Portuguese real-world experience with ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma

Background: Mantle cell lymphoma is usually characterized by an aggressive and recurrent course. Clinical trials and real-world series have demonstrated clinical benefits with the use of ibrutinib as a second-line treatment, compared to later relapses.

Objective: To evaluate the Portuguese experience with the use of ibrutinib in patients with relapsed or refractory mantle cell lymphoma since its approval in the country.

Methods: A multicenter retrospective cohort of patients with mantle cell lymphoma who received ibrutinib between 2015 and 2020 was studied.

Results: Ninety-five patients treated at 11 hospitals were included. At the ibrutinib starting date, 51% of patients had high-risk simplified mantle cell lymphoma international prognostic index, 9% had central nervous system involvement, and 21% had Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 10 (<1-75) months. The overall response rate was 66%, including 36% with complete responses. After 18 months of follow-up, seventy-two patients (76%) had discontinued ibrutinib, mainly due to progressive disease (61%) and toxicity (21%). At the last follow-up, 24% of patients were still on ibrutinib, and 60% had died, mostly (65%) due to lymphoma progression.

Conclusions: In this real-world series, the safety of ibrutinib is similar to the results described in clinical trials. However, new strategies are needed for the treatment of acquired resistance to ibrutinib.

1 Introduction

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B cell non-Hodgkin lymphoma (NHL) and accounts for approximately 5 to 7% of all NHL, with an incidence rate of 0.45 cases per 100, 000 person-years in Europe (1, 2). Most patients are diagnosed at an older age (median 65 years), making them unsuitable candidates for aggressive treatment, which may contribute to unsatisfactory clinical outcomes. Most patients have a multiple relapsing clinical course (3, 4).

Ibrutinib (IBT), a first-generation, once-daily, oral, covalently binding inhibitor of Bruton’s tyrosine kinase (BTK) has revolutionized the care of patients with relapsed or refractory (R/R) MCL and is currently established as standard-of-care in this setting since its approval in 2013 (5, 6). It has been associated with response rates of 54%–72% in patients with R/R MCL, with complete response (CR) rates in the 19%–23% range (7). Although no trials have compared it with immunochemotherapy, BTK inhibitors are now well accepted as standard second line therapy. A pooled analysis of three clinical trials in patients with R/R MCL treated with IBT demonstrated a significant benefit in progression-free survival (PFS) and overall survival (OS) for patients treated at first relapse (median PFS 25.4 months) compared to those treated at later relapses (median PFS 10.3 months), suggesting that earlier treatment with IBT may offer greater benefit (6, 8, 9). This is further demonstrated by the MANTLE-FIRST study that showed that IBT was associated with improved outcomes in patients with early progression of disease (10). Additionally, recent findings from the LATE-POD study showed improved outcomes in younger patients with MCL with late relapses also, with a more favorable response to IBT than immunochemotherapy in a non-randomized comparison (11).

In this real-world retrospective study, we describe the clinical characteristics, management and outcomes of patients with R/R MCL receiving IBT in a real-world setting.

2 Materials and methods

Eleven Portuguese centers were involved in this multicenter retrospective study. Eligibility criteria included patients diagnosed with MCL that started IBT between January 2015 and December 2020 for R/R disease. Data was collected from medical records concerning clinical characteristics at diagnosis, pathology and imaging data and therapies used pre-IBT. Response data were provided according to the Lugano classification (12). The safety profile of IBT was also evaluated based on the adverse events, according to CTCAE v5.0, reported during treatment with IBT, and the dose modifications and treatment discontinuations due to adverse events.

The clinical outcomes included overall response rate (ORR), CR rate, time to next treatment (TTNT), PFS and OS. ORR was defined as the proportion of patients achieving CR or partial response (PR) per investigator assessment according to standard criteria. TTNT was defined as the interval from day 1 of IBT therapy to the day 1 of the next line of treatment, whichever occurred first. PFS was defined as the time from day 1 of IBT therapy to disease progression or death from any cause, whichever occurred first. OS was defined as the time from day 1 of IBT therapy to death from any cause. Progression of disease (POD) after frontline treatment was categorized as occurring within 24 months (POD24) or later. Patients without an event were censored at the date of last follow-up. Discontinuation due to toxicity or stem-cell transplantation was treated as a censoring event at the corresponding date.

