Mantle cell lymphoma: optimizing responses in treatment-naïve and difficult-to-treat patients

The disappearing role of ASCT: TRIANGLE

The three-arm, randomized, phase III TRIANGLE trial has set a new first-line standard in younger patients with mantle cell lymphoma (MCL), showing that the addition of ibrutinib to standard immunochemotherapy improves efficacy [1]. Previously untreated patients aged 18-65 years who were eligible for autologous stem cell transplantation (ASCT) were randomized to either induction treatment with R-CHOP and R-DHAP followed by ASCT (group A; n = 288) or one of two experimental arms: In group A+I (n = 292), ibrutinib was added to R-CHOP and was administered as fixed-duration maintenance for two years after ASCT. In group I (n = 290), ibrutinib was administered in the same manner, while ASCT was omitted. Rituximab maintenance was added according to national guidelines in all arms. After a median follow-up of 31 months, the failure-free survival (FFS) rate at 36 months was higher in group A+I than in group A (88 % vs. 72 %; HR, 0.52; p = 0.0008) [1]. However, there was some criticism due to the short follow-up and the question of utility of ASCT in the era of ibrutinib-containing regimens.

According to the update reported by Dreyling et al. at ASH 2024 after a follow-up of up to 55 months, the FFS benefit observed for A+I vs. A was ongoing, with 4-year FFS rates of 82 % vs. 70 % (HR, 0.64; p = 0.0026) [2]. At the same time, no superiority was observed for group A compared to group I (4-year FFS rates, 70 % vs. 81 %); retrospectively, a two-sided test actually showed superiority of I vs. A (p = 0.0208). The two experimental arms were compared to explore the impact of ASCT. Here, the FFS curves were almost overlapping for groups A+I and group I. These results refuted superiority of the combined administration of ASCT and ibrutinib, although there was a trend towards superiority of A+I over I in patients with high-risk characteristics including Ki-67 > 30 %, blastoid cytology, and high p53 expression. However, A+I was associated with significantly increased toxicity compared to I.

Overall survival (OS) findings significantly favored the ibrutinib-containing arms. The 4-year OS rates for A+I and I were 88 % and 90 %, respectively, vs. 81 % for A (p = 0.0036 and 0.0019, respectively; Figure 1). The authors concluded that A+I might represent the preferred first-line treatment in younger patients with MCL.

Figure 1: Overall survival with the addition of ibrutinib to standard immunochemotherapy with or without ASCT compared to ASCT alone

Impact of rituximab maintenance

A retrospective analysis from the TRIANGLE study assessed the impact of rituximab maintenance in responding patients in the three treatment arms [3]. Non-randomized rituximab maintenance had been allowed according to national guidelines or center practice and thus differed across the study sites. Every arm was analyzed separately. Progression-free survival (PFS) after induction (arm I) or ASCT (arms A+I and I) was defined as the primary endpoint. Sixty-one to 68 % of patients started rituximab maintenance across the arms.

PFS was significantly longer with the addition of rituximab compared to the groups without maintenance in all three arms. At four years, the PFS rates were 90 % vs. 76 % within arm A+I, 85 % vs. 74 % within arm I, and 83 % vs. 51 % within arm A. The benefit appeared to be greater in arms A+I (HR, 0.23) and A (HR, 0.29) than in arm I (HR, 0.48). A subgroup analysis that accounted for disease characteristics indicated that patients with low risk according to MIPI derived particular PFS benefit from rituximab maintenance (HR, 0.22).

At the time of the analysis, no significant OS differences were detectable, although longer follow-up is required here. Rituximab maintenance was associated with a modest increase in infectious toxicity in all arms and an increase in hematological toxicity exclusively in arm A. Grade 5 adverse events (AEs) occurred at similar rates across the groups with and without maintenance. No new safety signals emerged. Overall, these results support the use of rituximab maintenance also in combinations with novel regimens.

No benefit of ASCT in ECOG-ACRIN

The role of ASCT in the treatment of MCL was further questioned by the randomized, phase III ECOG-ACRIN study. This trial enrolled patients with a primary diagnosis of MCL in first remission after any rituximab-containing induction, including those incorporating BTK inhibitors. Patients with complete response (CR) and undetectable minimal residual disease (uMRD) at a sensitivity level of 10^-6 (uMRD6) were randomized to either ASCT followed by rituximab maintenance for three years (arm A) or rituximab maintenance alone for three years (arm B). The primary objective for this comparison was OS. Arms A and B comprised 257 and 259 individuals, respectively. As some patients refused their assigned treatment, a “treated as assigned” analysis was performed in addition to the primary analysis that included all randomized patients.

