ASH 2022: Lymphomas and CLL

CME

Key Studies in Lymphomas and CLL: Independent Conference Coverage of ASH 2022

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit

Released: April 17, 2023

Expiration: April 16, 2024

John M. Burke
John M. Burke, MD
Peter Martin
Peter Martin, MD

Activity

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Course Completed

TRIANGLE: Phase III Trial of Ibrutinib + CIT ± ASCT vs CIT Followed by ASCT in Previously Untreated MCL

Peter Martin, MD:
The first 2 studies from ASH 2022 that we will discuss are in MCL. The first is the TRIANGLE trial, which is a randomized, open-label phase III trial evaluating the efficacy and safety of ibrutinib plus CIT with or without ASCT in younger patients (aged 65 years or younger) with MCL (N = 870).1 

Along with the development of BTK inhibitors such as the first-in-class BTK inhibitor ibrutinib, which is approved for use in patients with MCL who have received ≥1 prior therapy,2 the TRIANGLE study is the culmination of a series of trials in MCL conducted over the past decade.3,4 MCL Younger was a randomized, open-label phase III study carried out by the European MCL Network that showed longer median progression-free survival (PFS) (39 months vs 17 months, respectively; P = .010) and 3-year overall survival (OS) rate (83% vs 77%, respectively; P = .18) with ASCT plus interferon maintenance compared with ASCT alone in younger patients (aged 65 years or younger) with PR/CR with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy.5 

A second trial by the European MCL Network, also in younger patients with MCL, showed a significantly higher time to treatment failure with alternating doses of rituximab plus CHOP (R-CHOP) and rituximab plus dexamethasone/high-dose cytarabine/cisplatin (R-DHAP) followed by high-dose cytarabine conditioning and ASCT vs R-CHOP followed by myeloablative radiochemotherapy and ASCT at 6 years of follow-up (median time to treatment failure: 9.1 years vs 3.9 years, respectively; HR: 0.56; P = .038).6 Similar findings were observed in a subsequent analysis with 10 years of follow-up.7 Finally, a French phase III study carried out by the Lymphoma Study Association demonstrated a clear OS and PFS benefit with the addition of maintenance rituximab following ASCT (P ≤.001).8

The TRIANGLE study has 3 arms.1 Arm A (in green), the control, is composed of the current SoC for previously untreated MCL: alternating cycles of R-CHOP and R-DHAP followed by ASCT. Arm A + I (in blue) builds on the SoC by adding ibrutinib to the cycles of R-CHOP, along with 2-years of ibrutinib maintenance. Ibrutinib was given only with R CHOP, and not R DHAP, because of the risk of thrombocytopenia with both DHAP and ibrutinib. Finally, like arm A + I, arm I (in orange) includes ibrutinib with R-CHOP and as maintenance but excludes ASCT. 

The primary endpoint in this study was FFS, with secondary endpoints including response rates, PFS, OS, and safety.

TRIANGLE: Baseline Characteristics and Responses at End of Induction Therapy

Peter Martin, MD:
In TRIANGLE, patient characteristics for all 3 treatment arms were well balanced and consistent with other similar clinical trials.1 

Response rates at the end of the induction period observed in control arm A (SoC only) are consistent with those observed in the earlier European MCL Network trial mentioned above (94% in both).6 In patients who received ibrutinib during induction, there appears to be an increase in CR rate vs those who received SoC (45% vs 36%, respectively).

TRIANGLE: FFS (Primary Endpoint)

Peter Martin, MD:
Of interest, similar FFS outcomes were observed in both arms with ibrutinib despite one not including ASCT. The median FFS was not reached in any of the 3 treatment arms, but there appears to be a benefit to both ibrutinib-containing arms vs the SoC arm.  

