CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: August 23, 2024
Expiration: August 22, 2025
ECHO (ACE-LY-308): Acalabrutinib + BR vs Placebo + BR in Older Patients With Untreated MCL
At EHA 2024, one of the most anticipated presentations in MCL was the ECHO trial. This international, double-blind, placebo-controlled, randomized phase III trial assessed the combination of acalabrutinib and BR vs placebo with BR in older patients with previously untreated MCL. The goal was to assess if adding a second-generation well-tolerated covalent Bruton tyrosine kinase (BTK) inhibitor to the backbone of BR improved efficacy and met the requirements of minimal additional or no additional toxicity compared with the standard of care with BR.1,2 Patients enrolled on the trial had to be 65 years of age or older and have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Nearly 600 patients were randomized 1:1 to the experimental and placebo groups. Acalabrutinib was added to BR and was continued to disease progression or intolerable toxicity in the experimental arm. Similarly, placebo was continued to progression or intolerable toxicity in the control arm. PFS by independent review was the primary endpoint of the study. Key secondary endpoints included ORR by independent review, overall survival (OS), and safety endpoints.2
ECHO: Baseline Characteristics
In this study that enrolled patients aged 65 years or older, the median age in both arms was 71 years. Just more than two thirds of the patients were male, and most patients had an ECOG PS of 0/1.
A small proportion of patients had blastoid or pleomorphic morphology, and TP53 status was generally unknown in most patients since only a small number of patients were tested. The simplified Mantle Cell Lymphoma International Prognostic Index score was a stratification factor, and the groups were well balanced.2
ECHO: PFS (Primary Endpoint)
The primary endpoint of PFS improvement was met over the median follow-up of 45 months. Acalabrutinib plus BR improved PFS compared with placebo plus BR with a stratified HR of 0.73 (95% CI: 0.57-0.94; log-rank P = .0160). The median PFS with acalabrutinib was 66.4 months compared with 49.6 months with placebo. Overall, the acalabrutinib plus BR arm significantly prolonged the PFS by approximately 17 months compared with the control arm. Among the 99 patients with disease progression in the placebo plus BR arm, 69% subsequently received a BTK inhibitor.2
ECHO: Safety
The safety profile between the 2 arms was broadly comparable. Overall, there were similar rates of grade ≥3 treatment-emergent adverse events (AEs) and grade 5 treatment-emergent AEs in both groups. Deaths as a result of progressive disease were relatively similar, although there were numerically more progressive disease-related deaths in the placebo plus BR arm.2
ECHO: AEs of Interest and COVID-19–Related Events
AEs of special interest and COVID-19–related events were also reported in the trial since it took place during the COVID-19 pandemic.
Atrial fibrillation, hypertension, and bleeding are AEs known to be associated with BTK inhibitors. In ECHO, the addition of acalabrutinib to BR did not clearly increase the rates of any-grade or grade ≥3 atrial fibrillation, hypertension, or major bleeding.
Early in the trial, a prespecified COVID-19 sensitivity analysis was added to the study protocol. There were more COVID-19–related AEs in the acalabrutinib plus BR arm compared with placebo. Grade ≥3 and grade 5 COVID-19–related AEs and COVID-19–related serious AEs were numerically higher in the acalabrutinib plus BR arm. COVID-19–related AEs leading to discontinuation of acalabrutinib were also numerically higher compared with placebo.2
ECHO: Prespecified Sensitivity Analyses of PFS and OS With and Without COVID-19 Deaths
ECHO had a prespecified sensitivity analysis for survival endpoints and patients were censored for COVID-19 deaths. When a prespecified sensitivity analysis for PFS between the 2 treatment groups was performed, the HR for the full analysis population was 0.73 (P = .0160). After COVID-19 deaths were censored, the HR was 0.64 (P = .0017).
