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Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that comprises up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is 5 years, and for most patients who progress on targeted agents, survival remains at a dismal 3 to 8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives antitumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of prosurvival AKT signaling, which led to the nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing identified multiple proapoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382, and the BCL-2 inhibitor, venetoclax. Single-agent and combination treatments were performed in 9 MCL lines. Loewe synergy scores showed significant levels of synergy in most MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with an increased survival advantage in 2 patient-derived xenograft models (P ≤ .0001, P ≤ .0001). Our results provide mechanistic rationale for the combination of PRMT5 inhibition and venetoclax to treat patients with MCL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of blood cancers arising in lymphoid tissues that commonly effects both humans and dogs. Protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the symmetric di-methylation of arginine residues, is frequently overexpressed and dysregulated in both human solid and hematologic malignancies. In human lymphoma, PRMT5 is a known driver of malignant transformation and oncogenesis, however, the expression and role of PRMT5 in canine lymphoma has not been explored. To explore canine lymphoma as a useful comparison to human lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine lymphoma tissue microarrays, primary lymphoid biopsies, and canine lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility and whole-transcriptome changes in canine lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued use of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.B. has received research funding from Prelude Therapeutics, K.V. and P.S. are employees of Prelude Therapeutics, and V.E.V. was an employee of VDx Veterinary Diagnostics. No other conflicts of interest are relevant to this reported work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.

Pembrolizumab is a humanized monoclonal antibody directed against programmed cell death protein 1 (PD-1), a key immune-inhibitory molecule expressed on T cells and implicated in CD4+ T-cell exhaustion and tumor immune-escape mechanisms. Classical Hodgkin's lymphoma (cHL) is a unique B-cell malignancy in the sense that malignant Reed-Sternberg (RS) cells represent a small percentage of cells within an extensive immune cell infiltrate. PD-1 ligands are upregulated on RS cells as a consequence of both chromosome 9p24.1 amplification and Epstein-Barr virus infection and by interacting with PD-1 promote an immune-suppressive effect. By augmenting antitumor immune response, pembrolizumab and nivolumab, another monoclonal antibody against PD-1, have shown significant activity in patients with relapsed/refractory cHL as well as an acceptable toxicity profile with immune-related adverse events that are generally manageable. In this review, we explore the rationale for targeting PD-1 in cHL, review the clinical trial results supporting the use of checkpoint inhibitors in this disease, and present future directions for investigation in which this approach may be used., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The B-cell receptor pathway (BCR) is aberrantly activated in select B-cell malignancies. This knowledge has allowed for the development of inhibitors of different crucial steps of this pathway. Bruton's tyrosine kinase (BTK) is a key component of BCR signaling and functions as an important regulator of multiple cell functions including differentiation, proliferation, and survival in various B-cell malignancies. Ibrutinib is a potent, selective BTK inhibitor that has shown significant activity in specific subtypes of B-cell non-Hodgkin's lymphomas (NHLs). Given the high response rates, tolerability, and acceptable toxicities, ibrutinib was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed mantle cell lymphoma and chronic lymphocytic leukemia. It is also currently being evaluated in combination with chemotherapy and as frontline therapy in B-cell NHL. This review summarizes the preclinical and clinical development of ibrutinib in the treatment of B-cell NHL., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

Inhibition of the autophagic pathway has recently revealed promising results in increasing pro-death activity of multiple cancer therapeutics. Here, we discuss our findings regarding the autophagy-blocking and anti-neoplastic effects of a synthetic sphingosine analog, FTY720, in mantle cell lymphoma (MCL). We also emphasize how FTY720 enhances the pro-death activity of the fully humanized monoclonal antibody milatuzumab by inhibiting the autophagy-lysosome dependent degradation of its therapeutic target, CD74. Our results provide justification for further evaluation of FTY720 and milatuzumab as a combination therapy for this aggressive B-cell malignancy.

