumab (Opdivo). So we introduce checkpoint inhibitors into the initial treatment [patients with] Hodgkin lymphoma. In our establishment, we have not identified [A+AVD] as the [standard] first line therapy again. However, for the group of patients that we think is exposed to the risk of pulmonary toxicity due to bleomycin, it is a reasonable regimen. What he's doing [this regimen] should replace ABVD as a standard, I'm not sure yet. Analysis of North American subgroups suggests that, once again, brentuximab vedotin offers better progression-free survival (PFS) compared to bleomycin.

We are negotiating some toxicity, so patients who take brentuximab vedotin have more neutropenia and febrile neutropenia and require the use of a growth factor, which is not necessary with ABVD. I wonder if it will have long-term effects. I am also concerned about the use of pegfilgrastim (Neulasta) every other week for 6 cycles or 12 doses in young patients. Therefore, unless someone has a significant risk of pulmonary toxicity, we always use the ABVD as a standard.

TARGETED ONCOLOGY: Does new data containing checkpoint inhibitors appear in this space?

Gordon: We are excited about the use of checkpoint inhibitors. We did a study a few years ago on an adjuvant [immunotherapy] in [patients with] diffuse large B cell lymphoma (DLBCL) after autologous stem cell transplantation with a control point inhibitor; it was pidilizumab, which is no longer used. Therefore, we have reason to think, especially in Hodgkin's lymphoma, that [these drugs] will 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 the initial treatment for [patient with] Hodgkin's lymphoma in the early and advanced stages, and Winter presented the first results at [10th International Symposiumon Hodgkin Lymphoma].

We are very impressed with the response of an introduction of 3 doses of pembrolizumab in patients with advanced Hodgkin's lymphoma. We are seeing a fairly dramatic improvement in PET scans, especially in patients with large disease. This initial study has just been completed with approximately 30 patients in the Phase II study, and we are planning a larger study aimed at patients with a large disease. Unless there are unexpected toxicities, it will be there to stay in Hodgkin's lymphoma. Few data look at the response rate of patients who had not been treated before.

TARGETED ONCOLOGY: What other data was presented at the annual ASH 2018 meeting on Hodgkin's lymphoma?

Gordon: According to previous data, patients with DLBCL tell us that we can feel more comfortable with long-term success if patients stay in remission for 2 years because when you look at the curves of SSP, most relapses occur within 2 to 3 weeks. period of the year. Once people are 2 years old, the curves are relatively flat; although some relapses certainly occur. We have not been so clear about it in Hodgkin's lymphoma.

One study that did not receive a lot of attention, but which sparked my interest, was a retrospective badysis of 2,500 patients. What they did, it's a statistical badysis of patients who achieved event-free survival at 3 years and at 5 years. It appears that for each subgroup, if they reached EFS within 3 years and within 5 years, their overall survival (OS) could be expected to be similar to that of the general population. .

The risk of re-offending in the next 5 years is quite minimal. This gives us useful information when patients with Hodgkin's lymphoma ask, "When can I feel more comfortable with my visits – that's not as likely as I'm going to to have a relapse? [tell them]. That said, some patients relapse 10 years later. there are exceptions to all these rules, but in general, you can be a little more comfortable with this information.

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

The data seemed interesting, as the eBEACOPP group did better than expected. [given that those patients had] early PET2-positive badyzes. The initial study was presented with a follow-up of 3 to 4 years. The update was on the same study, but it was tracked for almost 6 years and the data is relatively reliable. Two lessons emerged from this study. The first is that although PET2-negative patients have performed well, this PET is not as predictive as we would like to think. Or, it can tell us that despite the Deauville scores, the interpretation of a PET scan is a bit more of an art than a science. And it reminds us that we are not all artists. Our ability to interpret PET-Scan leaves us speechless. We need to do a better job at a more formal scientific interpretation of [these scans] looking at the volume of the metabolic tumor and using numbers to interpret it. It may be better because at the moment we are only doing the subjective visual evaluation of the PET scan. It may be for this reason that PET is not as good as we thought.

In the PET2-positive group, although the data seem better, a higher risk of secondary malignancies still exists. Be careful and use eBEACOPP is not the definitive solution. We need to find better ways to deal with these [patients]. May be [we should try] previous use of checkpoint inhibitors, baduming that we do not see some late toxicities. This could be a way to go.

TARGETED ONCOLOGY: Turning now to follicular lymphoma, could you discuss the R² diet?

Gordon: Some data certainly show that a chemotherapy-free approach in patients with follicular lymphoma may be equivalent to chemotherapy with rituximab plus bendamustine or CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]. People are beginning to look for ways to improve this. Loretta J. Nastoupil, MD, MD Anderson Anderson Cancer Center, presented a small study of lenalidomide, rituximab and ibrutinib in patients with follicular lymphoma and marginal zone lymphoma.

The data are early, but the overall response rate (ORR) and full response rate (CR) are quite impressive; the ORR was about 90% and the CR about 80%. This was a bit surprising since ibrutinib in follicular lymphoma was a little disappointing, according to some of the early studies we have seen. Maybe something is there, and synergy exists in a small number of patients.

Data were presented on the combination of obinutuzumab (Gazyva) and lenalidomide as initial therapy in patients with follicular lymphoma. These patients underwent 1 year maintenance treatment with lenalidomide and with obinutuzumab for one year. It was a long treatment, but it's no different from what people experience in follicular lymphoma after chemotherapy. We found very good responses and reasonable toxicity; with IMiD, questions arise about secondary malignancies. This is something we are observing and nothing seems to be a major concern yet, but it is also an important issue. [area to study].

In the context of relapse, patients have many options. John Leonard, MD, of Weill Cornell Medicine, presented the AUGMENT study. It was a randomized trial comparing R² rituximab alone, and the results have shown a marked improvement in PFS and, until now, in patients with R² versus rituximab alone. Surprisingly, no increase in secondary malignancies was observed in the R group² group; in fact, they were slightly less in this group.[R[R[R[R² badociated]toxicities, such as rashes, light reactions and neutropenia. The question in this study is, "Is rituximab alone enough?"

TARGETED ONCOLOGY: Will T cell therapy of the chimeric antigen receptor (CAR) be potentially explored?

Gordon: CAR T-cell therapy certainly plays a role in this patient population; Early data on tisagenlecleucel (Kymriah) suggest very interesting response rates in patients with follicular lymphoma. We are interested in examining CAR-T-Cell therapy in not only patients with relapse or recurrence. [heavily] follicular lymphoma in relapse, but also in those who relapsed less than 24 months after chemotherapy or after initial treatment. We must do better to manage toxicities. We need to better manage costs.

In our facility, Reem Karmali, MD, MS, has proposed that radioimmunotherapy be better than data with cost, but this is yet to come. That said, [PI3K inhibitors] are in the field and are active studies using CAR T cells in patients with an early follicular follicular with certain toxicities of concern, such as diarrhea, hepatitis and pneumonitis. The CHRONOS-1 study examined copanlisib in lymphoma. Certainly people from across the country will do that. We have a study that is considering the use of ibritumomab tiuxetan (Zevalin) with pembrolizumab in patients with relapsed follicular lymphoma.

Preclinical laboratory studies examine the effects of radiation and the combined synergistic effects of radiation and inhibitors of control points. We have reason to believe that there is a strengthening of the effects of radiation and control point inhibitors, depending on the modulation of the immune system; Myeloid-derived suppressive cells and regulatory T cells may be affected by this combination. Creating a favorable environment is an exciting area of ​​research.