Initial Considerations in Frontline Therapy for FL

Jeff P. Sharman, MD: When I’m looking at a patient for frontline therapy, my initial considerations are going to be whether they have low or high tumor burden [TMB]. This is most easily considered by way of the GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria. And the GELF criteria talk about having lymph nodes in excess of 7 cm, or greater than 3 lymph nodes in excess of 3 cm. It talks about cytopenias, perhaps circulating components of the follicular lymphoma, or fluid accumulation such as pleural effusion or ascites.

For a patient with low tumor burden, it remains very reasonable to consider watchful waiting and not treating that patient at all. On the other hand, some patients might feel uncomfortable with watchful waiting, and rituximab monotherapy in the setting of low tumor burden would be a reasonable consideration as well.

This patient, however, has high tumor burden. Meaning he has cytopenias. There are lymph nodes in excess of 3 cm, and multiple of them. So this is a patient for whom either upfront therapy or therapies after relatively shorter time of observation would be reasonable to consider.

Now, when we’re talking about doing treatment in the frontline setting for somebody with high tumor burden, it’s helpful to think about their FLIPI [Follicular Lymphoma International Prognostic Index] status going into it. FLIPI doesn’t predict necessarily for an individual what their outcome is going to be, but when you look across a population of patients, it provides general characteristics for who’s going to be higher risk than not.

With high tumor burden disease, we don’t necessarily stratify treatments by their FLIPI score, but it might help us anticipate what their outcomes to treatment might be.

When I’m thinking about treating these patients, in general I’m thinking about a chemoimmunotherapy approach, and the backbone could be tailored to some degree based upon individual patient performance status, fitness, and so forth. And of the chemoimmunotherapy regimens that are utilized, you could use CVP [cyclophosphamide, vincristine, prednisone], you could use CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], but most commonly in the United States is bendamustine.

And then the question becomes, which of the CD20 antibodies to use. Historically rituximab has provided the backbone of therapy for chemoimmunotherapy, representing the immune component, but more recently with data from the GALLIUM study utilizing obinutuzumab, there have been some improved outcomes for those patients utilizing obinutuzumab. So the field is sort of in transition right now as to whether to use rituximab or obinutuzumab.

With frontline therapy, the goal of course is to get prolonged disease control—that’s what we want to obtain. And the duration of disease control is important because those patients with early relapse have less favorable outcomes. So the chemoimmunotherapy regimens that are largely available are CVP [cyclophosphamide, vincristine, prednisone], CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], and bendamustine, and then we can add in a CD20 antibody, either rituximab or obinutuzumab.

There have been data fairly recently presented using a non-chemoimmunotherapy regimen with lenalidomide/rituximab. That particular study I consider to be the most positive negative study out there, which is to say that the study was designed to show superiority of the non-chemotherapy regimen when in fact it really showed equivalence. It was not a study designed for noninferiority, and so it did not meet its endpoint, and it will not likely have FDA approval in frontline setting. But it is listed as an NCCN [National Comprehensive Cancer Network] compendia-listed regimen that might be appropriate for some patients.

So when selecting frontline therapy, I think the field for the most part is still focused primarily on the chemoimmunotherapy regimens. And the goals are to get as sustained duration of remission as we can. Those remissions for many patients can be a good number of years. However, it’s important to recognize that not everybody’s going to have the same favorable outcome.

Sequencing of therapy is a question that has been inadequately addressed by current studies. In the past we had 1 chemotherapy, then the next chemotherapy, and the next chemotherapy. It was always sort of felt that there would be diminishing durations of disease control with successive regimens.

Within the last 12 months we had a presentation and subsequent publication comparing lenalidomide/ rituximab to rituximab monotherapy. And that trial showed highly statistically significant improved outcomes with the addition of lenalidomide over rituximab monotherapy. So the combination did better than single therapy. And so for those patients who are treated with frontline chemoimmunotherapy, I think that the lenalidomide/rituximab oftentimes would be a reasonably logical second-line therapy.

The other class of drugs that has been approved are the PI3 inhibitors. And the PI3 inhibitors, their labels differ somewhat, but really aim them toward the third line. So for patients who are sequencing their therapies, I think there’s a reasonably approachable sequence, which might be chemoimmunotherapy followed by lenalidomide/rituximab, and then potentially followed by PI3 inhibitors, if patients don’t go an alternative route, which could be the case in the setting of an early relapse or if there are other variables that could knock people off that pathway, I should say.

Transcript edited for clarity.

Case: A 62-Year-Old Male with Follicular Lymphoma

H & P:

• A 62-year-old man presents with lower abdominal discomfort and rapid weight loss over last 3 months
• PMH: Hypertension managed by statin
• PE: palpable inguinal lymphadenopathy

Diagnostic Work-Up

• Hematologic results
  • ANC: 1200 /µL
  • Platelets: 89,000 /µL
  • β₂-microglobulin: 3.5 mg/L
  • Serum LDH: 230 IU/L
• Imaging: PET/CT reveals axillary and bilateral inguinal lymphadenopathy; 5 masses (~3cm each)
• Biopsy: FL, grade 2
• FLIPI status: High-risk
• Ann Arbor: Stage IV
• ECOG PS: 1

Treatment

• Patient treated with obinutuzumab + bendamustine
  • Completed 6 cycles, achieved CR