In older or unfit patients with mantle cell lymphoma (MCL), bendamustine plus rituximab (BR) is the most common first-line therapy, while intensive regimens are usually unsuitable in this population even though they provide durable responses [1, 2]. The addition of the first-in-class BTK inhibitor ibrutinib to first-line BR has been shown to prolong progression-free survival (PFS) in the SHINE trial [3]. However, there was no improvement in overall survival (OS), which was probably due to unexplained deaths in the experimental arm which suggests excess toxicity with the addition of ibrutinib.

First-line setting: acalabrutinib plus chemoimmunotherapy

The double-blind, placebo-controlled, phase III ECHO trial was designed to evaluate the second-generation BTK inhibitor acalabrutinib 100 mg BID until progression in addition to 6 cycles of BR in patients with untreated MCL aged ≥ 65 years who had an ECOG performance status of ≤ 2. Those who achieved at least partial response (PR) after 6 cycles of BR received maintenance treatment with rituximab for 2 years. In the control arm, placebo was administered in addition to 6 cycles of BR and maintenance rituximab in the group with ≥ PR. Cross­over to acalabrutinib or other BTK inhibitors was permitted after disease progression. The experimental and control arms each contained 299 patients who were enrolled at 195 sites in 26 countries across the world. PFS constituted the primary endpoint of the ECHO trial.

Acalabrutinib plus BR led to PFS improvement by approximately 17 months, with a 27 % in the risk of disease progression or death (median PFS, 66.4 vs. 49.6 months; HR; 0.73; p = 0.0160) [4], although this benefit is less than what was noted in the SHINE trial [3]. Whereas the overall response rates (ORR) were similar across the arms (91.0 % vs. 88.0 %), the proportion of patients who obtained complete response (CR) was higher with the combination than with BR alone (66.6 % vs. 53.5 %). For OS, the data demonstrated a trend in favor of the acalabrutinib-based regimen (HR, 0.86; p = 0.2743). This was sustained even with most patients in the control arm receiving BTK inhibition as salvage therapy after progression (69 %), although receipt of acalabrutinib was delayed due to logistical hurdles. As the trial had taken place during the pandemic, prespecified PFS and OS analyses censored for COVID-19 deaths were performed. According to these, PFS was improved by 36 % with the addition of acalabrutinib (HR, 0.64; p = 0.0017; Figure 1), and OS was improved by 25 % (HR, 0.75; p = 0.0797).

The safety profile of acalabrutinib plus BR was consistent with that of the individual drugs. Any-grade atrial fibrillation occurred in 6.1 % vs. 4.4 % with acalabrutinib plus BR vs. placebo plus BR (grade ≥ 3, 3.7 % vs. 1.7 %). For hypertension, the rates were lower in the experimental arm (any grade, 12.1 % vs. 15.8 %; grade ≥ 3, 5.4 % vs. 8.4 %), which also applied to major bleeding (any grade, 2.4 % vs. 5.4 %; grade ≥ 3, 2.0 % vs. 3.4 %). Infections were reported in 78.1 % vs. 71.0 % (grade ≥ 3, 41.1 % vs. 34.0 %). Treatment-emergent adverse events (TEAEs) led to discontinuation of acalabrutinib in 42.8 % (vs. 31.0 % for placebo). Median treatment exposure was longer in the experimental arm than in the control arm (29 vs. 25 months).

In their conclusion, the authors pointed out that the ECHO study provided first evidence of a positive trend in OS when adding a BTK inhibitor to frontline standard chemoimmunotherapy for older patients with MCL. These data suggest that acalabrutinib in combination with BR may represent an alternative treatment approach in older MCL patients as compared to the traditional sequential use of BR followed by a BTK inhibitor.

Figure 1: Progression-free survival censored for COVID-19 deaths: acalabrutinib plus BR vs. BR alone

BOVen in older patients

Another option for untreated older patients is the BOVen triplet including the second-generation BTK inhibitor zanubrutinib, obinutuzumab and venetoclax, which has the advantage of being devoid of cytotoxic chemotherapy agents. BOVen has demonstrated promising efficacy and safety in 25 patients with untreated TP53-mutant MCL [5]. A multicenter phase II trial is being conducted to characterize the triplet as a first-line approach in patients who are ≥ 65 years of age or have comorbidities precluding autologous stem cell transplantation. While zanubrutinib is being taken continuously from cycle 1, 10 doses of obinutuzumab are administered through cycle 8. The venetoclax therapy starts with a 5-week ramp-up from cycle 3 and is continued until the end of treatment (EOT). At 24 cycles, the investigators will use an MRD-driven approach to limit treatment duration in selected patients: Those with CR and undetectable MRD (uMRD) will discontinue their medication, while those with < CR and/or detectable MRD will continue zanubrutinib and venetoclax. At EHA 2024, Kumar et al. reported preliminary results for 46 patients with a median age of 71 years [6].

