Susan Woodward: Welcome to our roundtable discussion about follicular lymphoma. My name is Susan Woodward and I'm back with my colleagues Zanrha Esteban and Amy Sadorski. Zanrha and Amy, thank you for joining me today. In the first part of our discussion, we talked about the diagnosis of follicular lymphoma and frontline treatment. Now let's talk about treatment options for relapsed/refractory follicular lymphoma.
Okay, so some important points about relapsed/refractory follicular lymphoma is that an optimal therapeutic regimen in this setting have not been established. It's also important at the time of relapse to rule out histologic transformation. So, patients may need imaging with PET, biopsy of most avid lesion, and bone marrow biopsy of unexplained cytopenias. Indications for treatment: if they're asymptomatic even at time of relapse, we don't necessarily need to immediately treat them, but they should be followed closely. And we use the same indications for treatment that we used in first-line therapy. It's important to recognize early treatment failure. Patients with follicular lymphoma progressing within 24 months, also called POD24, of their initial immunochemotherapy, or within 12 months of single agent rituximab are the ones that we're concerned about.
We usually offer these patients more aggressive therapy because they do poorly with standard treatment approaches. However, no optimal regimen has been established even in this POD24 setting. For patients with late relapse, which is what we consider patients that relapse more than 20 months, or, I'm sorry, 24 months after initial chemoimmunotherapy or more than 12 months after single agent Rituximab generally will have a clinically indolent course. They'll require intermittent treatment over decades, and survival rates mirror the general population. Treatment focuses on alleviation of symptoms, reversal of cytopenias, and improvement in quality of life.
For second-line treatment options, preferred regimens, chemoimmunotherapy, bendamustine-Rituxan, or obinutuzumab-bendamustine can be used. Bendamustine is not recommended to be used again if you already used it in a frontline therapy because of the risk for cytopenias, and actually transformation to MDS (myelodysplastic syndromes) at some point. You can also use CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, prednisolone) plus obinutuzumab or rituximab. You can use lenalidomide plus or minus rituximab, lenalidomide plus obinutuzumab, and single agent obinutuzumab or rituximab. Keep in mind, you can't use single agent obinutuzumab in frontline setting. For elderly and frail patients, the preferred regimen is rituximab, but we also have available chlorambucil plus or minus rituximab, and Cytoxan plus or minus rituximab. And also, in this second-line setting, you can use tazemetostat, and that's irrespective of EZH2 mutation status.
For second-line consolidation or extended dosing, which is optional, preferred regimens would be rituximab maintenance or obinutuzumab maintenance. And other recommended regimens can be high dose therapy with autologous stem cell rescue or allogeneic hematopoietic cell transplantation (HCT) in selected cases. In third-line and subsequent therapies, which also add into that any previously unused second-line therapy regimens, and this is where we're going to be focusing the majority of our discussion, is small molecule inhibitors, PI3K inhibitor, copanlisib, and EZH2 inhibitor tazemetostat. Again, irrespective of whether the patient has an EZH2 mutation. We can also use T-cell mediated therapy, which is anti-CD19 chimeric antigen receptor or CAR T-cell therapy, which is axicabtagene ciloleucel, or tisagenlecleucel. Also, bispecific T-cell engager therapy, mosunetuzumab which was approved earlier in 2023.
So most of us have a lot of familiarity with working with anti-CD20 monoclonal antibodies, but I did want to highlight a few things that are important because both rituximab and obinutuzumab do have potentially serious side effects and some black box warnings. And I just kind of wanted to review those quickly before we get into some of these novel agents. So again, with Rituxan, common side effects, infusion-related reactions, up to 77% of patients, the frequency decreases with subsequent infusions, but there can be infections, bacterial, viral, fungal, unspecified. Generally people just experience fevers, chills, and asthenia. But the most common adverse events of at least grade 3 are lymphopenia and neutropenia. And there are black box warnings of fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.
So, despite the success of Rituxan, patients may develop Rituxan-refractory disease, which is defined as non-response or progression within 6 months of treatment with rituximab-containing regimen. So, you can use obinutuzumab as an alternative in combination with chemotherapy, Revlimid, or as a single agent in the relapsed/refractory setting. Again, fatal cardiac events have been observed as well as serious to fatal bacterial, viral, and fungal infections which can be during treatment and also months after receiving treatment. Patients with active infections shouldn't receive treatment with obinutuzumab. Most common adverse events of at least grade 3 are neutropenia. So, you want to be considering G-CSF for patients with grade 3 or IV neutropenia, again, because it can present after therapy completion. Antibiotic prophylaxis is highly encouraged.
Infusion-related reactions not as common with rituximab, but they can occur with subsequent infusions. And then other common adverse events are fatigue, musculoskeletal pain, upper respiratory tract , and cough. And I'm going to turn, as we move on to Revlimid and rituximab or R2 regimen, I'm going to turn that over to Amy or Zanrha. One of you can jump in and review those slides with us.