TRIANGLE: Survival

Peter Martin, MD:
Similarly, the median OS was not reached in any of the treatment arms. However, there appears to be slight superiority in OS in the ibrutinib-containing arms compared with the SoC arm, although no definitive conclusion can be made because of data prematurity and lack of statistical significance. However, it is apparent that OS is not negatively affected by ibrutinib, and with longer follow-up, a more favorable OS may emerge with ibrutinib, especially if longer term toxicities, including secondary malignancies, occur with ASCT.

Although a slightly higher death rate was observed for the SoC arm compared with the ibrutinib-containing arms, there was little difference between treatment arms regarding cause of death. There were slightly more lymphoma related deaths with SoC (5.6% vs 3.8% with ibrutinib only and 1.4% with the ASCT/ibrutinib combination), but the numbers are small, and longer follow-up is needed to draw any definitive conclusions.

TRIANGLE: Survival (cont'd)

TRIANGLE: Safety With Induction and ASCT

Peter Martin, MD:
Any therapeutic added to SoC therapy must be evaluated for increased toxicity. During the induction phase and with ASCT, no notable differences in grade 3-5 AEs were observed between those who received ibrutinib and those who did not. The most common grade 3-5 AEs were blood and lymphatic system disorders, such as thrombocytopenia, neutropenia, and anemia. These disorders were noted in 71% to 76% of patients in the induction phase and 59% of patients who received ASCT—again regardless of ibrutinib.

TRIANGLE: Safety With Induction and ASCT (cont'd)

TRIANGLE: Safety With Maintenance

Of interest, during maintenance/follow-up, patients receiving ASCT plus ibrutinib experienced significantly greater toxicity compared with patients receiving ibrutinib without ASCT and SoC; 50% of patients receiving ASCT plus ibrutinib had grade 3-5 blood and lymphatic system disorders compared with 21% receiving SoC and 28% receiving ibrutinib without ASCT. The rate of grade 3-5 infections and infestations was 25% with ASCT plus ibrutinib compared with 13% with SoC and 19% with ibrutinib without ASCT. Between the latter 2 arms, patients receiving ibrutinib experienced more AEs than their counterparts receiving SoC, although the results were not clinically meaningful.

TRIANGLE: Clinical Implications

Peter Martin, MD:
Multiple observational trials over the past decade have set the stage for eliminating ASCT in the frontline treatment of MCL. However, until now, there was no direct experimental evidence, which makes TRIANGLE one of the most exciting studies to report over the past 5 years. Although this study still needs to go through peer review, and longer follow-up will clarify the survival data, these data tip the scales toward elimination of ASCT for these patients and paves the way for future trials comparing nonchemotherapy based vs chemotherapy induction regimens. At some point in the future, studies may show that chemotherapy is entirely unnecessary in this setting.

John M. Burke, MD:
To me, 2 definite conclusions can be drawn from these data. First, adding ibrutinib to our conventional strategy of treating newly diagnosed MCL is clearly improving FFS over SoC, and this is the first time this has been shown in a transplant eligible population. However, in the SHINE study, ibrutinib also was shown to improve PFS compared with standard chemotherapy in a transplant-ineligible population.

Second, ASCT, the conventional strategy for first-line treatment of MCL, is not superior to leaving out the transplant, as long as ibrutinib is added. That said, I am not quite ready to entirely eliminate ASCT or use ASCT plus ibrutinib in my practice based on these results, but I do agree that it looks like where the data may be heading. Where these data already are affecting my practice is for patients who are borderline for ASCT, such as older patients with comorbidities. I discuss these data with such patients, and they may elect to eliminate ASCT entirely and instead add ibrutinib or another BTK inhibitor at some point in their therapy.

Peter Martin, MD:
Another question that needs to be addressed is whether a BTK inhibitor is required during the induction or if its use could be limited to maintenance. Unfortunately, this trial does not provide the answer to this question. Other points to consider are whether there is a way to avoid increased toxicity with drug combinations and whether outcomes would differ based on which BTK inhibitor was used. Head-to-head BTK inhibitor trials in MCL would be useful to answer the last question. 

