Frontline Ibrutinib May Be Effective and Well Tolerated in Low-Risk MCL

Frontline Ibrutinib May Be Effective and Well Tolerated in Low-Risk MCL

Most patients with mantle cell lymphoma (MCL) treated with frontline ibrutinib (Imbruvica) with or without rituximab (Rituxan) may be able to respond to and tolerate the regimen, although outcomes worsened in those with high-risk disease and patients ineligible for post-ibrutinib treatment, according to findings from a multicenter, real-world, observational cohort study published in Blood Advances.¹

Grade 3 or higher toxicities occurred in 20.3% of patients (n = 27/133); 33.8% of patients required an ibrutinib dose reduction or delay; and 41.6% of patients discontinued the agent for reasons that included progressive disease (PD; 22.1%), toxicity (8.1%), death from any cause (5.4%), patient choice (0.7%), and unknown reasons/other (5.4%). Among the patients who discontinued treatment, the median time to treatment discontinuation was 136 days (range, 5-918), and the median time to toxicity-related discontinuation was 67 days (range, 5-437).

Among the 104 patients assessed for response, the overall response rate (ORR) was 71.2%, including a radiological complete response (CR) rate of 20.2%. The ORRs were 78.7% and 64.9% in patients who received ibrutinib plus rituximab vs ibrutinib alone (odds ratio [OR], 2.0; 95% CI, 0.84-5.00; P = .135). The respective CRs in these cohorts were 27.7% and 14.0% (OR, 2.3; 95% CI, 0.89-6.35; P = .093).

Extended 3.5-year follow-up data from a 2019 pooled analysis of 370 patients with relapsed/refractory MCL who received ibrutinib in the phase 2 PCYC-1104-CA (NCT01236391), phase 2 SPARK (NCT01599949), and phase 3 RAY (NCT01646021) trials demonstrated that the most favorable outcomes with the agent occurred in the second-line setting.²

“[These findings raise] the question of whether first-line application could offer safer and potentially more effective treatment than standard immunochemotherapy, especially for older, transplant-ineligible patients,” Dr Ann Tivey, lead author of the observational cohort study, and coauthors, wrote in the paper.¹ “To our knowledge, no studies have yet reported outcomes of first-line, chemotherapy-free, ibrutinib-based therapy in high-risk MCL.”

Tivey is a fellow at the University of Manchester in the United Kingdom.

Furthermore, during the COVID-19 pandemic, from April 2020 to September 2022, ibrutinib as monotherapy or in combination with rituximab was available in England via the NHS England IBR5CV scheme.³

This interim COVID-19 approval was indicated for patients 18 years of age or older with histopathologically confirmed, previously untreated MCL and an ECOG performance status (PS) of 0 to 2. Prior treatments did not include steroids or local radiotherapy. This observational cohort study evaluated the safety and clinical outcomes of patients receiving treatment under this scheme.¹

Patient enrollment in this scheme vs treatment with other approaches, such as immunochemotherapy or active surveillance, was at the discretion of the clinician. The study team was notified of NHS centers with at least 1 patient registered to this scheme.

This observational cohort study included 149 adult patients with previously untreated MCL from 43 centers who received at least 1 dose of ibrutinib with or without rituximab. The target dose of ibrutinib was 560 mg once daily, and patients continued treatment until disease progression, unacceptable toxicity, death, or withdrawal for other reasons. At the clinician’s discretion, patients received optional intravenous or subcutaneous rituximab at 375 mg/m2 or 1400 mg for a maximum of 6 28-day cycles. Maintenance rituximab was allowed in addition to alternative ibrutinib cycles for a maximum of 2 years.

Patients were evaluated for treatment toxicity, response, and survival. Treatment outcomes in patients with high-risk MCL were also assessed. The primary outcomes were ORR and overall survival (OS). Key secondary outcomes included progression-free survival (PFS), incidence of toxicity-related ibrutinib discontinuation and dose reduction, and OS after ibrutinib discontinuation for patients with PD.

