Episode 138: Follicular Lymphoma Series, Pt 3 - Relapsed/Refractory Management (non-cellular therapy options)
This week, we shift our focus to talking about relapsed/refractory follicular lymphoma. In this episode, we will specifically discuss treatment options other than cellular therapy, which will be an upcoming episode. If you have not done so, we highly recommend listening to part 1 and part 2 of this follicular lymphoma series so that you can better follow this week’s conversation!
In our previous episode, we discussed the role of rituximab for patients with follicular lymphoma. What is the data behind “rituximab maintenance” after the first line of therapy?
Recall the the Deauville score (named for a meeting in Deauville, France) or Lugano score (named for a meeting in Lugano, Switzerland) which is a 5-point scoring system to assess response to therapy.
Note that in follicular lymphoma, residual adenopathy can be expected (possibly dead tissue) but do NOT ignore avid disease (i.e., highly consider biopsy)
May represent transformed component
Use PET/CT to assess for residual disease:
Scores of 1-3: Complete response
Score of 4: Indeterminate
Score of 5: Highly concerning for refractory lymphoma
This is based on comparison to the avidity of the mediastinal blood pool and the liver
Data for rituximab maintenance comes from the phase 3 randomized control trial called the PRIMA trial
Over 1000 patients were randomized to rituximab maintenance q2month x 2 years vs. observation after front line treatment with chemoimmunotherapy
The 6 year follow up showed improved PFS with rituximab maintenance at 59% vs. 47% but no difference in OS
There was a 9-year extended follow up was published in 2019 in JCO
This included about 600 patients who agreed to extended follow up from the original cohort
The median PFS in the rituximab maintenance arm was 10.5 years vs. 4.1 years in the observation arm
Our interpretation:
Remember though not all relapses in follicular lymphoma need to be treated if the patient is asymptomatic and PFS might have just picked up mild growth in adenopathy
Big differences between arms should raise suspicion that difference may be stemming from median hovering over 50% in the treatment arm
The percentage of patients not requiring lymphoma treatment at 10 years was 53% vs. 41% favoring the rituximab maintenance arm, roughly a 10% absolute difference
Note that this means coming to infusion every 2 months for 2 years
No difference at all in overall survival or transformation to large cell lymphoma
This underscores that decision regarding maintenance is individualized for the patient
There may be more of a benefit in those with more bulky disease (i.e. nodes greater than 5 or 6 cm and with multiple nodal areas involved)
What is the prognostic role of progression of disease within 24 months, also known as POD24?
While there are scoring systems for follicular (FLIPI, FLIPI24, PRIMA-PI), they have limitations and do not influence management
The biggest prognostic factor in follicular lymphoma is progression of disease within 24 months of the start of treatment with chemoimmunotherapy
“POD24” is defined as progression of disease at 24 months after receiving chemoimmunotherapy, such as R-CHOP or BR (not patients, for instance, on rituximab monotherapy)
This definition comes from a retrospective study utilizing a cohort from the National LymphoCare database including over 500 patients published in the JCO in 2015
All patients were treated with R-CHOP
The investigators chose progression of disease at 24 months given the consistency across clinical trials that roughly 20% of patients progress at this timepoint regardless of rituximab maintenance
The 5 year OS was 50% in POD24 patients compared to 90% in those who did not have POD24
This group of patients represents an important high risk population in follicular lymphoma, though the landscape today may be different due to more novel available therapies (bispecific antibodies and CAR T-cell)
Historically, these patients were treated with second line chemoimmunotherapy and considered for consolidative auto transplant
It is important to counsel patients that the most important prognostic factor is if the lymphoma relapses within 24 months of the start of chemotherapy treatment
What does surveillance imaging after treatment look like?
This is individualized to the patient; after a few years of regular imaging, thereafter it is reasonable to monitor the patient with history and physical exam and choose to re-image if there are new symptoms.
This does not impact overall survival
What are treatment options in the relapsed setting for patients with low burden of disease with minimal symptoms or in older, frail patients?
Not all relapsed follicular lymphoma needs to be treated if the patient is asymptomatic
It is reasonable to consider single agent anti-CD20 therapy with either rituximab or obinutuzumab for older and more frail patients or those with minimal disease burden
Recall that rituximab is the original immune therapy and is a type 1 antibody with a large amount of complement dependent cytotoxicity.
There is less antibody dependent cellular cytotoxicity, antibody dependent phagocytosis, and direct cellular cytotoxicity
Obinutuzumab is a type 2 antibody with increased antibody dependent cellular cytotoxicity, phagocytosis, and direct cellular cytotoxicity. It has less complement dependent cytotoxicity.
The thought was that this improved antibody would be more effective than rituximab therapy
In general, it seems that obinutuzumab has higher rates of infusion related reactions and infections likely due to more significant B cell depletion
Additionally, there are two additional infusions in the first cycle of therapy with obinutuzumab compared to rituximab which is often given monthly particularly when combined with chemotherapy
There was a phase 2 RCT in relapsed follicular lymphoma comparing rituximab to obinutuzumab published in JCO in 2015:
There were 150 patients randomized
There was improved ORR at 45% vs. 27% but no difference in PFS or OS
Notably few patients were rituximab refractory but it seems that there are high response rates with obinutuzumab without improved overall disease control
This is why it’s reasonable to use either agent but often obinutuzumab is preferred to improve the response rate
In patients who can’t tolerate rituximab, for instance, obinutuzumab is a reasonable option given fewer risk of reactions
Radiation therapy is also very reasonable for palliation or local control of disease relapse in sensitive areas without overt progression systemically
In patients who have previously been treated with chemoimmunotherapy in the past, what would be the next line of therapy?
