mln-8237 and Lymphoma--T-Cell--Peripheral

Peripheral T-cell lymphomas are aggressive lymphomas with poor outcomes for which novel treatments are urgently needed. Alisertib (MLN8237) is a second-generation oral Aurora A kinase inhibitor. Treatment with alisertib results in an accumulation of cells with abnormal mitotic spindles, leading to decreased proliferation and apoptosis in a range of human tumor cell lines. Alisertib has shown single-agent antitumor activity in animal xenograft models and promising antitumor activity alone or in combination with other agents in patients with solid and hematologic cancers, and T-cell lymphomas in particular. It is currently being tested in randomized controlled Phase III trials in relapsed/refractory peripheral T-cell lymphoma.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azepines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Discovery; Drug Evaluation, Preclinical; Humans; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome

Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. A greater understanding of how these tumours proliferate as well as how best to exploit these processes should lead to more durable tumour regression and better clinical outcomes for patients. New approaches include the histone deacetylase inhibitors, antifolates, fusion proteins, nucleoside analogues and agents targeting the immune system, which are being investigated either as single agents or as a combination.. The authors review the evidence for the orally administered aurora A kinase inhibitor MLN8237 ( alisertib ) in T-cell lymphoma. No significant association between clinical response and AAK expression has been observed but inhibition of this enzyme in a Phase II study has demonstrated tumour regression in 27% of heavily pretreated B- and T-cell NHL, with 50% of PTCL patients responding and 3 of 4 patients achieving durable responses.. A Phase III trial in relapsed PTCL is recruiting patients comparing MLN8237 against single agent comparators. With regards to the data; the response rate of MLN8237 in refractory NHL is promising. The authors believe that further preclinical work identifying the best combinations to take through into clinical trials is important, particularly as this agent is used in earlier lines of therapy.

Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Azepines; Humans; Lymphoma, T-Cell, Peripheral; Protein Kinase Inhibitors; Pyrimidines

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

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azepines; Female; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Survival Analysis; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aurora Kinase A; Azepines; Female; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Survival Analysis; Young Adult

Aurora A kinase (AAK) is upregulated in highly proliferative lymphomas, suggesting its potential as a therapeutic target. Alisertib is a novel oral AAK inhibitor without adverse safety signals in early-phase studies that demonstrated preliminary activity in T-cell lymphoma. This phase II study was conducted to further investigate the efficacy of alisertib in relapsed or refractory peripheral T-cell non-Hodgkin lymphoma (PTCL).. Eligible patients with histologically confirmed relapsed/refractory PTCL or transformed Mycosis fungoides (tMF) received alisertib 50 mg twice a day for 7 days on 21-day cycles.. Of 37 eligible patients, the histologic subtypes enrolled included PTCL not otherwise specified (n = 13), angioimmunoblastic T-cell lymphoma (n = 9), tMF (n = 7), adult T-cell lymphoma/leukemia (n = 4), anaplastic large-cell lymphoma (n = 2), and extranodal natural killer/T-cell lymphoma (n = 2). Grade 3 and 4 adverse events in ≥ 5% of patients included neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), and rash (5%). Treatment was discontinued most commonly for disease progression. Among the PTCL subtypes, the overall response rate was 30%, whereas no responses were observed in tMF. Aurora B kinase was more commonly overexpressed than AAK in tumor specimens. Analysis of AAK, Aurora B kinase, MYC, BCL-2, phosphatidylinositol 3-kinase γ, and Notch1 expression revealed no association with response.. Alisertib has antitumor activity in PTCL, including heavily pretreated patients. These promising results are being further investigated in an ongoing international, randomized phase III trial comparing alisertib with investigator's choice in PTCL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azepines; Biomarkers, Tumor; Cytokines; Drug Administration Schedule; Female; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mycosis Fungoides; Pyrimidines; Survival Rate; Treatment Outcome

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Aurora Kinase A; Azepines; Chimera; fms-Like Tyrosine Kinase 3; Fusion Proteins, bcr-abl; Hematology; Humans; Leukemia, Myeloid, Acute; Lymphoma, T-Cell, Peripheral; Multiple Myeloma; Pyrimidines; Societies, Medical; Staurosporine; T-Lymphocytes; United States

Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. Alisertib (MLN8237) an investigational agent that inhibits Aurora A Ser/Thr kinase has shown activity in PTCL patients. Here we demonstrate that aurora A and B are highly expressed in T-cell lymphoma cell lines. In PTCL patient samples aurora A was positive in 3 of 24 samples and co-expressed with aurora B. Aurora B was positive in tumor cells in 22 of 32 samples. Of the subtypes of PTCL, aurora B was over-expressed in PTCL (NOS) [73%], T-NHL [100%], ALCL (Alk-Neg) [100%] and AITL [100%]. Treatment with MLN8237 inhibited PTCL cell proliferation in CRL-2396 and TIB-48 cells with an IC50 of 80-100nM. MLN8237 induced endo-reduplication in a dose and time dependent manner in PTCL cell lines leading to apoptosis demonstrated by flow cytometry and PARP-cleavage at concentrations achieved in early phase clinical trials. Moreover, inhibition of HisH3 and aurora A phosphorylation was dose dependent and strongly correlated with endo-reduplication. The data provide a sound rationale for aurora inhibition in PTCL as a therapeutic modality and warrants clinical trial evaluation.

Topics: Antineoplastic Agents; Apoptosis; Aurora Kinase B; Aurora Kinases; Azepines; Cell Line, Tumor; Endoreduplication; Humans; Lymphoma, T-Cell, Peripheral; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrimidines