CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: March 06, 2024
Expiration: March 05, 2025
SYMPATICO: Ibrutinib + Venetoclax vs Ibrutinib + Placebo for Patients With R/R MCL
Starting with ASH 2023 updates in the setting of indolent lymphomas, I will begin by discussing 2 studies in MCL. The first is the SYMPATICO trial, which randomized patients with previously treated R/R MCL to ibrutinib plus venetoclax vs ibrutinib plus placebo.1 In SYMPATICO, patients may have received 1 to 5 prior lines of therapy, not including a BTK inhibitor or BCL inhibitor. At 2 years, venetoclax or placebo was discontinued, and ibrutinib was continued until progressive disease or toxicity. The primary endpoint was PFS, and key secondary endpoints included complete response (CR) and ORR by investigator assessment.
SYMPATICO: Baseline Characteristics
With regards to the baseline characteristics, the 2 arms were well balanced. Overall, patients in this trial were older, which is typical for this population, with a median age of 69 and 67 for the ibrutinib plus venetoclax and ibrutinib plus placebo arms, respectively.
Approximately 29% of patients had TP53-mutated disease, which is a negative prognostic factor, and the majority had intermediate- or high-risk Mantle Cell International Prognostic Index (MIPI) score.
SYMPATICO: PFS (Primary Endpoint)
The primary endpoint of PFS was significantly improved with the addition of venetoclax to ibrutinib, with a median of 31.9 months vs 22.1 months when compared to ibrutinib plus placebo (HR: 0.65; 95% CI: 0.47-0.88; P = .0052).
SYMPATICO: Other Efficacy Outcomes
ORR was numerically higher but not statistically significantly different between arms (82% vs 74%; P = .1279), but there was a significant improvement in the CR rate with ibrutinib plus venetoclax vs ibrutinib plus placebo (54% vs 32%; P = .0004). The median duration of response (DoR) was longer in patients in the ibrutinib plus venetoclax arm (42.1 months vs 27.6 months).
SYMPATICO: Safety
Certainly, efficacy is only half of the equation when assessing a regimen’s benefit, and toxicity must be considered as well. Overall, there was not much difference between the arms in terms of grade ≥3 or serious adverse events (AEs).
SYMPATICO: Most Common Adverse Events
With respect to specific AEs, there was an increase in cytopenias, particularly neutropenia, observed in the ibrutinib plus venetoclax arm. Venetoclax is known to cause hematopoietic toxicity, so this was not unexpected with the addition of venetoclax to ibrutinib. There was also a substantial increase in diarrhea with the addition of venetoclax to ibrutinib, 65% vs 34%, which was more than I would have anticipated. Rates of grade ≥3 neutropenia (31% vs 11%), thrombocytopenia (13% vs 8%), and anemia (10% vs 3%) were higher with ibrutinib plus venetoclax compared to ibrutinib plus placebo. The rate of grade ≥3 diarrhea was slightly higher in the ibrutinib plus venetoclax arm (8% vs 2%), but the diarrhea was mostly grade 1 to 2.
SYMPATICO: Clinical Implications
The SYMPATICO trial demonstrates the benefit of the addition of venetoclax to ibrutinib. However, one aspect to consider is that the US FDA approval of ibrutinib for MCL has been withdrawn. As for how this regimen will be used, I anticipate that some healthcare professionals might extrapolate from this study regimen of venetoclax plus ibrutinib to combine venetoclax with other approved BTK inhibitors such as acalabrutinib or zanubrutinib. However, none of these combination regimens are currently FDA approved.
Should the combination of venetoclax plus ibrutinib receive FDA approval—which it may not given the withdrawal of single-agent ibrutinib in MCL—I would use it broadly in the relapsed setting. The PFS benefit is drastically improved with the combination. If this regimen were included in national clinical guidelines in the absence of approval, I would consider using it and substituting another BTK inhibitor for ibrutinib as mentioned above.
The combination of venetoclax plus ibrutinib has previously been evaluated in CLL, and no unexpected AEs were observed in this trial in MCL.
