Novel Agents Strengthen Treatment Armamentarium in Non-Hodgkin Lymphoma

Parameswaran Venugopal, MD

In recent years, the field of non-Hodgkin lymphoma (NHL) has gained several novel agents that have shown significant activity when used alone and in combination, explained Parameswaran Venugopal, MD, a professor in the Department of Internal Medicine at Rush Medical College.

“We are living in a very exciting time. We have new tools available and a much better understanding of these diseases, particularly the lymphoid disorders, whereby we are able to provide patients with a beneficial treatment with a much more favorable safety profile,” said Venugopal.

In May 2019, the FDA approved the combination of lenalidomide (Revlimid) and rituximab (Rituxan; R²) in patients with previously treated follicular lymphoma. The approval was based on findings from the phase III AUGMENT trial wherein the combination led to a 39.4-month median progression-free survival (PFS) versus 14.1 months with rituximab alone (HR, 0.46; 95% CI, 0.34-0.62; P <.001).¹

Results of a subgroup analysis from AUGMENT that was presented at the 2019 ASH Annual Meeting showed that R² led to a 34% reduction in the risk of disease progression or death versus rituximab plus placebo in patients ≥70 years old with indolent non-Hodgkin lymphoma, although it was not found to be statistically significant.²

Monoclonal antibodies, such as rituximab, are also the subject of investigation in the relapsed, indolent setting in combination with PI3K inhibitors in the phase III CHRONOS-3 (NCT02367040) and CHRONOS-4 trials (NCT02626455).

In diffuse large B-cell lymphoma (DLBCL), the FDA granted an accelerated approval to polatuzumab vedotin (Polivy) in June 2019 for use in combination with bendamustine and rituximab (BR) in patients with relapsed/refractory disease who received ≥2 prior therapies. The approval was based on data from the phase Ib/II GO29365 trial, in which the combination led to a 40% complete response rate versus 18% with BR alone.³ The agent is now being investigated in the phase III POLARIX trial (NCT03274492), which is randomizing treatment-naïve patients to receive either the combination of polatuzumab vedotin and R-CHP or R-CHOP alone.

Due to the rarity of the disease, progress in peripheral T-cell lymphoma (PTCL) has trailed behind. However, the November 2018 approval of brentuximab vedotin (Adcetris) for use in combination with chemotherapy in previously untreated patients with CD30-expressing PTCL established a new standard of care. Data from the trial demonstrated a 34% reduction in the risk of death versus CHOP alone (HR, 0.66; 95% CI, 0.46-0.95; P = .024),⁴ which, with longer follow-up, could reduce the need for transplant.

Finally, in mantle cell lymphoma (MCL), ibrutinib (Imbruvica), which is a staple of treatment in the relapsed setting, is also under investigation in combination with BCL-2 inhibitors, such as venetoclax (Venclexta).

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Venugopal, who also serves as The Elodia Kehm Chair of Hematology, and director of the Section of Hematology at Rush University Medical Center, discussed current and emerging treatment strategies in NHL.

OncLive: Could you discuss some of the advances we’ve seen in follicular lymphoma?

Venugopal: In the past 2 years, we have seen significant advances in follicular lymphoma. What’s particularly interesting is the fact that for the first time, we have non-chemotherapy options. For example, the combination of lenalidomide and rituximab was FDA approved earlier this year. With this approval, we have an option for patients in whom chemotherapy is contraindicated or not desirable.

What are some of the challenges faced in the treatment of this disease?

We don't have [regimens with which cure is possible] for patients with follicular lymphoma. All of the exciting combinations we have increase PFS. The data we have with R² indicate a PFS advantage, but not an overall survival (OS) advantage. We need to discover the combination that will lead to the most durable remissions, potentially via minimal residual disease (MRD) negativity, and ultimately cure.

Hopefully, some of the combinations that are being tested now—those examining monoclonal antibodies, PI3K inhibitors, etc.—[will do that]. Moreover, we have BTK inhibitors and BCL-2 inhibitors like ibrutinib (Imbruvica) and venetoclax (Venclexta) which, by themselves, don’t seem to be very active; however, when they’re used in combination, they seem to be very promising. That's what I'm looking forward to in follicular lymphoma.

We don't have CAR T-cell therapy data in low-grade follicular lymphoma [yet], but I'm hoping to see some in the near future. There are already plans for evaluating [CD19- and CD22-directed] CAR T-cell therapy in this space.

How is MRD being used in follicular lymphoma?

We’re looking at MRD within the context of maintenance therapy. Maintenance therapy is the best way to prolong remission; there's no question about that. Typically, we define remission by complete remission or partial remission. However, if you're able to document MRD negativity, and maintain that, those patients have the highest likelihood of long-term remission.

