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Review | Therapies available or in clinical development for patients with aggressive mantle cell lymphoma in 2020

Jun 30, 2020
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Chemoimmunotherapy with rituximab followed by autologous stem cell transplant (auto-HSCT) has been the gold standard and the only effective option for eligible patients with aggressive mantle cell lymphoma (MCL). However, when patients were not eligible for transplantation or upon relapse, their therapeutic alternatives were limited, leading to poor survival. 

The incorporation of novel agents to the treatment arsenal for aggressive MCL, represented an important breakthrough for all patients presenting with this particular subtype of B-cell non-Hodgkin lymphoma (NHL). This article summarizes the approved agents and the newest combinations in clinical trials in frontline and relapse setting for patients with MCL, and was adapted from the recently published article in Leukemia & Lymphoma by Jia Ruan and colleagues.  

Clinical and molecular characteristics of patients with MCL2

According to the World Health Organization classification of lymphoid neoplasms, there are two major subtypes of MCL:

  1. Conventional MCL: affects up to 70% of patients, involves lymph nodes and other extra-nodal sites
  2. Non-nodal MCL: minimal nodal disease, with involvement of blood, bone marrow, and/or spleen; less aggressive clinical course compared with conventional MCL

Patient prognosis is usually estimated according to age, performance status, levels of lactate dehydrogenase, and leukocyte count. These variables are evaluated jointly in the MCL International Prognostic Index (MIPI), which stratifies patients into low, intermediate, and high-risk groups. The MIPI can also be combined with the independent prognostic marker Ki-67 index (MIPI-c), and this combined version defines four prognostic risk groups with different 5-year overall survival (OS) rates (17–85%) and, more importantly, helps to identify young patients with a more aggressive MCL.

Mutations and/or deletions of TP53 are present in 23% of patients and are associated with a more aggressive MCL and, thus, inferior and shorter responses to chemotherapy. Moreover, they have been observed more frequently in patients presenting a blastoid morphology (up to 10% of patients) and are associated with inferior OS.

This previous article on the Lymphoma Hub provides a more thorough overview of the above and other key features at diagnosis, as well as conventional chemo-regimens for patients with MCL.

Biological agents and combinations in MCL

New therapies have been incorporated as single-agent or in combination in frontline and relapsed settings, aiming to overcome resistance to conventional chemotherapy.

Bortezomib-based treatment

Bortezomib is a reversible proteasome inhibitor initially developed for the treatment of multiple myeloma, that later demonstrated to be effective in some lymphomas. In 2007, the U.S. Food and Drug Administration (FDA) approved bortezomib single-agent for relapsed/refractory (R/R) MCL, and later, in 2015, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) as frontline treatment for MCL.2

Table 1 summarizes key clinical trials exploring bortezomib efficacy in MCL.

Lenalidomide-based treatment

Lenalidomide is an orally administered thalidomide analogue, also referred as immunomodulator drug or IMiD®. It was approved by the FDA as single-agent for the treatment of patients with relapsed MCL after two prior therapies, if one of which included bortezomib.3 Several combinations with lenalidomide are being evaluated, especially as frontline treatment (Table 1).

Table 1. Relevant clinical trials evaluating bortezomib- and lenalidomide-based regimens for patients with MCL1

B, bendamustine; CAP, cyclophosphamide, doxorubicin, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; main, maintenance; D, dexamethasone; L, lenalidomide; MCL, mantle cell lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression free survival; R, rituximab; V or Vc, bortezomib

Backbone therapy

Setting

Regimen

Clinical trial

Key efficacy outcomes

Bortezomib

Relapsed

V

PINNACLE

ORR 33%; PFS 6.5 months; OS 23.5 months

Frontline

 

VR-CAP

LYM-3002

ORR 92%; PFS 24.7 months; OS 90.7 months

VR-CHOP + V main

NCT00376961

Ongoing trial

VcR-CVAD

NCT00581776

ORR 95%; 3-year PFS 72%; 3-year OS 88%

V + BRD

NCT01457144

ORR 83%; 2-year PFS 69%; 2-year OS 80%

Benda ± VR ± R main ± L

NCT01415752

Ongoing trial

Lenalidomide

Relapsed

L

EMERGE

ORR 28%; PFS 4.0 months; OS 19.0 months

L + BR

NCT01737177

ORR 79%; 2-year PFS 51%; 2-year OS 66%

Frontline

L + BR

NCT00963534

ORR 80%; PFS 42 months; OS 53 months

LR

NCT01472562

ORR 92%; 2-year PFS 85%; 2-year OS 97%

LR main

NCT01865110

NCT01415752

Ongoing trials

Bruton’s tyrosine kinase inhibitors (BTKi)

