Treatment Approach in Follicular Lymphoma

Jonathan Friedberg, MD:When I meet a patient with follicular lymphoma, I incorporate patient wishes as well as tumor features when I’m trying to make a decision on a management approach. And there are at least 3 different major management approaches you can choose. Often, we think about observation or no initial treatment for a period of time for certain patients. We might think about single-agent rituximab as the therapeutic intervention. And then we think about chemoimmunotherapy.

For this particular patient, I think most people would agree that chemoimmunotherapy is indicated. This patient is relatively young, so 1 of the things you’re going to want to try to achieve is a prolonged disease-free interval.

The other advantage of chemoimmunotherapy is that the responses tend to be fast. And in this patient who’s beginning to get symptomatic, he’s having some night sweats, his mass is relatively large, and you want a rapid response.

I think that the chemoimmunotherapy is a pretty clear decision. Perhaps the harder decision is what the appropriate chemoimmunotherapy is, and there are a few choices. You can choose a bendamustine-based regimen or a CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]—based regimen. There are advantages and disadvantages to each of these.

There have been randomized trials that have suggested prolonged progression-free survival with a bendamustine-based regimen. Although there’s some controversy in how really the difference is between bendamustine and CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]. Certainly, bendamustine is not inferior. Bendamustine also may have a slightly more favorable adverse-effect profile in that it does not cause alopecia, and you don’t have to worry about cardiac toxicity.

However, the advantage of CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], particularly for a patient like this, is that it does cover the possibility of transformed components. And I mentioned earlier in this patient that I was a little worried that there could be transformation here. The LDH [lactate dehydrogenase] was up, the patient was getting B symptoms. It was behaving a little more aggressively than you might expect for follicular lymphoma. The other advantage with CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] is that I do believe that the responses happen a little earlier.

The final question, if you’re thinking of chemoimmunotherapy, is what is the right antibody to use? There was a randomized trial that compared rituximab-based treatment with obinutuzumab-based treatment and suggested a modest benefit in progression-free survival with the use of obinutuzumab up front as compared with rituximab. However, obinutuzumab is also a bit more toxic. There were more infusion-related adverse events seen with obinutuzumab, and that trial did incorporate maintenance for all patients, which may not be preferred by all providers.

I think the choice of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin, hydrochloride, vincristine, prednisone] in this patient was very reasonable. It did cover the possibility of transformation, and I think the decision was made that the modest benefit of obinutuzumab seen in the randomized trial was perhaps not necessary, and clearly there’s no evidence of an overall survival benefit to using obinutuzumab versus rituximab up front.

I’ll just close by talking about more indolent presentations of follicular lymphoma. And in those settings my general thought is to consider an observation period. I think there is not really even controversy. There’s never really been a demonstration that early intervention in follicular lymphoma affects overall survival. And for an asymptomatic patient I think it’s still very reasonable to watch that patient for a period of time.

If you end up watching a patient for a few years if the disease is progressing slowly, single-agent rituximab can be a very effective treatment. That can also be a treatment for low tumor burden disease where you don’t want to observe or the patient wants treatment quickly. And it’s also a good option for patients who have a lot of comorbidities, like older patients.

Single-agent rituximab has a very low CR [complete remission] rate, but it has a very reasonable PR [partial response] rate. Most patients will respond. The duration of single-agent rituximab is probably on the order of 1 to 2 years, but you can always retreat. The RESORT trial taught us that the retreatment was as effective as continuous treatment with single-agent rituximab. So there are several good options to treat the patient.

In this case R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin, hydrochloride, vincristine, prednisone] was a very reasonable choice for this particular patient. Then the patient went on to get rituximab maintenance. I think there’s a controversy still to the use of maintenance treatment in follicular lymphoma. We know that long follow-up maintenance continues to provide a progression-free survival benefit. Usually maintenance is given for 2 years of duration after the end of treatment. However, we also know with prolonged follow-up, there is no impact on overall survival.

