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Follicular Lymphoma Case Studies

Advancements in the Treatment of Follicular Lymphoma

Jonathan Friedberg, MD
Published Online:Oct 22, 2019
Jonathan Friedberg, MD, discusses the clinical features, diagnostic work-up, treatment options, and the future advancements in follicular lymphoma.

A 59-Year-Old Man With Relapsed Follicular Lymphoma


Jonathan Friedberg, MD: The GADOLIN trial was a trial focused on patients who were refractory to rituximab, meaning they didn’t respond, or they progressed within 6 months of a rituximab-containing regimen. It randomized patients to bendamustine alone or bendamustine with obinutuzumab. A couple of important points, the dose of bendamustine alone was a higher dose than the dose of bendamustine in combination with obinutuzumab, based on FDA labeling.

The initial results of this trial suggested improved responses and improved progression-free survival with the bendamustine and obinutuzumab as compared with bendamustine alone. Longer follow-up that incorporated the maintenance phase also demonstrated an overall survival benefit to the combination of bendamustine and obinutuzumab as compared with bendamustine alone.

Many have criticized this trial for not having a rituximab-containing arm. Because even if somebody is relatively resistant to rituximab, it could still mean that the rituximab allows some sensitization to chemotherapy like bendamustine. But that said, I think many of us have really adapted obinutuzumab as a preferred antibody to be used in the second line and greater in follicular lymphoma, particularly if rituximab is used up front.

As said before, I think in this particular patient I would be favoring an autologous stem cell transplant as consolidation after obinutuzumab and bendamustine. Other options, if a patient declined that or wasn’t appropriate for that, would be to consider obinutuzumab maintenance. That was incorporated in the GALLIUM trial. There are other treatment options as well. I think we should mention lenalidomide.

A recent randomized trial demonstrated that the combination of lenalidomide and rituximab was better than rituximab alone. That was not targeting the early progressing patient population, but there were some patients included in that who had early disease progression, although they were still considered sensitive to rituximab. The combination of lenalidomide and rituximab is quite active. The combination of lenalidomide and obinutuzumab has also been studied. I don’t think we know to what degree lenalidomide compares with, say, bendamustine in the relapsed setting. And our randomized trial in the Intergroup is going to help answer that question. But until we have those data, I think another reasonable treatment approach for a patient like this may be lenalidomide and obinutuzumab.

I think that we’ve seen the incorporation of several new agents into the armamentarium for the treatment of follicular lymphoma over the last several years. Certainly, the class of drugs of PI3-kinase inhibitors are quite active in follicular lymphoma. They’re relatively toxic drugs, particularly when given over a prolonged period of time, so we’re still refining our understanding of how best to use them. But they’re important drugs that we have for follicular lymphoma.

As mentioned, the new antibody obinutuzumab and the drug lenalidomide clearly have important roles in the management of follicular lymphoma. We have older drugs, too, that are quite active for some of these patients, including radioimmunotherapy and bendamustine, of course, as was mentioned throughout this case presentation. Looking forward there are a lot of even more exciting things coming down the line for follicular lymphoma. Early results suggest that CAR-T cells are extremely effective in patients with follicular lymphoma. As we understand better how to manage toxicity for CAR-T cells, we may be able to choose a certain group of patients where that’s appropriate therapy, and we have some optimism that it could even be curative therapy for follicular lymphoma.

And then there are some new specific inhibitors that may target subsets of patients with follicular lymphoma like the EZH2 inhibitors. A subset of patients have mutated EZH2, and they seem to be particularly responsive to these drugs. There are randomized trials that are focused on that patient population. And should those trials be positive, that may suggest we’re heading toward a precision medicine approach. That’s where I’d really like to see follicular lymphoma go. Five years may be a little too soon, but maybe in 10 years. I think we can be optimistic that incorporating molecular and genomic data that we have from all these ongoing studies, we may be able to better assign up-front therapy to patients to minimize treatment in the large group of patients who are going to do well with follicular lymphoma and escalate or change treatment for the smaller group of patients who are going to do less well.

I think we should celebrate the progress that we’ve made in follicular lymphoma. Median overall survival has improved from 6 to 10 years when I started training, which wasn’t that long ago, to now well over 20 years even for patients with advanced-stage presentations. And we even know that with standard chemoimmunotherapy with 10 years of follow-up, up to 40% of patients will still remain progression-free, which really raises the question about whether we may be curing a subset of patients with follicular lymphoma today with our current treatments. I think all that is just tremendous progress, so we shouldn’t lose sight of that—most patients with follicular lymphoma are probably going to die with follicular lymphoma rather than of follicular lymphoma. So we’ve highlighted today some of the challenges in follicular lymphoma and a typical case that really needs to be treated differently and does need new therapeutics. But we should also celebrate the fact that with the progress that we’ve made, most patients will not be in that situation.

Transcript edited for clarity.

Case: A 59-Year-Old Man With Symptomatic Follicular Lymphoma

A 59-year-old man presented to his physician with a 10-lb weight loss and chronic night sweats for the past couple of months. He complained of intermittent fatigue but is able to maintain his current exercise regimen.

H & P

  • PE: enlarged bilateral axillary lymph nodes; enlarged spleen, palpable
  • CBC: WBC, 12 X 104 /L; platelets,103 X 109 /L; Hgb, 9.2 g/dL
  • LDH: 400 U/L

Biopsy

  • Excisional biopsy showed grade 2 follicular lymphoma; CD20+, CD10+
  • Bone marrow biopsy; 60% involved

Imaging

  • PET/CT showed widespread lymphadenopathy and a large splenic mass measuring 10 cm
  • Diagnosis: Stage IV follicular lymphoma

Teatment

  • Started on R-CHOP; tolerated induction well
  • Post-therapy PET showed partial remission
  • Followed by Rituximab maintenance until evidence of disease progression

Follow-up

  • Core needle biopsy; performed confirmed persistent follicular lymphoma; no transformation
  • PET at 12 months showed increased size of splenic mass
  • ECOG, 0
  • Patient started on obinutuzumab + bendamustine
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