Current guidelines: the expanding role of Bruton kinase inhibitors in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a lymphoma of B‑cell lineage and accounts for about 8% of all newly diagnosed lymphomas [1]. According to the most recent World Health Organization classification, the less common “smouldering mantle cell lymphomas” (including nonnodal leukemic MCL, in situ mantle cell neoplasia, and the monoclonal lymphocytosis with t(11;14)/cyclin D1) are thought to be less aggressive and may be subject to a wait-and-see approach, while classical MCL and the highly aggressive pleomorphic and blastic MCL usually require immediate treatment [2].

While the prognosis for patients with MCL has improved over the years, it is still currently thought to be an incurable disease which—even after initial complete remission (CR)—will inevitably recur [3]. Treatment approaches until recently had been tailored according to patients age, as autologous stem cell transplant after intensive induction with chemoimmunotherapy followed by rituximab (R)-maintenance had been the standard of care for younger (< 65 years) and fitter patients [4]. As opposed to this, chemoimmunotherapy with either R‑bendamustine or VR-CAP (including bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone) again followed by R‑maintenance is preferentially used in older patients [5, 6]. For both cohorts, application of BTK inhibitors such as ibrutinib was thought to be the most effective therapy in case of relapse, followed by CAR-T cell treatment with brexucabtagene autoleucel (BrexuCel) in case of relapse or progression to the BTK inhibitor (BTKis). In view of the rapidly changing treatment landscape, algorithms to define the role of BTKis are currently being refined [7].

The most recent version of the Onkopedia guidelines (www.onkopedia.com) developed as the standard of care by Austrian, German and Swiss Societies of Hemato-Oncology has also seen a profound change in the therapeutic algorithm, suggesting that autologous transplantation might be obsolete in most patients with MCL. The objective of this short review is to briefly outline the current role of BTKis in the therapeutic algorithm according to these guidelines.

The most pronounced change in the current guidelines (Onkopedia) has occurred in this cohort of patients based on the TRIANGLE results [8]. This was a 3-arm investigator-initiated randomized superiority trial including patients with newly diagnosed MCL aged 18–65 years from 165 centers. Patients were randomized between the three arms in a 1:1:1 ratio, with Arm A constituting the current standard, i.e., induction with chemoimmunotherapy consisting of R‑CHOP alternating with R‑DHAP followed by ABMT (according to the NORDIC protocol), Arm A + I including ibrutinib for 19 days during ever R‑CHOP cycle followed by ABMT and a 2-year maintenance with daily ibrutinib and Arm I using chemoimmunotherapy plus ibrutinib without ABMT followed by 2‑year maintenance with ibrutinib. Due to the data defining a 3-year maintenance with R as significantly improving progression-free survival (PFS) and also overall survival (OS) following chemoimmunotherapy induction and ABMT [9], the trial was amended to also include R‑maintenance every 2 months for 3 years in all three groups, and roughly 50% of patients were treated with this amended protocol. Primary endpoint of the study was failure-free survival (FFS) as assessed by the investigators. A total of 870 patients (662 men and 208 women were randomized in the TRIANGLE study with Arm A: 288, arm A + I: 292, and Arm I: 290 patients).

Not surprisingly, a higher rate of CR at 45% was seen in both groups including ibrutinib over the 36% in the Arm A after the induction phase of the study. After a median follow-up of 31 months, Arm A + I was superior in terms of FFS to Arm A (88% versus 72% 3‑year FFS). In addition, the superiority of Arm A over Arm I could be rejected for FFS, which was 72% for Arm A and 86% for Arm I at 3 years. The analysis of Arm A + I versus Arm I was still ongoing at the time of publication (with the Kaplan–Meier plots for both ibrutinib-containing arms, however, still overlapping at the time of analysis), and the follow-up time is too short to draw conclusions in terms of OS.

Of interest is the fact that no relevant differences in terms of toxicity could be found during the induction phase, suggesting ibrutinib as well tolerated in this schedule; nevertheless, a significantly higher rate of hematological and infectious toxicities was documented in the maintenance phase following ABMT (irrespective of the addition of R).