Background: In vitro studies in mantle cell lymphoma (MCL) cell lines and patient-derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib) compared with single-agent bortezomib. Therefore, the authors of this report evaluated R-bortezomib in a preclinical model and in a phase 2 clinical trial., Methods: A Hu-MCL-severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m(2) rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m(2) bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5 cycles)., Results: R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2-year progression-free survival (PFS) rate was 24% (95% confidence interval [CI], 10%-53%) in all patients and 60% (95% CI, 20%-85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R-bortezomib compared with HH and RR homozygotes., Conclusions: R-bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination., (Copyright © 2010 American Cancer Society.)

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

Purpose: Despite the progress that has been made in the treatment of mantle cell lymphoma (MCL), all patients invariably relapse with the currently available therapies. Because of the absence of curative therapy for MCL, we explored FTY720 as a novel agent against MCL., Experimental Design: The cytotoxic effect of FTY720 in primary MCL tumor cells and cell lines were evaluated in vitro. The effects of FTY720 on caspase activation, generation of reactive oxygen species, and modulation of Cyclin D1 and Akt, which are implied in the pathogenesis of MCL, were investigated. The in vivo efficacy of FTY720 was evaluated in a Jeko-severe combined immunodeficient xenograft model of human MCL., Results: FTY720 mediated time- and dose-dependent cytotoxicity in primary MCL tumor cells and MCL cell lines in vitro. FTY720-induced cytotoxicity occured independent of caspase activation but dependent on the generation of ROS in MCL. In addition, FTY720 treatment resulted in the time-dependent downmodulation of Cyclin D1 and accumulation of cells in G(0)-G(1) and G(2)-M phases of the cell cycle with concomitant decrease in S-phase entry. Furthermore, concentrations of FTY720 that induced cytotoxicity led to decreased phospho-Akt in primary MCL cells and cell lines. Most importantly, the in vivo therapeutic activity of FTY720 was shown in severe combined immunodeficient mice engrafted with the Jeko MCL cell line., Conclusions: These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of FTY720 in clinical trials to treat patients with MCL., ((c) 2010 AACR.)

T-cell lymphomas (TCL) are characterized by poor response to chemotherapy and generally poor outcome. While molecular profiling has identified distinct biological subsets and therapeutic targets in B-cell lymphomas, the molecular characterization of TCL has been slower. Surface markers expressed on malignant T-cells, such as CD2, CD3, CD4, CD25, and CD52 were the first TCL-specific therapeutic targets to be discovered. However, the presence of these receptors on normal T-cells means that monoclonal antibody (mAb)- or immunotoxin (IT)-based therapy in TCL inevitably results in variable degrees of immunosuppression. Thus, although some mAbs/IT have significant activity in selected subsets of TCL, more specific agents that target signaling pathways preferentially activated in malignant T-cells are needed. One such novel class of agents is represented by the histone deacetylase (HDAC) inhibitors. These molecules selectively induce apoptosis in a variety of transformed cells, including malignant T-cells, both in vitro and in vivo. Several HDAC inhibitors have been studied in TCL with promising results, and have recently been approved for clinical use. Immunomodulatory drugs, such as interferons and Toll Receptor (TLR) agonists have significant clinical activity in TCL, and are particularly important in the treatment of primary cutaneous subtypes (CTCL). Although most classical cytotoxic drugs have limited efficacy against TCL, agents that inhibit purine and pyrimidine metabolism, known as nucleoside analogues, and novel antifolate drugs, such as pralatrexate, are highly active in TCL. With improved molecular profiling of TCL novel pharmacological agents with activity in TCL are now being discovered at an increasingly rapid pace. Clinical trials are in progress and these agents are being integrated in combination therapies for TCL, both in the relapsed/refractory setting as well as front line.

Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NFkappaB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the Akt pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NFkappaB and phosphorylated Akt depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.