Patients had a median age of 75 years (range, 41-94). Most patients were male (74.1%) and had an ECOG PS of 0 or 1 (75.2%). Additionally, 7.8% of patients were candidates for high-dose chemotherapy plus autologous transplant in a hypothetical prepandemic setting. Most patients (92.8%) had stage III or IV disease, and 55.7% and 42.0% of patients had extranodal involvement and B symptoms, respectively. Furthermore, 6.7% and 2.7% of patients had TP53 mutations and TP53 deletions, respectively, and 36.2% of patients had at least 1 high-risk disease feature. Per the Simplified MCL International Prognostic Score Index (sMIPI), 13.3%, 36.3%, and 50.4% of patients had low-, intermediate-, and high-risk disease, respectively.

At a median follow-up of 15.6 months (range, 0-31.0), all patients had received at least 1 cycle of ibrutinib for a median of 8 cycles (range, 1-33). Ninety-two percent of patients started at a full dose of ibrutinib.

Thirty-nine percent of patients received rituximab co-administered with ibrutinib for a median of 6 cycles (range, 1-17). Additionally, 42.6% of patients had received more than 6 cycles of rituximab at the time of the study analysis, although data were missing for 1 patient. ECOG PS of 0 to 1 vs 2 to 4 were significantly associated with rituximab use (OR, 2.493; 95% CI, 1.158-5.444; P = .0260), and a trend was observed toward an association between the presence of bulky disease and rituximab use (OR, 2.127; 95% CI, 1.015-4.589; P = .055) and the absence of high-risk features (OR, 2.014; 95% CI, 0.9738-4.299; P = .0739).

Grade 3 to 4 bleeding was observed in 4.0% of patients, including intracranial hemorrhage, gastrointestinal bleeding, and epistaxis in 2 patients each. One case of epistaxis was associated with grade 4 thrombocytopenia.

Four percent of patients experienced grade 3 to 4 myelosuppression, including thrombocytopenia (n = 2), neutropenia (n = 2), anemia (n = 1), and not stated (n = 1). Grade 3 to 5 nonneutropenic infections occurred in 7.4% of patients. Two patients experienced cerebrovascular accidents, including 1 grade 5 ischemic stroke that occurred 1 week after the start of ibrutinib, which was not associated with atrial fibrillation. New-onset atrial fibrillation was observed in 6.6% of evaluable patients (n = 9/137), 6 of whom had a history of coronary artery stenosis or hypertension. Eight cases of new atrial fibrillation were grades 1 to 2, and 1 new case was grade 3 to 4. Patients who received rituximab were more likely to experience grade 3 to 5 toxicities than those who received ibrutinib alone (OR, 3.221; 95% CI, 1.202-8.201; P = .019). A numerically increased rate of grade 3 to 5 infections was observed in patients who received ibrutinib rituximab vs ibrutinib monotherapy, at 14.8% vs 4% (OR, 4.174; 95% CI, 1.169-14.99; P = .051).

A total of 32.1% of patients died during the study period. Causes of death included MCL (70.5%), COVID-19 (6.8%), heart failure (4.5%), and nonneutropenic infection (4.5%). Additionally, 1 patient each died from ischemic heart disease, stroke, neutropenic sepsis, subarachnoid hemorrhage, suicide, and an unknown reason.

In total, 45 patients were not evaluable for inclusion in the efficacy analysis because data were missing (n = 34) or their responses were assessed using clinical criteria only (n = 11). In patients with low-risk MCL or missing data, as well as those with at least 1 high-risk feature, the respective ORRs were 77.3% and 59.0% (P = .047). The respective CR rates in these cohorts were 20.5% and 19.7% (P = .92). In patients with high-risk sMIPI criteria, the ORR was 66.7% vs 75.0% for those with low- or intermediate-risk sMIPI criteria (P = .50), and the CR rates were 23.5% vs 17.3%, respectively (P = .23).

Among the group of patients with and without radiological response assessment, 93 patients had at least 6 months of follow-up, 87.1% of whom continued treatment 6 months after initiating ibrutinib. At a median of 17.9 months (range, 5.9-28.7), 76.2% of patients who achieved CR were in ongoing treatment. Among these patients, 8 with high-risk features achieved CR, 1 of whom died of COVID-19 and 2 of whom were alive with PD.