We used to re-treat patients with chemotherapy such as R-CHOP or BR if they are some years out from their prior treatment
Recall, though, that these are toxic regimens
We also may want to save the anthracycline containing regimen for patients who may transform into large B cell lymphoma
This occurs in roughly 7-10% of patients so it’s important to not play all our cards at once
In the relapsed setting, some advocate for the use of obinutuzumab with O-CHOP or Bendamustine + obinutuzumab
The best data are for rituximab containing regimens.
We had discussed the use of lenalidomide, often called by the brand name revlimid, for the R^2 regimen, in the front line setting
This has excellent activity in the relapsed setting and much less toxic with lower risk of secondary leukemia than traditional chemotherapy
R^2 regimen (Phase 3 RCT called AUGMENT published in JCO 2019)
Like in most indolent lymphoma studies they included both follicular and marginal zone lymphoma with predominant follicular lymphoma
There were over 350 patients randomized to rituximab monotherapy + placebo or rituximab + lenalidomide
Rituximab was given weekly x 4 doses in cycle 1 followed by monthly cycle 2-5
Lenalidomide was given at 20 mg, 3 weeks on and one week off for 12 cycles
Only 17% were refractory to their last line of therapy and there were 50% of POD24 patients
There was improved ORR at 78% vs. 50% with improved CR at 34% vs. 18%
There was improved PFS with median 39 months vs. 14 months favoring the lenalidomide rituximab arm
In the lenalidomide arm, roughly one third of patients developed rash and over half of the patients developed infection with ANC < 1000
As we discussed back in our myeloma pharmacology episode:
Monitor for rash, cytopenias, neutropenia
Increased risk of thrombosis; we consider starting aspirin
Some patients have fatigue and dose reductions to 15 or 10 mg might be required
Drug is renally cleared; start at a lower dose (10 mg) if the CrCl is 30-59
Tafasitamab + lenalidomide + rituximab regimen (Phase 3 RCT inMIND presented at ASH 2024)
Tafasitamab is a humanized monoclonal antibody against CD19 that works through antibody dependent cellular cytotoxicity, phagocytosis, and direct cellular toxicity but not complement dependent like the anti-CD20 agents
It is given weekly for 3 months and then q2week for an additional 9 months
The rituximab and lenalidomide follow the same protocol as the AUGMENT trial: Double blind placebo control trial of tafasitimab + R^2 vs. R^2 + placebo
Over 500 patients were randomized
Unlike the AUGMENT trial, roughly 40% of patients were refractory to prior anti-CD20 representing a higher risk patient population
NOTE: Only 17% were refractory to their last regimen in AUGMENT
Median PFS was improved with the triplet at 22 months vs. 14 months in the R^2+placebo arm
NOTE: PFS was 39 months in the AUGMENT trial likely reflecting more patients who were refractory to anti CD20 in this study
CR rates improved with the triplet regimen at 50% vs. 40%
While technically this improves PFS, the regimen is very cumbersome with weekly infusions followed by every 2 weeks for a year total
Could consider in a highly-motivated patient who would prefer the PFS benefit or in a patient who may have been refractory to anti CD20 therapy.
Many new options now available!
What about the use of obinutuzumab with lenalidomide in the relapsed setting?
There is a lack of prospective phase 3 RCT data for the use of obinutuzumab for patients who have relapsed disease and were previously treated with rituximab.
There was a phase 2 single arm study called GALEN that looked at obinutuzumab + lenalidomide followed by obinutuzumab maintenance
The major downside to this regimen is that it is 18 months of lenalidomide and 2 year obinutuzumab maintenance
This increased time on therapy is likely excessive in the era of bispecific antibodies and would be reasonable to truncate this regimen if used in practice to omit the second year of maintenance obinutuzumab
There is a higher risk of infection with prolonged maintenance
The 2 year PFS in the study was 65% which is similar to the AUGMENT lenalidomide + rituximab regimen which is much less time on therapy
What is the data behind oral tazemetostat in follicular lymphoma?
We also still currently have approval for the EZH2 inhibitor tazemetostat
EZH2 is an epigenetic regulator and roughly 20% of follicular lymphoma patients have an activating mutation in EZH2
There was a single arm phase 2 trial that including both mutated and wild type EZH2 as the thought was the drug would have activity through epigenetic modification in either case
99 patients were enrolled with 45 patients having an EZH2 mutation and 54 patients with EZH2 wild type
The ORR was 70% in the mutated cohort and 35% in the wild type cohort
Median PFS was around 12 months
The drug was very well tolerated with minimal side effects and can be a palliative option for some patients
This led to the approval for all comers regardless of EZH2 status as single agent anti CD20 therapy had similar response rates to the wild type cohort
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
