Maintenance Therapy Remains Challenging Strategy in DLBCL

Pieternella J. Lugtenburg, MD, PhD

Maintenance therapy with rituximab (Rituxan) did not lead to an improvement in disease-free survival (DFS) among patients who achieved complete remission (CR) following 4 cycles of R-CHOP. Finding a means to improve outcomes for patients with diffuse large B‐cell lymphoma (DLBCL) continues to pose a challenge, said Pieternella J. Lugtenburg, MD, PhD.

In a study presented at the 2019 International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, a subgroup of patients who achieved CR were randomized to receive either 24 months of rituximab maintenance 375 mg/m² administered intravenously every 8 weeks (n = 199) or to undergo observation (n = 199).

At median follow up of 79.9 months, the 5‐year DFS rate was 79% with rituximab maintenance versus 74% with observation (HR, 0.83; 95% CI, 0.57‐1.19, P = 0.31), showing no statistically significant benefit with rituximab. The secondary endpoints, overall survival and adverse events, were also not between the 2 groups.

The number of available therapy options for patients with DLBCL may be expanding with the recent FDA approval of polatuzumab vedotin (Polivy) for use in combination with bendamustine and rituximab for the treatment of patients with relapsed/refractory DLBCL who have received ≥2 prior therapies, but options for patients who achieve CR remain limited.

In an interview with OncLive during the 2019 ICML, Lugtenburg, an internist and hematologist at Erasmus MC, shed further light on the study evaluating rituximab maintenance therapy in patients with DLBCL in first remission and highlighted challenges in the treatment of extending survival for this population.

OncLive: Could you discuss the rationale for the phase III trial evaluating rituximab as maintenance therapy?

Lugtenburg: The prognosis of patients with DLBCL has certainly improved when rituximab was added to CHOP, the standard chemotherapy; however, 40% of the patients still relapse or have refractory disease. When we started our phase III study in 2007, no new drugs were available. We decided to investigate the use of rituximab because at that time, the dose, and the right regimen or schedule of the agent were not known. As such, we investigated whether intensification during the first 4 cycles of the R-CHOP chemotherapy would improve their prognosis and we presented that data 3 years ago at the annual ASCO meeting. That was a negative study; [the regimen] did not improve the progression-free survival.

There was a second randomization in this trial for those [patients who] achieved complete remission after R-CHOP. They were eligible for either rituximab maintenance therapy for 2 years or observation and it is the results of this part of the trial that I have presented.

Could you expand on the efficacy data for the second randomization in this trial?

The primary endpoint of the study was disease-free survival, and this was also a negative trial. We could not improve disease-free survival for patients in first complete remission after R-CHOP by giving them rituximab maintenance therapy. We also could not identify a subgroup of patients that actually benefitted [from the regimen].

What does the toxicity profile look like for this regimen?

The toxicity of the rituximab maintenance therapy was mild, and [the regimen] is well-tolerated. About half of the patients [experienced] adverse events and one-quarter of them were grade 3 or 4 events. However, I think the main toxicity was infection, but only 6% of the patients had a grade 3 infection necessitating the use of intravenous antibiotic use. We saw grade 3 or grade 4 neutropenia in 4% of the patients.

What are the next steps for research with R-CHOP in these patients?

R-CHOP is still the standard therapy and several trials have failed to improve the prognosis [for these patients]. For instance, there were 3 big trials in the ABC [activated B-cell] subtype of [DLBCL] adding, for instance, bortezomib (Velcade), ibrutinib (Imbruvica), or lenalidomide (Revlimid) to R-CHOP and these were all negative trials. Therefore, we [know that we] should do something different, but this is not easy.

In the Netherlands, we do have the HOVON (the Haemato Oncology Foundation for Adults in the Netherlands) cooperative research group and we now have 2 trials running. First, a trial in the double-hit lymphomas because [these patients] have a really poor prognosis. In these patients we try to improve that prognosis by giving a consolidation treatment and an immune checkpoint inhibitor. We also have a trial running for the patients with [DLBCL who have] a high-risk IPI (International Prognostic Index) score. Also, in the patients who have a response we will try to improve their prognosis with consolidation therapy and other immune checkpoint inhibitors.

How would you describe the current DLBCL treatment paradigm?

We have been discussing the first-line therapy of patients with DLBCL, if we talk about second-line or even further-line therapies then I believe that for the patients who relapse and are eligible for autologous stem cell transplant (ASCT), that is is still the way to go. In first relapse, they will get solvent-based therapy and then ASCT; however, they do not respond well. Only 25% of these patients survive.

Now we have trials with investigational agents, such as CAR T-cell therapies, that are challenging ASCT for patients who are not eligible. For [those patients who are eligible for] ASCT, there are several things you can do, but none of these therapies will be curative. One [future potential] option [will be] to treat them with the bendamustine and polatuzumab [vedotin], once it is registered in their country.

Lugtenburg P, de Nully Brown P, van der Holt B, et al. Rituximab maintenance for patients with diffuse large B‐cell lymphoma in first complete remission: results from a randomized HOVON‐Nordic Lymphoma Group phase III study. Hem Oncol. 2019;35(S2):176-177. doi.org/10.1002/hon.49_2629.