Mantle Cell Lymphoma

High-grade B-cell lymphomas are subclassified based on morphologic and genetic features. There are differences in the nomenclature and definition of these lymphomas in the WHO-5 and ICC classifications. Distinguishing HGBLs from other mature B-cell lymphomas and B-LBL/ALL is critical so that patients receive appropriate treatment.

She was treated with intrathecal chemotherapy with improvement in symptoms and resolution of ophthalmoplegia but was left with residual anisocoria and mild ptosis. This presentation (concomitant Horner and ipsilateral ONP) is rare and typically localises to the ipsilateral cavernous sinus, which appeared radiologically normal in this case.

P2, N=3, Active, not recruiting, M.D. Anderson Cancer Center | N=24 --> 3 | Trial completion date: Jun 2024 --> Dec 2025

P2, N=62, Active, not recruiting, Guangzhou Lupeng Pharmaceutical Company LTD. | Recruiting --> Active, not recruiting

P1, N=54, Recruiting, Roswell Park Cancer Institute | N=36 --> 54

P2, N=360, Active, not recruiting, ECOG-ACRIN Cancer Research Group | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=141, Active, not recruiting, Fondazione Italiana Linfomi - ETS | Trial completion date: Jul 2025 --> Nov 2025

P1/2, N=11, Completed, Mayo Clinic | Active, not recruiting --> Completed

P1, N=3, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Jan 2026 --> Mar 2025

An Ara-C-containing intensified induction therapy followed by autologous stem cell transplantation (ASCT) is considered a highly effective treatment strategy in younger mantle cell lymphoma (MCL) patients, inducing long-lasting remissions...With the recently published results of the TRIANGLE trial, showing superiority of an ibrutinib-containing immunochemotherapy induction followed by ASCT compared with the standard therapy and, more strikingly, a noninferiority of an ibrutinib-containing regimen without ASCT compared with the standard regimen with ASCT, we consider the addition of ibrutinib to first-line therapy in younger MCL patients as a new standard of care...For patients with TP53 aberrations, ASCT should not be recommended due to potential toxicity and limited efficacy in this high-risk subgroup. Large randomized clinical trials such as ECOG-ACRIN 4151 will help to ultimately clarify the role of ASCT.

TP53 aberrations, particularly mutations, currently identify patients with the highest risk, limited benefit from CIT, and greatest need for novel therapies. Other genetic aberrations and biological clusters are being identified but currently have limited clinical utility.

Background : Maintenance therapy with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib following ibrutinib-containing chemoimmunotherapy with or without high-dose chemotherapy and autologous stem cell rescue (HDT/ASCR) in younger patients (pts) with mantle cell lymphoma (MCL) has demonstrated superior efficacy over standard chemoimmunotherapy with ASCR (Dreyling et al...Concurrent maintenance with rituximab was not used...At 2 years, the PFS rate (95% confidence interval) was 73.5% (35.9, 91.1) in the overall study population, 37.5% (1.1, 80.8) in pts with MRD+, and 88.9% (43.3, 98.4) in pts with MRD-U (MRD based on status at Day 100).Conclusions : Acalabrutinib demonstrated a tolerable safety profile and promising results in maintaining MRD-U, supporting the use of acalabrutinib as maintenance therapy post-HDT/ASCR in pts with MCL. Given the early study closure, the limited sample size, and the need for longer follow-up for PFS, additional investigations may provide further insights into the role of BTKi maintenance in the post-HDT/ASCR setting.

Base substitution or indel variants were detected in TP53 (28% of cases), KMT2D (25%), CREBBP (14%), EZH2 (8%), MYD88 (8%), TNFRSF14 (8%), ATM (8%), NOTCH1 (7%), ARID1A (6%), B2M (6%), TNFAIP3 (6%), PIM1 (4%), CD79B (3%), BTK (2%, 97% of which were C481X ibrutinib resistance mutations in cases of CLL), MEF2B (2%), BCL2 (1%), and PLCG2 (1%)...Overall, 75% of FLs harbored a canonical IGH : : BCL2 rearrangement and 86% of MCLs harbored a canonical IGH : : CCND1 rearrangement.Conclusions : This analysis of 3,692 samples demonstrated that the F1H assay platform reliably detects a broad landscape of genomic alterations across a range of mature B-cell lymphoma/leukemia subtypes. By detecting all classes of genomic alterations in a single sequencing reaction, F1H provides an important advantage over single-gene and small-panel molecular tests in an era when the diagnosis, prognosis, and treatment of hematological malignancies increasingly rely on assessing the presence, as well as the absence, of numerous genomic alterations.

