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Therapy of Relapsed/Refractory Mantle Cell Lymphoma after BTKis: History
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Subjects: Hematology
Contributor: Madelyn Burkart

Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton’s tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4–9 months. With the introduction of ibrutinib, the median PFS improved to 13–14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished.

  • mantel cell lymphoma
  • relapsed/refractory mantle cell lymphoma
  • BTK inhibitors
  • CAR-T cells

1. Introduction

Mantle cell lymphoma (MCL) is a rare and aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor long-term survival rates. In western countries, MCL comprises about 7% of adult-onset NHL [1][2]. The incidence increases with age, with a median age of diagnosis of 68 years [3]. MCL is characterized by the t(11;14) (q13; q32) translocation, which leads to the overexpression of cyclin D1. The disease is heterogeneous, with some patients presenting with aggressive disease and others with a more indolent course. MCL remains an incurable disease with conventional therapy, resulting in serial relapses, making treatment extremely challenging. Survival depends on initial prognostic factors and high-risk disease features, such as a high mantle cell lymphoma international prognostic index (MIPI) score, elevated Ki-67, TP53 mutations, del 17p, complex karyotype and blastoid/pleomorphic variants. Patients with high-risk disease have inferior survival rates compared to patients without high-risk MCL; however, long-term survival remains poor for all, with a median time to treatment failure of 4.1 years and 7.7 years, depending on initial treatment with R-CHOP or R-DHAP, respectively, and a 10-year overall survival (OS) rate of 55–60% [4][5].
The current standard of care for advanced MCL is based on patient age and comorbidities. Younger, fit patients are generally treated with three components: cytarabine-containing induction chemotherapy, followed by autologous stem cell transplant (ASCT) and rituximab maintenance; while less fit patients receive less intensive chemoimmunotherapy without ASCT, such as bendamustine-rituximab (BR) with or without cytarabine, followed by rituximab maintenance therapy [4][6][7]. Despite the initial response rates of 50–70% with these upfront regimens, the median progression-free survival (PFS) remains only 7 to 10 years as patients will eventually progress after treatment, resulting in successive relapses each with shorter periods of remission, each being more challenging to treat [3][5][8].
Additionally, it is clear that patients with high-risk disease features derive minimal benefit from induction with conventional cytarabine-based immunochemotherapy regimens, including HCT. Patients with a combined high MIPI and Ki-67 expression score were shown to have a median OS of only 2 years. Patients with TP53-mutated MCL are also known to have inferior outcomes and are associated with high ki-67% and blastoid morphology, with a significantly shorter median OS of 13 months compared to 43 months seen in wild-type TP53 [9]. Patients with the blastoid or pleomorphic variants, which comprise less than 20% of cases, suffer from what are among the most aggressive subsets of MCL. Clinical trials investigating conventional chemoimmunotherapy, followed by ASCT, showed that patients with the blastoid variant had a significantly inferior 5-year OS rate of 38%, compared to 75% in patients with classical MCL [10]. Patients with high-risk features are also at increased risk of developing CNS disease, which is a rare yet serious condition, and are known to have a high mortality rate, with a median survival of only 3.7 months [11]. This poor response to frontline therapy suggests that novel treatment strategies are needed for these groups.
Recent progress in understanding the biology of MCL has led to the development of a number of novel targeted therapies, and the treatment landscape for MCL continues to evolve. The introduction of Bruton’s tyrosine kinase (BTK) inhibitors has shown promising results in survival outcomes in relapsed/refractory (R/R) MCL and is the primary choice of treatment, especially in patients in the early stages of the disease. Ibrutinib was shown to be effective for R/R disease, with an overall response rate (ORR) of 68% when used as a single agent, and ORRs of 71% and 88% when ibrutinib was combined with venetoclax and rituximab, respectively [12][13]. However, many patients will inevitably experience progression on BTK inhibitors (BTKi), which is associated with poor outcomes and a median OS of only 6 to 10 months [14][15][16]. Several agents have been investigated after BTKi failure, including combination therapies and new cellular therapies. However, the optimal approach to treating R/R disease after BTKi failure remains to be defined, and challenges in the treatment of R/R MCL persist.

2. Beyond BTK Inhibitors: Targeted Therapies

Patients who progress while receiving BTKi therapy typically have aggressive disease with relatively short survival. Treatment beyond BTKi remains unclear, and although agents have shown activity in this setting, the DOR is poor and consolidation with allogeneic hematopoietic cell transplantation (HCT) or other emerging cellular therapy approaches should be considered. It should also be noted that some of the trials did not include patients previously exposed to BTKi; therefore, their value as a treatment after BTKi is uncertain.

