Research Abounds Across Lymphomas, But More Work Remains

Jing-Zhou Hou, MD, PhD

The emergence of novel therapeutics has led to impressive survival gains in both patients with Hodgkin lymphoma and non-Hodgkin lymphoma (NHL), said Jing-Zhou Hou, MD, PhD, but more work is needed to further progress along.

“We have made important advances [in this space] but clearly there is a great need and we still have a lot of room to improve,” said Hou, co-chair of the Hematological Malignancies program, and medical oncologist, hematologist, and clinical instructor at University of Pittsburgh Medical Center Hillman Cancer Center. “This is particularly true for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, which are the 2 most common types of non-Hodgkin lymphoma.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Hou highlighted the research being conducted in the realm of lymphoma, including positive and negative trials that have read out in the space, and provided insight into novel approaches under investigation.

OncLive: What key updates that have been shared in the realm of Hodgkin lymphoma?

Hou: There has been a great deal of progress made in the frontline setting for advanced-stage Hodgkin lymphoma. There was a new trial published last year [on the use of] brentuximab vedotin (Adcetris) in combination with AVD [doxorubicin, vinblastine, and dacarbazine] compared with the traditional therapy of ABVD [doxorubicin, bleomycin, vinblastine and dacarbazine] in advanced-stage Hodgkin lymphoma. That trial really showed that progression-free survival (PFS) with brentuximab vedotin and AVD was superior to ABVD. However, overall survival (OS) at 3 or 4 years of follow-up did not show a significant difference. Time will tell.

In the relapsed setting of Hodgkin lymphoma, there was a big study that was just published in December 2018. This study looked at the use of brentuximab vedotin as consolidation therapy for patients who failed or relapsed on standard therapy and underwent bone marrow transplant. Traditionally, we know that the patient probably still has a 50% chance of relapse after autologous stem cell transplant (ASCT). Therefore, one of the areas under clinical investigation is dedicated to determining how we can improve the long-term survival and PFS in patients with Hodgkin lymphoma after bone marrow transplant.

In the third-line [setting, there is] immunotherapy with PD-1 blockade. [Two agents have been] approved by the FDA: one is nivolumab (Opdivo) and the other is pembrolizumab (Keytruda). Both agents show significant activity in patients who have relapsed after ASCT or second-line therapy. They have similar efficacy and toxicity profiles. The complete response (CR) as monotherapy for both agents [ranges from] 20% to 25%; the overall response rate (ORR) is about 70% with about a 50% partial response rate.

The third study also shows that by combining brentuximab vedotin with nivolumab, the CR rate, as well as duration of response and PFS, were further improved. Additionally, the toxicity profile [of the combination] is manageable.

Right now, there is a clinical trial ongoing for an anti-CD30 CAR T-cell product. There are several [trial] sites [available to patients with Hodgkin lymphoma] who are interested in the use of CAR T-cell therapy.

Has any headway been made in NHL in recent years?

Over the last 20 years or so, several phase III trials have been completed [in an effort to] improve outcomes of [patients with] DLBCL. Several agents have been tested, and, unfortunately, [to date], nothing beats R-CHOP.

One trial evaluated R-CHOP in combination with ibrutinib (Imbruvica) in activated B-cell (ABC) DLBCL; this was a big trial published early this year. However, the trial was initially presented at a prior ASH Annual Meeting. Unfortunately, this trial did not show any PFS or OS benefit when ibrutinib [was added] to R-CHOP, even in ABC DLBCL. Another trial was also a little disappointing; it hasn’t been published yet, but the abstract was presented at the 2018 ASCO Annual Meeting.

In February 2019, Celgene announced the phase III trial of lenalidomide combined with R-CHOP. Unfortunately, this trial did not meet the primary [endpoint] and did not show a PFS or OS [benefit]. The final data have not been published yet; this was just presented by Celgene in a press release or financial report. This news is quite disappointing because these 2 agents showed promising [results in DLBCL in] phase II trials. Therefore, we need to look for more agents.

There has also been a trial comparing dose-adjusted EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] with R-CHOP. Unfortunately, this trial showed that there was no difference in OS. There was no significant difference in PFS either, for all groups.

However, a subgroup analysis showed some benefit for those with high-risk features, such as a high International Prognostic Index score or maybe those with [double expressor status]. [It’s important to note that with] the dose-adjusted EPOCH-R, the toxicity is clearly much higher than [what has been seen with] R-CHOP. I don’t feel that patients should receive dose-adjusted EPOCH-R upfront; as such, R-CHOP remains the standard.

