How should we use ibrutinib in patients with mantle cell lymphoma?

Mantle cell lymphoma (MCL) is not among the most common forms of lymphoid malignancies, representing around 6% of all lymphomas.¹ Nevertheless, it may be the lymphoma subtype where management, as well as treatment outcome, has undergone the most changes during the last decades. This dynamic shift in treatment strategies is still very much ongoing.

MCL is currently considered a non-curable disease, but as response duration continues to improve, this statement may soon be contradicted. The reason for optimism is the access to several novel agents that have all shown particular high activity in MCL. Arguably, MCL may be the type of lymphoma where the application of anti-CD20 antibodies as single agents has the most significant impact on outcome, as maintenance with rituximab leads to improvement not only in terms of progression-free survival (PFS), but also overall survival. This has been shown both in younger patients and in the elderly population.^{2, 3}

During the last years, we have witnessed the development of a number of agents with impressive activity, specifically in MCL. This includes agents blocking the B-cell receptor pathway, inhibitors of BCL2 such as venetoclax,⁴ immunosensitizers such as lenalidomide,⁵ chimaeric antigen receptor T-cells (CAR-T),⁶ and bispecific antibodies. Among B-cell receptor blockers, one group has emerged as the most active in MCL, inhibitors of Bruton’s tyrosine kinase (BTK). The first BTK inhibitor (BTKi), ibrutinib, has consistently shown response rates around 70% in patients with relapsed MCL, and has secured its place in treatment algorithms.^{7, 8}

How should we use this agent in the clinic? As per current standard, patients with MCL will receive chemotherapy in combination with rituximab as initial treatment. In addition, younger patients usually undergo consolidative high-dose chemotherapy with autologous stem cell support (ASCT).⁹ Most patients will also receive maintenance rituximab, as this has been shown to improve survival.^{2, 3} For non-responders, a shift to a BTKi is the treatment of choice, followed by consolidation with an allogeneic stem cell transplant in eligible patients. This is also true for patients with an early relapse (<24 months), where ibrutinib has been shown to be superior to alternative chemoimmunotherapy regimens.¹⁰

In a series of pooled data from clinical trials, it was noted that outcome with ibrutinib is superior when used as second-line treatment, compared to later lines, associated with a median PFS of 25 vs 10 months, indicating that earlier use may be of benefit.¹¹ In a recent issue of BJHaem, McCulloch et al.,¹² report a multicentre retrospective analysis of 211 MCL patients from the UK, investigating the approach of giving ibrutinib as second-line therapy. Although not all patients could be included nation-wide, these data should provide a more realistic picture of efficacy and safety outside of the clinical trial situation. Data are comforting to clinicians, confirming a high overall response rate, 69%, and a median PFS of 18 months in this situation, slightly lower than shown in the pooled trial data analysis. Only a small minority (7%) stopped ibrutinib due to adverse events, indicating that this is a safe and well-tolerated treatment. This is clinically useful information. Among the 17 patients that proceeded to an allogeneic transplant, median PFS was considerably longer, 34 months, confirming ibrutinib to be an effective bridge to allo-SCT.

On the other hand, there are patients for whom treatment with ibrutinib is not efficacious. In this report, patients with blastoid histology could be identified as faring considerably worse, with a more than threefold higher risk for death in a multivariable analysis. This is a patient population clearly in need of experimental, novel treatment strategies.

Two other important biological high-risk factors have been established for MCL: proliferation rate, measured by the fraction Ki67-positive cells, and aberrations of TP53. Data on TP53 abnormalities were not available in this report, as this is not yet part of the routine work-up for MCL, but interestingly, high Ki67 (>30%) did not in any way affect the efficacy of ibrutinib.

Ibrutinib is not a curative treatment in relapsed MCL. This means that management of patients progressing on this treatment is an increasingly more common clinical situation, for which there is no current standard approach. In this report, the authors confirm that the combination of rituximab, bendamustine and cytarabine (R-BAC), could be the treatment of choice here, possibly as a bridge to an allo-SCT or CAR-T. Twenty-three patients received R-BAC post ibrutinib, associated with a median survival of 14 months, markedly superior to other therapies (median 3·6 months).

The next step in the use of ibrutinib in MCL is its introduction as part of first-line treatment. This is being studied in several randomised phase 3 trials; the large European TRIANGLE trial for patients up to 65 years (NCT02858258), evaluates the addition of ibrutinib in the induction phase and as maintenance, as well as if ASCT may be omitted. This trial recently stopped enrolment after the inclusion of 870 patients. The second trial is the SHINE trial (NCT01776840), for elderly patients with MCL, assessing the efficacy of adding ibrutinib to a backbone of rituximab and bendamustine (RB). This trial fulfilled its enrolment several years ago, and results may be expected within the coming year. The third, and possibly most innovative, as it challenges the use of chemotherapy in MCL, is the UK ENRICH trial, comparing chemoimmunotherapy [cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (R-CHOP) or RB] to rituximab + ibrutinib. Enrolment to the latter is likely to be concluded during early 2021.

The management of patients with MCL is evolving at a rapid pace. For younger patients that are eligible for intensive therapies that may include ASCT, but also allo-SCT¹³ and/or chimaeric antigen receptor (CAR)-T-cell products for selected populations, the aim will be to provide a cure for this disease. For elderly and frail patients, highly efficacious, but likely not curative, low-toxic combinations are being developed. In both scenarios, BTK inhibitors such as ibrutinib, are likely to play an important role in the foreseeable future.