Could you highlight some of the recent advances in DLBCL?

In the third-line setting, we still need a breakthrough. Many agents are being combined with standard R-CHOP; some have shown preliminary promise. We need to understand which patients with DLBCL are the most likely to respond, perhaps by way of molecular factors.

In the relapsed setting, the most important advance is the development of the antibody-drug conjugate polatuzumab vedotin. [We have seen a] significant change in the way that we are treating these patients. Now, [we can use polatuzumab vedotin] as a bridge to a more definitive procedure, like transplant or CAR T-cell therapy. The agent could also be used for patients in whom more intensive treatments are not an option. I am really looking for data to see how polatuzumab vedotin will make a difference in the frontline setting. The large phase III POLARIX trial is comparing R-CHOP with R-CHOP minus vincristine plus polatuzumab vedotin; I’m hoping those results will lead to a practice-changing treatment as it recently did in classical Hodgkin lymphoma.

Could you discuss the mechanism of action and tolerability of vedotin?

Vedotin is a spindle toxin, so it does cause neuropathy. Some of the newer data with brentuximab vedotin (Adcetris) from the ECHELON-2 trial is a classic example [of these agents’ acceptable toxicity profile]. In the trial, investigators compared CHP and brentuximab vedotin with CHOP without vincristine. The grade ≥3 adverse events were essentially the same in both arms. I don't believe that vedotin [will cause] peripheral neuropathy [in all patients]. In the up-front setting, it seems to be better [tolerated], even in [those with] Hodgkin lymphoma. The toxicity is mostly seen in patients who had previous neuropathy that was not recognized that gets exacerbated with the use of vedotin.

What updates are we seeing in T-cell lymphoma?

T-cell lymphomas are a very difficult group of diseases to treat. Finally, we have some indication that we may be making a breakthrough. This is the first time we are seeing an OS advantage with the combination of brentuximab vedotin in the frontline treatment of diseases like PTCL where there has been no real breakthrough since the diagnosis of the histology.

What are some of the reasons behind this lack of progress?

I would attribute the lack of progress to several reasons, one being the fact that it’s a less common disease; it would be very difficult to do a big randomized study. Secondly, T-cell lymphomas, unlike B-cell lymphomas, lack targeted antigens. However, that may also be due to the fact that more research has been done with B-cell lymphoma.

What kind of clinical trials are you keeping your eye on in this space?

I’m excited for long-term data from the ECHELON-2 trial. I want to see whether these patients need a transplant or not. Right now, the standard in T-cell lymphoma is CHOP followed by transplant. However, if the patient is receiving brentuximab vedotin in the frontline setting with CHOP or CHP, do they need transplant? We don't know the answer to that question. Investigators have looked at that, but they weren’t able to conclude anything. Therefore, at this time, we proceed with transplant.

Could you speak to recent developments in MCL?

The most exciting thing is MCL is that we now have options for patients who relapse. In the past, once patients relapsed after chemoimmunotherapy and transplant, there were not many good options that we could offer. Now, we’re seeing data with the combination of venetoclax and ibrutinib, which is exciting. The initial results are exciting, and my personal experience [with the combination] has been very good.

Could you elaborate on your experience with the combination of venetoclax and ibrutinib?

I have 2 patients who are receiving the combination. One of them is a 50-year-old man, who is otherwise very healthy, and has gone through every single treatment you can think of, including stem cell transplant. We even tried to get him to CAR T-cell therapy, but he had central nervous involvement, so he wasn’t eligible. He's been on the combination for about 9 months without evidence of disease, which is very impressive. I just started the other patient on the combination recently.

References

1. Leonard JP, Trn&#283;ný M, Izutsu K, et al. AUGMENT: a phase III randomized study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi: 10.1200/JCO.19.00010.
2. Trn&#283;ny M, Leonard JP, Zhang H, et al. Subgroup analyses of elderly patients aged ≥ 70 years in AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R²) vs rituximab plus placebo (r-placebo) in patients with relapsed/refractory (r/r) indolent non-Hodgkin lymphoma (iNHL). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 347. bit.ly/353kfmQ.
3. Sehn LH, Herrera AF, Matasar MJ, et al. Polatuzumab vedotin (pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (ph) Ib/II study. Blood. 2018;132(suppl 1):1683. doi: 10.1182/blood-2018-99-118551.
4. Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomized phase 3 trial. Lancet. 2018;393(10168):229-240. doi: doi.org/10.1016/S0140-6736(18)32984-2.