Pirtobrutinib or LOXO-305 is a highly selective, non-covalent next generation BTKi with potent inhibition of both wild-type BTK and C481 mutant BTK[17]. The BRUIN phase I/II study demonstrated promising efficacy of pirtobrutinib  in B cell malignancies. It included 323 patients, 61 evaluable patients with MCL, who had received a median of three prior therapies; 93% had prior covalent BTKi exposure. The ORR was 52% in all MCL patients, with a 25% CR rate. In patients with prior exposure to BTKi, the ORR was 52%, and was 60% for those patients without (including all disease types)[18][19][20]. In 20 patients harboring the C481 mutation the ORR was 75%[18].  Pirtobrutinib was relatively well tolerated; 87% of adverse events reported were grade 1–2 and 10% of adverse events reported were grade ≥3 AE, with the most common being neutropenia[20]. The durability of response of pirtobrutinib remains unknown and longer follow up data is needed.

Other targeted agents have previously been shown to have clinical activity in R/R MCL, including the approved agents, bortezomib, lenalidomide, and temsirolimus. Bortezomib, a proteasome inhibitor, received FDA approval in R/R MCL, based upon phase-II clinical data demonstrating a median PFS of approximately 6 months and the landmark PINNACLE trial [21][22]. Temsirolimus was approved in Europe after a phase-III trial demonstrated its superiority with a median PFS of 4.8 months compared to the investigators’ choice [23]. Lenolidomide is a second-generation immunomodulator that has been studied extensively and demonstrated efficacy in R/R MCL prior to the introduction of BTKi [24][25]. However, these drugs have not shown promising results after BTKi failure. The observational MCL-004 study showed that lenolidomide (including monotherapy and in combination with rituximab or other agents) had a 27% ORR and 14% CR, with a median DOR of 18 weeks in patients who had previously failed on ibrutinib. Patients treated solely with lenalidomide monotherapy (N = 13) had an ORR of 15%, with no patients achieving a CR [26]. There are also no clinical trials that have studied the other aforementioned agents used alone beyond BTKi treatment and, given their inferior response compared to BTKi alone, they have limited utility as single-agent therapies and are likely best used in combination strategies in this setting.
There is a small report of 20 patients with R/R MCL and prior BTKi treatment treated with venetoclax alone in the United Kingdom, with a 53% ORR and 18% CR; however, the median PFS was only 3 months[27]. Another retrospective study of 24 R/R MCL patients, 22 of which had prior BTKi failure, achieved an ORR of 50% and CR of 21% with venetoclax; however, only half of the patients received single agent venetoclax[28]. More research has focused on combining the two agents, due to the synergistic relationship between BTKi and venetoclax.

Two monoclonal antibody that brought about significant improvements in B cell NHL was obinutuzumab and rituximab. Rituxmab based induction regimens and maintenance therapy has shown to improve overall survival for front line therapy[4][12]. However, single agent activity has been limited in R/R mCL and less impressive than other indolent B cell malignancies, especially after BTKi therapy. Patients with R/R disease treated with obinutuzumab alone had a 27% response rate, which was superior to single agent rituximab[29][30]. In a second trial, patients treated with rituximab and ibrutinib had an ORR of 88% with a median DOR of 46 months and 3-year PFS of 54%. High-risk patients (those with high ki67%, blastoid variant and high risk mipi score) had inferior survival, with a median PFS of only 8 months[12][31]. Similarly, to venetoclax, there are several studies investigating combinational approaches with these drugs.

To date, no single agent has demonstrated superiority after failed BTKi therapy, and not all trials included patients after BTKi failure. The optimal therapy for the management of R/R MCL after BTKi therapy has not been established, and it is likely that combination strategies are needed to provide durable responses in patients, along with a possible bridge to allogeneic HCT or cellular therapies, such as chimeric antigen receptor (CAR) T cells. That being said, although BTKi monotherapy has remained the treatment of choice for relapsed disease, clinical trials may soon support a shift in practice patterns toward the combination of BTKi with other agents in the R/R MCL, which could enhance the durability of response (Table 1).
Table 1. Combination strategies to overcome ibrutinib resistance/failure for R/R MCL.
NCT # (Trial Phase) Drug Combination N= ORR CR Median PFS Ongoing Investigation
NCT02471391 (Phase II) [13] Venetolax + ibrutinib 23 71% 71% 29 months NCT03112174 (Phase III)
NCT01880567 (Phase II) [12] Rituximab + ibrutinib 50 88% 40% 3 year−54% --
NCT02159755 (Phase I) [32] Obinutuzumab + venetoclax + ibrutinib 12 66.6% 25% Not reached --
NCT02460276 (Phase II) [33] Lenalidomide + Rituximab + ibrutinib 50 76% 56% Not reached --
NCT02159755 (Phase I) [34] Palbociclib + ibrutinib 27 67% 37% 2 year−59.4% NCT02159755
(Phase II)
NCT02268851
(Phase I/Ib) [35]		 Umbralisib + ibrutinib 21 67% 19% 10.5 months NCT02268851 (Phase II)

