Episode 139: Follicular Lymphoma Series, Pt 4 - Relapsed/Refractory Management (Cellular therapy options)
This week, we continue talking about relapsed/refractory follicular lymphoma, this time focusing on cellular therapy options, namely bispecific agents and CAR T therapy. If you have not done so, we highly recommend listening to part 3 of our follicular lymphoma series.
You may also recall that we discussed these agents in our DLBCL series. Be sure to review our show notes from those episode for some awesome graphics and chart.
Briefly, what are important steps to keep in mind for patients with suspected relapsed follicular lymphoma?
Always repeat biopsy of the most avid lesions to rule out transformation to large B-cell lymphoma
Ideally, we would get an excisional biopsy but, in cases where the most avid node is in the abdomen, it is reasonable to obtain a core biopsy of that lymph node if there is a significant discrepancy in SUV uptake
Bone marrow biopsy is not necessary unless there are significant cytopenias and/or trying to rule out a myeloid malignancy.
What is the normal process by which the immune system interacts with cancer cells?
How does the normal immune system interact with cancer cells?
B-cells secrete antibodies that target non-self proteins, such as those on cancer cells
Recall that there are two main types of T cells:
CD4+ helper T cells: Coordinates the immune system by activating killer T cells and memory B cells
CD8+ killer T cells: Have direct cytotoxic activity against cancer cells
In order to function, the CD8+ T cell needs to both recognize the cancer cell and get a costimulation signal
The T cell receptor is what can recognize foreign antigens but does not have the same sort of high affinity targeting as an antibody. It requires binding to MHC I complexes on the tumor cell and often presentation from antigen presenting cells
These T cells are developed in the thymus and undergo a process called “negative selection” where only T cells that have a very low affinity for self antigens survive
Cancer cells will have self-antigents, which makes this process more difficult to find them
T-cells also requiring costimulation and antigen presenting cells (B-cell or dendritic cells) to identify tumor cells
Once T cells are activated, they then expand
What are the principles behind CAR T therapy?
CAR-T is defined as “chimeric antigen receptor T-cell” therapy
Native T cell receptors are modified in the lab to directly target a specific antigen and elicit an immediate cytotoxic response when bound. These modified T-cells have the targeting ability of an antibody and the effector function of a killer T cell while bypassing the normal activation steps and costimulation
The target is CD19, which is universally expressed on B-cells
Keep in mind if we target CD19 then we will kill all B cells - both normal and tumor cells so the patients will essentially have B cell aplasia temporarily after therapy
“Chimeric” because it’s a genetically modified receptor that combines multiple fusion proteins to allow for direct binding to a prespecified antigen like an antibody would and kill the target with automatic self stimulation instead of requiring co-stimulation
These modified CAR-T cells are able to expand after infusion into the body to do maximal damage to the tumor
How are CAR T cells manufactured?
First, a letter of medical necessity is submitted by the oncologist to get insurance approval. The approval process can take a few weeks.
Once approved, the patient undergoes a process called “leukapheresis”, where patient’s cells are collected, and T-cells are separated.
These autologous T-cells are sent off to the manufacturing lab of companies that produce commercial CAR T products (eg. Kite, Novartis pharmaceuticals etc.)
Transduction of the CAR construct occurs with a retrovirus or lentivirus vector to modify the native T-cell receptors to express the target antigen receptor. These modified CAR T-cells expand over 1-2 weeks and undergo multiple quality checks.
The product is shipped back to treatment center.
Patient gets a few days of lymphodepleting chemotherapy (Fludarabine/Cyclophosphamide or Bendamustine) to get rid of native lymphocytes to not disrupt the efficacy of the product. Following this, the CAR T-cells are infused.
How does this compare and contrast to bispecific antibodies?
The antibody is shaped like a “Y” with one arm binding CD3 on the T cell and the other arm binds to CD20 on the B cell
This will trigger cytotoxic T cell activity resulting in death of the CD20 B cell
Instead of a one and done treatment like CAR T-cell therapy, this is given initially at low doses and then increased over the first few weeks to prevent side effects
The treatment is then continued either as a fixed duration every 3 weeks or continuously until progression depending on the product used
What are the biggest side effects to worry about with bispecific agents and CAR T-therapy?