John M. Burke, MD:
Data from CLL studies suggest that some of the newer BTK inhibitors have less toxicity and may, in some cases, have advantages in terms of efficacy, but no such data exist for MCL to my knowledge.

When discussing treatment options with a 74-year-old patient with newly diagnosed mantle cell lymphoma (MCL), what would you tell them regarding failure-free survival (FFS) reported from the phase III TRIANGLE trial in previously untreated MCL, which compared the standard of care (SoC) of chemoimmunotherapy (CIT) followed by autologous stem cell transplant (ASCT) with either SoC plus ibrutinib or the ASCT-free option of CIT plus ibrutinib, each with ibrutinib maintenance therapy being given for 2 years?

Acalabrutinib + R2 With MRD Monitoring in Previously Untreated MCL

Peter Martin, MD:
The second study in MCL builds on a prior phase II trial in patients with previously untreated MCL where induction and maintenance R2 was associated with an overall response rate (ORR) of 92%, with a CR rate of 64%.10,11 The goal of the phase II trial reported at ASH 2022 by Ruan and colleagues12 was to build on that efficacy while reducing some of the long term toxicity seen with R2, with the idea being that addition of a BTK inhibitor may enhance efficacy, thereby allowing for response-adapted treatment adjustments of R2 to reduce the risk for AEs.12 The BTK inhibitor selected for this combination was acalabrutinib because of prior issues with rash when the BTK inhibitor ibrutinib was combined with R2.13

Patients with previously untreated MCL (N = 24) received 1-12 cycles (up to 12 months) of acalabrutinib plus R2 during induction and upon reaching CR/PR could progress to receiving maintenance acalabrutinib plus R2.12 After 24 cycles (ie, 2 years), patients who were negative for MRD could stop acalabrutinib and lenalidomide while continuing rituximab until progression of disease, whereas those who were MRD positive remained on combination therapy.

The primary endpoint for this study was MRD-negative CR rate, and the secondary endpoints were ORR, survival, and safety.

Acalabrutinib + R2 in Untreated MCL: Baseline Characteristics

Peter Martin, MD:
Patient characteristics in this trial were very similar to those in the prior trial evaluating R2 in untreated MCL.10 However, TP53 status also was assessed in this study.12 Here, 25% of patients had a TP53 mutation, and approximately 33% had elevated Ki 67 (>30%).

Acalabrutinib + R2 in Untreated MCL: Response

Peter Martin, MD:
At the end of induction (upon completion of 12 cycles), the ORR with acalabrutinib + R2 was 100%, with a CR rate of 83%. This is an improvement compared with the phase II study evaluating R2 alone, where the ORR was 92%, with a CR rate of 64%.10

Acalabrutinib + R2 in Untreated MCL: Molecular Remission in Peripheral Blood

Peter Martin, MD:
Molecular remission was evaluated in patient blood samples. By the end of induction, approximately two thirds of patients, including those with TP53 mutations, had achieved an MRD negative CR.

Acalabrutinib + R2 in Untreated MCL: Survival

Peter Martin, MD:
Although follow-up is still somewhat limited, the 2-year OS and PFS rates were 100% and 87%, respectively. Of interest, of the 7 patients with TP53 mutations, 2 patients who previously had responded to therapy experienced disease progression, which raises the concern that even with novel therapies, challenges continue to exist in treating disease with TP53 mutations.  

Acalabrutinib + R2 in Untreated MCL: Safety

Peter Martin, MD:
A challenge unique to conducting a clinical trial during a pandemic presented itself during this study, with almost all patients on this trial experiencing a COVID 19 infection and pneumonia. However, they all received monoclonal antibodies and antivirals and recovered.  

During the induction phase, the rate of any-grade rash was 88%, and the rate of grade ≥3 rash was 42%. During the maintenance phase, the rate of any-grade rash dropped to 14%, with no grade >3 events. Although the incidence of rash was high during induction, it may not have been as prevalent as in previous studies.13 Other AEs were consistent with former findings for these drugs. 