BOVen appeared to be safe and well tolerated in untreated older MCL patients. No new safety signals emerged. The most common AEs included bruising (any grade, 39 %), diarrhea (39 %), neutropenia (26 %), and thrombocytopenia (24 %). With the exception of neutropenia, AEs were mostly grade 1 and 2. No grade 5 events occurred. The efficacy analysis revealed an ORR of 98 %, with CR obtained in 79 %. At cycle 3, uMRD5 and uMRD6 were achieved in 50 % and 26 % of patients, respectively. These percentages rose to 100 % and 87 %, respectively, at cycle 13. Almost all patients remained on treatment at the time of data cut-off.

Relapsed/refractory MCL: fixed-duration glofitamab

In the relapsed/refractory setting, there is an unmet medical need as response duration decreases after each relapse. New treatment options are called for, ­particularly in light of the growing ­importance of first-line BTK-inhibitor (BTKi)-based regimens. One of these options might be the CD20 x CD3 bispecific antibody glofitamab that has already shown high CR rates and durable ­responses as monotherapy in patients with heavily pretreated relapsed/refractory MCL in the multicenter, phase I/II NP30179 study [7]. In this study, glofitamab 30 mg is administered in 21-day cycles for a maximum of 12 cycles. Mea­sures for the mitigation of cytokine ­release syndrome (CRS) include obinutuzumab pretreatment with either 1,000 mg or 2,000 mg in addition to step-up dosing of glofitamab from 2.5 mg to 10 mg during the first cycle. Phillips et al. presented updated findings after a median follow-up of 19.6 months [8]. Among 60 patients, 31 had previously received BTK inhibitor treatment, while 29 were BTKi-naïve. Refractoriness to the last prior therapy was present in 87.1 % and 58.6 %, respectively, in these two groups. Their median number of prior lines was 3.0 and 2.0, respectively.

High overall response and CR rates were observed in both BTKi-pretreated and BTKi-naïve patients (Figure 2). Responses also proved durable as they lasted for a median of 16.2 and 12.6 months in the overall population and the BTKi-pretreated cohort, respectively. Median duration of CR was 15.4 and 12.6 months, respectively. Almost 60 % of CRs were still ongoing at data cut-off in the total group. Moreover, the analysis revealed clinically significant PFS and OS results. In all patients, the 15-month PFS and OS rates were 54.0 % and 71.4 %, respectively, and in the BTKi-pretreated cohort, 33.0 % and 55.0 %, respectively. According to landmark analyses performed by response, the majority of patients who had achieved CR at EOT remained alive and progression-free at 15 months after EOT, with PFS and OS rates of 59.2 % and 72.7 %, respectively.

The incidence and severity of AEs were consistent with the known safety profile of glofitamab. CRS, which occurred as the most frequent AE, was less common with the higher obinutuzumab dose (87.5 % and 63.6 % with 1,000 mg and 2,000 mg, respectively); also, events took longer to occur and resolved sooner with obinutuzumab 2,000 mg pretreatment. The CRS rates were higher than those observed with glofitamab in the setting of relapsed/refractory diffuse large B-cell lymphoma [9]. Other common AEs included neutropenia, COVID-19, pyrexia, and anemia. Glofitamab-related grade 3/4 AEs emerged in 58.3 %. No patient died due to the study medication. The majority of CRS events were grade 1 or 2 and predominantly occurred in cycle 1. Median duration of CRS was shorter in patients in the 2,000 mg obinutuzumab cohort than in the 1,000 mg cohort.

Any-grade infections were reported in 73.3 % in the overall group; 31.7 % ­of patients developed COVID-19/COVID-19 pneumonia, with 8.3 % dying due to the infection. All patients who died due to COVID-19 had achieved a CR, with six of the seven still in remission at the time of death. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in only 5.0 %. All ICANS events were restricted to grade 1 and 2 and resolved. The 2,000 mg obinutuzumab pretreatment regimen is being used in the ongoing phase III GLOBRYTE study that is comparing glofitamab monotherapy with treatment according to investigators’ choice in patients with relapsed/refractory MCL (NCT06084936).