Cytokine release syndrome (CRS):
CRS is essentially inflammation that starts with fever and can progress to a severe SIRS reaction with hypotension and hypoxia.
Higher grade CRS can result in vasopressor requirement and stay in the intensive care unit
This side effect is expected early on (and is seen more frequently) for CAR T compared to bispecific therapy due to more T-cell activation and expansion
For CAR T, the patient may experience fever that commonly progresses to hypotension often requiring steroids and the anti IL-6 agent tocilizumab in the inpatient setting
For bispecific antibody therapy, most patients have low grade CRS where they get a fever that can often be managed in the outpatient setting with home dexamethasone prescriptions
Unlike CAR T, for CRS associated with bispecific agents, steroids can be used more judiciously over a much longer period of time rather than all at once
Also for bispecific antibody, CRS is generally confined to cycle 1 where doses are generally increased weekly up to a full dose
Immune effector cell associated neurotoxicity syndrome (ICANS):
ICANS has a wide range of neurologic manifestations and a scoring system called the ICE score was developed for grading
This is more delayed from CRS but can occur concurrently
Higher rates and with worse severity for CAR T compared to bispecific therapies
This is managed with steroid therapy exclusively
Be sure to check out our discussion about CRS and ICANS in our DLBCL series
Both therapies also increase risk of infection:
Hypogammaglobulinemia: requires IVIg supplementation
Vaccine re-administration: Important for CAR T patients; patients treated with bispecifics can have increased infection susceptibility even after treatment is completed
How does patient selection vary between these two strategies?
Bispecific antibodies:
“Off the shelf” allows for faster treatment administration
Patients don’t need to go through rigorous cardiac and pulmonary clearance as it is very well tolerated even in an older, frail population
The toxicities are manageable primarily in the outpatient setting and are very low grade
These can safely be given without the need for a specialized academic center
CAR T:
It requires more stringent patient selection (NOTE: Though this is more relaxed than autologous stem cell transplant)
Long “brain to vein time” meaning the time you think about giving CAR T to the time you can because of insurance approval, apheresis, and manufacturing, which may increase toxicity because of the need for holding therapies
Increased risk of ICANS, CRS,a nd higher infection risk in the first few months after treatment
The big advantage though is that it may be more effective for patients with rapidly progressive disease and is a one time treatment rather than a treatment given at a regular frequency for numerous cycles possibly for years
Some people also think that it will lead to durable cures but the data is not mature enough yet to validate that belief
Comparing bispecific agents and CAR T
What are currently available bispecific antibody options for patients with relapsed/refractory follicular lymphoma
There are two products approved in the US as single agents:
Mosunetuzumab: IV fixed duration for either 8 cycles or 14 cycles (Potentially 6 months of therapy because each cycle is 3 weeks)
Epcoritimab: subcutaneous until disease progression
There is another product approved in other countries
Odronextamab: IV until disease progression
There was a phase 2 multicenter study including follicular lymphoma patients in the third line or higher
Patients must have received an alkylator and anti CD20 agent previously
Mosunetuzumab was given weekly at increasing doses in cycle 1 for 3 doses and then q3week for 8 cycles if the patient achieved a CR
The treatment was extended up to 17 cycles if a PR was achieved after 8 cycles
A total of 90 patients were enrolled
About 80% of patients had received prior anthracycline, one third had prior auto transplant, and over 50% were POD24 and refractory to both anti CD20 and alkylator therapy (A high risk cohort)
Long term 3 year follow up was published in Blood in February 2025
ORR was 80% and CR rate was 60%
Median time to first response was 1.4 months and 3 months to first CR
The 3 year PFS rate was 43%
For those in CR, about three quarters (72%) of these patients remained in CR at 30 months
For those who achieved a PR as best response, the median duration of response was much shorter at 4 months though this only occurred in 16 patients
These results were outstanding and showed that patients who attain CR tend to have a durable response at 3 years
The median time to B cell recovery in exploratory analysis in a small subgroup of patients was about 18 months with this fixed duration approach
Side effect profile:
