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Molecular Cancer Therapeutics Jan 2020The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of...
The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m) and pralatrexate (Dose level 1 [D1], 120 mg/m; dose level-1 [D-1] 100 mg/m). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The polymorphism in rs11951910 was significantly associated with lower progression-free survival (PFS; ≤ 0.01), whereas the presence of the rs2838957 polymorphism was associated with improved PFS ( = 0.02). Presence of the rs3780130 and rs1051266 polymorphisms were significantly associated with better overall survival (OS; = 0.01), whereas rs7010484 polymorphism was associated significantly with reduced OS ( = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.
Topics: Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Esophageal Neoplasms; Female; Humans; Male; Oxaliplatin; Stomach Neoplasms
PubMed: 31575653
DOI: 10.1158/1535-7163.MCT-19-0240 -
Case Reports in Oncology 2019Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous group of hematological malignancies involving T or NK cells. PTCLs are generally associated with an...
Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous group of hematological malignancies involving T or NK cells. PTCLs are generally associated with an aggressive course and poor prognosis. Pralatrexate (PDX) is the first FDA-approved agent for the treatment of refractory/recurrent PTCL. It has single-agent activity against PTCLs; however, oral mucositis represents dose-limiting toxicity in clinical practice. We report on the case of a patient administered with modified THP-COP therapy (pirarubicin [tetrahydropyranyl adriamycin], cyclophosphamide, and prednisone), who had bone or bone marrow as the primary lesion, which was treated successfully with PDX for an extended period of 1 year, with prophylactic use of leucovorin for oral mucositis. The maintenance dose of PDX was 30 mg/m IV, over 3 consecutive weeks dosing with a 1-week rest period due to bone marrow suppression. The patient also received leucovorin 5 mg PO 3 times daily from days 2 to 6 after each PDX administration. Disease activity was well controlled, stable, and no oral mucositis was observed over the course of treatment.
PubMed: 31427947
DOI: 10.1159/000501070 -
Journal of the American Academy of... Feb 2020
Topics: Aged; Aminopterin; Female; Humans; Lymphohistiocytosis, Hemophagocytic; Lymphoma, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Panniculitis; Retrospective Studies; Young Adult
PubMed: 31319088
DOI: 10.1016/j.jaad.2019.07.021 -
Blood Aug 2019Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are...
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are limited because reported outcomes are from small retrospective series, and standardized treatment guidelines are lacking. The interleukin-3 cytotoxin conjugate tagraxofusp was recently tested in phase 1/2 trials that led to US Food and Drug Administration approval, the first ever for BPDCN. However, because there was no matched internal comparator in this or any clinical study to date, results of BPDCN trials testing new drugs are difficult to compare with alternative therapies. We therefore sought to define the clinical characteristics and outcomes of a group of patients with BPDCN treated at 3 US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months, and outcomes were similar in patients with "skin only" or with systemic disease at presentation. Intensive first-line therapy and "lymphoid-type" chemotherapy regimens were associated with better outcomes. Only 55% of patients received intensive chemotherapy, and 42% of patients underwent stem cell transplantation. Clinical characteristics at diagnosis associated with poorer outcomes included age >60 years, abnormal karyotype, and terminal deoxynucleotidyltransferase (TdT) negativity in the BPDCN cells. We also identified disease responses to pralatrexate and enasidenib in some patients. This study highlights poor outcomes for patients with BPDCN in the modern era and the need for new treatments. Outcomes from ongoing clinical trials for BPDCN can be evaluated relative to this contemporary cohort.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benchmarking; Child; Cohort Studies; Dendritic Cells; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multicenter Studies as Topic; Skin Neoplasms; Treatment Outcome; Young Adult
PubMed: 31243042
DOI: 10.1182/blood.2019001144 -
Leukemia & Lymphoma Dec 2019
Review
A peripheral T-cell lymphoma (PTCL) arising as a post-transplant lymphoproliferative disorder: efficacy of pralatrexate in primary refractory disease and review of the literature.
Topics: Adult; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cardiomyopathies; Deoxycytidine; Drug Resistance, Neoplasm; Female; Folic Acid Antagonists; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heart Failure; Heart Transplantation; Humans; Lymphoma, T-Cell, Peripheral; Organoplatinum Compounds; Peripartum Period; Positron Emission Tomography Computed Tomography; Postoperative Complications; Treatment Outcome
PubMed: 31184235
DOI: 10.1080/10428194.2019.1622102 -
Leukemia & Lymphoma Dec 2019Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Pralatrexate has demonstrated...
Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Pralatrexate has demonstrated efficacy in T-cell lymphomas; however, mucositis has been reported as the most common dose-modifying adverse event. Leucovorin has been shown to minimize mucositis incidence, without sacrificing pralatrexate efficacy. We retrospectively studied 34 patients (7-PTCL/27-CTCL) treated with pralatrexate alone or pralatrexate and leucovorin. Leucovorin was administered preemptively prior to any mucositis occurrence. Pralatrexate dosing ranged from 10-30 mg/m and clinical response or disease stabilization was observed in 85.2%. The incidence of mucositis was reduced in CTCL patients to 17% and was ameliorated in all but one patient with PTCL. There was no change the incidence of skin reactions with the addition of leucovorin. The response rates were similar to those previously reported in CTCL and PTCL. The addition of leucovorin reduced the incidence of mucositis in patients with CTCL and PTCL.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Female; Humans; Leucovorin; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mucositis; Neoplasm Staging; Premedication; Retrospective Studies; Skin Diseases; Treatment Outcome
PubMed: 31119966
DOI: 10.1080/10428194.2019.1612061