Acalabrutinib + R2 in Untreated MCL: Safety (cont'd) 

Acalabrutinib + R2 in Untreated MCL: Clinical Implications

Peter Martin, MD:
Given that this is a small phase II trial with limited follow-up, it is hard to draw firm conclusions. However, these data do further the concept that began with the earlier R2 trial, which is that nonchemotherapy containing regimens can be effective in select patients with untreated MCL. There has been a proliferation of other similar trials evaluating various nonchemotherapy regimens, and the future question likely will not be whether these regimens are used instead of chemotherapy, but rather which regimen to use instead of chemotherapy. This research already has been carried out for CLL, and those results may help guide our studies in MCL. 

John M. Burke, MD:
Acalabrutinib plus R2 certainly looks like a promising regimen, but the study has limitations in that it was a single-arm, single-institution study that enrolled a small number of patients. Unlike the TRIANGLE study,1 which included approximately 900 patients, the limited number of patients in this study12 make it unlikely that community healthcare professionals would adopt this regimen in routine care. However, for patients in special circumstances, acalabrutinib plus R2 may be a viable option.

ELM-2: Phase II Trial of Odronextamab in R/R FL

Peter Martin, MD:
The next 3 trials being discussed are on FL.

A new drug class emerging in the treatment landscape for indolent non-Hodgkin lymphoma (NHL) is the CD20xCD3 bispecific antibodies, which bind 2 epitopes simultaneously: CD20 on malignant B-cells and CD3 on T-cells.14 Currently, several bispecific agents are being studied for NHL, with the first approved by the FDA being mosunetuzumab for adults with R/R FL after ≥2 lines of systemic therapy.15 This approval was based on a single-arm, multicenter phase II study in adults with R/R FL after ≥2 lines of prior therapy including an anti-CD20 monoclonal antibody and an alkylating agent.16 An ORR of 80% (95% CI: 70%-88%) was achieved with mosunetuzumab, and 60% of patients had a CR (95% CI: 49.1%-70.2%). 

In the phase I ELM-1 trial, the safety and efficacy of another CD20xCD3 bispecific antibody, odronextamab, was evaluated in patients with CD20-positive B-cell NHL (grade 1-3a FL or diffuse large B-cell lymphoma [DLBCL]) who had received ≥2 lines of therapy, including an anti-CD20 monoclonal antibody.17 In patients with FL, odronextamab achieved an ORR of 91%, with a CR rate of 72%. 

The results of ELM-1 led to the pivotal phase II ELM-2 trial evaluating odronextamab monotherapy in adults with R/R B-cell NHL, which has 5 disease-specific cohorts: FL, DLBCL, MCL, marginal zone lymphoma, and other B-cell NHL types (NCT03888105). The FL cohort reported at ASH 2022 included patients with low-grade or slow-growing FL (grades 1-3a).18

Patients were given odronextamab IV in 21-day cycles with step-up dose escalation to mitigate risk for CRS. In cycle 1, patients received 1 of 2 step-up regimens, along with premedication to the first single full dose. Premedication included 20 mg dexamethasone IV 1-3 hours before the infusion of odronextamab, along with 25 mg diphenhydramine IV or PO and 650 mg acetaminophen PO 30-60 minutes before.

For cycle 1, the study was initiated with 0.5 mg on Day 1 and 2, 10 mg on Day 8 and 9, and 80 mg on Day 15. This was modified to 0.2 mg on Day 1, 0.5 mg on Day 2, 2 mg on Day 8 and 9, and 10 mg on Day 15 and 16. In cycles 2-4, patients received 80 mg odronextamab on Days 1, 8, and 15, then 160 mg every 2 weeks as maintenance until disease progression.