A similar analysis was performed for OS. The HR in the full analysis population was 0.86, which was not statistically significant. When the COVID-19 deaths were censored, the HR was reduced to 0.75 (P = .0797), suggesting a trend toward an overall improvement in survival. Acalabrutinib plus BR reduced the risk of progression or death overall by 36% and reduced the risk of death by 25% with the censoring of COVID-19 deaths.2
ECHO: Clinical Implications
This is an important clinical trial because it demonstrates that adding a well-tolerated second-generation BTK inhibitor to one of our standard chemotherapy backbones improves PFS compared with a standard-of-care chemoimmunotherapy regimen. When COVID-19 is set aside, the AE profile for the addition of a BTK inhibitor does not seem to be concerning since there were no significant differences in BTK-related AEs of particular interest. This study was performed in the depths of the pandemic, prior to when vaccination and therapies for COVID-19 were available for most patients. When the COVID-19 sensitivity analysis is performed, patient survival in terms of PFS and OS does seem to be greater. A key question is therefore what would the study look like if it were performed today with COVID-19 being a lesser clinical issue with improved treatments and vaccination?2
Phase II Trial of BOVen in Older Patients With Untreated MCL
This study is the phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in patients aged 65 years or older and in those who are younger but with comorbidities that precluded an autologous stem cell transplant with previously untreated MCL. The regimen was given in combination in 28-day cycles. At the end of 24 cycles, if patients demonstrated a CR and had undetectable measurable residual disease (MRD), they could stop treatment. The primary endpoint of the study is 3-year PFS rate with other endpoints including response, MRD, and safety.3
BOVen in MCL: Baseline Characteristics
Just fewer 50 patients were enrolled on the study. The patients have a median age of 71 years and most were enrolled based on age alone rather than comorbidities. A small percentage of patients (9.8%) had blastoid disease and 28% of patients had mutated TP53, as determined by next-generation sequencing.3
BOVen in MCL: Efficacy and Patient Disposition
The combination of BOVen had an ORR of 98% and a CR rate of 79%, with undetectable MRD rates increasing over time. At the end of cycle 13, all patients achieved an undetectable MRD to the sensitivity level of 1 x 10-5. At a median follow-up of 11 months, most patients still are receiving treatment with very few progression events at the time of presentation.3
BOVen in MCL: Most Common TRAEs
The triplet combination was well tolerated, with bruising and diarrhea being the most common treatment-related AEs reported. In addition, a small number of patients developed COVID-19 and other infections.3 However, there were very few treatment discontinuations because of AEs, and generally, the delivery of the treatment was manageable.
BOVen in MCL: Clinical Implications
These data provide further information regarding the BOVen regimen that uses a chemotherapy-free approach with the use of a covalent BTK inhibitor, a BCL-2 inhibitor, and an anti-CD20 antibody.4,5 This approach is highly active and likely to be developed further in MCL. The use of BOVen is favorable since it may allow patients to discontinue therapy and because it can be used across a range of patient ages and in patients with comorbidities who may not be good candidates for chemoimmunotherapy.6
SYMPATICO: Ibrutinib Plus Venetoclax in TP53 Mutations Subgroup of Patients With Previously Untreated and R/R MCL
These data area from a subanalysis of the SYMPATICO trial in patients with a TP53 mutation. Patients with TP53 mutations typically do poorly with chemoimmunotherapy, so new treatments are required for this subgroup of patients. At EHA 2024, Jurczak and colleagues7 reported a pooled analysis of patients from the open-label cohort, the safety run-in cohort in relapsed disease, and the randomized trial cohort in the SYMPATICO trial receiving a combination of ibrutinib and venetoclax. Overall, there were 74 patients with TP53 mutations: 29 in the frontline setting and 45 in the R/R setting.
SYMPATICO—TP53 Mutation Subgroup Analysis: Response to Ibrutinib Plus Venetoclax
Among the 74 patients, the CR rate with ibrutinib and venetoclax was 57% and the ORR was 84%. The CR rate was similar in patients who had previously untreated MCL and those with R/R disease.7
SYMPATICO—TP53 Mutation Subgroup Analysis: PFS and OS in Patients With vs Without TP53 Mutation
The median PFS of the TP53 mutation subgroup was just less than 21 months, with a median OS of just less than 3 years. Patients with R/R disease and those receiving first-line treatment in the TP53 mutation subgroup had similar PFS. The PFS and OS for those without a TP53 mutation is substantially longer than those with a TP53 mutation, regardless of whether they received ibrutinib plus venetoclax or ibrutinib plus placebo. Patients with a TP53 mutation do worse than those without a TP53 mutation, even when they have access to novel targeted therapies.7
SYMPATICO—TP53 Mutation Subgroup Analysis: MRD-Negative Remission Rates in Patients With vs Without TP53 Mutation
Among patients who achieved a CR with ibrutinib plus venetoclax and who were evaluable for MRD, the MRD-negative remission rates were similar regardless of the presence of a TP53 mutation.