BOVen: Zanubrutinib, Obinutuzumab, and Venetoclax in Treatment-Naive TP53-Mutated MCL
Transitioning to frontline treatment for MCL, the BOVen trial evaluated the combination of zanubrutinib, obinutuzumab, and venetoclax in patients with treatment-naive TP53-mutated MCL.2 Patients with TP53-mutated MCL have poor outcomes with standard of care first-line chemoimmunotherapy.3 In BOVEN, it is important to note in the treatment schedule that the standard 5-week ramp-up of venetoclax starts with Cycle 3, after initial cytoreduction with zanubrutinib and obinutuzumab.2 Furthermore, obinutuzumab is administered for 8 total cycles, longer than we typically see with other regimens, so treatment with obinutuzumab and venetoclax overlap by 6 months. After 24 cycles, treatment with zanubrutinib and venetoclax followed a minimal residual disease (MRD)–guided approach; those in CR with undetectable MRD discontinued treatment, and those who were not in CR and/or had detectable MRD continued both medications.
BOVen: Response
The ORR was very high with this triplet regimen of zanubrutinib, obinutuzumab, and venetoclax. The best ORR was 96% with a complete metabolic response of 88%. At Cycle 3 Day 1, the ORR was 76% with a complete metabolic response of 68%. Of note, the combination of zanubrutinib plus obinutuzumab is fast-acting, with most patients achieving a response within 2 cycles prior to the addition of venetoclax.
Five patients experienced progressive disease and there were 4 deaths on this regimen: 2 COVID-related, 1 of unknown etiology, and 1 from pneumonia/respiratory failure.
BOVen: Survival
The survival data for this study is relatively immature at this point, with a 2-year PFS rate of 72%. This is impressive compared with historical controls, particularly in this difficult-to-treat population with TP53-mutated disease.
BOVen: Clinical Implications
Although the results of BOVen are very early, the PFS data with the triplet regimen of zanubrutinib, obinutuzumab, and venetoclax are impressive. I anticipate that we will see other 3-drug regimens combining venetoclax with a BTK inhibitor being evaluated in the front-line setting in MCL, not just in the TP53-mutated patient population but a larger group as well.
First-line Mosunetuzumab Subcutaneous for High Tumor Burden Follicular Lymphoma
Now I want to discuss several studies in follicular lymphoma (FL). One of the mainstays of front-line treatment for FL has been chemoimmunotherapy. The BRIGHT4 and StiL5 trials demonstrated that the combination of bendamustine and rituximab is superior to other frontline chemoimmunotherapy regimens. This is a commonly used regimen, but the hope is to move towards a chemotherapy-free approach. One way to achieve this is through the use of bispecific antibodies such as mosunetuzumab which targets CD20 and engages T-cells via CD3. Mosunetuzumab administered intravenously has accelerated approval for the treatment of adult patients with R/R FL after 2 or more lines of systemic therapy based on response rates in a phase II study.6,7
This phase II trial evaluated mosunetuzumab in the front-line setting, administered subcutaneously (SC), which is an investigational approach.8 Included were patients with grade 1 to 3A advanced stage FL who met the GELF criteria for treatment. It is important to note that the BRIGHT trial4 did not include grade 3A patients, which is typically a more difficult population to treat. Here, patients received 8 cycles of SC mosunetuzumab administered every 21 days and then were assessed for response. Those in CR went onto observation, those with PR continued mosunetuzumab for up to 17 cycles, and those without response came off study.8
First-line Mosunetuzumab SC for FL: Baseline Characteristics
The median age in this study was 58 years, which is somewhat younger than expected for FL. The patients did have higher FLIPI scores—55.6% with FLIPI 2 and 25.9% with FLIPI 3 to 4. The level of bulky disease was also high with 33.3% having a mass >7 cm.
First-line Mosunetuzumab SC for FL: Response
The ORR with first-line mosunetuzumab was 96%, with a CR rate of 76%. This is one of the highest ORR and CR rates that I am aware of for any therapy for front-line treatment of FL. Looking at some higher risk subgroups, patients with grade 3A (n = 11) and bulky disease (n = 14) also did well, with CR rates of 73% and 79%, respectively, although these were small subgroups.