Amy Sadorski: Sure, I'm happy to do it. So R2 was approved based on a phase 3 randomized superiority trial, which was the RELEVANCE trial that looked at rituximab plus lenalidomide as compared with rituximab plus chemotherapy. In patients with previously untreated follicular lymphoma, R2 continued for 18 cycles followed by 12 cycles of maintenance rituximab every 8 weeks. The chemotherapy arm was rituximab plus chemo, which was investigator's choice of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine Rituxan), or R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone), followed by 12 cycles of maintenance rituximab every 8 weeks. Complete response after 120 weeks was 48% in the R2 arm vs. 53% in the R-chemo arm. Three-year progression-free survival was similar between both arms at 77% in the R2 arm, and 78% in the R-chemo arm. So R2 based on this trial was felt to be non-inferior to the standard of care of R-chemo.
As far as adverse events go, the R-chemo arm was noted to have higher grade 3/4 neutropenia at 50% vs. 32%, and higher rates of febrile neutropenia at 7% vs. 2% in the R2arm. The R2 arm, however, was associated with higher cutaneous reactions at 7% vs. 1%. So, rituximab, as Susan was discussing, is a monoclonal antibody that targets CD20, which is a specific B-cell surface antigen. Lenalidomide or Revlimid is an analog of thalidomide and is an immunomodulatory agent. And as far as when we manage our patients who are on this treatment, of course the rituximab, there's the reactions. Revlimid is given as a pill which is nice for patients, but some of the barriers are that there's a high copay associated with this. We usually have to get prior authorizations for patients before we can get them started and get them copay assistance, and it has to come from the specialty pharmacy. We have to enroll them in the REMS (Risk Evaluation and Mitigation Strategy) program because of the risk of birth defects. And then when we look at potential side effects of Revlimid, as most of you know, it doesn't come without side effects. We can see cytopenias, infection, fatigue, we can see GI side effects. Nausea and vomiting usually not as much, but we can see some diarrhea with this. Rash can often happen also with the lenalidomide, which sometimes is limiting for us to be able to give the drug to patients. We can see some muscle spasms and muscle cramps, and then some swelling and peripheral neuropathy. There is a risk of blood clots with lenalidomide, so we do need to have patients on some type of prophylactic anticoagulation, either daily aspirin if they've never had a history of a clot, or if they have had a history of a clot, a lot of times we'll put them on prophylactic DOAC (direct oral anticoagulant).
Susan Woodward: I think the rash can be particularly challenging to manage and patients don't like to have rashes, and they can be disfiguring as well is very pyretic for them. Do you have any strategies that you've used when patients have developed a rash and you really want to try to keep them on therapy?
Amy Sadorski: Usually what we'll do if we feel like it's a significant rash is that we stop the Revlimid until the rash has resolved, and then we will restart it at a lower dose and we'll have them take an over-the-counter antihistamine like loratadine or cetirizine in combination with an H2-blocker like famotidine, and then we just keep a very close eye on them.
Susan Woodward: Yes, that seems to be pretty consistent. I would say with our practice, it seems to me that there is often dose reduction involved with administering Revlimid. And sometimes we've even had to be creative about the dosing schedule because it's generally 3 weeks on and a week off, and we've sometimes altered that dosing schedule a bit. Maybe Monday through Friday and then weekends off, just to help the patients tolerate the side effects. Zanrha, did you have anything you wanted to add?
Zanrha Esteban: Yes, and then we also use topical steroids to also help with the itching because that's probably the most debilitating for the patients. And sometimes we even consider maybe some PO steroid, like a Medrol Dosepak, when stopping the Revlimid.
Susan Woodward: Okay. Well, Zanrha, would you like to discuss the copanlisib or Aliqopa?
Zanrha Esteban: Yes. So, copanlisib (Aliqopa) is a pan-class I phosphoinositide 3-kinase inhibitors. It's a PI3K inhibitor with potent activity against PI3K-α and PI3K-δ isoforms approved the treatment of relapse follicular lymphoma in patients who have received more than 2 lines of systemic therapy. The approval was based on results from the phase 2 CHRONOS-1 study in 142 patients with relapsed or refractory indolent B-cell lymphoma. Fifty-nine percent achieved an overall response rate of 59% and 14% with a CR (complete response) rate, with an mDOR (median duration of response) of 12.2 months. So there's more toxicity profile with copanlisib. Most commonly we have hyperglycemia, diarrhea, hypertension, we see neutropenia, fevers. We don't typically use this in practice here at Moffitt, especially if they have a history of diabetes or hypertension, especially if it's uncontrolled. But if you really do have to start it, we do close monitoring of their sugars, maybe getting their endocrine or local PCP on board, getting their blood pressure under control, and coordinating with the PCP and also cardiologists for a tight BP management.
Susan Woodward: Amy, what's been your experience with using copanlisib? Do you have very many patients that you've treated with that?
Amy Sadorski: I am not sure if we've even used this drug specifically. We've used PI3-kinase inhibitors in other disease states, and I've found that their side effects often can be prohibitive. Usually we have to end up taking patients off therapy at some point due to side effects.
Susan Woodward: Yes, that class of drugs can be challenging from the infection, diarrhea, and some autoimmune-type of side effects, certainly.
This brings us to the end of this part of the discussion. For more information and to view our other discussions on follicular lymphoma, please visit JADPRO online at jadpro.com.