SYMPATICO—TP53 Mutation Subgroup Analysis: Most Common AEs and Tumor Lysis Syndrome
The results from the trial suggest that ibrutinib plus venetoclax was relatively well tolerated, with no specific safety signals compared with the overall clinical trial patient population regarding diarrhea, neutropenia, fatigue, and thrombocytopenia.7
SYMPATICO—TP53 Mutation Subgroup Analysis: Clinical Implications
It is uncommon to see large datasets of patients with the TP53 mutation analyzed, so the impact of ibrutinib plus venetoclax in that group of patients is important. It suggests that there are good levels of activity initially with a relatively high ORR and high CR rate with the combination. Therefore, disease control for patients with high-risk genetic features seems possible with this combination. The PFS is reasonable in patients with R/R disease at 21 months and superior to patients who received only ibrutinib. However, for those receiving first-line therapy, a 21-month median PFS is still relatively modest, even with the use of 2 nonchemotherapy-based highly active agents, suggesting that more work needs to be done in this patient population.
Phase I/II Trial of Fixed-Duration Glofitamab, a CD20 x CD3 Bispecific Antibody, in R/R MCL: Updated Analysis
Another study presented at EHA 2024 was an updated analysis of the international, open-label phase I/II study of glofitamab administered as a fixed duration therapy for patients with relapsed MCL who had previously undergone at least 1 line of therapy. Glofitamab is a bispecific antibody targeting CD3 and CD20 and has demonstrated high efficacy in relapsed MCL. Patients were debulked with either obinutuzumab 1000 mg or 2000 mg before initiating step-up dosing of glofitamab. Subsequently, patients received up to 12 cycles of glofitamab as fixed duration treatment.8
Glofitamab in R/R MCL: Baseline Characteristics
There were 2 patient groups presented in this study: patients who were BTK naive and patients who were BTK exposed, with approximately 30 patients in both groups. The BTK-exposed patients were more heavily pretreated with a median of 3 prior lines of therapy. Most of these patients had previously received chemotherapy, a CD20 antibody, and a BTK inhibitor. Most patients in this group were refractory to the last prior line of therapy.8
Glofitamab in R/R MCL: Investigator-Assessed Response
Across the entire cohort, the ORR was 85%, with a CR rate of 78%. In patients who were BTK inhibitor naive, the ORR was 96%, with a CR rate of 86%. Among the 31 patients who had previously received a BTK inhibitor and were heavily pretreated, the ORR was 74%, with a CR rate of 71%. The study was conducted during the COVID-19 pandemic, affecting the results and complicating the analysis of certain endpoints such as the median PFS, duration of CR, and duration of response. The median duration of CR was 12.6 months in patients who had previously received a BTK inhibitor.8
Glofitamab in R/R MCL: PFS and OS
Overall, for the entire patient population, the median PFS was 16.8 months and the median OS was just less than 30 months. In patients who had previously received a BTK inhibitor, the median PFS was 8.6 months and the median OS was approximately 21 months.8
Glofitamab in R/R MCL: Safety
The safety data were analyzed based on the dose of obinutuzumab pretreatment given. Obinutuzumab effectively mitigated some of the AEs commonly associated with bispecific antibodies, most notably cytokine-release syndrome (CRS). The overall incidence rate of CRS was 87.0% in patients who had received obinutuzumab 1000 mg compared with 63.6% in patients who received obinutuzumab 2000 mg.8
Glofitamab in R/R MCL: CRS
Looking at CRS a little more closely, there was a notable decrease in high-grade CRS events. Only 6.8% of patients receiving obinutuzumab 2000 mg experienced a grade ≥3 CRS event compared with 25% of patients who received obinutuzumab 1000 mg.8
Glofitamab in R/R MCL: Clinical Implications
The data from this updated analysis are intriguing as they indicate that bispecific antibodies are highly effective in heavily pretreated patients with MCL and suggest that further investigation into this drug class is needed. The ongoing randomized phase III GLOBRYTE clinical trial is evaluating glofitamab vs investigator’s choice of therapy of either BR or lenalidomide/rituximab in patients who have been previously exposed to covalent BTK inhibitors but who are CAR T-cell naive in R/R MCL.9 It is important to note that the CR rates for patients who have previously received a covalent BTK inhibitor are comparable to those achieved with CAR T-cell therapy.10
MCL Biobank Observational Study: Study Design and Patient Disposition
The UK MCL Biobank was an observational study performed between 2014 and 2019 across 73 centers in the United Kingdom. Patients with newly diagnosed MCL were recruited and key baseline criteria were collected, including the healthcare professional’s (HCP's) intent to either start treatment immediately or to initially observe a so-called “watch-and-wait” approach. The primary outcome was the time to the first treatment. The study aimed to determine which factors influenced the decision to initiate treatment vs continue observation and to predict the duration of observation in these patients. Of interest, nearly 40%, or 222 patients of the approximately 600 patients enrolled on this study, were initially observed with HCP intent to use the watch and wait approach.11
MCL Biobank Observational Study Association Between Baseline Characteristics and HCP Intent
Associations between baseline characteristics and HCP intent were analyzed within this study. ECOG PS, stage, MIPI score, B symptoms, bulky disease, and Ki67 level were all characteristics associated with clinician intent to initiate treatment or observe the patients.11
