FL: Switching to Bendamustine/Rituximab at Progression

Peter Martin, MD:Consistent with this patient being relatively high risk by FLIPI score, he unfortunately began to experience disease progression while he was receiving rituximab maintenance. So, just towards the end of the rituximab maintenance, 23 months after starting it, he began to experience progression of symptoms with worsening fatigue. Again, evaluations with the old diffuse lymphadenopathy. A PET/CT scan revealed diffuse lymphadenopathy. The maximum size was in the 5 cm to 6 cm range. But the SUVmax was 12. At that point, when somebody’s having symptoms of SUVmax of 12, it’s reasonable to consider transformation. In his case, I think the physician felt it was less likely. So, labs were done, which were the old—some cytopenias again. On that basis, the physician elected to start treatment with bendamustine and rituximab. After completing bendamustine and rituximab, repeat imaging was done, which revealed a partial response.

Unfortunately, in this case, things aren’t playing out in a way that we might expect. He had a high-risk disease to begin with, and he is experiencing disease progression at a relatively early time point. There have been now pretty widely disseminated data coming from the National LymphoCare study, that were first presented by Carla Casulo and other groups, that have since been shown to suggest that people who progress within 2 years of frontline immunochemotherapy unfortunately have a worse overall survival than people who don’t. So, Dr Casulo showed that these people have an average survival of about 5 years, which is significantly less than the majority of people with follicular lymphoma.

So, unfortunately in this case, this man is faced with a follicular lymphoma that’s behaving in a way that we don’t want it to behave. It’s more resistant to chemotherapy. He hadn’t had a long duration from it. And, importantly, he’s refractory to rituximab by definition. His disease has started to grow while he has been receiving rituximab maintenance. These are all important considerations not only in terms of what the next line of therapy entails, but also, they’re important information to give to the patient, his family, his caregivers. Right? This is somebody who needs to know that this disease is going to take a different turn than we might have discussed during the initial presentation. This is somebody who needs to know that this disease may become problematic earlier than expected, and we may be forced to consider treatment options that might be more aggressive or different than we would have otherwise considered at an earlier time point.

That said, here we are now 23 months later. He has got symptoms. He has got progressive disease. Clearly, there’s an indication for therapy. This is not somebody who we can just observe. Things will continue to get worse. Clearly, we can’t use single-agent rituximab because that’s what he has been receiving and he’s refractory to it. So, common approaches at this point might include immunochemotherapy. I think that there are now reasonable data to suggest that obinutuzumab plus bendamustine might have been a better choice in this situation.

In a clinical trial that looked at rituximab-refractory patients, people were randomized to either bendamustine as a single agent at a relatively high dose or bendamustine/obinutuzumab plus maintenance with obinutuzumab. And there are some details of the trial that make it a little bit difficult to interpret. Nonetheless, there was an actual overall survival benefit. And so, I think it’s reasonable to consider a combination of obinutuzumab and bendamustine in somebody with rituximab-refractory follicular lymphoma. So, that might have been better than bendamustine and rituximab, which was selected in this case. That said, those data are relatively recent.

Other options include lenalidomide and rituximab. We don’t have a lot of data for that regimen. We do have some data for it in the relapsed setting, but we don’t have a lot of data for it in a high-risk population like this. This is an opportunity to plug an intragroup trial that recently started. It is R-CHOP versus lenalidomide/rituximab versus obinutuzumab/CHOP versus obinutuzumab/lenalidomide versus obinutuzumab/PI3-kinase inhibitor in early progressive patients with follicular lymphoma. So, that’s something that’s worth considering. And, in general, I think clinical trials are worth considering in people with a high-risk disease like this.

Another consideration has to include autologous stem cell transplant for a long time. People have considered autologous stem cell transplant in higher-risk follicular lymphoma patients. We know that it can result in relatively durable remissions. That said, this gentleman is now in his mid- to late 70s. My bias is not to use age alone to exclude somebody from an intensive therapy. I rely a lot on our colleagues from the transplant service, who are experts at determining who is likely to tolerate that, so I would definitely have that conversation and ask our transplanters to have that conversation with him.

Nonetheless, all of these things considered, bendamustine/rituximab is a reasonable option in this case. But we have to be realistic about what we’re going to expect from it. It’s probably not going to result in a really durable remission. We’re probably looking at something in the range of 1 to 2 years. So, in other words, 6 months of therapy followed by a remission that lasts somewhere between 6 and 18 months, probably not a lot longer than that.

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