Lymphoma Expert Weighs Treatment Advances in the Context of Toxicity

John M. Timmerman, MD

The field of Hodgkin and non-Hodgkin lymphoma has seen slight advances with treatment modifications, however John M. Timmerman, MD, cautioned that with these combination therapies, synergistic toxicity remains a challenge.

For example, data from the phase III ECHELON-1 trial showed a modest improvement in progression-free survival (PFS) with the addition of brentuximab vedotin (Adcetris) to standard chemotherapy in treatment-naïve patients with advanced Hodgkin lymphoma (HR, 0.77).

"This was seen at the expense of additional toxicity," said Timmerman.

Additional strategies evaluating the combination of PD-1 antibodies to standard chemotherapy, though active, have also shown a higher incidence of mortality.

In non-Hodgkin lymphoma, treatments are beginning to shift away from chemotherapy in the hope of lessening treatment-emergent adverse events.

"We're trying to get away from some of these frontline chemotherapy regimens. Other recent studies have evaluated the combination of lenalidomide (Revlimid) and rituximab (Rituxan) which is very promising. It’s a completely chemotherapy-free regimen that appears to be equivalent to rituximab plus chemotherapy," said Timmerman.

In an interview during the 2019 OncLive State of the Science Summit™ on Hematologic Malignancies, Timmerman, an associate professor of medicine, UCLA Lymphoma Program, Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, discussed the research being conducted across the spectrum of Hodgkin and non-Hodgkin lymphoma.

OncLive: Could you discuss recent developments that have been made in Hodgkin lymphoma?

Timmerman: The first is the addition of brentuximab vedotin to our traditional chemotherapy. This came from the ECHELON-1 trial which was published in the New England Journal of Medicine. The data showed that if you add that antibody-drug conjugate to standard chemotherapy you can slightly improve PFS, but with greater toxicity. Because of that, this regimen has not necessarily been widely adopted yet. We need longer follow-up to see whether that should be the case. I personally have not begun to use this regimen widely in my practice yet. I'm waiting for longer-term follow-up. Though, I might use it in selected patients.

Secondly, given the spectacular efficacy of anti-PD-1 checkpoint inhibitors in Hodgkin lymphoma, a lot of people have asked if we should be using in the frontline setting. This last month, we saw the results of a study looking at adding an anti-PD-1 antibody to chemotherapy. We saw some good responses. However, we saw a little bit of excess toxicity, and one death that was due to the combination. For that reason, we should be reserving checkpoint inhibitors for relapsed/refractory patients. Although, perhaps we can explore this in additional studies.

What were the reported toxicities?

There was a higher incidence of grade 3/4 neutropenia and a 10% incidence of febrile neutropenia which is higher than what you see with doxorubicin, vinblastine, dacarbazine (AVD), and bleomycin (ABVD). That was somewhat surprising, and there were some other abnormalities including hyperthyroidism and hypothyroidism which is rare with chemotherapy but is a known toxicity of the anti—PD-1 drugs.

Could you discuss the ongoing study evaluating the addition of brentuximab vedotin to nivolumab (Opdivo)?

There is an ongoing study looking at that. We don't have long-term results of that study yet, but it's another promising combination.

Could you shed light on additional studies that have altered your practice?

One of the important studies over the last couple years looked at reducing and stopping bleomycin after the first 2 cycles of treatment. It seems that you can stop bleomycin after the first 2 cycles of ABVD with only a slight detriment in the overall cure rate. That may be important because if you can reduce the risk of death from bleomycin, that might help improve outcomes further. So far, we’ve shown that in order to get rid of bleomycin from ABVD in the frontline setting, we can replace it with brentuximab vedotin or stop the bleomycin early. It remains to be seen in long term follow-up which approach is most advantageous.

What advances have been made in non-Hodgkin lymphoma?

In non-Hodgkin lymphoma, one of the major questions is what the optimal anti-CD20 monoclonal antibody treatment is. Obinutuzumab (Gazyva) has been compared with rituximab in combination with chemotherapy. That study was published in the New England Journal of Medicine about a year and a half ago. It showed a modest PFS advantage. We can use obinutuzumab-based therapy for the frontline treatment of patients with follicular lymphoma. Though, you're not sacrificing much if you continue to use rituximab.

People forget that there was a study published several years ago that randomized rituximab-sensitive patients to rituximab alone or obinutuzumab alone. Investigators showed that they were identical. There was no difference in outcomes despite our great efforts to find a better CD20 antibody. Obinutuzumab is slightly better in some settings, but in a head-to-head comparison, it was a wash. There is some controversy about the use of obinutuzumab/chemotherapy versus rituximab/chemotherapy due to differences in dosing, so it’s fair to say it's ok to continue using rituximab if you're comfortable with it. Though, we can certainly use obinutuzumab.

For me, there is some concern about the toxicities that were seen with the combinations in that trial. Specifically, with obinutuzumab and bendamustine.

I focus on immunotherapy, so I'm most interested in the new immunotherapeutic combinations. Some of these include bispecific antibodies. We’re seeing excellent response rate with bispecific antibodies, several reports of which were made at the 2018 ASH Annual Meeting. Also coming down the pike for refractory disease are CAR T cells. There's one registration trial ongoing with the Kite product. The trial recently wrapped up accrual for patients with follicular lymphoma. We expect to see those results about a year from now. That would give patients who have chemotherapy- and antibody-refractory follicular lymphoma another option.

How do you see the FDA approved PF-05280586 (rituximab-pvvr; Ruxience), a biosimilar for rituximab, impacting the treatment paradigm for patients with CD20-positive B-cell NHL?

The rituximab biosimilar story is interesting. It probably is a comparable agent. The one caution I have is that rituximab is a very special antibody; it's our most active antibody in the whole cancer space. It's been very difficult for people to make an antibody better than rituximab despite decades of trying. Since we don't have lots of long-term follow-up data on the biosimilar, I'm going to be a little hesitant if I have to use it. For now, I hope I can use good old rituximab. Though, the biosimilars are coming, and we may see a big cost savings for certain payers. Those payers may require that we use the biosimilar. The data that are present look like it is similar. That's probably ok, but as long as I can, I'm going to prefer to use rituximab. It has been so hard to find something that works as good or better than rituximab. It's a very special reagent we have.