Survival curves were estimated using the Kaplan–Meier method, and differences between groups were compared using the log-rank test. The median survival times and 95% confidence intervals (CIs) were reported from the Kaplan–Meier estimates. To adjust for potential confounders [age, Eastern Cooperative Oncology Group performance status (ECOG PS), simplified mantle cell lymphoma international prognostic index (sMIPI), blastoid morphology, POD24, and prior lines of therapy], Cox proportional hazards regression models were fitted to estimate hazard ratios (HRs) with corresponding 95% CIs. The proportional hazards assumption was verified by examining Schoenfeld residuals and log–log survival plots. In analyses with competing events (e.g., non–disease-related death), competing risks models were applied using the Fine–Gray subdistribution hazard approach. The median follow-up time was estimated using the reverse Kaplan–Meier method, considering censoring as the event.

Statistical analyses were conducted with Stata BE version 18.0 (StataCorp, College Station, TX, USA). Two-sided p < 0.05 was considered statistically significant.

All patient data were anonymized and treated according to the principles of the declaration of Helsinki.

3 Results

3.1 Patient characteristics

Ninety-five eligible patients were included. At diagnosis, the median age was 66 years (range: 32-86) and 72% were male. Eighty-eight (96%) had stage III–IV disease, 17% (13/78) presented a blastoid histology and 48% (24/50) had a Ki-67 expression ≥ 30% (Table 1).

Table 1

Table 1. Patients baseline characteristics at diagnosis (n=95).

Regarding pre-IBT therapy, 45% of patients were treated with only one line before IBT. As to the first line, 80% of patients received up-front conventional immunochemotherapy. Twenty-five percent received rituximab combined with high-dose cytarabine-based frontline therapy (Table 1). The most frequent conventional non-intensive regimen was R-CHOP (41%) followed by R-Bendamustine (14%) (Table 1). Nineteen percent of patients had a primary refractory disease. Twenty-four percent of patients received autologous hematopoietic stem cell transplant (ASCT) as a first-line consolidation therapy (Table 1) and 33% received rituximab maintenance.

3.2 Ibrutinib therapy

The median time from diagnosis to the start of IBT was 31 months (range: 2-158). After the end of first-line therapy, 53% (23/43) patients relapsed within the first 2 years (POD24).

The median age at IBT start was 70 years old (range: 37–87). The ECOG PS at this time was 0–1 in 79% (60/76) of the patient and sMIPI was high in 51% (39/76). Central nervous system (CNS) involvement was demonstrated in 9% (7/76). In the subgroup who had CNS involvement, 71% had one prior line, 71% presented with primary refractory disease and 5/7 relapsed within the first 2 years (POD24).

In the subgroup who had one prior line of treatment, the median age at start of IBT was 72 years (range: 37–87), 46% (15/33) had high risk sMIPI, 53% (23/43) were POD24, 19% (8/43) had a primary refractory disease and 15% (5/33) had ECOG PS 2-4.

Forty-one percent of patients started IBT less than 24 months after the diagnosis of MCL, independently of the number of prior lines of treatment.

With a median treatment duration of 10 months (range: <1-75), the ORR of IBT was 66% (95%CI 56-75) (62/94) with CR in 36% (95%CI 27-46) (34/94).

The median duration of follow-up was 22.6 months (95% CI, 33.8-52.0).

