Using Frontline R-CHOP and Maintenance Rituximab in FL

Peter Martin, MD:In this case, the physician elected to choose a treatment with R-CHOP, and I think that was a reasonable treatment. Rituximab probably would not have accomplished what we wanted to accomplish in this case. We would have wanted to accomplish a relatively rapid cessation of his symptoms related to lymphoma. He was losing weight. He was having fatigue. So, probably some form of chemotherapy plus rituximab, or plus an anti-CD20 drug, is the most appropriate line of therapy. Bendamustine/rituximab is a reasonable treatment option in a lot of these people. I suspect in this case, the physician selected CHOP, or an anthracycline, because there was some concern for transformation on the basis of weight loss. In any case, rituximab plus CHOP is a treatment that is commonly used in follicular lymphoma and has a long history of activity and tolerability, so it’s always a reasonable treatment option.

In addition to bendamustine/rituximab or rituximab/CHOP, now there are data from the GALLIUM study that say that obinutuzumab can be substituted for rituximab. So, I think that you could argue to use obinutuzumab/CHOP or obinutuzumab/bendamustine as well in this case. One caveat from the GALLIUM study, I suppose, that requires some consideration is that although this was not a randomized comparison of the chemotherapy arm, the people selected for treatment with bendamustine in the GALLIUM study seemed to have a higher mortality rate than the people treated with CHOP. This is totally contrary to phase III trials comparing bendamustine/rituximab with rituximab/CHOP. It gives us some cause for concern that bendamustine may be doing things that we haven’t otherwise been aware of. Certainly, it’s an immunosuppressive drug and does things to the immune system that maybe we weren’t entirely cognizant of, but nonetheless, I think it’s still a very reasonable regimen for most people with follicular lymphoma. In this case, R-CHOP was a perfectly reasonable regimen.

Maintenance rituximab was demonstrated to be useful in the PRIMA study, which evaluated 2 years of rituximab maintenance after rituximab plus chemotherapy in the frontline setting. That was R-CHOP, RCVP, and that’s where the best data for rituximab maintenance exists right now. Importantly, although rituximab maintenance prolongs progression-free survival, it doesn’t seem to have an impact on overall survival. So, the goal really has to be, or the consideration really has to be, do the benefits outweigh the risks?

So, the risks of rituximab maintenance are relatively modest. Somewhere around 3% to 5% of people receiving 2 years of rituximab maintenance might require intravenous antibiotics for some sort of infection. There’s a little bit of a hassle associated with returning to the physician’s office. You might assume that patients have more anxiety related to returning to the physicians that frequently. Studies do not bear that out, interestingly. They suggest that maybe the opposite is actually true, that patients like the concept of ongoing therapy.

And, interestingly, in a follow-up study—10 years of follow-up presented at ASH 2017 by Dr. Sal—roughly 50% of people who were randomized to rituximab maintenance were still in remission 10 years after starting treatment with rituximab chemotherapy. So, it clearly is a reasonable strategy to help people experience a maximum treatment-free interval. Nonetheless, it’s not to suggest that everybody needs rituximab maintenance. There are a lot of people who don’t want to be treated for a prolonged period of time, who finish chemotherapy and say, “I’m done with it.” It doesn’t impact overall survival. And, as I mentioned, it does have some downsides, so it’s not something that is in the books for everybody to receive.

Transcript edited for clarity.

October 2014

• A 72-year-old man presents to his physician complaining of fatigue lasting several months, recent weight loss of 15 lbs. and a mass on his right side of neck
• PMH: GI reflux controlled on PPI, obstructive sleep apnea
• PE: Right supraclavicular lymph node (7 cm.), spleen palpable 5 cm. below the costal margin
• Performance status, 1
• Laboratory findings:
  • Hb, 9.9 g/dL ,
  • Leukocytes, 3.21 X 10⁹/L
  • Platelets, 110 X 10⁹/L
  • AST, 162 U/L; ALT 201 U/L
  • LDH, 302 U/L
• Excisional biopsy of the right supraclavicular node:
  • IHC staining, CD10+, Bcl2+, CD5-
  • Follicular lymphoma, grade 2
• Bone marrow; paratrabecullar infiltration by small cleaved lymphocytes
• PET-CT showed enlargement of right supraclavicular lymph node (3 X 7 cm) and 3 mediastinal lymph nodes (3.2 cm, 3.5 cm, 4.4 cm); diffusely enlarged nodes in the retroperitoneal, mesentery, and inguinal regions: SUVmax, 9
• FLIPI, 5 points, high risk
• The patient was treated by the local oncologist with R-CHOP (6 cycles)
• Post-treatment he achieved a partial metabolic response
• He was continued on rituximab maintenance therapy and his disease remained stable

July 2016

• 23 months later, the patient complained of his symptoms returning
• PET revealed enlargement of the affected mediastinal nodes
• SUVmax of all nodes was 12
• Repeat CT revealed progression of disease
• The patient was started on bendamustine + rituximab (6 cycles) and achieved a partial response after completing induction therapy

January 2018

• Sixteen months later, the patient reports feeling tired but could resume most normal activities (ECOG 1)
• PET with diagnostic CT showed diffuse¹⁸F-FDG uptake in multiple lymph nodes and spleen; the largest involved nodes are the right supraclavicular (6.2 cm), left mesenteric (4.8 cm), and splenic hilar (2.7 cm) nodes
• Repeat biopsy showed grade 2 follicular lymphoma
• The patient was started on copanlisib
• After three months, he developed a partial response with>50% reduction in lymphadenopathy in all involved nodes