The BTKi are considered the most effective class amongst all novel agents incorporated in R/R MCL treatment. They are generally well-tolerated, and some class-specific adverse events have improved with second-generation BTKi. Table 2 summarizes the most promising combinations containing BTKi (ibrutinib, acalabrutinib, and zanubrutinib) in MCL. 

Ibrutinib received accelerated approval by the FDA as a single-agent treatment for patients with R/R MCL due to the response rates achieved in this setting.4 Initial results were promising, but eventually, patients relapsed within 2 years. Consequently, multiple combinations in frontline and relapsed settings started to be investigated to improve the efficacy of ibrutinib and overcome resistance.

Preliminary results from the trials included in Table 2 anticipate that ibrutinib could be added to the induction, consolidation, and maintenance immunochemotherapy. This practice-changing event could significantly improve response rates and survival outcomes for patients eligible and ineligible for auto-HSCT.

Remission rates and durability of response with ibrutinib are considerable, even in chemo-free combinations with rituximab ± lenalidomide (a triple combination that might overcome mutated TP53 poor prognosis); or with venetoclax, a BH3-mimetic that inhibits BCL-2 (dual-targeting).

Second-generation BTKi are also being investigated in MCL. Up to date, acalabrutinib and zanubrutinib are approved as single-agents for the management of R/R MCL.5-6

Table 2. Combinations approved or in advanced clinical development containing BTKi for the treatment of patients with MCL1

Aca, acalabrutinib; B, bendamustine; BTKi, Bruton’s tyrosine kinase inhibitors; CR, complete response; DHAP, cisplatin, cytarabine, dexamethasone; hyperCVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; I, ibrutinib; L, lenalidomide; main, maintenance; MCL, mantle cell lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab; Ven, venetoclax; Z, zanubrutinib

Backbone therapy

Setting

Regimen

Clinical trial

Key efficacy outcomes

Ibrutinib

Relapsed

I

RAY

ORR 68%; PFS 12.8 months; OS 25 months

IR

NCT01880567

ORR 88%; CR 44%

I + Ven

SYMPATICO

Ongoing trial

I + LR

PHILEMON

ORR 76%; PFS 16 months; OS 22 months

I + Palbociclib

NCT02159755

ORR 67%; 2-year PFS 59%; 2-year OS 61%

Frontline

 

IR

NCT01880567

ORR 82%; 15-month PFS and OS 96%

I + BR

NCT01776840

Ongoing trial

I + R-hyperCVAD

NCT02427620

ORR 100%; 3-year PFS 89%; 3-year OS 100%

I + R-DHAP + I main

NCT02858258

Ongoing trial

IR main

NCT01776840

Ongoing trial

IR + Ven

NCT03710772

Ongoing trial

Acalabrutinib

Relapsed

Aca

ACE-LY-004

ORR 81%; 1-year PFS 67%; 1-year 87%

Frontline

Aca + BR

NCT02972840

Ongoing trial

Aca + LR

NCT03863184

Ongoing trial

Zanubrutinib

Relapsed

Z

NCT03206970

ORR 84%; 24-weeks PFS 82%

Frontline

Z + R

NCT04002297

Ongoing trial

 Relapse treatment options after BTKi1

Due to the rapid inclusion of BTKi at first relapse and the more than probable move into earlier stages of MCL, several novel treatment approaches are already being tested after progression on ibrutinib, including:

  • Venetoclax: although being investigated mainly in combination and earlier settings, as a single-agent, venetoclax has demonstrated moderate efficacy in patients who progressed after ibrutinib (ORR 75%; median PFS 14 months; and 1-year OS 82%)
  • Rituximab, bendamustine, and cytarabine (R-BAC): a valid option for high-risk MCL after BTKi therapy
  • Next-generation BTKi (LOXO-305): still in early development but might overcome resistance to other BTKi
  • Cell therapies: allogeneic stem cell transplantation (allo-HSCT) when feasible, and chimeric antigen receptor T-cell therapy (CAR T-cell), are being investigated in patients with high-risk R/R MCL

Cellular therapy in MCL

Auto-HSCT

Auto-HSCT has been a preferred option as a frontline treatment for young patients with MCL. Different induction regimens can be used depending on patient tolerance and physician’s preference, and currently, rituximab maintenance is administered after transplantation every 2 months for 3 years in most cases.