3. Beyond BTK Inhibitors: Combination Therapies

There have been multiple efforts to combine therapies to induce deeper and more durable responses in R/R MCL, as it is clear that the sequential use of these single targeted agents in the post-BTKi setting has not been as effective (Table 2). In addition, not all trials included patients previously exposed to BTKi; therefore, their value as salvage therapy after BTKi failure remains unclear and additional research in this area is needed. A few notable studies evaluating combination therapies are discussed below.
A retrospective review of rituximab-bendamustine-cytarabine (R-BAC) after progression on ibrutinib demonstrated an ORR of 83% with a median PFS of 10.1 months and OS of 12.5 months. Although these responses were not very durable, 31% of patients were able to successfully bridge to an allogeneic HCT[36]. Therefore, this regimen may be a potential bridge for patients awaiting HCT or CAR T cell therapy, however challenges with toxicities exist.

The combination of bortezomib and lenalidomide in R/R MCL has been disappointing, with an ORR of 40%[37]. However, the combination of rituximab, bortezomib, lenalidomide, and dexamethasone (DR2IVE) was reported to be generally well tolerated and active in a very small population of heavily pretreated MCL patients sequenced after BTKi treatment. A median of 2 cycles were received, with an ORR of 100% in 3 of 5 patients still alive at last follow up ranging from 3- 11 months[38]. A trial with a larger sample size is needed to better understand the safety and efficacy of this regimen after BTKi treatment.

Table 2. Available treatment for R/R MCL and after BTK inhibitor failure.
Data in all R/R MCL Patients Data in Patients with Prior BTKis
N= ORR CR Median PFS N= ORR CR Median PFS
LOXO-305
(pirtobrutinib) [39][40]		 56 52% 23% NR * 52 52% NR * NR *
Bortezomib [21] 155 33% 8% 9.2 months -- -- -- --
Temsirolimus [23] 170 22% 2% 4.8 months -- -- -- --
Lenalidomide
Monotherapy [24][26]		 54 78% 19% 8.7 months 13 15% 0% NR *
Venetoclax [41][42][43] 28 75% 21% 11.3 months 20 53% 18% 3.2 months
R-BAC [6][44] 20 80% 75% NR * 36 83% N/A 10.1 months
Parsaclisib [45][46] 108 70% 15.2% 11.1 months 53 25% 2% 3.7 months
Brexucabtagene autoleuel [47] -- -- -- -- 74 85% 59% 12.3 months −61%
Blinatumomab [48][49] 24 71.1% 37% ** 6.7 months ** -- -- -- --
Mosunetuzumab [50] 23 37.1% ** 19.4% ** NR * -- -- -- --
Glofitamab [51][52] 4 75% 75% NR 17 82.4% 64.7% NR
* Data not reported; ** denotes data for total NHL population instead of only MCL patients.

4. Beyond BTK Inhibitors: Cellular Therapy—CAR T Cell Therapy

CAR T cell therapy has been a revolutionary cancer breakthrough in otherwise incurable diseases, such as R/R aggressive B cell NHLs and acute lymphoblastic lymphoma, and has been promising after BTKi failure in MCL patients. Brexucabtagene autoleuel (Tecartus) was FDA-approved for the treatment of fit patients with R/R MCL after chemoimmunotherapy and BTKi treatment, based on the results of the ZUMA-2 trial [47]. It included 74 patients with R/R MCL who were previously treated with up to 5 prior lines of therapy. Prior BTKi treatment included ibrutinib and acalabrutinib. A total of 62% of patients had primary BTKi resistance, while 26% had a relapse after an initial response to BTKi therapy, 7% relapsed after stopping BTKi therapy, and 4% were intolerant of BTKi (mainly ibrutinib) due to its adverse effects. The ORR was 85%, with a CR rate of 59%, and the ORRs remained high among patients despite high-risk disease features including the blastoid variant, TP53 mutation, high MIPI score and a Ki-67 index of 50% or higher. At a median follow-up at 12.3 months, the PFS and OS rates were 61% and 83%, respectively. Common adverse events (grade 3 or higher) included cytopenias (94%), infections (32%), cytokine release syndrome (CRS) (15%) and neurologic events (31%) [47]. In the ongoing phase-I TRANSCEND-NHL-001 trial, lisocabtagene maraleucel (Breyanzi) demonstrated promising clinical activity, with an ORR of 84% and a CR in 19 of 32 R/R MCL patients, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events. There was also a 75% ORR among 12 patients with blastoid morphology, and 58% achieved a CR [53]. CAR T cells have shown impressive activity in R/R MCL, with durable complete responses in a significant percentage of patients [47][53]. Undoubtedly, CAR T cell therapy will play a paramount role in the treatment of R/R MCL after BTKi failure, even in patients with poor prognostic features. However, about 40% of patients will still not respond to CAR T cell therapy [47][53]. A longer follow-up from the ZUMA-2 trial and the results of other clinical trials will help elucidate the exact role that CAR T cell therapy has in the treatment of R/R MCL, and if there is the potential for a possible cure for some patients.

