Preclinical Development of a Romidepsin Nanoparticle Demonstrates Superior Tolerability and Efficacy in Models of Human T-Cell Lymphoma and Large Granular Lymphocyte Leukemia.

Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL.

Peripheral T-cell lymphoma: From biology to practice to the future.

Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases.

Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma.

Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.

Mature T-cell and NK-cell lymphoma involvement of the central nervous system: a single center experience.

Mature T-cell and NK-cell lymphomas (MTNKL) are rare and heterogeneous lymphoproliferative disorders with poor clinical outcomes despite novel therapeutic advances. Although infrequent, central nervous system (CNS) involvement by MTNKL is associated with poor outcomes with a median overall survival (OS) of <12 months based on retrospective studies. We performed a retrospective analysis of patients who developed CNS involvement of MTNKL diagnosed at a single center from 1999 through 2020.

HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models.

Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity.

Role of stem cell transplant in CD30+ PTCL following frontline brentuximab vedotin plus CHP or CHOP in ECHELON-2.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.

Targeting pathogenic mechanisms in marginal zone lymphoma: from concepts and beyond.

Marginal zone lymphoma (MZL) represents a group of three distinct though overlapping lymphoid malignancies that includes extranodal, nodal and splenic marginal lymphoma. MZL patients usually present an indolent clinical course, although the disease remains largely incurable, save early stage disease that might be irradiated. Therapeutic advances have been limited due to the small patient population, and have largely been adapted from other indolent lymphomas.

Targeting the T-Cell Lymphoma Epigenome Induces Cell Death, Cancer Testes Antigens, Immune-Modulatory Signaling Pathways.

The peripheral T-cell lymphomas (PTCL) could be considered the prototypical epigenetic disease. As a disease, they are uniquely sensitive to histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, both alone and in combination, are characterized by a host of mutations in epigenetic genes, and can develop spontaneously in genetically engineered murine models predicated on established recurring mutations in () and , an epigenetic gene governing DNA methylation. Given the clinical benefit of HDAC inhibitors (HDACi) and hypomethlyation agents alone and in combination in PTCL, we sought to explore a mechanistic basis for these agents in PTCL.

R-Loop-Mediated ssDNA Breaks Accumulate Following Short-Term Exposure to the HDAC Inhibitor Romidepsin.

Histone deacetylase inhibitors (HDACi) induce hyperacetylation of histones by blocking HDAC catalytic sites. Despite regulatory approvals in hematological malignancies, limited solid tumor clinical activity has constrained their potential, arguing for better understanding of mechanisms of action (MOA). Multiple activities of HDACis have been demonstrated, dependent on cell context, beyond the canonical induction of gene expression.

Management of Angioimmunoblastic T-Cell Lymphoma (AITL) and other T Follicular Helper Cell lymphomas (TFH PTCL).

Despite the remarkable improvements in the treatment and outcome of patients with aggressive B-cell lymphoma, the peripheral T-cell lymphomas (PTCL) continue to carry a poor prognosis with the presently available treatment options. The PTCL are very rare diseases that account for only 10,000 to 15,000 new cases per year in the United States. The World Health Organization's 2016 classification describes 29 distinct subtypes of PTCL, thus making these both rate and incredibly heterogenous.

Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma.

Purpose: Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors.

Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.

Patients And Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD).

-quinoline-benzenesulfonamide derivatives exert potent anti-lymphoma effect by targeting NF-κB.

We previously identified the -quinoline-benzenesulfonamide (NQBS) scaffold as a potent inhibitor of nuclear factor-κB (NF-κB) translocation. Now, we report the structure-activity relationship of compounds with the NQBS scaffold in models of diffuse large B-cell lymphoma (DLBCL). We identified CU-O42, CU-O47, and CU-O75 as NQBS analogs with the most potent cytotoxic activity in DLBCL lines.

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma.

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL.

Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL.

A perspective on improving the R-CHOP regimen: from Mega-CHOP to ROBUST R-CHOP, the PHOENIX is yet to rise.

The integration of rituximab (R) into cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) by Coiffier and colleagues was the first, and last, successful modification of this backbone regimen, which has endured now for almost 20 years. Countless attempts to redefine R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) have migrated from a focus on dose-intense and dose-dense regimens, to the use of maintenance therapies, and most recently the addition of novel agents. To date, none have changed the basic formula.

Low dose continuous lenalidomide in heavily pretreated patients with relapsed or refractory classical Hodgkin lymphoma: a retrospective case series.

Patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) following autologous stem cell transplant (ASCT) remain a management challenge with few reliably effective treatments. Lenalidomide, an immunomodulatory drug approved for patients with myelodysplastic syndrome with del(5q), multiple myeloma, and mantle cell lymphoma, has demonstrated some activity in patients with R/R cHL, though the toxicity of traditional doses and schedules has been a barrier to consistent use. Low dose continuous (LDC) schedules have emerged as promising, with a more favorable safety profile.

The peripheral T-cell lymphomas: an unusual path to cure.

Over the past 30 years, the scientific community has made little progress in changing the natural history of peripheral T-cell lymphomas. Of the haematological malignancies, T-cell lymphomas have an extremely poor prognosis. One reason for this poor outcome has been that no treatment programme has ever been developed specifically for the broader category of the disease-peripheral T-cell lymphoma-let alone any of the specific subtypes, except advances made for patients with CD30-positive anaplastic large cell lymphoma.

ATM inhibition overcomes resistance to histone deacetylase inhibitor due to p21 induction and cell cycle arrest.

The antiproliferative effect induced by histone deactylase inhibitors (HDACi) is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug. The direct targeting of p21 is not feasible.