CRS: 40% of patients and was predictable with a majority of events occurring after the first and third doses in the weekly step up for cycle 1
Nearly all cases were grade 1 or grade 2 and few patients required hospitalization or tocilizumab
ICANS: occurred in 5 patients
Were all grade 1 with mild confusion, and all resolved entirely
Neutropenia and hypophosphatemia occurred in about one fourth of patients
Itching and rash were reported in about 20% of patients
Serious infections with many requiring hospitalization occurred in 20% of patients
Only 4 patients developed COVID infection which all resolved even though patients were enrolled between 2019 and 2020 during the COVID pandemic
Overall it was very well tolerated
This was approved based on the EPCORE NHL-1 trial published in Lancet Hematology in 2024
Epcoritamab is a subcutaneous injection
In cycle 1, the dose is increased weekly until full dose at week 4
Dosing schedule:
Weekly for 3 months then
Every other week for 6 months and then
Monthly until disease progression or unacceptable toxicity (as opposed to fixed duration)
There were 128 patients enrolled who were similar to the mosunetuzumab study in the third line or higher setting
The ORR was 82% and CR rate was 63%
Over 60% of patients developed CRS
ICANS was uncommon in only 6% of patients and again just minor confusion without progression to aphasia, coma, or seizure
After an optimized step up dosing weekly schedule tested in over 80 patients, CRS rates dropped to about 50% and there were no ICANS events
Neutropenia occurred in one quarter of patients
Generalized fatigue occurred in one quarter of patients
Minor inject site reactions were common occurring in about half of the patients in the study
There was a higher incidence of COVID 19 occurring in 40% of patients though we should not compare this number to the mosunetuzumab trial which had a much lower incidence
We are awaiting long term follow up for this study
Since the side effect profile is similar, what are some other things to consider when selecting one of these agents?
If you have a patient where you are clinically concerned for possible large cell transformation due to more rapid disease progression or very high SUV uptake in nodes that may not be easily accessible for excisional biopsy to rule out large cell transformation, then you might consider epcoritimab over mosunetuzumab
This recommendation stems from data that suggests epcoritimab works well as a single agent in DLBCL
Duration of treatment: Fixed duration (mosunetuzumab) vs. indefinite (epcoritimab)
There has been a press release for what will likely become a standard of care option in the second line setting for fixed duration epcoritimab + lenalidomide + rituximab x 2 years total (the R squared regimen we previously discussed)
The field is evolving as we also move these therapies in the front line which has very promising results
What about odronextamab?
This is approved outside of the United States based on the phase 2 ELM-2 trial
The major downside to this bispecific antibody is the schedule
It is given on Day 1 and Day 2 in week 1, then day 8 and day 9 in week 2, then day 15 and day 16 in week 3, then weekly for about 2 months and then every other week until disease progression
For patients with CR for over 9 months, they were transitioned to a monthly dosing
Patients also required inpatient admission for 24 hour monitoring after each step up dose in the trial protocol
This is much more cumbersome than the other products when it comes to the patients time in clinic
The efficacy was similar with a 60% CR rate and side effect profiles also mirrored the other products
What is the data behind axi-cel and liso-cel for follicular lymphoma?
Check out our DLBCL series for more details on these CAR T products
These are both CD19 directed products unlike the CD20 directed bispecific antibodies
Axicabtagene ciloleucel (Axi-cel) was approved based on the pivotal ZUMA 5 phase 2 trial
This included patients in the third line setting
The CR rate was 79%
The 3 year PFS rate was 54% which is nearly identical to the mosunetuzumab trial
The 5 year follow up showed 50% of patients who achieved a CR remained in CR at 5 years suggesting a potential cure in these patients
CRS and ICANS were much higher grade and this does come with the other toxicities associated with CAR T which we will take a deeper dive in a future episode
Liso-cel was approved based on the TRANSCEND-FL phase 2 trial
This included some patients in the second line setting so a different patient population though most were POD24 if in the second line
The CR rate was an astounding 94%
Longer follow up is needed to fully understand the durability of that response
There was lower toxicity when compared with axi-cel for CRS and ICANS
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