In addition to these 3 trials, other trials published about 1 or 2 years ago added other agents such as bortezomib (Velcade) to R-CHOP, and unfortunately, the phase III trial did not show a difference in the long-term OS. It did show a PFS benefit, but there were also toxicities.

A new drug called polatuzumab vedotin (Polivy) was approved for [use in patients with] relapsed/refractory DLBCL, based on [data from] small, randomized phase II trials that compared polatuzumab vedotin plus bendamustine (BR) compared with BR alone. Each arm had 40 patients, and compared with BR alone, polatuzumab vedotin plus BR seemed to be superior in terms of ORR and CR. PFS and OS was more than doubled compared with BR. Therefore, [this agent received accelerated] approval from the FDA for use in patients with relapsed/refractory DLBCL.

Polatuzumab vedotin seems very promising, and phase III trials [exploring its use in] the frontline setting have just been completed. Hopefully, in a couple of years we’ll have some preliminary reports which [will provide us with insight into whether this agent can] improve outcomes in patients in the frontline setting.

Could you expand on the clinical implications of the recent approval of the polatuzumab vedotin combination in DLBCL?

This is a very important drug for DLBCL. We have upfront therapy with R-CHOP, and we can offer the CAR T-cell therapy. However, even with CAR T-cell therapy, you only see a 40% CR rate. The majority of patients, or half of patients, don’t respond to or relapse after CAR T-cell therapy. For these patients, we have very little options available.

Therefore, this drug, polatuzumab vedotin, in combination with BR and rituximab, shows very promising data; it also shows improvement in OS. This drug is relatively easy to give and comes with toxicities such as neuropathy; however, in general, it is very well tolerated when used in combination with BR and rituximab.

What are the latest developments with CAR T-cell therapy in DLBCL?

In the relapsed setting, there is also an update on CAR T-cell therapy for DLBCL. Updated data from the ZUMA trials with axicabtagene ciloleucel (axi-cel; Yescarta) were just released earlier this year. At 24 months of long-term follow-up, the CR [rate continues to look] pretty good. The CR rate is 40% with an ORR of over 50%. The OS is also improved [with this product], so it’s very promising. This CAR T-cell product was approved by the FDA [for use in patients with DLBCL] about 1.5 years ago. Clearly, we’ll [be looking into using] more CAR T-cell products for these transplant-ineligible patients.

Data from the JULIET trial [which evaluated tisagenlecleucel (Kymriah)] were also published. Updated data showed a very similar response rate at 12-months follow-up; [specifically], it showed a 40% CR rate and the duration of response [proved to be] pretty durable for the patients who had a complete response.

The third trial, TRANSCEND-NHL-001 trial, is evaluating lisocabtagene maraleucel (JCAR017; liso-cel). The abstract for this trial was presented a few years ago but [there has not been] a new update on this trial. They just completed accrual for a phase II trial, so we are waiting for more data with this very exciting agent.

What key agents have impacted mantle cell lymphoma treatment?

In relapsed/refractory MCL, there are several data [on new agents] that have been published. Number one is ibrutinib, which was approved a few years ago; the other agent is a second-generation BTK inhibitor called acalabrutinib (Calquence) and it was approved by the FDA based on phase II data.

In both trials, the agent showed significant activity. No head-to-head comparison [has been made with ibrutinib and acalabrutinib] but it seems that acalabrutinib may have a better response rate based on these non-comparative phase II trials. In terms of overall response and toxicity, it seems that both agents are pretty active. They come with toxicities, including increased risk of bleeding and atrial fibrillation. Acalabrutinib has not been reported to have a significant increase in atrial fibrillation. However, there seems to be a slight increase of cardiac risk [with ibrutinib].

Another promising agent in MCL treatment is venetoclax (Venclexta), which also showed very encouraging data; however, it has not been approved yet and further data are needed.

In addition to the single agents, the combination of lenalidomide plus rituximab is also being studied. One is being done in the frontline setting for patients who are now transplant candidates. At 4 to 5 years of follow-up in the small studies, responses appear to be very durable.

What is some of the research being done in follicular lymphoma?

In terms of follicular lymphoma, it has been a little bit disappointing; we have not made a big impact or much progress [in this space]. However, there are several agents in clinical investigation, such as CAR T-cell therapy, and we’re waiting for the report of the phase II trials. There’s a biological agent [that we’re hoping] will be active for follicular lymphoma—CD22-targeted antibody-drug conjugate (ADC). The [agent was already evaluated in a phase I trial and is in a phase II trial]; it appears to be a very promising drug.

In addition to anti-CD22 ADCs, polatuzumab vedotin has also been shown to be very active in follicular lymphoma. The larger trial [with this agent] in [this space is] ongoing. Beyond this agent, there are PI3K inhibitors.