ELM-2: Baseline Characteristics of FL Cohort

Peter Martin, MD:
The patient population in ELM-2 is similar to the study that led to the approval of mosunetuzumab for R/R FL with ≥2 prior lines of therapy.16 The median age was 61 years, with roughly equal sex distribution.18 Of the 131 patients, 30.5% had undergone prior ASCT, 71.0% were refractory to the last line of therapy they received, 74.8% were refractory to an anti-CD20 antibody, 43.5% were refractory to both alkylating agents and anti-CD20 antibodies, and 48.1% experienced progression of disease or relapse within 2 years of diagnosis.

ELM-2: Response in FL Cohort

Peter Martin, MD:
In patients with indolent FL, odronextamab achieved an ORR of 82%, with a CR rate of 75%. This is quite promising for a single agent in a population of patients who have been fairly heavily pretreated, as described above. 

ELM-2: DoR and PFS in FL Cohort

Peter Martin, MD:
The 18-month duration of response (DoR) and PFS rates with odronextamab were 55.0% and 55.3%, respectively. These data are attractive, but not overwhelmingly so. Similar to what we are seeing with CAR T-cells in patients with FL, bispecific antibodies are active in a heavily pretreated patient population, but it is unlikely that this will translate into a cure.

ELM-2: Safety in FL Cohort

Peter Martin, MD:
Approximately three quarters of all patients experienced grade ≥3 treatment-emergent AEs with odronextamab. Treatment-related CRS was observed in 56% of patients, with 5.9% and 1.6% of patients experiencing grade 3 CRS with the shorter step-up regimen vs the slightly longer step-up regimen, respectively, in cycle 1. Most patients received corticosteroids, tocilizumab, or vasopressors as supportive care for CRS.

ELM-2: Clinical Implications in FL Cohort

Peter Martin, MD:
The CD20xCD3 bispecific antibody odronextamab, like mosunetuzumab, is clearly active in R/R FL. It is promising to see this new class of agents consistently demonstrating efficacy, and I look forward to seeing how the FDA interprets all of these results.

John M. Burke, MD:
Yes, I agree. These results look very similar to those seen with mosunetuzumab in this population, and because mosunetuzumab was just approved by the FDA, I anticipate that odronextamab may be headed for the same approval and may be available in the clinic within the next year or so.

Peter Martin, MD:
I will add that maybe I was overly optimistic that these treatments would have longer benefit than what we are seeing. However, as we will discuss next with the EPCORE NHL-2 study,19,20 their full potential might be realized when used in combination with other agents.

EPCORE NHL-2: Phase Ib/II Trial of Epcoritamab + R2 in Treatment-Naive and R/R FL

Peter Martin, MD:
Like mosunetuzumab and odronextamab, epcoritamab is a CD20xCD3 bispecific agent that is under active study for NHL. In November 2022, it was accepted for priority review by the FDA for R/R large B-cell lymphoma (LBCL)21 based on the findings in the LBCL cohort of the EPCORE NHL-1 trial, which evaluated the safety and efficacy of epcoritamab monotherapy.22 

EPCORE NHL-2 is evaluating the combination of epcoritamab and R2, the latter of which is indicated for the treatment of adults with previously treated FL.19,20,23 The rationale for combining these therapies in the treatment of R/R FL includes their nonoverlapping mechanisms of action and the potential for the immunomodulatory properties of lenalidomide to increase the therapeutic potential of epcoritamab.24,25

This trial has multiple arms, with the initial results for arm 6 reported at ASH 2022 composed of patients with untreated CD20-positive grade 1-3a FL (N = 41)20 and arm 2b composed of patients with R/R CD20-positive grade 1-3a, stage II-IV FL (N = 76).19

Epcoritamab was administered at 48 mg SC in 28-day cycles, with step-up dosing in cycles 1 and 2 comprising priming and intermediate doses prior to first full dose, along with corticosteroids as CRS prophylaxis. For cycles 3 and beyond, epcoritamab 48 mg SC was given every 4 weeks for up to 2 years. R2 was administered at the recommended dosage (rituximab: 375 mg/m2 IV once weekly for cycle 1, then every 4 weeks for cycles 2-5 in arm 2b or cycles 2-6 in arm 6; lenalidomide: 20 mg PO once daily for 21 days in cycles 1-12). 