There was also a signal from the randomized trial with obinutuzumab that maintenance after bendamustine may confer some higher risk of deaths, including infection-related deaths. Maintenance after bendamustine has not been well studied until that particular time. Taken together, I generally don’t recommend maintenance for most patients. In this particular patient who achieved only a PR after R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], I might think about doing something more aggressive. But in any case, maintenance was chosen.

Subsequently, the patient progressed within about a year of starting the maintenance treatment. And this is 1 of the most important points of today to emphasize, that these patients who progress early after initial chemoimmunotherapy have a particularly poor outcome. When you see a patient with relapsed follicular lymphoma you can say they’re going to do very well. In fact, the median overall survival of a patient with advanced-stage follicular lymphoma exceeds well over 20 years.

However, once a patient has an early relapse event, as defined within the first 2 years after either diagnosis or completing chemoimmunotherapy, those patients have a markedly inferior overall survival with a median overall survival of only about 5 years. So they really need to be treated very differently. And you can’t treat these patients like any other garden variety, early, or standard relapse of follicular lymphoma. It’s these early progressions of events that really confer high risk.

When I meet a patient with early progression of follicular lymphoma, I have to first decide whether the patient can tolerate aggressive treatment. This patient can, they’re only 59 years old. And then decide what the appropriate treatment is.

The short answer is we don’t know the appropriate treatment. And in fact, the North American Intergroup Study, including ECOG, SWOG, and Alliance for Clinical Trials in Oncology, have a clinical trial now targeting this group of patients with early disease progression. And just to give you a sense as to the equipoise that we have in managing these patients, this is a clinical trial that randomizes patients to either chemoimmunotherapy — so if they were treated initially with CHOP [cyclophosphamide, hydroxydaunorubicin, hydrochloride, vincristine, prednisone], they would get bendamustine. If they were treated initially with bendamustine they would get CHOP cyclophosphamide, hydroxydaunorubicin, hydrochloride, vincristine, prednisone], with obinutuzumab as the antibody. The second arm has lenalidomide and obinutuzumab. And the third arm has umbralisib and obinutuzumab. Umbralisib is a PI3-kinase inhibitor.

It’s really a sense that we don’t even know whether chemotherapy or targeted agents are the appropriate treatment for these patients. The primary endpoint of this study is CR rate at 6 months, just to get an early signal and their extensive correlates built in. And I would really encourage everybody to try to participate in these studies, because this is not a very common event, and it’s really the only way we’re going to understand the complex biology and the right treatment for these patients.

I’ll emphasize that in this trial obinutuzumab is the antibody that’s used across all 3 arms. That really speaks to the fact that the Intergroup feels that this is the right choice for patients who have had early disease progression on rituximab.

That’s largely based on a randomized trial that took patients who had rituximab-refractory disease and randomized them to bendamustine alone or bendamustine with obinutuzumab. And the combination of bendamustine and obinutuzumab not only showed progression-free survival benefit, but an overall survival benefit, as well. In that trial obinutuzumab was given as maintenance treatment after the bendamustine with obinutuzumab.

The other point to make about management of early progressing follicular lymphoma is that there is a role for high-dose therapy and autologous stem cell transplantation in select patients. This patient may be a good candidate for that. Although there’s no randomized trial, there are several studies that suggest that for patients who have early progression of follicular lymphoma, there may be some benefit to consolidating a response to second-line therapy with high-dose therapy and autologous stem cell transplantation.

There are also trials ongoing looking at CAR [cancer antigen receptor]—T cell interventions in this patient population. So, I think for practicing oncologists it’s important to know that these patients ought to potentially be seen in a transplant or specialty center, and at least consider some of these more aggressive options given their poor overall survival with conventional treatment.

In this particular case, the choice was made to treat the patient with bendamustine and obinutuzumab. I think that’s a very reasonable choice as long as you’re sure that there’s evidence of transformed elements. I always recommend a repeat biopsy, as was done in this case, to make sure there isn’t transformation. I think the question is whether to potentially consolidate a response to the bendamustine with obinutuzumab with high-dose therapy and autologous stem cell transplant. And I would certainly have such a conversation with this patient.

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