Figure 2: Responses to glofitamab monotherapy in BTKi-pretreated and BTKi-naïve patients

Indirect comparison of zanubrutinib and acalabrutinib

The second-generation BTK inhibitors zanubrutinib and acalabrutinib have demonstrated clinical benefits in separate single-arm trials elucidating their activity in patients with relapsed/refractory MCL [10-14]. In the absence of head-to-head clinical trials, Shah et al. evaluated the comparative efficacy of the two agents using population-adjusted indirect treatment comparison via a simulated treatment comparison approach [15]. The analysis was based on the pooled individual patient-level data from the BGB-3111-206 and BGB-3111-AU-003 trials assessing zanubrutinib, as well as on the published aggregated data of the ACE-LY-004 study that investigated acalabrutinib [10-14]. A key difference among these was that BGB-3111-206 had a Chinese population, whereas BGB-3111-AU-003 included Western patients and ACE-LY-004 was a global trial. Overall, the zanubrutinib and acalabrutinib populations included 123 and 124 individuals with relapsed/refractory MCL, respectively.

According to the simulated treatment comparison, zanubrutinib therapy was associated with advantages regarding several efficacy endpoints. PFS was statistically significantly longer compared to acalabrutinib (HR, 0.57; p = 0.0272), as was OS (HR, 0.43; p = 0.0105). For ORR, the difference did not reach statistical significance, although the odds of responding were higher in the zanubrutinib-treated group (OR, 2.05; p = 0.1798). The proportion of patients with high LDH levels and > 2 prior treatment lines was found to be significantly predictive of survival outcomes in the regression models. Overall, these data provide some evidence to support the superiority of zanubrutinib over acalabrutinib in relapsed/refractory MCL. Limitations arise from differences in designs, treatment regimens and populations across the studies (i.e., Chinese vs. Western and other ethnicities) that potentially affect the validity of indirect comparisons.

Real-world data on covalent BTK inhibitors

A retrospective observational cohort study compared the covalent BKI inhibitors zanubrutinib, acalabrutinib and ibrutinib as second- or third-line single-agent treatment of US-based patients with relapsed/refractory MCL [16]. Overall, the investigators identified 602 individuals from the Flatiron Health database. Zanubrutinib, acalabrutinib and ibrutinib had been administered in 107, 301 and 194 patients, respectively. Most received the BTK inhibitor as their second-line treatment.

Unadjusted median time to next treatment (TTNT) was 16.8 months for zanubrutinib, 11.5 months for acalabrutinib, and 8.6 months for ibrutinib. Median OS had not been reached for zanubrutinib, while the unadjusted median OS for acalabrutinib and ibrutinib was 27.4 and 29.3 months, respectively (Figure 3). The fully adjusted inverse probability of treatment weighting model took the following factors into account: age, sex, time from first to second line, time from second to third line, ECOG stage at initial diagnosis, LDH status, bulky disease status, and Ki67 status. According to this, zanubrutinib performed significantly better than ibrutinib regarding both TTNT (HR, 0.64; p = 0.02) and OS (HR, 0.56; p = 0.02), with the caveat that with retrospective studies, certain nuances such as discontinuation or medical non-compliance are hard to truly take into account. The respective differences between zanubrutinib and acalabrutinib showed trends favoring zanubrutinib (TTNT: HR, 0.84 and p = 0.30; OS: HR, 0.74 and p = 0.20), although the number of patients on acalabrutinib was much higher in this dataset. Future research is warranted to identify factors influencing the utilization of covalent BTK inhibitors and reasons for differences in real-world TTNT and OS.

Figure 3: Real-world overall survival for zanubrutinib, acalabrutinib and ibrutinib as second- or third-line treatment of relapsed/refractory MCL

Adherence and resource utilization

Data from the Symphony Integrated Dataverse database were used to examine treatment adherence and healthcare resource utilization of patients with MCL undergoing BTK inhibitor treatment in the USA [17]. The scientists identified two cohorts: One included patients receiving their first BTK inhibitor (zanubrutinib, acalabrutinib, or ibrutinib) during the index period, while the other contained patients who received ibrutinib as their first BTK inhibitor and initiated acalabrutinib or zanubrutinib thereafter during the index period. Compliance was calculated as the proportion of days covered using 30-day intervals from initiation of treatment to 1 year. Persistence, on the other hand, was measured as the proportion of patients who remained on treatment within the cohort that had sufficient follow-up.

Among the first-ever BTK inhibition patients (n = 2,122), 519, 878 and 725 initiated zanubrutinib, acalabrutinib and ibrutinib, respectively. Compliance at 1 year was numerically highest for zanubrutinib (16.73 %) followed by acalabrutinib (16.45 %) and ibrutinib (11.80 %). Likewise, treatment persistence at 1 and 2 years was numerically highest for zanubrutinib (33.1 %; 18.6 %) compared to acalabrutinib (32.8 %; 16.3 %) and ibrutinib (30.6 %; 15.7 %).