The median OS was 23.3 months (95% CI 8.6-NR) (Figure 1). In univariate analysis, only ECOG PS>=2 (HR 2.18, 95% CI 1.13-4.20; p=0.020), sMIPI high risk (vs low/moderate) (HR 2.08, 95% CI 1.12-3.88; p=0.021) (Figure 1), POD24 (HR 2.29, 95% CI 1.33-3.94; p=0.003) and Ki-67 expression >30% (HR 5.78, 95% CI 2.34-14.26; p<0.001) were significantly associated with inferior OS. There was a trend toward worse OS with an increasing number of previous treatment lines (2 lines: HR 1.50, 95% CI 0.78-2.89; p=0.224; ≥3 lines: HR 1.67, 95% CI 0.88-3.19; p=0.119) (Figure 1). Age and blastoid morphology were not significantly associated with outcome (p=0.112 and 0.231, respectively).

Figure 1

Figure 1. Overall survival of relapsed and/or refractory mantle cell lymphoma patients treated with ibrutinib (A). Overall survival of relapsed and/or refractory mantle cell lymphoma patients from the initiation of ibrutinib treatment by number of previous lines (B). Overall survival of relapsed and/or refractory mantle cell lymphoma patients from the initiation of ibrutinib treatment according sMIPI (C).

After multivariate Cox regression model, POD24 (HR 6.59, 95% CI 1.69-25.69; p= 0.007) and Ki-67 expression (HR 12.02; 95% CI 4.46-32.90; p<0.001) remained independent predictors of inferior overall survival.

The median PFS was 12.9 months (95% CI 2.9-34.1) (Figure 2). In the univariate analysis, older age (HR = 1.03; 95% CI 1.01-1.06; p=0.011), ECOG PS ≥2 (HR 2.19; 95% CI 1.20-3.99; p=0.010), POD24 (HR 2.02; 95% CI 1.23-3.31; p=0.006), and Ki-67 expression >30% (HR 4.96; 95% CI 2.26-10.86; p<0.001) were significantly associated with inferior PFS. A trend toward shorter PFS was also observed in patients with ≥3 treatment lines (HR 1.78; 95% CI 1.00-3.18; p= 0.051) (Figure 2) and in those with blastoid morphology (HR 1.87; 95% CI 0.98-3.56; p=0.056), whereas s-MIPI was not significantly associated with PFS (p=0.244) (Figure 2).

Figure 2

Figure 2. Progression-free survival of relapsed and/or refractory mantle cell lymphoma patients treated with ibrutinib (A). Progression-free survival of relapsed and/or refractory mantle cell lymphoma patients from the initiation of ibrutinib treatment by number of previous lines (B). Progression-free survival of relapsed and/or refractory mantle cell lymphoma patients from the initiation of ibrutinib treatment according sMIPI (C).

In the multivariate Cox regression model for PFS, POD24 (HR 5.03; 95% CI 1.84-13.97; p=0.002) and Ki-67 expression >30% (HR 9.30; 95% CI 2.11-40.95; p=0.003) remained independent predictors of inferior PFS.

3.3 Safety

At the time of last follow-up, 23 patients (24%) were still on treatment and 76% patients stopped IBT, 21% due to adverse event.

Thirty-five (36%) patients had grade 3/4 adverse events. The most frequent toxicities were hematological in 17% of patients, followed by infectious (9%), gastrointestinal (4%) and musculoskeletal (4%) (Table 2). Dose reductions of IBT were required in 25 (26%) patients.

Table 2

Table 2. Grade 3–4 adverse events during treatment with ibrutinib.

At the time of last follow-up, 57 (60%) patients died because of progressive disease (65%), toxicity (11%) or unknown causes (25%).

3.4 Post-ibrutinib treatment

At the time of last follow-up, 76% patients discontinued IBT: 61% due to progressive disease, 21% due to adverse event, 7% to receive consolidation with allogeneic SCT and 11% for unknown causes.

Forty-six percent of patients received subsequent therapy for MCL after discontinuation of IBT, with a median TTNT of 25.9 months (95% CI, 9.3-NR).

The first subsequent therapies used after IBT consisted of rituximab, bendamustine, cytarabine (R-BAC)-like regimens (26%), R-bendamustine regimens (24%), lenalidomide-based regimens (13%), R-CHOP-like regimens (5%), palliative care regimens (24%) and others (8%).