EPCORE NHL-2: Baseline Characteristics 

Peter Martin, MD:
Patient characteristics in arm 2b were typical of the usual patient population with FL for whom R2 is indicated, where the majority of patients with R/R disease had received 1 (54%) or 2 (28%) prior lines of therapy.19 For arm 6, which was composed of patients with untreated disease, most patients were diagnosed with stage III/IV disease (93%) with a histologic grade of 2 (71%) and had an Eastern Cooperative Oncology Group performance status of 0 (83%).20 

EPCORE NHL-2: Safety

Peter Martin, MD:
Although it is challenging to attribute specific AEs to epcoritamab alone because of its combination with R2, it is clear that the regimen resulted in grade ≥3 treatment related AEs in approximately three quarters of all patients; this was independent of whether patients had untreated or R/R disease.19,20 Of note, there were fatal treatment-emergent AEs in both arms, including septic shock (n = 1) and COVID 19–related pneumonia (n = 1) in patients with untreated disease and COVID-19 infection (n = 3) in patients with R/R FL. Furthermore, the overall rates of treatment-emergent AEs are consistent with expected rates for the R2 regimen alone. The rates of grade 3/4 neutropenia are not significantly higher than what might be expected otherwise.

EPCORE NHL-2: Safety (cont'd)

EPCORE NHL-2: CRS Events

Peter Martin, MD:
All bispecific antibodies being used in FL have CRS as a potential AE. In cohort 2b and 6 of EPCORE NHL-2, all CRS events were grade 1 or 2, with the median time to onset being 2-3 days. There appears to be a slightly higher rate of CRS in patients who were treatment naive compared with those who had prior therapies, although this could be a statistical coincidence. In all cases, the CRS resolved, although tocilizumab was required in a small number of patients.  

EPCORE NHL-2: Response

Peter Martin, MD:
Complete metabolic response rates with epcoritamab were remarkable at 86% in patients who were treatment naive and 80% in patients with R/R disease. This regimen appears to have clear activity in FL and is worthy of further study.

EPCORE NHL-2: Clinical Implications

Peter Martin, MD:
What we see with this trial is the natural progression of drug development in the current era, which is to take an effective regimen, R2, and try to build on it. Based on the very high complete metabolic response rates observed, it does appear as though the addition of epcoritamab may improve efficacy in the treatment of FL. However, given there was no control arm, it is difficult to draw such conclusions. It is not surprising to see an increase in AEs, including CRS. CRS can sometimes be troubling, although in this study, the events were all grade 1 or 2. Overall, epcoritamab plus R2 appears to be a very promising combination regimen, but there is still work to be done. A randomized trial will be required to elucidate whether the AEs we see with the addition of drugs to R2 are justified by the improvement in efficacy.

John M. Burke, MD:
I agree—these are clearly outstanding results. The addition of epcoritamab appears to achieve deeper remissions than would be expected with R2 alone, as evidenced by the complete metabolic response rates of 80% to 86% being approximately double what one would expect with R2 alone. Also, so far the toxicity does not look too prohibitive. The unfortunate COVID-19 deaths may, sadly, be the new normal for some of the trials conducted during this new era. The CRS rates appear to be consistent with what would be expected from single agent epcoritamab. However, even if single-agent epcoritamab achieves FDA approval, I do not think combining it with R2 is ready for routine use. Rather, I would wait on randomized trial data comparing R2 with or without epcoritamab, even if the wait is a few years.

Which of the following was reported at ASH 2022 for the phase Ib/II EPCORE NHL-2 trial evaluating the combination of epcoritamab and lenalidomide/rituximab (R2) in patients with treatment-naive or relapsed/refractory (R/R) follicular lymphoma (FL)?

