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Blood Advances Jun 2024Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and...
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; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.
Topics: Humans; Aminopterin; Lymphoma, T-Cell, Peripheral; Middle Aged; Male; Female; Aged; Adult; Aged, 80 and over; Treatment Outcome; Recurrence; Young Adult
PubMed: 38429077
DOI: 10.1182/bloodadvances.2023010441 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2012Transformed mycosis fungoides (tMF) is an aggressive disease with a median survival of 12-24 months. In this retrospective analysis of 12 patients with tMF, treatment...
UNLABELLED
Transformed mycosis fungoides (tMF) is an aggressive disease with a median survival of 12-24 months. In this retrospective analysis of 12 patients with tMF, treatment with pralatrexate resulted in an objective response of 25% per independent central review and 58% per investigator assessment. Pralatrexate was well tolerated, with no toxicity-related discontinuations, which makes this an additional option for tMF treatment.
BACKGROUND
Transformed mycosis fungoides (tMF) is an aggressive disease, with poor prognosis and a median survival of 24 months.
PATIENTS AND METHODS
In the Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, 12 patients with tMF were treated with a median of 10 pralatrexate doses (starting dose of 30 mg/m(2)) administered weekly for 6 weeks in a 7-week cycle. The median number of prior systemic therapies was 3.
RESULTS
This retrospective analysis showed that the objective response rate in this subgroup was 25% (n = 3) per independent central review and 58% (n = 7) per investigator assessment, with this discrepancy likely attributed to challenges with photodocumentation of cutaneous lesions. The median duration of response and the median progression-free survival were 2.2 and 1.7 months, respectively, per central review, whereas median duration of response was 4.4 months, and median progression-free survival was 5.3 months per investigator assessment. Median survival was 13 months. Grade 1-3 mucositis was reported in 7 (58%) patients. Grade 4 adverse events were fatigue (n = 1) and thrombocytopenia (n = 1). Pralatrexate was well tolerated, with no toxicity-related discontinuations.
CONCLUSIONS
Based on these results, pralatrexate may be a treatment option for patients with relapsed or refractory tMF.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Folic Acid Antagonists; Humans; Middle Aged; Mycosis Fungoides; Prognosis; Recurrence; Retrospective Studies; Survival Analysis
PubMed: 22542448
DOI: 10.1016/j.clml.2012.01.010 -
British Journal of Cancer Jan 2011Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in...
BACKGROUND
Pralatrexate is a dihydrofolate reductase (DHFR) inhibitor with high affinity for reduced folate carrier 1 (RFC-1) and folylpolyglutamate synthetase (FPGS), resulting in extensive internalization and accumulation in tumour cells. Pralatrexate is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies. Here, we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents.
METHODS
Antiproliferative effects of pralatrexate were evaluated in 15 human-cancer cell lines using the MTT assay. Gene expression was evaluated using qRT-PCR.
RESULTS
Pralatrexate and methotrexate had a similar pattern of cytotoxicity, pralatrexate being more potent. Pralatrexate potentiated the effects of platinum drugs, antimetabolites and EGFR inhibitors. Dose- and time-dependent cytotoxicity of pralatrexate correlated with high mRNA expression of FPGS. Acquired resistance to pralatrexate was associated with decreased RFC-1 expression, whereas methotrexate resistance correlated with increased DHFR expression, suggesting different mechanisms of acquired resistance.
CONCLUSION
Pralatrexate was more potent than methotrexate in a panel of solid tumour lines. Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies, and suggest that RFC-1, FPGS and DHFR may be potential biomarkers of outcome.
Topics: Aminopterin; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Folic Acid Antagonists; Humans; Methotrexate; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 21179031
DOI: 10.1038/sj.bjc.6606063 -
BMC Cancer Jul 2021Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic...
BACKGROUND
Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance.
METHODS
To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay.
RESULTS
Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3β (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines.
CONCLUSIONS
The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.
Topics: Aminopterin; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; DNA Methylation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Folic Acid Antagonists; Gene Expression Profiling; Humans; Tumor Cells, Cultured
PubMed: 34332580
DOI: 10.1186/s12885-021-08607-9 -
Journal of Medical Case Reports Mar 2020Extranodal natural killer/T cell lymphoma, nasal type, is one of the more common subtypes of mature T cell lymphoma, especially in the Far East Asian population. This...
Pralatrexate as a bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage extranodal nasal-type natural killer/T cell lymphoma refractory to first-line chemotherapy: a case report.
BACKGROUND
Extranodal natural killer/T cell lymphoma, nasal type, is one of the more common subtypes of mature T cell lymphoma, especially in the Far East Asian population. This aggressive histologic subtype of peripheral T cell lymphomas is frequently susceptible to exposure of Epstein-Barr virus infection. The optimal treatment is not well elucidated. For stage IV disseminated extranodal natural killer/T cell lymphoma, induction chemotherapy with consolidative autologus or allogeneic hematopoietic stem cell transplantation is recommended as the major first-line treatment. However, there is controversy over which type of chemotherapy is most appropriate and effective as a bridge to autologus or allogeneic hematopoietic stem cell transplantation in patients with newly diagnosed disseminated advanced-stage or relapsed extranodal natural killer/T cell lymphoma because of cancer chemoresistance or associated complications. Pralatrexate is the first US Food and Drug Administration-approved novel agent for the treatment of refractory/recurrent peripheral T cell lymphomas. In our case, pralatrexate was used as a successful bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage disseminated extranodal natural killer/T cell lymphoma refractory to first-line chemotherapy.