A total of 228 patients switched from ibrutinib to acalabrutinib (n = 140) or zanubrutinib (n = 88). In this group, the analysis showed numerically improved 1-year compliance for zanubrutinib compared to acalabrutinib (p = 0.2176), as well as numerically better treatment persistence at 1 and 2 years (p = 0.2687 and p = 0.6270; Figure 4).

In similar vein, healthcare resource utilization favored zanubrutinib. In patients who switched from ibrutinib to zanubrutinib, the mean number of outpatient visits was lower than in those who switched from ibrutinib to acalabrutinib (1.12 vs. 1.62; p = 0.1755). This observation also applied to inpatient services (0.22 vs. 0.68; p = 0.1693). Taken together, zanubrutinib, when used as the first BTK inhibitor and after prior ibrutinib, was associated with a trend toward improved compliance, persistence, and health care resource utilization compared to acalabrutinib.

Zanubrutinib in patients intolerant to BTK inhibitors

Zanubrutinib has been designed to maxi­mize BTK occupancy and minimize ­off-target kinase binding and associated AEs [16]. Patients with B-cell malignancies who are intolerant of other BTK inhibitors are being treated with zanubrutinib in the ongoing, single-arm, phase II BGB-3111-215 study. Cohort 1 is intolerant of ibrutinib (n = 44), while Cohort 2 shows intolerance of acalabrutinib (n = 9) or both ibrutinib and acalabrutinib (n = 8). Previously published results have demonstrated that zanubrutinib is effective and well tolerated in this setting [17]. At ICML 2023, Shadman et al. reported preliminary longer-term findings in ­patients with CLL/SLL after a median ­follow-up of 28.2 and 10.1 months in Cohorts 1 and 2, respectively [18]. In both cohorts, > 65 % of patients remained on treatment. The median zanubrutinib treatment duration was 27.1 and 8.1 months, respectively.

With zanubrutinib, 68.4 % of ibrutinib-intolerance AEs and 71.4 % of acalabrutinib-intolerance AEs did not recur. No intolerance AE recurred with increased severity; among those that did recur, 73.3 % of ibrutinib-intolerance AEs and 33.3 % of acalabrutinib-intolerance AEs recurred at lower grades. The most common grade ≥ 3 treatment-emergent AE (TEAE) on zanubrutinib was neutropenia (11.5 %). TEAEs leading to dose interruption and reduction occurred in 49.2 % and 24.6 %, respectively.
In terms of efficacy, the analysis revealed an ORR of 71.9 % and a disease control rate of 94.7 % across both cohorts. At 12 months, 88.3 % of patients were ­progression-free. In their summary, the authors concluded that ibrutinib- and acalabrutinib-intolerant patients are likely to benefit from a switch to zanubrutinib, which appears to be a viable option in this setting.

HRQoL data from the
ALPINE study

Zanubrutinib 160 mg BID (n = 327) was compared to ibrutinib 420 mg OD (n = 325) until progression in patients with relapsed/refractory CLL/SLL in the ran­domized, open-label phase III ­ALPINE study. At the time of the final PFS analysis, zanubrutinib was significantly superior
to ibrutinib regarding PFS (HR, 0.65; p = 0.0024) and ORR (86.2 % vs. 75.7 %; p = 0.0007) [19]. Eichhorst et al. presented data on health-related quality of life (HRQoL), which was a secondary objective of the study, at EHA 2023 [20]. Patient-reported outcomes were assessed using the EORTC QLQ-C30 questionnaire and the EuroQoL visual analog scale (EQ-VAS).

Global health status as well as physical and role functioning improved in both arms from baseline to both cycle 7 and 13. All improvements were clinically meaningful for the zanubrutinib arm, although no clinically meaningful differences resulted across the two arms by cycle 13. Regarding the symptom scales, both arms showed decreases in fatigue and pain (Figure 4). Zanubrutinib gave rise to clinically meaningful improvements for both of these symptoms at cycles 7 and 13. For diarrhea, zanubrutinib-treated patients experienced more pronounced improvement, although this difference did not reach the predefined clinically relevant threshold. The mean change from baseline in the EQ-VAS demonstrated a similar pattern of improvement with both agents up to cycle 13.

Overall, the data suggested that treatment with zanubrutinib improved HRQoL over time, although the differences were not significant given the generally good HRQoL at baseline in both arms. Long-term follow-up and additional analyses linking patient-reported endpoints to clinical outcomes will further determine the effect of zanubrutinib on HRQoL.

Figure 4: Mean changes in EORTC QLQ-C30 symptom scales from baseline at cycle 7 with ­zanubrutinib vs. ibrutinib

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