Phase 2 Trial of Acalabrutinib-Lenalidomide-Rituximab (ALR) with Real-Time Monitoring of MRD in Patients with Treatment-Naïve Mantle Cell Lymphoma

Ruan, Jia; Leonard, John P.; Chen, Gui Zhen; Chen, Zhengming; Allan, John N.; Rutherford, Sarah C.; Hobbie, Brittany; Greig, Katie; Rodríguez, Á; Bond, David A.; Shah, Bijal; Maddocks, Kami J.; Binder, Bhavneet; Inghirami, Giorgio; Elemento, Olivier; Chen‐Kiang, Selina; Martin, Peter

doi:10.1182/blood-2022-158656

Cited by 10 publications

(4 citation statements)

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“…Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL. 87 , 88 Given the high relapse rate observed with ibrutinib and other BTKis, there is an urgent need to identify mechanisms of resistance to enhance the efficacy of these BTKis. Here, we have demonstrated that targeting DNMT3A by genetic knockout overcomes ibrutinib resistance in various MCL clonal cell lines.…”

Section: Discussionmentioning

confidence: 99%

Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

Hoang,

Liu,

Bates

et al. 2024

Cell Reports Medicine

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Section: Discussionmentioning

confidence: 99%

Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

Hoang,

Liu,

Bates

et al. 2024

Cell Reports Medicine

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“…The reported incidences of the hematologic toxicities in two previous clinical trials on ibrutinib, rituximab, and lenalidomide combination for R/R DLBCL reported incidence ranging from 20 to 44% 11 , 23 . Another clinical trial on R2A for mantle cell lymphoma reported hematologic toxicity in up to 38% of patients 24 . Notably, in our study, the toxicities were manageable and most of the patients recovered within a cycle.…”

Section: Discussionmentioning

confidence: 99%

Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

Park,

Lee,

Kang

et al. 2024

Nat Commun

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Potential synergism between Bruton’s tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142)

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“…Based on the first formal evaluation in the Triangle study incorporating upfront BTKi, it is unclear whether or not upfront len + chemoimmunotherapy approaches will be further developed. Noteworthy ongoing upfront studies include venetoclax-lenalidomide-rituximab 31 and acalabrutinib-lenalidomide-rituximab 32 from which we await further results. Given len’s immunomodulatory mechanism of action and the advent of chimeric antiden receptor T cell 33 and bi-specific antibodies 34 in treating MCL, there may be rational synergistic combinations that can be pursued wherein len augments the efficacy of these immune-based therapies.…”

Section: Discussionmentioning

confidence: 99%

Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation

Epstein-Peterson,

Drill,

Aypar

et al. 2023

haematol

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Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured MRD using an NGS-based assay after each phase of treatment and at 6 months following end-of-treatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% WT versus 38% ALT, P = 0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53-wildtype MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.

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Phase 2 Trial of Acalabrutinib-Lenalidomide-Rituximab (ALR) with Real-Time Monitoring of MRD in Patients with Treatment-Naïve Mantle Cell Lymphoma

Cited by 10 publications

References 0 publications

Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation

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