Uni- and multi-variate analyses of clinical variables that may be associated with clinical and MRD outcomes are underway.Conclusions : Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated in a relatively elderly population with a toxicity profile consistent with the utilized drugs and not greater than that seen with BR and Placebo in the randomized ECHO trial in untreated Mantle Cell Lymphoma. Initial clinical results show that this treatment is associated with a very high proportion of CR + VGPRs as well as MRD negativity.

P1, N=3, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=88 --> 3

P3, N=700, Recruiting, Janssen Research & Development, LLC | Enrolling by invitation --> Recruiting

P2, N=622, Recruiting, Genmab | Trial completion date: Nov 2032 --> Jun 2031 | Trial primary completion date: Nov 2032 --> Jun 2031

P1, N=18, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2026 --> Feb 2025 | Trial primary completion date: Oct 2026 --> Feb 2025

Following incubation with nivolumab, the duration of contacts between CD4-positive T cells and CD30-positive Hodgkin-Reed-Sternberg cells was documented. The preliminary data indicate that 3D and 4D experiments in hematopathology may facilitate new insights into diagnostics, biology, and clinical applications, including the development of new lymphoma classifications.

Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination.

Furthermore, we observed that overexpression of CXCR3 rescued the impaired tumorigenicity of USP35-deficient JeKo-1 cells, and the mechanism may be related to the fact that USP35 promotes CXCR3 deubiquitination to stabilize its expression. These findings collectively demonstrate the oncogenic role of the USP35-CXCR3 axis in JeKo-1 MCL cells.

Furthermore discussed about the benefits, possible challenges, viewpoints, comparison with other targeted protein degraders (LYTACs, AUTOTACs) and the most current research results of PROTACs technology in multiple oncology therapies. Abbreviations: PROTACs, Proteolysis Targeting Chimeras; PK, Pharmacokinetic; PD, Pharmacodynamic; MetAP-2, (methionine aminopeptidase 2); BCL6, B-cell lymphoma 6; GCN5, General Control Nonderepressible 5; BKT, Bruton's tyrosine kinase; BET, Bromodomain and extra-terminal; AR, Androgen or Androgen receptor; ER, Estrogen or Estrogen receptor; FDA, Food and Drug Administration; mCRPC, Metastatic castration-resistant prostate cancer; STAT3, Signal Transducer and Activator of Transcription 3; FAK, Focal adhesion kinase; POI, Protein of interest; PEG, Polyethylene glycol; UPS, Ubiquitin-Proteasome System; VHL, Von Hippel-Lindau; CRBN, Cereblon; MDM2, Mouse Double Minute 2 homologue; cIAP, Cellular Inhibitor of Apoptosis; RNF, Ring Finger Protein; BRD, Bromodomain; CDK, Cyclin-dependent kinase; PAMPA, Parallel Artificial Membrane Permeability studies; BRET, Bioluminescence Resonance Energy Transfer; MCL, Mantle cell lymphoma; MCL-1, Myeloid Cell Leukemia 1; BCL-XL, B-cell lymphoma extra-large; TRK, Tropomyosin Receptor Kinase; RTKs, Transmembrane Receptor Tyrosine Kinase; NTRK, Neurotrophic Tyrosine Receptor Kinase; DHT, Dihydrotestosterone; EGFR, Epidermal Growth Factor Receptor; EGFR-TKIs, EGFR tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer; BCR, B-cell receptor; CML, Chronic myelogenous leukemia; TKI, Tyrosine kinase inhibitors; MoA, Mechanism of action; TPD, Targetted protein degraders; LYTACs, Lysosome targeting chimeras; ASGPR, Asialoglycoprotein receptor; AUTOTACs, Autophagy-Targeting Chimeras; ATTECs, Autophagy-tethering compounds; CRISPR-Cas9, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9; TALEN, Transcription Activator-Like Effector Nuclease; ZFN, Zinc Finger Nuclease.

Finally, according to our model and computational drug sensitivity analysis, four small molecule compounds, BMS-754807, SB216763, Doramapimod, and Trametinib, were identified as potential therapeutic agents for patients with MCL. This study provides a prognostic model with ferroptosis-related gene signature for MCL. The results show that the model helps predict prognosis in MCL.