4 Discussion

This multicentric Portuguese retrospective analysis centered in the use of IBT in the management of patients with R/R MCL supports the tolerability and effectiveness of IBT in MCL in a real-world context.

This series is enriched with high-risk MCL patients, displaying distinct characteristics when compared to other real-world series: our cohort included 96% of patients with advanced-stage MCL, a significantly higher percentage compared to the 78.3% reported by Cencini et al. (13). CNS involvement was observed in 9%, markedly higher than the 4% reported by McCulloch et al. (4). High sMIPI was present in 51% of our cohort, considerably more than the 30.4% in Cencini et al. (13) and the 26.3% in the PCYC-1104, SPARK, and RAY trials (8). In our study, 21% of patients had a ECOG PS ≥2. This specific variable is not directly compared in the cited studies, but underscores the frailty of our cohort. The blastoid/pleomorphic variant was identified in 17% of our patients, higher than the 10.2% reported by Cencini et al. (13). In our study, 55% of patients had received ≥2 prior lines of therapy, in contrast to McCulloch et al. (4), where all patients had only one prior line of therapy. Our cohort included elderly patients, reflected in the high proportion of non-intensively pre-treated individuals. These significant differences in patient characteristics likely may explain the lower median PFS observed in our study in comparison with previously reported real-world series. Despite these challenges, we observed favorable outcomes with IBT treatment, with an ORR of 66% and an OS of 23.3 months, consistent with results from other real-world retrospective analyses (4, 13, 14).

Given the sample size of our study population, no significant benefit in PFS and OS was observed for treatment with IBT at first relapse compared to latter lines. The median PFS was longer in patients at first relapse compared with those in later treatment lines. This finding may be explained by more aggressive disease characteristics in this group, including POD24, elevated Ki-67 expression, poor ECOG PS and an elderly population.

Despite 35% of the toxicities being grade 3-4, they were manageable. The majority of those were hematological, highlighting the low cardiovascular and hemorrhagic toxicities observed in this series.

In this study, 7% of patients were consolidated with allogeneic SCT, supporting the use of IBT as a possible bridging therapy to allogeneic SCT in R/R MCL, and leading us to hypothesize that a similar or higher proportion would have been candidates to cellular therapy (not approved in Portugal at that time).

Sixty-one per cent of the patients stopped IBT because of disease progression, demonstrating the need for new treatments and combinations in this population. In this setting, CAR-T cell therapy (15) and bispecific antibodies (16) have proven to be promising approaches. The results of phase 3 TRIANGLE trial (17) can change the paradigm of first line treatment of MCL by demonstrating that high-dose regimens are not superior to IBT-containing regimen without ASCT as consolidation. This will most probably have consequences upon second line treatment options and the role of T cell engaging therapies in the treatment algorithm.

This study has several limitations, including missing data inherent to its retrospective nature, the lack of central histological and response evaluation review and the absence of data on high-risk characteristics, including TP53 mutations and deletions. Despite these limitations, this study provides real-world evidence on the use of IBT in R/R MCL in clinical practice, with 24% of the patients still in remission at last follow-up.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Comissão de Ética da ULS Coimbra Unidade Local de Saúde de Coimbra. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

CF: Writing – original draft, Writing – review & editing. RC: Writing – original draft, Writing – review & editing. PS: Writing – review & editing. CA: Writing – review & editing. AR: Writing – review & editing. AP: Writing – review & editing. JM: Writing – review & editing. AN: Writing – review & editing. MR: Writing – review & editing. RC: Writing – review & editing. FM: Writing – review & editing. MF: Writing – review & editing. MB: Writing – review & editing. CJ: Writing – review & editing. SL: Writing – review & editing. AT: Writing – review & editing. MC: Writing – review & editing. SD: Writing – review & editing. Md: Writing – review & editing. JF: Writing – original draft, Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, and/or publication of this article.

Acknowledgments

The authors thank the following healthcare professionals for assisting with the data collection for this study. They would also like to thank the Portuguese Lymphoma Group for supporting this project.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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