pyrimidinones and Lymphoma--T-Cell--Peripheral

Though peripheral T-cell lymphoma (PTCL) is an area of significant unmet therapeutic need, a number of new treatment options are available for patients, especially those with relapsed or refractory disease. A plethora of drugs are now in development for PTCL, but drugs that truly target novel disease biology are noticeably absent. Combinations of T-cell centric agents could produce novel platforms of therapy to replace the relatively ineffective CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimens. Among agents with T-cell activity are the folate analog pralatrexate, histone deacetylase inhibitors (HDACi) like romidepsin, the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the purine nucleoside phosphorylase (PNP) inhibitor forodesine, the nucleoside analog gemcitabine, and BH3-only mimetics like ABT-263 and ABT-737.

Topics: Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Depsipeptides; Drug Design; Drugs, Investigational; Histone Deacetylase Inhibitors; Humans; Immunologic Factors; Lenalidomide; Lymphoma, T-Cell, Peripheral; Purine Nucleosides; Pyrazines; Pyrimidinones; Salvage Therapy; Thalidomide

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.

Topics: Administration, Oral; Adult; Aged; Female; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Purine Nucleosides; Pyrimidinones; Recurrence

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Area Under Curve; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Exanthema; Female; Humans; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphopenia; Male; Metabolic Clearance Rate; Middle Aged; Mycosis Fungoides; Natural Killer T-Cells; Purine Nucleosides; Pyrimidinones; Recurrence; Skin Neoplasms; Treatment Outcome

Topics: Central Nervous System; Humans; Lymphoma, T-Cell, Peripheral; Purine Nucleosides; Pyrimidinones

Topics: Humans; Lymphoma, T-Cell, Peripheral; Purine Nucleosides; Pyrimidinones; Retrospective Studies

Peripheral T-cell lymphomas (PTCLs) are a rare and diverse group of neoplasms with a poor prognosis. Management of these disorders has been largely extrapolated from the treatment of aggressive B-cell lymphomas; however, therapeutic responses to this approach are neither adequate nor durable for most patients with PTCL. Given the rarity of PTCL, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed/refractory PTCL. This article reviews promising novel approaches in the treatment of PTCL and its subtypes. Investigation into the pathogenesis of PTCL has also identified new targets for treatment. These emerging therapies include new uses of existing agents and the development of novel agents specifically targeted against T-cell lymphoma. Results using antimetabolites, immunotherapies, and histone deacetylase inhibitors have been particularly encouraging. These novel therapies are being tested as single agents and in combination with conventional lymphoma regimens in the frontline and salvage settings. Because of the rarity and heterogeneity of PTCL, national and international cooperation is needed to conduct the clinical studies required for the development of more effective treatment paradigms. These efforts are ongoing and will hopefully guide new strategies to improve the historically poor outcome of PTCL.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Arabinonucleosides; Deoxycytidine; Diphtheria Toxin; Gemcitabine; Histone Deacetylase Inhibitors; Humans; Immunosuppressive Agents; Interleukin-2; Lymphoma, T-Cell, Peripheral; Practice Guidelines as Topic; Protease Inhibitors; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A