Indeed, the 3-year OS rates were similar between the two arms after a median follow-up of 2.7 years. In all randomized patients, these rates were 82.1 % vs. 82.7 % for arms A and B, and in patients treated as assigned, 86.2 % vs. 84.8 % (HRs, 1.11 and 1.00, respectively). Likewise, there were no differences regarding PFS for arm A vs. arm B in all ran­domized patients and patients treated as assigned. OS remained similar across the arms in patients with either high or low risk according to the MIPI-c score; equally, receipt of ASCT was not associated with OS differences across patients with intensive induction (i.e., regimens containing high-dose cytarabine) and non-intensive induction. Taken together, MCL patients in first CR with uMRD6 do not appear to benefit from consolidative ASCT in the era of highly effective induction and maintenance regimens.

On the other hand, ASCT seemed to improve outcomes in patients who remained MRD-positive or only achieved partial response after induction, i.e., the population included in arm C of the ECOG-ACRIN study. All of these underwent ASCT and rituximab maintenance. An exploratory study demonstrated that the 3-year OS rate in patients who converted to uMRD6 post ASCT was 100 % compared to 63.6 % in those who remained MRD-positive. The 3-year PFS rates for these two groups were 100 % and 48.8 %, respectively. The authors stressed that longer follow-up will be important to confirm these findings.

MRD negativity after induction: OASIS II

Ibrutinib in combination with the anti-CD20 antibody obinutuzumab ± venetoclax was assessed in the randomized phase II OASIS II trial to estimate the MRD rate at the end of induction treatment in previously untreated patients with stage II-IV MCL. Arms A and B of the OASIS II study received ibrutinib through cycles 1-24 in addition to 42 cycles of obinutuzumab. In Arm B only, venetoclax was administered from cycle 2 through cycle 24. The induction phase included the first 6 cycles, while the consolidation phase comprised cycles 7-12 and the maintenance phase cycles 13-42. Le Gouill et al. reported the interim futility analysis of the OASIS II trial at ASH 2024 [5].

At the end of induction, 79.2 % of patients responded to treatment, with no difference for the triplet vs. the doublet treatment regimen (80 % vs. 78.5 %; Table). CRs resulted in 64 % vs. 56.9 %. Regarding MRD negativity at the end of induction, which was the primary efficacy endpoint, the analysis favored ibrutinib/obinutuzumab/venetoclax versus ibrutinib/obinutuzumab without venetoxlax (82.1 % vs. 53.8 %), although both combinations provided MRD negativity according to the predefined upper limit of the 80 % confidence interval (≥ 64 %). This limit was chosen based on MRD findings obtained with standard chemotherapy. According to the authors, the MRD negativity rate in the triplet combination arm is among the highest reported so far, including rates following immunochemotherapy in transplant-eligible patients. Pooled data from the two arms were used to calculate PFS and OS in the total group of 101 patients. This revealed encouraging 2-year rates for both PFS (87.9 %) and OS (91.9 %).

Patients treated with the triplet, as compared to those receiving the doublet, naturally experienced higher rates of AEs including neutropenia, diarrhea, and arrhythmia. Grade ≥ 3 serious AEs included respiratory tract infections (4 % vs. 3.9 %) and arrhythmia (6 % vs. 2 %). Overall, the safety profiles of both combinations were acceptable. In keeping with the initial statistical analysis plan, both arms were re-opened for inclusion in part II of the OASIS II study, with 205 patients having been randomized to date. The final results of the trial are expected in autumn 2026.

Table

Acalabrutinib/rituximab in elderly patients

The aim of the multinational phase II ALTAMIRA trial was to explore a risk- and response-adapted approach using acalabrutinib and rituximab in elderly patients (≥ 60 years) with untreated MCL. In this study, high-risk patients were treated until progression, while those with low risk were able to stop acalabrutinib upon achieving MRD negativity after a minimum of one year. All patients received a total of three years of rituximab therapy. High risk was defined as TP53 abberations or blastoid histology. Jerkeman et al. presented results for 81 patients after a median follow-up of 19.3 months [6]. The median age of this group was 75 years. Twenty-one patients had high-risk disease as defined above.

At six months, the overall response rate (ORR) was 76 % in the total population, with 51 % demonstrating CRs (Figure 2). Notably, the low-risk group fared better than the high-risk group, as disease progression occurred far less frequently (8 % vs. 38 %). MRD negativity rates favored the low-risk group both at six months (43 % vs. 17 %) and at 12 months (66 % vs. 22 %). The MRD-guided risk- and response-adapted approach appeared feasible in this elderly population. In the low-risk group, 56 % of patients were able to stop treatment with acalabrutinib, mostly due to MRD negativity at 12 months.

