mln-8237 and Lymphoma--T-Cell

T-cell lymphomas are rare and conventional treatments are not typically curative. Integration of biologic agents into routine practice is especially difficult given the breadth of emerging drugs currently or recently in trials.. This is an overview of the management of T-cell lymphoma as it stands today. The authors review clinically active biological and novel chemotherapeutic agents, which have a niche in current practice or are being actively developed and have a potential future role in the management of this challenging group of diseases. Clinical trial data were retrieved from journals and current major conference proceedings following interrogation of online search engines. Pralatrexate, the histone deacetylase inhibitors and brentuximab vedotin have reached the market and have provided new and useful treatment options. No novel agent has yet demonstrated a survival advantage for patients with this disease, or shown an ability to improve the low response rate to first-line chemotherapy that these diseases frequently exhibit. New randomized studies of these emerging drugs that may finally move the field forward with evidence of superiority from large Phase II and III trials currently open to accrual.

Topics: Alemtuzumab; Anaplastic Lymphoma Kinase; Antibodies, Monoclonal, Humanized; Azepines; Brentuximab Vedotin; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Lenalidomide; Lymphoma, T-Cell; Pyrimidines; Receptor Protein-Tyrosine Kinases; Thalidomide

Topics: Azepines; B-Lymphocytes; Depsipeptides; Humans; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Pyrimidines; Treatment Outcome

Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.. Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles.. We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response.. The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.

Topics: Adult; Aged; Antineoplastic Agents; Aurora Kinase A; Azepines; Burkitt Lymphoma; Drug Administration Schedule; Female; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, T-Cell; Male; Middle Aged; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Treatment Outcome

Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of pralatrexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure.. A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results.. In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell-specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure.. These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.

Topics: Aminopterin; Animals; Aurora Kinase A; Azepines; Boron Compounds; Cell Cycle; Cell Line, Tumor; Centrosome; Cytokinesis; Depsipeptides; Drug Synergism; Glycine; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Inhibitory Concentration 50; Kaplan-Meier Estimate; Lymphoma, T-Cell; Mice; Mice, SCID; Mitosis; Neoplasm Transplantation; Protein Kinase Inhibitors; Pyrimidines; Spindle Apparatus; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Aurora Kinase A; Azepines; Burkitt Lymphoma; Female; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, T-Cell; Male; Protein Kinase Inhibitors; Pyrimidines