The role of auto-HSCT has been questioned, given the improvement of response rates and tolerability with novel agents. Although for a correct assessment of the risk-benefit profile of intensive approaches, such as transplantation, the cumulative toxicities of more prolonged exposure to newer therapies also need to be further elucidated.

Allo-HSCT

Conversely to auto-HSCT, reduced-intensity non-myeloablative allo-HSCT is a treatment strategy usually saved for the R/R setting. Studies are limited, mostly retrospective, and with small sample size, but despite toxicities, allo-HSCT can be an effective option for patients who do not have other treatment options left. Some novel agents, i.e., ibrutinib, could have a role also in this setting as a bridge therapy for allo-HSCT.

CAR T-cell therapy

Most trials with CAR T-cell therapies are exploring efficacy in R/R lymphoma, mainly in follicular and diffuse large B-cell lymphoma. However, there is already some exploratory analysis in trials that included patients with R/R MCL (Table 3).

CAR T-cell therapies represent an emerging highly active treatment option, particularly for patients who progress after BTKi therapy, but they also come with important associated toxicities that need to be managed carefully such as cytokine release syndrome (Grade 3–4, up to 18% of patients), and neurologic events (Grade 3–4, up to 46% of patients).

Table 3. Clinical studies with CAR T-cell therapies in NHL1

BTKi, Bruton’s tyrosine kinase inhibitors; CAR, chimeric antigen receptor; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression free survival; R/R, relapsed/refractory

CAR

R/R MCL

Conditioning regimen

Clinical trial and key efficacy outcomes

Lisocabtagene maraleucel (Liso-cel)

9 patients, all relapsed to ibrutinib

Fludarabine + cyclophosphamide

TRANSCEND NHL 001

ORR 73%; 12-month PFS 44.1% and OS 57.9%

KTE-X19 construct (anti-CD19 CAR)

68 patients, all previously exposed to BTKi

Fludarabine + cyclophosphamide

ZUMA-2

ORR 93%; 12-month PFS 61% and OS 83%

Conclusions

After reviewing the current and near-future options for the management of MCL, Jia Ruan and colleagues consider novel agents, specifically BTKi, to represent a clinical revolution that could benefit nearly all patients. Moreover, CAR T-cell therapy could potentially be a significant efficacious option for patients with very high-risk features or who have no treatment options left.

However, the following unmet medical needs in MCL have also been identified, and the authors advocate for their assessment in future studies:

  1. The role of minimal residual disease assessment in MCL for risk-stratification treatment approaches in frontline (transplantation vs no transplantation)
  2. The identification of reliable predictors of treatment response to be able to personalize therapy approaches
  3. The role of novel agents in chemo-containing and chemo-free combinations in the frontline setting
  4. The possibility of a risk-adapted induction and maintenance therapy
  5. The optimal sequence of treatments, especially in the relapsed setting

  1. Ruan J, Yamshon S, van Besien K, et al. An update on options of therapy for aggressive mantle cell lymphoma. Leuk Lymphoma. 2020;1‐14. DOI:1080/10428194.2020.1755860
  2. U.S. Food and Drug Administration. Bortezomib prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021602s040lbl.pdf. Revised Oct 2014. Accessed Jun 15, 2020
  3. U.S. Food and Drug Administration. Lenalidomide prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021880s057lbl.pdf. Revised May 2019. Accessed Jun 15, 2020.
  4. U.S. Food and Drug Administration. Ibrutinib prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210563s000lbl.pdf. Revised Feb 2018. Accessed Jun 15, 2020.
  5. U.S. Food and Drug Administration. Acalabrutinib prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf. Revised Oct 2017. Accessed Jun 15, 2020.
  6. U.S. Food and Drug Administration. Zanubrutinib prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213217s000lbl.pdf. Revised Nov 2019. Accessed Jun 15, 2020.

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