At 2 years, 84 % of the overall population were alive, and 75 % were progression-free. Compared to a synthetic control arm derived from the Swedish MCLcomplete project, the ALTAMIRA regimen demonstrated a trend towards superior PFS and OS outcomes [7].

Subgroup analyses indicated that while age, comorbidity and MIPI scores did not notably impact the PFS, biology made a clear difference. The 2-year PFS rate was considerably higher in the low-risk group than in the high-risk group (91 % vs. 32 %). Low-risk patients without Ki-67 > 30 % had even better outcomes, with a 2-year PFS rate of 96 %. In this cohort, nobody died due to the MCL. The AEs were generally mild and tolerable but some severe toxicity was seen in these elderly patients (cardiovascular disease and aplastic anemia).

As the authors noted, acalabrutinib plus rituximab is safe and effective specifically in elderly patients with biological low-risk MCL, potentially representing a future standard approach. Fixed-duration treatment for 12 months should be explored. In patients with high risk, however, the acalabrutinib/rituximab doublet regimen cannot be considered sufficient.

Figure 2: ALTAMIRA: responses in all patients treated with acalabrutinib and rituximab and in the low- and high-risk subgroups

Zanubrutinib plus obinutuzumab

Another chemotherapy-free regimen evaluated as first-line treatment in elderly patients in the clinical trial setting is the combination of zanubrutinib and obinutuzumab. An open-label, multicenter, single-arm, phase II trial was initiated to assess the efficacy and safety of this regimen in individuals aged ≥ 65 years. Induction treatment consisted of obinutuzumab for 4 cycles and zanubrutinib from cycle 2. Patients who achieved CR at the end of this period went on to zanubrutinib maintenance. In contrast, those with partial response (PR) received the combination for another 2 cycles and then switched to zanubrutinib maintenance. The CR rate constituted the primary endpoint. Zhu et al. presented findings for 19 patients at ASH 2024 [8]. The median age of the study population was 72 years. Fourteen patients had bone marrow involvement, and TP53 mutation was present in four individuals. High MIPI risk scores were observed in seven patients. Ten had Ki-67 index scores ≥ 30 %.

Zanubrutinib plus obinutuzumab demonstrated favorable efficacy and a manageable safety profile in this elderly cohort. At the time of the analysis, nine patients had completed induction therapy. All of them responded, with eight (88.9 %) achieving CR and one achieving PR. After a median follow-up of seven months, no progression events had occurred. Two patients experienced grade 2 infusion-related reactions during the first obinutuzumab dose. Grade 3 or 4 thrombocytopenia developed in two cases, with both recovering within a week. Most AEs events were grade 1 or 2, and no patient discontinued therapy.

ViPOR: multi-agent oral regimen

While oral targeted agents are active in MCL, they fail to induce deep responses as monotherapy and require long-term intake. A fixed-duration, multi-agent targeted regimen containing venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) has been developed that simultaneously targets multiple key survival pathways in B-cell lymphomas. ViPOR has been demonstrated to be safe and able to induce durable remissions in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma [9].

Melani et al. assessed ViPOR in patients with both treatment-naïve and R/R MCL in a phase IB/II study based on the hypothesis that multi-targeted treatment might improve efficacy in this patient group. The ViPOR regimen was modelled akin to chemotherapy; all study agents were given in non-continuous cycles, with two weeks of study drug followed by one-week breaks. Six cycles of induction were administered without maintenance or planned consolidation. Venetoclax treatment started at cycle 2 for all patients. Post-treatment surveillance followed the induction phase.

At the time of the analysis reported at ASH 2024, a total of 37 individuals were participating in the trial [10]. In the phase IB cohort, patients with R/R MCL received two doses of venetoclax, with an accelerated 12-day ramp-up. In the phase II cohort, 20 patients each with R/R and treatment-naïve MCL were included at the recommended phase II venetoclax dose of 400 mg. Thirty-four percent had TP53 mutation/deletion, and 27 % exhibited blastoid or pleomorphic morphology. High-risk MCL according to MIPI score and MCL35 proliferation signature was identified in 32 % and 20 %, respectively. In the R/R cohort, the median number of prior therapies was 3, with 59 % of patients being refractory to their last treatment.

The ViPOR regimen was safe, with manageable grade 3/4 hematologic AEs. No episodes of febrile neutropenia occurred over a total of 212 cycles of therapy. Dose reductions and delays were infrequent (5 % and 11 % of cycles, respectively). Overall, 89 % of patients completed all 6 cycles. Non-hematologic toxicities were common but generally mild, with the most frequently observed AEs being hypokalemia (grade 1/2, 65 %; grade 3, 27 %), diarrhea (grade 1/2, 62 %; grade 3, 3 %), and rash (grade 1/2, 46 %; grade 3, 14 %). No tumor lysis syndrome events, dose-limiting toxicities or treatment-related mortality events were reported.

