An article to understand new therapies for relapsed/refractory mantle cell lymphoma

In recent years, the application of Bruton's tyrosine kinase inhibitor (BTKi) has changed the treatment model of relapsed/refractory mantle cell lymphoma (R/R MCL).
At present, the FDA has approved 3 types of irreversible BTKi for treatment R/R MCL patients, including the first approved BTKi ibrutinib and the more selective BTKi acatinib and zebutinib
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The overall response rate (ORR) of these drugs for single-agent R/R MCL treatment is 67%-84%, and the median progression-free survival (PFS) is 13-22 months.
As a second-line treatment, the durability of patient remission is improved
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Although the remission rate of monotherapy is high, almost all patients will relapse, and the overall survival (OS) of patients who progressed after BTKi treatment is poor
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Therefore, it is urgent to explore the combined treatment plan of BTKi, in order to improve the depth and durability of patients' remission, and explore the feasibility of other treatment methods
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Chimeric antigen receptor T (CAR-T) cells have been proven to be an effective method for R/R MCL patients.
The FDA has also approved the CD19-targeting autologous CAR-T product brexucabtagene autoleucel for the treatment of R/R MCL
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Other new treatments with therapeutic prospects are being researched and developed.
This article reviews the new therapies under study for the treatment of R/R MCL patients for readers
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1 Non-covalent BTKi Most R/R MCL patients who respond to covalent BTKi will progress during treatment, and a small number of patients will stop treatment due to intolerance of adverse reactions
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The efficacy of selective and reversible BTKi Pirtobrutinib (LOXO-305) has been evaluated in a phase I/II clinical study, which included 57 patients with evaluable R/R MCL and 52 (91%) patients Received covalent BTKi treatment
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The results showed that the ORR was 52% and the complete remission (CR) rate was 25%.
A similar remission rate was observed in patients who had previously received BTKi treatment (ORR was 52%, CR rate was 25%), 5/29 cases Remission patients stopped treatment at a median follow-up of 6 months (4 cases progressed), and the median DOR was not reached
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The reported adverse events (AE) resulted in a low rate of discontinuation (1.
5%), and grade 3 AEs were uncommon
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A phase III clinical trial is currently in preparation.
It is planned to randomly allocate R/R MCL patients to receive the approved covalent BTKi treatment or Pirtobrutinib treatment selected by the investigator
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2BTKi's combination therapy A number of studies have evaluated multiple BTKi combination drug regimens in order to improve the depth and durability of single-agent therapy
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Although the ideal combination scheme has not yet been determined, the most promising one so far is the combination with the BCL-2 inhibitor Venecla
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A phase II clinical study evaluated the efficacy of BTKi combined with Vinekalla regimen.
The results showed that the ORR of 24 patients (23 R/R MCL patients) was 71%, and all patients in remission (including patients with high-risk characteristics) All reach CR
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A large phase III study (NCT03112174) comparing ibrutinib monotherapy and ibrutinib combined with Venecla therapy has been recruited, but relevant research results have not yet been reported
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In addition, the benefit of the triple therapy of Ibrutinib, Venecla and anti-CD20 monoclonal antibody in R/R MCL is still unknown
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When considering these combined treatments, attention should be paid to the balance between improving clinical outcomes and managing AEs.
In addition, this combined treatment may have opportunities for time-limited treatment
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3 Phosphatidylinositol 3-kinase inhibitor (PI3Ki) Although there is no PI3Ki drug approved, PI3Ki has good activity in R/R MCL
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Selective PI3Ki Parsaclisib is active in MCL patients who have not been treated with BTKi and have previously received BTKi therapy
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In a phase II clinical study evaluating two doses of PI3Ki, 108 patients with R/R MCL who had not received BTKi treatment were treated with PI3Ki.
The overall ORR was 70%, the CR rate was 15%, and the median The PFS was 11.
1 months, while the ORR of the 53 patients who had previously received ibrutinib was 25%, the CR rate was 2%, and the median PFS was 3.
7 months
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The most common AE was diarrhea (any grade).
The incidence of diarrhea in the cohort who did not receive BTKi and the BTKi treated cohort were 31% and 23%, respectively.
In the cohort who did not receive BTKi treatment, 22% of patients were due to AEs.
And discontinue treatment
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4 Antibody-drug conjugate (ADC) ADC has been proven to be effective against a variety of B-cell malignancies, but no ADC has been approved for R/R MCL
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VLS-101 is an anti-ROR1 monoclonal antibody conjugated to monomethyl Auristatin E (MMAE), which has shown promising activity in early studies of R/R MCL patients
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The preliminary results of the first human phase I clinical study (including 15 patients with R/R MCL) confirmed the clinical activity of its single agent.
The ORR was 47%, the CR rate was 13%, and 9% of the patients had grade 3 diarrhea, 35 % Of patients had neuropathy of grade ≥2
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5CAR-T cell therapy Brexucabtagene Autoleucel is the first CD19-targeting autologous cell therapy approved by the FDA for R/R MCL.
In the approved key Phase II clinical trial report, the ORR of 60 patients with evaluable efficacy was 93% , The CR rate is 67%
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With a median follow-up of 12 months, the 1-year PFS rate and OS rate were 61% and 83%, respectively
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Subgroup analysis showed that patients with high-risk characteristics (including TP53 mutation, blast-like morphology, and high-risk MIPI) still have similar activity
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91% of patients had any grade of cytokine release syndrome (CRS), and 63% of patients had any grade of neurotoxicity
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All patients treated in this phase II clinical trial have previously received BTKi treatment, so the timing of the application of CAR-T cell therapy is still unclear, especially in high-risk patients with limited response to BTKi treatment
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Lisocabtagene Maraleucel is the second CD19-targeted autologous CAR-T cell therapy.
The relevant clinical research for the treatment of R/R MCL patients is underway.
The rate was 66%.
At a median follow-up of 6 months, the median PFS and OS were not reached
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The incidence of CRS of any grade was 59%, and the incidence of neurotoxic events of any grade was 34%
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Summary Almost all patients with MCL will relapse.
When recurrence occurs, BTKi has become the first choice of treatment
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However, almost all patients will progress when receiving BTKi treatment.
Therefore, it is urgent to use BTKi-based combination therapy to further improve the prognosis of such patients.
It is also necessary to use effective treatment methods when the disease progresses
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As BTKi gradually enters the front line of treatment options, this will become even more critical
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The approval of CAR-T cell products provides an effective treatment option for MCL patients who have progressed after BTKi treatment.
This treatment method is also expected to be applied forward in the treatment of patients with high-risk characteristics
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Reference source: Kami Maddocks.
2021 SOHO.
EXABS-239-MCL.
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