First-line Mosunetuzumab SC for FL: TEAEs
A key point with mosunetuzumab that is different from other bispecific antibodies that we use in multiple myeloma and DLBCL, is that it does not require hospitalization to administer.6 Although CRS is a concern with administration of bispecific antibodies in general, in this study there was a low rate of CRS, which was entirely grade 1/2, with mosunetuzumab SC8; this is consistent with previous reports for mosunetuzumab IV.6 There also was no immune effector cell–associated neurotoxicity syndrome (ICANS) with mosunetuzumab SC.8 With regard to other toxicities, low-grade rash occurred in 54%. Generally, grade ≥3 AEs were uncommon, with grade ≥3 neutropenia occurring most often, in 13% of patients.
First-line Mosunetuzumab SC for FL: CRS
To further evaluate the occurrence of CRS in this study, grade 1 CRS—which is essentially a fever and something most people consider an infusion reaction—was observed in 53.7% of patients. Grade 2, where we begin to see hypotension, was less common, occurring in 3.7%. Most CRS events happened following the initial injection on Cycle 1 Day 1, which is why we use step-up dosing to mitigate the risk of CRS.
As seen in the table, CRS does not necessarily happen immediately following the SC injection, but may occur hours later, with the episodes being increasingly delayed the longer the therapy is administered (median time of onset of 27.4 hours, 46.0 hours, and 79.5 hours with episodes 1, 2, and 3, respectively).
Fortunately, CRS resolved quickly in all patients in this study, and most did not require corticosteroids or tocilizumab for CRS.
Overall, mosunetuzumab is very well tolerated. If patients present with a fever, they can be treated with acetaminophen and observed as long as they are not neutropenic. Some centers send patients home with a prescription for dexamethasone to use in the event of a fever. It is very rare to see higher grade CRS with mosunetuzumab requiring tocilizumab therapy, but it is important to be prepared and to know where to send patients if they do need it. Not all hospitals stock tocilizumab as it is costly and has a relatively short shelf life.
First-line Mosunetuzumab SC for FL: Clinical Implications
This phase II data with mosunetuzumab SC is very exciting and important. The ongoing MorningSun trial (NCT05207670) is a larger study evaluating mosunetuzumab SC in various settings in B-cell lymphomas, including untreated FL. Currently, mosunetuzumab (IV or SC) is not FDA-approved in the frontline setting for FL, but I am hopeful that we will be able to use it in the future for patients with untreated FL. In general, I anticipate that we will see more non–chemotherapy-based treatments being evaluated in FL.
TRANSCEND FL: Lisocabtagene Maraleucel as Second-line Therapy for High-Risk R/R FL
Now I am going to talk about 2 studies evaluating CAR-T cell therapy in FL. Axicabtagene ciloleucel9 and tisagenlecleucel10 are the 2 CD19-directed CAR T-cell therapies currently approved by the FDA for the treatment of R/R FL and I will provide an update on the latter below.
Lisocabtagene maraleucel is another CD19-directed CAR T-cell therapy currently approved for large B-cell lymphoma, including grade 3B FL, in the R/R setting.11 In the TRANSCEND FL study, lisocabtagene maraleucel was evaluated in patients with R/R FL with high risk features.12
TRANSCEND FL: Baseline Characteristics
In this analysis, patients were separated by line of therapy, with 23 receiving lisocabtagene maraleucel in the second line and 107 receiving it as third line or higher. The patients receiving therapy in the second line were slightly younger than those in the third-line or higher setting, median age of 53 vs 62 years, respectively. Patients in the third-line or higher setting had received a median of 3 prior therapies (range: 2-10). A greater percentage of patients in the third-line or higher setting were refractory to anti-CD20 and alkylator therapy vs those in the second-line setting (64% vs 48%, respectively).
However, more patients in the second-line setting had progression of disease within 24 months (POD24) of first chemoimmunotherapy (65% vs 54%) and from diagnosis (52% vs 43%) compared to those in the third-line or higher setting.12 POD24 from chemoimmunotherapy or diagnosis defines a very poor-risk group of patients. As shown in the LymphoCare study, approximately 20% of patients with FL will have POD24.13 In the 80% without POD24, who can have a near-normal life expectancy, we want to be cautious about which therapy we use. For the difficult-to-treat group of patients with POD24 who are more likely to have adverse outcomes from their disease, more aggressive therapies such as CAR T-cell therapy may provide important treatment options.