Durable CRs with fixed-duration combination

Tumor reduction was observed in all patients, with all but one R/R patient achieving CR. Among the 36 evaluable patients who had completed therapy, the ORR was 100 % and included a CR rate of 97 % (Figure 3). In the R/R cohort, 94 % obtained CR, while the treatment-naive cohort achieved a 100 % CR rate. This included multiple high-risk subsets such as those with Ki-67 ≥ 30 %, blastoid morphology, BTK inhibitor pretreatment and TP53 mutations. Most CRs were ongoing at cutoff, with only one R/R MCL patient receiving consolidative allogeneic transplantation. Four high-risk patients relapsed; among these, three had R/R disease. COVID-19 was the cause of death in two out of three fatalities. Both of these patients had been in remission.

After a median follow-up of 27.6 months, 2-year time-to-progression (TTP) rates were 95 % and 92 % in the treatment-naïve and R/R cohorts, respectively. For PFS that factored in the two COVID-related deaths in remission, the 2-year rates were 95 % and 77 %, respectively. The 2-year TTP rate was lower in patients with Ki-67 > 30 % compared to those with Ki-67 < 30 % (82 % and 100 %, respectively), which was also true for those with blastoid or pleomorphic morphology vs. those without (79 % and 100 %, respectively). Patients with high-risk MCL35 proliferation signature showed a trend towards shorter TTP, while no significant difference was observed between the groups with and without TP53 aberrations.

The amount of circulating tumor cell DNA rapidly decreased on treatment, with the greatest drop occurring between cycles 1 and 2 following venetoclax initiation. The rate of patients achieving uMRD rose from 13 % after cycle 1 to 81 % after cycle 2. By the end of treatment, 97 % of patients had developed uMRD. In the group of those achieving CR, 27 (87 %) remained in clinical remission, while four (13 %) relapsed. All of the non-progressors have been showing persisting uMRD for a median of 16.1 months. Three of the four progressors experienced molecular relapse prior to clinical relapse with a median lead time of 2.3 months.

At present, study enrollment is continuing in the phase II expansion cohorts to better define response and durability of ViPOR in both treatment-naïve and R/R MCL. Multicenter phase II assessment is in development to confirm the activity of fixed-duration ViPOR in additional MCL patients.

Figure 3: Response rates with the ViPOR regimen at the end of treatment

R/R MCL: zilovertamab vedotin

BTK inhibitors are a standard-of-care therapy for patients with R/R MCL, although effective options are limited for patients whose disease has progressed during or after BTK inhibition [11]. At ASH 2024, results were presented for cohort A of the multicenter, open-label, phase II waveLINE-006 study that investigated the efficacy and safety of the ROR1-targeting antibody-drug conjugate zilovertamab vedotin in this setting [12]. Glimelius et al. reported findings for 40 patients with R/R MCL after ≥ 2 therapies including a BTK inhibitor. They had either received CAR T-cell therapy or were ineligible for it. The median number of prior lines of therapy was 4. In 55 % of cases, Ki-67 index scores ≥ 30 % were present, and seven patients (18 %) had a TP53 mutation. The ORR constituted the primary endpoint of the waveLINE-006 trial.

Zilovertamab vedotin gave rise to an ORR of 40 %, with five patients (13 %) achieving CR. Reductions in target lesions of ≥ 50 % were observed in 57 %. Responses lasted for a median of 3.0 months. Median PFS was 3.4 months, and median OS was 9.0 months. At six months, 67 % of patients were alive, and 26 % were progression-free. Treatment-related AEs included neutropenia (58 %), peripheral neuropathy (43 %), diarrhea (28 %), and cytopenias. Neutropenia was the most common grade 3/4 AE (50 %), followed by peripheral neuropathy (18 %). Median time to onset of the first peripheral neuropathy event was 61 days. One patient had grade 3 tumor lysis syndrome, while no patients experienced infusion reactions. In 18 %, treatment-related AEs led to discontinuation of the study treatment. No grade 5 events were reported.

Overall, zilovertamab vedotin monotherapy demonstrated antitumor activity and manageable safety in this heavily pretreated patient group with R/R MCL. Future analyses will evaluate the role of the antibody drug conjugate within the treatment landscape of MCL, although it represents a potential option in CD20-negative patients since ROR-1 is a new target.