MCL Biobank Observational Study: TTT Among Patients Assigned to Watch and Wait (Primary Outcome)
The median time to treatment for patients assigned to the watch-and-wait group was 21.3 months, with approximately one half of these patients being observed for more than 2 years. Very few patients required treatment within the first 6 months following their diagnosis, suggesting that the selection of these patients for observation was clinically appropriate. At longer follow-up, a significant minority, 22% of patients, continued to remain under observation, and 14% of patients died without requiring treatment, suggesting that 36% of patients with longer-term follow-up still never required any therapy, either because of death for another cause or because treatment for their MCL was not deemed necessary. This observation suggests that a substantial minority of patients with MCL (36%) may not require treatment in the long term.11
MCL Biobank Observational Study: OS From Diagnosis and Following First-line Treatment
The median OS for the overall patient population was 6.7 years. Patients in the watch-and-wait group had longer OS compared with those in the immediate treatment group. This is not surprising, given the lower risk clinical features associated with the observation group. However, when OS was analyzed from the time of needing treatment in the watch-and-wait group compared with the immediate treatment group, there was no difference observed, suggesting that an initial period of observation following diagnosis is not detrimental to the patients’ survival.11
MCL Biobank Observational Study: Clinical Implications
The important implications of this study include the establishment of a clinical database and biobank that allows for the characterization and identification of patients with indolent MCL who may be suitable for observation following diagnosis. This study reinforces the concept that nodal MCL can be indolent, and patients with classical histology and small-volume lymphadenopathy without symptoms can be reasonably managed with just observation.12 Another key point from the study is that with a follow-up of more than 5 years, more than one third of patients still have not required therapy. This may be because of competing mortality risks or the indolent nature of their disease that does not require treatment, suggesting that an observation approach is highly relevant and reasonable for these patients. The observation approach can allow a substantial minority of patients to benefit from never receiving potentially toxic treatment.
Typically, patients are monitored on a 3-month basis and frequency can be adjusted based on their specific clinical features. For patients with particularly indolent disease, follow-up can be less frequently. However, in MCL, patients are often monitored relatively frequently, even if they are observed, because of the relatively high chance of progression and potential need to start therapy within the first 2 years.12 Therefore, a 3-month follow-up strategy is generally considered reasonable for most patients.
Outcomes of Swedish Patients Aged 80 Years or Older With MCL: Study Design
At EHA 2024, survival outcome data from a Swedish population study of patients aged 80 years and older with MCL was presented. This registry-based study included 476 patients who were diagnosed with MCL between January 2000 and December 2019. These patients were compared with healthy individuals matched by year of birth and gender. Patients were followed until death, emigration, or the last follow-up. Because of this patient age group, 83% of the participants had died by the time of the final analysis.13
Outcomes of Swedish Patients Aged 80 Years or Older With MCL: Patient Characteristics
Among the patients with MCL, two thirds were male, and a large proportion had a substantial comorbidity score. At the time of diagnosis, 60% of the patients were aged 80-84 years, 31% were between 85 and 89 years of age, and 9% were 90 years of age or older. Not all patients received chemotherapy, but among those who did, bendamustine, chlorambucil, and CHOP-like regimens were the most common, and two thirds of patients received rituximab alongside chemotherapy treatment.13
Outcomes of Swedish Patients Aged 80 Years or Older With MCL: OS in Patients vs Comparators
When analyzing the OS of patients with MCL, patients with MCL had significantly shorter survival of only 1.5 years compared with 5.1 years for the healthy comparators. Factors associated with shorter OS include older age, worse comorbidities, a higher Ann Arbor stage, a worse ECOG PS, and the absence of rituximab treatment. Patients who did not receive any treatment had a median OS of only 6 months.13
Outcomes of Swedish Patients Aged 80 Years or Older With MCL: PFS in Patients
A similar pattern was seen in terms of PFS after initiation of first-line treatment, with a median PFS of only 1.1 years. This was significantly shorter among patients with more severe comorbidities, advanced disease stage, poorer overall ECOG PS, and those who did not receive rituximab.13
Outcomes of Swedish Patients Aged 80 Years or Older With MCL: Clinical Implications
The implications of this study are clinically significant. It is clear that improvements are needed in the treatment of older patients with MCL, as survival outcomes and PFS outcomes with standard immunochemotherapy options are very poor in this demographic. We need to identify the patients in this group that can survive longer periods of time, as they may benefit the most and have the greatest impact from novel, nonchemotherapy-based approaches.
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