Approaches for High-Risk FL With POD24

Jeff P. Sharman, MD:The GALLIUM study has been one of a limited number of frontline studies to address novel treatment strategies in follicular lymphoma. This particular study, individual treatment centers picked whether they were going to administer CVP [cyclophosphamide, vincristine, prednisone], CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or bendamustine/rituximab, and then treated all patients at their center with that chemotherapy backbone. The patients were then randomized to either rituximab or obinutuzumab.

The treatment was slightly different. Rituximab was administered according to the standard 375 mg per meter squared, whereas obinutuzumab has flat dosing of 1000 mg. In addition, there’s a little bit more front loading of the obinutuzumab given on days 1, 8, 15, and then day 1 of each successive cycle. So patients do get a little bit more CD20 antibody, which has been one of the questions as to is it possible that that’s explanation for better outcomes or not.

Patients with follicular lymphoma, it was a very large study—1200 patients—which is a very large study by follicular lymphoma’s standard, were randomized to either R-chemo [rituximab chemotherapy] or obinutuzumab chemotherapy.

The initial results were presented in the plenary session at the American Society of Hematology, and subsequently published, and now we’re starting to get updates of the trial, sort of annual updates, so we can look at this.

At the initial presentation of the data, there was clearly an incremental benefit to utilization of obinutuzumab over rituximab. However, I think it’s fair to say that the patients who received rituximab did pretty well also. And so the incremental gain was under 10% when you look at the progression-free survival. With longer follow-up that number’s gotten to be a little bit bigger. I think at the 4-year follow-up, the incremental gain in progression-free survival is closer to 11%, whereas it was less than 10% previously.

However, the overall survival really overlaps with one another, and I think it’s difficult to anticipate that there will be a survival benefit. Some of the secondary outcomes such as time to next treatment favored the obinutuzumab; progression-free survival favors obinutuzumab.

One of the interesting things that favors obinutuzumab is a fairly substantial reduction in those patients who progress within 24 months. It was a 46% relative risk reduction, which is a change from approximately 17% down to 10%. And the patients who have early progression are the ones who do poorly. It would stand to reason that you would begin to see a survival benefit at some point, but that certainly hasn’t yet materialized in the data.

In the recent updates by John F. Seymour ,MBBS, PhD,et al, looking at the GALLIUM study, they looked at the rates of progression within 24 months. And in that data set the rate of progression on the bendamustine/rituximab within 24 months was 17%. And in the obinutuzumab arm it was about 10%. It ended up being a relative risk reduction of about 46%.

For those patients who had early progression of disease, outcomes were relatively similar whether they had been on the obinutuzumab arm or the rituximab arm. And for those patients who have early progression of disease on the study, the mortality rates were approximately 12-fold higher than their counterparts who lacked early progression of disease. This study really confirms the dangerous situation that patients would find themselves in, in the setting of early progression.

Obinutuzumab has a slightly higher frequency of infusion reactions relative to rituximab. I think that a lot of providers are comfortable and familiar with the rituximab experience. Infusion reactions with obinutuzumab can be a little bit more significant. I think with regard to the GALLIUM study, the safety considerations were perhaps a little bit less about the choice of CD20 antibody and more about the combination of obinutuzumab with bendamustine.

Since bendamustine is the predominant frontline chemotherapy regimen given, there have been a number of studies recently that looked at T-cell depletion in response to bendamustine. And it does look like there’s a slightly higher rate of infectious complications for patients who receive bendamustine, as well as for those patients who get obinutuzumab. So some of the reason that we may not be seeing the outcome benefits for the novel combination of bendamustine, obinutuzumab could be related to the higher risk of infectious complications seen among those patients as well.

So not necessarily acute infusional toxicity but related to infections that occur later. In many cases those could even occur after the bendamustine was done during the maintenance phase, also potentially impugning the obinutuzumab component.

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