Sézary Syndrome (SS) is an aggressive T-cell malignancy often presenting in advanced age and associated with poor prognosis. There is no standard therapy and because of co-morbidities, elderly patients are particularly challenging to treat. Alemtuzumab is an anti-CD52 monoclonal antibody that has activity in SS but is profoundly immunosuppressive, leading to great hesitation about its use in older patients. We treated five octogenarian patients with SS with subcutaneous (SQ) alemtuzumab, at relapse or as initial therapy, for 5-9 weeks. With the exception of transient grade 1-2 hematological toxicity and asymptomatic cytomegalovirus (CMV) (two patients) and Epstein-Barr virus (EBV) (one patient) reactivation, no other toxicities were observed. The clinical and hematological complete response (CR) rate was 100%. Three patients achieved durable responses (8+ to 17+ months). Alemtuzumab was safely administered and showed significant activity in very elderly SS patients.

Purpose: To determine the antitumor activity of the proteasome inhibitor bortezomib in patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma unspecified (PTCLU) with isolated skin involvement., Patients and Methods: From May 2005 to June 2006 at our institute, we treated patients with previously pretreated CTCL or PTCLU using bortezomib as a single agent, at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, every 21 days for a total of six cycles., Results: Fifteen patients were registered, of whom 12 (10 CTCL, all mycosis fungoides, and two PTCLU with isolated skin involvement) were assessable. The overall response rate was 67%, with two (17%) complete remissions and six (50%) partial remissions. The remaining four patients had disease progression. Histologically, the responder patients were seven with CTCL and one with PTCLU with isolated skin involvement. All responses were durable, lasting from 7 to 14 or more months. Overall, the drug was well tolerated, with no grade 4 toxicity. The most common grade 3 toxicities were neutropenia (n = 2), thrombocytopenia (n = 2), and sensory neuropathy (n = 2)., Conclusion: This study suggests that bortezomib was well tolerated and has significant single-agent activity in patients with cutaneous T-cell lymphoma.

Background and Objectives: The aim of this study was to evaluate the efficacy of pegfilgrastim, in combination with salvage chemotherapy, in mobilizing CD34(+) stem cells into the peripheral blood of pretreated lymphoma patients., Design and Methods: This was an open-label phase II study including 25 pretreated patients (Hodgkin's disease=4; aggressive non-Hodgkin's lymphoma=21). The primary end-point of the study was the successful mobilization of a target cell dose of 2x10(6) CD34(+) cells/kg in lymphoma patients receiving ifosfamide, epirubicin and etoposide (IEV) chemotherapy and a fixed dose (6 mg) of pegfilgrastim given as single subcutaneous injection., Results: Following chemotherapy, all patients had grade 4 neutropenia that lasted a median of 1.5 days (1-3). Pegfilgrastim treatment was well tolerated and only 2/25 patients required pain-control medication. CD34+ cells were mobilized in all patients. The median (range) peak value of peripheral blood CD34+ cells after IEV chemotherapy and pegfilgrastim was 141x10(6)/L (12.8-386) and occurred almost invariably on day +14 (13-16). Twenty-three of the 25 patients underwent a single standard volume leukapheresis to collect a median of 8.7x10(6) CD34(+) cells/kg (1.78-17.3). Twenty four/25 patients (96%) reached the target cell dose of 2x10(6) CD34(+) cells/kg. High concentrations of circulating CD34+ cells (> 50x10(6)/L) were observed for several days after the achievement of the peak value. All the study patients were transplanted with their pegfilgrastim-mobilized CD34(+) cells and showed a rapid and sustained engraftment after high-dose chemotherapy., Interpretation and Conclusions: Our results show that pegfilgrastim as an adjunct to chemotherapy is a predictable and highly effective mobilization regimen in pretreated lymphoma patients.

Our experience with a patient with a primary conjunctiva lymphoma who was treated with conventional dose of rituximab obtaining a complete response without acute and late local toxicity for the eye.