A total of 26.2% of patients progressed on ibrutinib. The estimated median PFS in the entire patient cohort was 26.0 months (95% CI, 14.4–not reached [NR]), and the 12-month PFS rate was 61.8% (95% CI, 53.3%-71.3%). Among patients with low-risk and high-risk disease, the median PFS was NR (range, NR-NR) and 13.7 months (range, 5.49-NR), respectively (HR, 2.19; 95% CI, 1.28-3.73; P = .004).

The estimated median OS in the overall patient cohort was NR (95% CI, 19.9-NR), and the 12-month OS rate was 69.4% (95% CI, 61.3%-78.4%). Among patients who experienced PD at any time, the median time to progression was 5.2 months.

A univariable analysis conducted to determine baseline features predictive of PFS and OS showed that the presence of at least 1 high-risk feature was significantly associated with shorter PFS and OS, but the presence of sMIPI criteria was not. Among patients with low-risk and high-risk disease, the median PFS was NR (range, NR-NR) and 13.7 months (range, 5.49-NR), respectively (HR, 2.19; 95% CI, 1.28-3.73; P = .004). The median OS was NR (range, NR-NR) for patients with low-risk features vs 14.8 months (range, 11.3-NR) for those with high-risk features (HR, 2.36; 95% CI, 1.35-4.27; P = .005).

Patients with pleomorphic or blastoid histology had shorter PFS and OS. The median PFS was 4.4 months (range, 3.0-NR) vs 28.5 months (range, 21.6-NR; HR, 4.31; 95% CI, 2.32-8.01; P ≤ .001), and the median OS was 10.9 months (range, 4.9-NR) vs NR (range, 21.6-NR; HR, 3.15; 95% CI, 1.58-6.26; P = .001).

There were no significant differences in PFS and OS based on sMIPI classification. The median PFS for low-, intermediate-, and high-risk sMIPI groups was 16.8 months, 28.5 months, and 21.6 months, respectively. The median OS in these respective groups was 16.8 months, NR, and 21.6 months.

Seventeen patients had TP53-positive disease and available survival data, and 29 patients had TP53-negative disease. The median PFS in the TP53-positive and -negative groups was 6.72 months (range, 4.41-NR) vs 21.57 months (range, 13.7-NR), respectively (HR, 2.05; 95% CI, 0.89-4.71; P = .091). The median OS in these respective groups was 11.3 months (range, 6.71-NR) vs 21.6 months (range, 14.9-NR; HR, 2.26; 95% CI, 0.86-5.91; P = .097).

A multivariable analysis demonstrated that ECOG PS of 2 or higher and pleomorphic/blastoid histology were particularly strongly predictive of inferior outcomes after ibrutinib in the second-line setting. Another model, when adjusted for other features, showed that the presence of at least 1 high-risk feature and poorer ECOG PS were strongly and independently predictive of adverse outcomes. A third model confirmed that these findings were consistently predictive of adverse outcomes.

The median post-ibrutinib survival was 1.4 months and was significantly longer in patients who received subsequent treatment (41.9%) at 8.6 months vs 0.6 months in those who did not receive subsequent treatment (HR, 0.34; P = .002). The best responses to second-line therapy were CR (23.1%), partial response (3.8%), stable disease (3.8%), PD (34.6%), and unknown (34.6%). Notably, no patients received autologous stem cell transplant consolidation. The median time to ibrutinib progression in patients who received second-line therapy was 5.5 months.

“Results of this study support a role for ibrutinib with or without rituximab in previously untreated MCL, especially in patients [with] low-risk [disease],” the authors concluded. “Notably, poor outcomes in patients with high-risk MCL, in particular blastoid morphology, and very poor post-ibrutinib survival indicate that ibrutinib is unlikely to be the right approach for these patient groups.”

References

1. Tivey A, Shotton R, Eyre TA, et al. Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study. Blood Adv. 2024;8(5):1209-1219. doi:10.1182/bloodadvances.2023011152
2. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica. 2019;104(5):e211-e214. doi:10.3324/haematol.2018.205229
3. NHS England interim treatment options during the COVID-19 pandemic. Updated January 6, 2021. Accessed March 27, 2024. https://www.theacp.org.uk/userfiles/file/resources/covid_19_resources/nhs-england-interim-treatment-options-during-the-covid19-pandemic-pdf-8715724381-6-jan-2021.pdf