Zilovertamab vedotin plus nemtabrutinib

Cohort C of the waveLINE-006 study evaluated the safety and efficacy of zilovertamab vedotin in combination with the non-covalent BTK inhibitor nemtabrutinib. Paszkiewicz-Kozik E et al. reported results for 28 patients with R/R MCL who had received ≥ 1 prior therapy but were naïve for non-covalent BTK inhibition [13]. High-risk disease per MIPI score was present in 21 %, TP53 mutations in 21 %, and Ki-67 ≥ 30 % in 57 %. Patients had a median of three prior therapies, with 43 % having undergone ASCT. In 25 %, CAR T-cell therapy had been administered. Zilovertamab vedotin was given intravenously Q3W at three different dose levels ranging from 2 mg/kg to 2.5 mg/kg, while nemtabrutinib was administered at a fixed dose of 65 mg orally OD across the groups.

After a median follow-up of 7.3 months, the ORR was 72 %, with complete and partial responses observed in 36 % each. Among patients with measurable disease, 95 % achieved reductions in target lesion size, and ≥ 50 % reductions were noted in 64 % (Figure 4). The combination demonstrated a manageable safety profile. Grade 3/4 treatment-related AEs were reported in 79 % of patients, most commonly neutropenia (54 %), thrombocytopenia (14 %), and peripheral neuropathy (11 %). AEs related to zilovertamab vedotin or nemtabrutinib led to treatment discontinuation in 14 % and 11 %, respectively. No treatment-related deaths occurred.

Overall, zilovertamab vedotin and nemtabrutinib showed clinically meaningful antitumor activity and a manageable safety profile in patients with R/R MCL after ≥ 1 prior therapy without exposure to non-covalent BTK inhibition. Ongoing study efforts aim to further assess efficacy and finalize the recommended phase II dose for combination therapy. It will be of interest to observe the introduction of non-covalent BTK inhibition into the MCL treatment landscape.

Figure 4: Best percentage change from baseline in target lesions on zilovertamab vedotin plus nemtabrutinib

REFERENCES

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2. Dreyling M et al., Role of ASCT in the context of ibrutinib-containing first-line treatment in younger patients with mantle cell lymphoma: results from the randomized TRIANGLE trial by the European MCL Network. ASH 2024, abstract 240
3. Ladetto M et al., Impact of rituximab maintenance added to ibrutinib-containing regimens with and without ASCT in younger, previously untreated MCL patients: An analysis of the TRIANGLE data embedded in the Multiply Project. ASH 2024, abstract 237
4. Fenske TS et al., Lack of benefit of autologous hematopoietic cell transplantation in mantle cell lymphoma patients in first complete remission with undetectable minimal residual disease: Initial report from the ECOG-ACRIN EA4151 phase 3 randomized trial. ASH 2024, abstract LBA 6
5. Le Gouill S et al., Ibrutinib, venetoclax plus CD20 monoclonal Ab provides very high MRD negativity in previously untreated MCL patients. Initial results of OASIS II, a randomized phase 2 trial. ASH 2024, abstract 745
6. Jerkeman M et al., Acalabrutinib and rituximab in elderly patients with untreated mantle cell lymphoma – an open label Nordic Lymphoma Group phase II trial. ASH 2024, abstract 747
7. Jerkeman M et al., Nationwide assessment of patient trajectories in mantle cell lymphoma: The Swedish MCLcomplete project. Hemasphere 2023; 7(8): e928
8. Zhu Y et al., The efficacy and safety of obinutuzumab with zanubrutinib as first-line treatment in older patients with mantle cell lymphoma. ASH 2024, abstract 1630
9. Melani C et al., Combination targeted therapy in relapsed diffuse large B-cell lymphoma. N Engl J Med 2024; 390(23): 2143-2155
10. Melani C et al., Phase 1b/2 study of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed/refractory and treatment-naïve mantle cell lymphoma: Preliminary analysis of safety, efficacy, and minimal residual disease. ASH 2024, abstract 750
11. Kumar A et al., New directions for mantle cell lymphoma in 2022. Am Soc Clin Oncol Educ Book 2022; 42: 1-15
12. Glimelius I et al., Zilovertamab vedotin monotherapy for patients with relapsed or refractory mantle cell lymphoma: Cohort A of the multicenter, open-label, phase 2 waveLINE-006 study. ASH 2024, abstract 4405
13. Paszkiewicz-Kozik E et al., Zilovertamab vedotin in combination with nemtabrutinib for patients with relapsed or refractory mantle cell lymphoma: Cohort C of the open-label, phase 2 Waveline-006 Study. ASH 2024, abstract 3025

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