P2, N=35, Active, not recruiting, Weill Medical College of Cornell University | Trial primary completion date: Sep 2024 --> Feb 2025

The TRIANGLE trial (Dreyling et al, Lancet 2024) suggested that auto-HCT may not add benefit to more effective induction and maintenance regimens containing high-dose cytarabine, rituximab and BTK inhibitors. Pts who remain MRD+ after induction may benefit from auto-HCT. Longer follow-up will be important to confirm these findings.

With this in mind, clinical trials have focused on novel targeted therapies to improve outcomes. This review details the recent advances in the understanding of MCL biology and outlines the recommended diagnostic strategies and evidence-based approaches to treatment.

Comprehensive Cyclin D1 quantification, especially above a threshold, significantly correlates with better overall survival in MCL. This highlights its prognostic importance in MCL management. Full quantification of CyclinD1 aids MCL prognosis, while QDB technology for biomarker quantification supports precise clinical prognostic stratification.

We then discuss currently available diagnostic approaches and we conclude with future directions. We also suggest that the more specific terms CCND2-rearranged MCL or CCND3-rearranged MCL be used for neoplasms in which the rearranged gene is known, and that we reserve the term cyclin D1-negative MCL for neoplasms in which the rearranged gene in unknown.

Patients will receive obinutuzumab 2000 mg IV on C1D1-2, followed by glofitamab step-up dosing of 2.5 mg IV on C1D8, 10 mg on C1D15, and 30 mg on day 1 of C2-12 (21-day cycles). In the current trial we evaluate a regimen which we anticipate will be tolerable and highly active in R/R MCL, with the potential for MRD-guided limited-duration therapy. The trial is currently open for enrollment at UCSF and is expected to open at multiple centers through the University of California Hematologic Malignancies Consortium.

P2, N=30, Suspended, C. Babis Andreadis | N=50 --> 30 | Recruiting --> Suspended

P1/2, N=23, Active, not recruiting, Joshua Brody | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Nov 2026

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2024 --> Dec 2025

P1/2, N=54, Completed, Incyte Corporation | Active, not recruiting --> Completed

P1, N=18, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=40 --> 18

Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

Our NGS testing found tier 1 or 2 variants in the majority of cases, supporting its use in the clinical setting. Additionally, a subset of variants identified with the pan-Heme list likely represents mutations of clonal hematopoiesis of indeterminate potential, which could be removed with a more lymphoma-specific gene list. Given these findings, and a growing number of targets in indolent B cell lymphomas, future studies focusing on evaluation of a lymphoma-specific gene list is of interest for clinical validation and implementation.

P=N/A, N=150, Not yet recruiting, Department of Nuclear Medicine, West China Hospital of Sichuan University; West China Hospital of Sichuan University

Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.

All pts received obinutuzumab pretreatment (1000mg or 2000mg) on Cycle (C) 1 Day (D) 1. Conclusions : Glofitamab induces high response rates in pts with heavily pretreated R/R MCL, including those who have clinical and/or histological features associated with poor prognosis. Clinical and molecular remissions are achieved early in the course of treatment, with durable responses lasting beyond the length of the treatment.

The combination of the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, the BCL-2 inhibitor venetoclax (V), and the anti-CD20 monoclonal antibody (mAb) obinutuzumab (O) has demonstrated safety and efficacy in R/R and TN MCL (Le Gouill, Blood 2021). Conclusions : AVO is safe and active in pts with R/R and TP53-aberrant/transplant ineligible TN MCL. Preliminary efficacy and feasibility of an MRD-guided treatment approach is encouraging in this high-risk TN cohort B. Our data supports further investigation of a targeted triplet approach, and the phase II TN transplant eligible and TP53 wild type cohort is enrolling based on demonstrated safety and efficacy in cohort B. Updated results will be presented at the meeting.

Introduction – We previously reported the efficacy and safety results of a combination of ibrutinib with rituximab in patients (pts) with mantle cell lymphoma (MCL) ≥ 65 years. Conclusions – Chemotherapy-free frontline therapy with AR is highly effective, safe, induces deep MRD negative responses and alters immune landscape in older pts with MCL. Randomized studies are needed to confirm whether this regimen can be the new first line standard treatment for older MCL patients.

ABR provides this clinical benefit without excess toxicity as shown by attenuated differences between arms in exposure-adjusted incidence rates, suggesting that higher AE rates in the ABR arm are likely due in part to the longer duration of acalabrutinib treatment vs placebo. These data emphasize the benefits of acalabrutinib in frontline MCL treatment in high-risk pts and the additional benefit of continuous therapy.