Purpose: Promising new therapeutic options for follicular lymphoma (FL) include fludarabine plus mitoxantrone (FM) and the mouse/human anti-CD20 antibody, rituximab. We performed a randomized comparative trial of FM with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) front-line chemotherapy with and without sequential rituximab., Patients and Methods: All previously untreated CD20(+) FL patients presenting in 15 Italian cooperative institutions from October 1999 were randomly allocated to FM or CHOP. Following clinical or molecular restaging, patients in complete remission (CR) with bcl-2/IgH negativity (CR(-)) received no further treatment; those in CR with bcl-2/IgH positivity (CR(+)) received rituximab, as did those in partial remission (PR) with bcl-2/IgH negativity (PR(-)) or positivity (PR(+)); nonresponders (NR subgroup) were off study., Results: After chemotherapy, the FM arm achieved higher rates of CR (68% [49 of 72 patients] v 42% [29 of 68 patients]; P =.003) and CR(-) (39% [28 of 72 patients] v 13 of 68 patients [19%]; P =.001). Rituximab elicited CR(-) in 55 of 95 treated patients (58%). The final CR(-) rate was higher in the FM arm (71% [51 of 72 patients] v 51% [35 of 68 patients]; P =.01). However, with a median follow-up of 19 months (range, 9 to 37 months), no statistically significant difference was found among the various study arms in terms of both progression-free (PFS) and overall survival (OS)., Conclusion: These results indicate that FM is superior to CHOP for front-line treatment of FL and that rituximab is an effective sequential treatment option. However, they also confirm that this superiority is unlikely to translate into either better PFS or OS.

Background: Mucosa-associated lymphoid tissue (MALT) lymphoma is a specific clinicopathologic entity with gastric and nongastrointestinal site involvement. The authors reported the clinical outcome of patients with Stage IE nongastrointestinal MALT lymphoma treated with a frontline fludarabine-containing regimen or with a regimen containing cyclophosphamide, vincristine, and prednisone (CVP)., Methods: Between 1998 and 2001, 31 patients with Stage IE disease were referred to the Seràgnoli Institute of Hematology and Medical Oncology at the University of Bologna (Bologna, Italy). Presenting sites included periorbital soft tissue (n = 8), lung (n = 5), skin (n = 5), salivary glands (n = 5), lacrimal glands (n = 5), and thyroid (n = 3). Twenty patients were treated with fludarabine and mitoxantrone (FM), and 11 were treated with the CVP regimen. The median follow-up was 3 years., Results: All patients achieved complete responses (CR). Four patients, all treated with CVP, experienced disease recurrence and then achieved a second CR after FM salvage treatment. No tumor recurrence was observed in patients with thyroid, lacrimal gland, or pulmonary lymphoma. The projected 5-year overall survival and disease-free survival rates were 100% and 85%, respectively., Conclusions: The fludarabine-containing FM regimen provided a relatively effective frontline (or salvage) treatment option for patients with nongastrointestinal Stage IE MALT lymphoma and probably was superior to CVP in terms of efficacy., (Copyright 2004 American Cancer Society.)

Background and Objectives: Although remission of hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) appears to be long lasting, few reports currently provide results from follow-up exceeding 5 years., Design and Methods: We reviewed our HCL patients treated with front-line 2-CdA (by 2-hour infusion) either for 5 consecutive days at 0.14 mg/kg/day (daily subset, n=21) or once a week at 0.14 mg/kg for 5 cycles (weekly subset, n=16)., Results: Of the 37 eligible patients, 30 (81%) achieved complete response (CR) and 7 (19%) partial response (PR) (overall response rate, 100%); identical response rates were recorded in the daily and weekly subsets. After a median follow-up of 122 months (range, 54-156), the overall relapse rate was 27% (8/30): 24% (4/17) had relapsed in the subset treated daily whereas 30% (4/13) had done so in the subset treated weekly (p=ns). The projected 13-year overall and the relapse-free survivals are 96% and 52%, respectively. In terms of hematologic toxicity, the weekly 2-CdA schedule was associated with significantly fewer cases of grade 3-4 neutropenia., Interpretation and Conclusions: In HCL patients, a single dose of 2-CdA induces a long-term CR. Over 90% of patients are alive 13 years later and over 50% of patients appear to be clinically cured by this treatment. The weekly schedule seems to be a safer option for neutropenic HCL patients, while apparently providing equivalent results in terms of response rates and long-term outcome.