5. Beyond BTK Inhibitors: Cellular Therapy—Bispecific Antibodies

Bispecific antibodies (BsAb) comprise two single-chain variable fragments that simultaneously bind to two different antigens: one recognizes an epitope on T cells (typically CD3) and the other recognizes an epitope on the tumor cell of interest. This results in the host’s own immune system attacking the cancer cell through the activation of cytotoxic T cells, leading to the direct T cell-mediated death of the tumor cells [54]. In B cell NHL, ideal antigen targets for malignant cells include CD19, CD20 and CD47. Compared to CAR T cell products, BsAbs have the advantage of being immediately available off the shelf. Below discusses the emerging BsAbs that have shown promising anti-lymphoma activity in R/R B cell NHL, including MCL.
The bispecific t-cell engager (BiTE) with the most evidence to date in B cell malignancies is blinatumomab. Blinatumomab targets both the CD3 subunit on the T cell receptor complex and the CD19 antigen on B cells, which crosslinks T cells and B cells, leading to T cell activation and T cell-mediated lysis of both normal and malignant B cells [48][54]. The phase-I trial MT103-104 investigated blinatumomab in patients with R/R B-NHL with a median of 3 prior treatment lines, including 24 MCL patients. Blinatumomab demonstrated an ORR of 69% and a CR rate of 37% in all patients, with an ORR of 71% in MCL patients [55]. In a follow-up study of 38 patients that included 13 MCL patients, the median OS was 4.6 years, the median PFS was 6.7 months, and the median treatment-free survival (TFS) was 7.6 months [49]. The most frequent AEs reported with blinatumomab were lymphopenia, pyrexia and infections. The most significant toxicity leading to early treatment discontinuation in 13 patients was neurologic. However, the follow-up analysis did not report any long-term neurologic abnormalities secondary to treatment [48][49].
Mosunetuzumab is a full-length BsAb that binds CD3 and CD20, to direct T cells to engage and destroy malignant B cells. In contrast to blinatumomab, which is given as a continuous infusion over 4–8 weeks, mosunetuzumab is given in intermittent doses, with initial weekly dosing during the first cycle and then every 21 days for a maximum of 17 cycles [56]. In an ongoing phase-I/Ib dose-escalation trial of R/R NHL patients (270 enrolled patients; 23 MCL patients), mosunetuzumab had an ORR of 37.1%, with a CR rate of 19.4% [50][56]. Interestingly, 30 patients had prior CAR T cell therapy for which the ORR was 38.9%, with a CR rate of 22%. This demonstrates mosunetuzumab’s promising activity in heavily pretreated B cell NHL patients, even with prior CAR T therapy. Mosunetuzumab also had lower rates of CRS (28.9%) and neurotoxicity (43.7%) than was previously observed with blinatumomab [50][56]. Unfortunately, there has not been a subgroup analysis for a histology-specific response, although the results remain seemingly encouraging for R/R MCL.

6. Conclusions

Over the past decade, there have been exciting developments in MCL that have made substantial improvements in patient outcomes, even those presenting high-risk features. Unfortunately, despite these advancements, many patients still succumb to this aggressive and resistant disease. Once BTKi failure occurs, there remains no standard of care for subsequent treatment. In patients who experience an intolerance of certain BTKi or who develop resistance, switching to a more selective next-generation BTKi, such as LOXO-305, is a reasonable next step. Potential therapies, such as R-BAC or venetoclax, alone or in combination with another agent, have demonstrated favorable short-term responses post-BTKi failure and could be effective as a potential bridge to allogeneic HCT or CAR T cell therapy or in those patients unable to receive these more intensive therapies. Results from the CAR T cell studies have been impressive, and it is eagerly awaited that the long-term follow-up of these clinical trials to clarify the durability of remissions. It is anticipated that the results of more randomized trials, and the development of other targeted therapy will lead to the availability of more effective agents for patients with R/R MCL who have experienced BTKi failure.

This entry is adapted from the peer-reviewed paper 10.3390/jpm12030376

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