TRANSCEND FL: Efficacy
In TRANSCEND FL, the ORR was 96% in the second-line setting and 97% in the third-line or higher setting, with almost all patients achieving a CR (96% and 95%, respectively).12 The median follow-up of approximately 17 months is relatively short at this time, thus the median DoR, median PFS, and median OS have not been reached. However, if you look at the 12-month analysis, the PFS rate was 91.3% and 80.7% in the second-line and third-line or higher settings, respectively. This is dramatically better than would be expected with other available treatment options in this patient population.
TRANSCEND FL: Safety
In terms of safety, the toxicity profile observed for lisocabtagene maraleucel is different than that of the bispecific antibodies discussed above, but improved relative to what we typically expect to see with CAR T-cell therapy in other settings. As expected, there is some hematopoietic toxicity, as well as CRS, which is predominantly low-grade.12
TRANSCEND FL: CRS and Neurologic Events
Grade 1/2 CRS was common, occurring in 52% of patients receiving second-line therapy and in 58% of patients receiving third-line or higher therapy, with a median time to onset of 6 days. Neurologic events did occur in a small group of patients—15% in second-line and 17% in the third-line or higher—and was predominantly low-grade.
TRANSCEND FL: Other AEs of Special Interest
It is becoming increasingly evident to those who administer CAR T-cell therapy that prolonged cytopenias can be seen across the different disease types where these agents are used. Prolonged cytopenias also were observed in this study, with grade ≥3 at Day 29 occurring in 13% of patients in the second-line setting and 24% of those in the third-line or higher setting.12 The incidence of prolonged cytopenias observed here with lisocabtagene maraleucel is not significantly different than what we have seen with other CAR T-cell therapies administered in the same setting.
This is important because if a patient has prolonged, persistent cytopenias and then experiences disease progression after receiving CAR T-cell therapy, it can be a challenge to administer further therapies that also are associated with a risk of cytopenias.
ELARA: Tisagenelecleucel in R/R Follicular Lymphoma
As mentioned above, tisagenlecleucel currently has accelerated FDA approval for R/R FL after 2 or more lines of systemic therapy, based on results of the phase II ELARA trial.10 Presented here is longer follow-up of ELARA in patients with R/R FL, with a median follow-up of 40.6 months.14
ELARA 3-Yr Follow-up: Baseline Characteristics
ELARA included 97 patients with a median age of 57 years. Approximately two thirds of patients had POD24 from the first anti-CD20 monoclonal antibody (mAb)–containing therapy and 78% were refractory to their last therapy. Many (68%) were double refractory to both an anti-CD20 mAb and an alkylating agent, and 14% were refractory to a PI3K inhibitor.
ELARA 3-Yr Follow-up: Safety
All-grade CRS occurred in 50%, with only 1 patient experiencing grade 3 or higher CRS. This is similar to what was seen with lisocabtagene maraleucel above in terms of CRS events. Incidence of prolonged cytopenias was not reported.
ELARA 3-Yr Follow-up: PFS by POD24 Status
PFS varied according to POD24 status. The patients with POD24 had lower PFS than those who did not, with 36-month PFS rates of 50% and 59%, respectively. The median PFS for the entire population was 37 months, with a 36-month PFS rate of 53%.
ELARA 3-Yr Follow-up: OS by POD24 Status
OS was also reported according to POD24 status, and there was no difference in OS between those who did and did not have POD24, with 36-month OS rates of 83% and 80%, respectively.
CAR-T Cell Therapy in FL: Clinical Implications
In my opinion, the role of CAR T-cell therapy is rather limited in patients with R/R FL. Most patients can achieve good outcomes with other therapies that are less toxic, such as mosunetuzumab. Where CAR T-cell therapy may have a role in FL is for patients with POD24, after 2 or 3 prior therapies. The ongoing randomized phase III ZUMA-22 trial evaluating axicabtagene ciloleucel vs standard chemoimmunotherapy regimens in R/R FL (NCT05371093) will hopefully also shed light on how best to incorporate CAR T-cell therapy into the management of FL.
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