SUMMARY: It is estimated that approximately 3,300 new cases of Mantle Cell Lymphoma (MCL) are diagnosed in the US each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.
Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation. The four BTK inhibitors presently approved by the FDA for MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, BRUKINSA® (Zanubrutinib) approved in 2019 and JAYPIRCA® (Pirtobrutinib) approved in 2023.
Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation, and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Single agent Ibrutinib is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. By virtue of their unique and complementary mechanism of action, Ibrutinib in combination with Venetoclax demonstrated promising clinical activity in early phase MCL studies (N Engl J Med 2018; 378:1211-1223).
The Sympatico trial, is a multinational, randomized, double-blind, phase III study conducted to compare the combination of Ibrutinib and Venetoclax with Ibrutinib plus placebo, in patients with relapsed or refractory Mantle Cell Lymphoma (MCL). In this study, a total of 267 adult patients (N=267) with relapsed or refractory MCL who had previously received at least one prior line of therapy were randomly assigned in a 1:1 ratio to receive Ibrutinib 560 mg orally once daily concurrently with, either oral Venetoclax given at a standard 5-week ramp-up dose to a target dose of 400 mg once daily (N=134), or Placebo (N=133) for 2 years, followed by single-agent Ibrutinib until progressive disease (PD) or unacceptable toxicity. The median age was 68 years, 96% of patients had an ECOG PS of 0-1, 17% had 3 or more prior lines of therapy, and 22% were at increased risk for Tumor Lysis Syndrome (TLS). Both treatment groups were well balanced, and randomization was stratified based on ECOG PS, prior lines of therapy, and TLS risk based on tumor burden and Creatinine Clearance. The study evaluated the efficacy of the combination therapy across various subgroups, including those with high-risk features such as blastoid variant or TP53-mutated MCL. The Primary endpoint was investigator assessed Progression Free Survival (PFS) using Lugano criteria, and key Secondary endpoints included Complete Response (CR) rate, Time To Next Treatment (TTNT), Overall Survival (OS), and Overall Response Rate (ORR) by investigator assessment.
With a median follow up of 51.2 months, the median PFS was significantly longer with the Ibrutinib-Venetoclax combination, compared with the Placebo group (31.9 months versus 22.1 months; HR=0.65; P=0.0052). These PFS benefits were consistent across patient subgroups, including those with blastoid-variant or TP53-mutated MCL. In the combination group, 54% of patients achieved a Complete Remission, compared to 32% in the Placebo group (P=0.0004). The Time to Next Treatment in the combination group was median Not Reached (NR) versus 35.4 months in the Placebo group. At the time of this primary analysis, the median OS was 44.9 months with the Ibrutinib-Venetoclax combination versus 38.6 months with Ibrutinib plus Placebo, but the difference was not statistically significant. Adverse events were more common among patients who received the combination therapy, and included cytopenias and pneumonia.
It was concluded that a combination of Ibrutinib and Venetoclax was synergistic and demonstrated efficacy and safety, for the treatment of relapsed or refractory Mantle Cell Lymphoma, providing a potential new standard of care for this patient population. This chemo-free treatment option represents a milestone achievement in Mantle Cell Lymphoma treatment.
Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study. Wang M, Jurczak W, Trněný M, et al. Presented at the 2023 ASH Annual Meeting & Exposition December 9-12, 2023. LBA-2.