SYMPHONY-1: Phase Ib Confirmatory Study of Tazemetostat + R2 in R/R FL 

Peter Martin, MD:
The last study in FL is the phase Ib/III SYMPHONY 1 trial—which I consider a rational combination study, in that it was predicated on evidence from multiple groups around the world—demonstrating that tazemetostat, an EZH2 inhibitor, not only has direct antilymphoma effects, but also has the potential to affect the tumor microenvironment favorably such that other immune directed therapies, such as lenalidomide, may have improved efficacy.26,27 

Batlevi and colleagues28 reported the results of the fully enrolled dose-escalation phase 1b portion at ASH 2022. Tazemetostat was given in 28-day cycles, with dose escalation from 400 mg up to 800 mg twice daily, which is the current FDA-approved dose for a single-agent tazemetostat.29 R2 was given at its standard dose and schedule.23 

SYMPHONY-1: Baseline Characteristics

Peter Martin, MD:
The patient characteristics of SYMPHONY-1 are what would be expected from a clinical trial with R2, with the majority of patients having a history of 1 (68.2%) or 2 (15.9%) prior lines of therapy and all patients having received an anti-CD20 monoclonal antibody (either alone or with chemotherapy).28   

SYMPHONY-1: Study Drug Exposure and Dose Modifications

Peter Martin, MD:
Although doses of 400 mg and 600 mg twice daily also were evaluated, 800 mg twice daily was determined to be the recommended phase III dose of tazemetostat to use in combination with R2 for the phase III portion of SYMPHONY-1.   

Dose interruptions of any study drug were not uncommon, occurring in 68.2% of patients. Dose reductions and discontinuations occurred in 13.6% and 20.5% of patients, respectively. In patients who received ≥1 dose of tazemetostat, 61.4%, 4.5%, and 13.6% experienced tazemetostat dose interruption, reduction, or discontinuation, respectively. 

SYMPHONY-1: Safety

Peter Martin, MD:
The combination of tazemetostat plus R2 was fairly well tolerated. There were some cytopenias, as expected with R2, and potentially some mild gastrointestinal AEs that tazemetostat may contribute to, but no definitive conclusions can be made without randomized trial data.

SYMPHONY-1: Response in Overall Population and by EZH2, Rituximab Sensitivity, and POD24 Status

Peter Martin, MD:
The ORR achieved with this regimen was 97.6% in the overall population, with a CR rate of 51.2%. As expected, there was a higher response rate among patients with an EZH2 mutation vs wild type EZH2 (100% vs 97.0%). An ORR of 100% also was demonstrated in patients with progression of disease within 24 months or rituximab-refractory disease.

SYMPHONY-1: PFS in Overall Population and by EZH2, Rituximab Sensitivity, and POD24 Status

Peter Martin, MD:
It is difficult to draw conclusions about the PFS results given that the median follow-up in SYMPHONY-1 is only 11.2 months, but responses do appear durable, with a 12-month PFS of 84.8% in the overall population and similar results across the subgroups tested. I look forward to seeing these data after longer follow-up.

SYMPHONY-1: Clinical Implications

Peter Martin, MD:
In summary, SYMPHONY-1 is based on strong preclinical science, and these early results show that the combination of tazemetostat plus R2 is active and reasonably well tolerated, enough so to be worthy of evaluation in a randomized setting.

John M. Burke, MD:
I agree that it is difficult to draw any conclusions about PFS from these early results with a median follow-up of only 11 months. Even so, achieving CR in one half of the patients is still impressive—although not as impressive as the results we just saw with the combination of epcoritamab plus R2

This is not a regimen I plan to use today or tomorrow, but I certainly will be enrolling patients on the randomized phase III trial evaluating R2 with tazemetostat or placebo in patients with R/R FL after ≥1 prior systemic therapy (NCT04224493), and I encourage our readers to do the same if they have access to the trial.