As a conclusion, these results have led to incorporation of ibrutinib into current guidelines as standard of care along with induction chemoimmunotherapy as well as for maintenance for a total of 2 years in patients < 65 years requiring therapy. While a potential advantage of A + I over I alone cannot be ruled out at the moment, the overlapping curves for both ibrutinib arms after a median follow-up of 31 months and the elevated toxicity following ABMT have also resulted in the recommendation to skip ABMT for the majority of patients with MCL. While ABMT should still be discussed with patients showing high risk features in terms of Ki67 (although the cutoff does not seem to be clear at 30% as included in the MCL-prognostic index MIPI), the main adverse prognostic feature, i.e., TP53 alteration does not appear influenced by ABMT as shown by recent results. In addition, the subgroup of patients with TP53 alterations appears to benefit from BTKis, which might also explain the higher rate of CR in the two ibrutinib-containing arms as opposed to conventional chemoimmunotherapy for induction. When assessed for TP53 < 50% versus more than 50%, a more pronounced hazard ratio (HR) for FFS probability of 0.14 was found for the latter group (with the HR for patients with p53 < 50% being 0.57) in the TRIANGLE study.

As opposed to the radical change that has occurred in younger patients, chemoimmunotherapy remains the mainstay of treatment in first-line treatment for the time being. The two most commonly applied regimens which have both been shown to be superior to the R‑CHOP are R‑bendamustine [6] and the VR-CAP regimen [5], which has substituted vincristine with bortezomib. While R‑bendamustine has been shown to be superior in terms of PFS (69.5 months vs 31.2 months) and also toxicity compared to R‑CHOP, VR-CAP has been demonstrated to be superior both in terms of PFS and OS (90.7 vs 55.7 months). In view of this, current guidelines favor VR-CAP in patients fit for anthracycline-based treatment over R‑bendamustine. Recent data have also suggested a detrimental effect of pretreatment with R‑bendamustine on quality of T‑cells required for CAR-T cell therapy in case of relapse. Real-life data from the US have also shown that even patients with sufficiently viable T‑cells might have a poorer outcome with CAR-T cell therapy if the interval to prior bendamustine application was less than 24 months [10].

In an attempt to further improve outcomes for older patients with first-line therapy, BTKis have also been combined with chemoimmunotherapy in untreated patients with MCL. In the SHINE trial [11], combination of R‑bendamustine plus ibrutinib resulted in a PFS improvement by 2.3 years (6.7 versus 4.4 years) over the R‑bendamustine plus placebo arm, but no influence on OS could be demonstrated, with a higher rate of nonlymphoma-related deaths in the experimental arm. In view of this, the combination was not approved for first-line therapy. More recently, the ECHO study has combined the less toxic acalabrutinib with R‑bendamustine [12], also resulting in a PFS advantage (66.4 versus 49.6 months) of 17 months in the experimental arm. However, a high rate of crossover to acalabrutinib (69%) from the placebo arm occurred, and at the moment there is no significant benefit in OS. In view of these data, there is no clear benefit of a combination of chemoimmunotherapy with a BTKi over sequential therapy in standard risk MCL; and the combination has not been approved to date.

A recent study has tested the BTKi zanubrutinib in combination with obinutuzumab and venetoclax in patients with TP53 mutations [13]. The results of the BOVen study are promising in this poor risk cohort, with an ORR of 96% (24/25 patients) and a CR rate of 88%. Furthermore, a high rate of negativity for minimal residual disease was seen (95% at cycle 13) and the toxicity profile of the combination, suggesting the combination to be of further interest in patients with TP53 mutations.

In spite of the pronounced activity of these agents in MCL, it has increasingly been recognized that patients progressing during therapy face a dismal prognosis. In the SCHOLAR‑2 retrospective chart review study published by Hess et al., the median OS was a sobering 9.74 months after analyzing results obtained with various regimens according to investigator’s choice [14].

The major “game changer” for patients failing BTKis has been the approval of CAR-T cell therapy with BrexuCel following the pivotal trial by Wang et al. [15]. The response rate was impressive for a highly pretreated collective (three median lines of prior therapies) with 93% response rate including 67% CR. In the latter cohort, the median PFS was 48 months, with a 24-month PFS rate of 71.8%. However, fabrication of the CAR‑T construct requires at least some immunological competence of the patients and is time consuming, resulting in the danger of disease progression or even death, resulting in relevant drop-out rates with up to 30% of patients not being infused following T‑cell collection. In view of this, “off-the shelf” products immediately available for bridging therapy are clearly needed to cover the gap.

The first noncovalent BTKi pirtobrutinib has shown promising results in patients failing covalent BTKis [16, 17], and the results from the BRUIN study [16] have shown an overall response rate of 56.7% with an OS of 23.5 months in the MCL cohort. In addition, treatment was well tolerated without relevant treatment-limiting toxicities.