CASE PRESENTATION
We presented a case report of a 29-year-old Asian man diagnosed as having stage IV disseminated extranodal natural killer/T cell lymphoma, nasal type, with skin and bone marrow involvement, whose disease was primary refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy, but obviously responded to treatment with two cycles of single-agent pralatrexate treatment. Monitoring Epstein-Barr virus viremia revealed dramatic downregulation. In addition to complete remission of the involvement of bone marrow and nasal cavity, skin involvement also obtained partial remission. The extranodal natural killer/T cell lymphoma successfully achieved complete remission after a bridge to allogeneic hematopoietic stem cell transplantation.
CONCLUSIONS
This is the first study to present pralatrexate as a successful bridge to allogeneic hematopoietic stem cell transplantation in a 29-year-old Asian male patient with advanced-stage extranodal natural killer/T cell lymphoma refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy. This case provides a novel treatment opinion for extranodal natural killer/T cell lymphoma, especially for the Far East Asian population.
Topics: Adult; Allografts; Aminopterin; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Neoplasm Staging; Remission Induction; Taiwan; Transplantation Conditioning
PubMed: 32183896
DOI: 10.1186/s13256-020-02363-3 -
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 -
Cancer Chemotherapy and Pharmacology Sep 2013To characterize, directly and for the first time, the membrane transport and metabolism of pralatrexate, a new-generation dihydrofolate reductase inhibitor approved for... (Comparative Study)
Comparative Study
PURPOSE
To characterize, directly and for the first time, the membrane transport and metabolism of pralatrexate, a new-generation dihydrofolate reductase inhibitor approved for the treatment for peripheral T-cell lymphoma.
EXPERIMENTAL DESIGN
[(3)H]pralatrexate transport was studied in unique HeLa cell lines that express either the reduced folate carrier (RFC) or the proton-coupled folate transporter (PCFT). Metabolism to active polyglutamate derivatives was assessed by liquid chromatography. These properties were compared to those of methotrexate (MTX).
RESULTS
The pralatrexate influx K t, mediated by RFC, the major route of folate/antifolate transport at systemic pH, was 0.52 μΜ, 1/10th the MTX influx K i. The electrochemical potential of pralatrexate within HeLa cells far exceeded the extracellular level and was greater than for MTX. In contrast, MTX transport mediated by PCFT, the mechanism of folate/antifolate absorption in the small intestine, exceeded that for pralatrexate. After a 6 h exposure of HeLa cells to 0.5 μM pralatrexate, 80 % of intracellular drug was its active polyglutamate forms, predominantly the tetraglutamate, and was suppressed when cells were loaded with natural folates. There was negligible formation of MTX polyglutamates. The difference in pralatrexate and MTX growth inhibition was far greater after transient exposures (375-fold) than continuous exposure (25-fold) to the drugs.
CONCLUSIONS
Pralatrexate's enhanced activity relative to MTX is due to its much more rapid rate of transport and polyglutamation, the former less important when the carrier is saturated. The low affinity of pralatrexate for PCFT predicts a lower level of enterohepatic circulation and increased fecal excretion of the drug relative to MTX.
Topics: Aminopterin; Biological Transport; Chromatography, Liquid; Electrochemistry; Folic Acid Antagonists; HeLa Cells; Humans; Methotrexate; Polyglutamic Acid; Proton-Coupled Folate Transporter; Reduced Folate Carrier Protein; Time Factors
PubMed: 23881211
DOI: 10.1007/s00280-013-2231-9 -
Blood Advances Jan 2024Pralatrexate is a folate antagonist that selectively enters cells expressing reduced folate carrier type 1 and competitively inhibits dihydrofolate reductase, leading to...
Pralatrexate is a folate antagonist that selectively enters cells expressing reduced folate carrier type 1 and competitively inhibits dihydrofolate reductase, leading to interruption of RNA synthesis, DNA replication, and apoptosis. This phase 1 study was conducted to evaluate the maximum tolerated dose (MTD) of pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (part 1) and the response and pharmacokinetics of 6 cycles of this combination (CHOP + Folotyn 30 mg/m2 [Fol-CHOP]) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL). In part 1, on days 1 and 8 of each cycle, patients were treated with 10, 15, 20, 25, or 30 mg/m2 of pralatrexate in combination with CHOP, per dose escalation, in 5 sequential cohorts. No patients experienced DLTs in cohorts 1, 2, 3, 4, and 5. The pralatrexate dose of 30 mg/m2 was selected to be combined with CHOP for part 2 and administered to 33 additional patients in the expansion cohort. At the MTD, the Fol-CHOP regimen was generally well tolerated in patients with PTCL, with an overall response rate (ORR) of 83.9% (20 complete response and 6 partial response), as assessed by treating investigators. Thirty-five patients (67.3%) experienced grade 3/4 treatment-emergent adverse events, the most common of which were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea, and vomiting (7.7% each). In conclusion, Fol-CHOP was found to be a safe and effective treatment for newly diagnosed PTCL and deemed worthy of further investigation. This trial was registered at www.ClinicalTrials.gov as #NCT02594267.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Aminopterin; Treatment Outcome; Fatigue
PubMed: 38029357
DOI: 10.1182/bloodadvances.2023011095 -
Antiviral Research Jan 2024Varicella zoster virus (VZV) is associated with herpes zoster (HZ) or herpes zoster ophthalmicus (HZO). All antiviral agents currently licensed for the management of VZV...
Varicella zoster virus (VZV) is associated with herpes zoster (HZ) or herpes zoster ophthalmicus (HZO). All antiviral agents currently licensed for the management of VZV replication via modulating different mechanisms, and the resistance is on the rise. There is a need to develop new antiviral agents with distinct mechanisms of action and adequate safety profiles. Pralatrexate (PDX) is a fourth-generation anti-folate agent with an inhibitory activity on folate (FA) metabolism and has been used as an anti-tumor drug. We observed that PDX possessed potent inhibitory activity against VZV infection. In this study, we reported the antiviral effects and the underlying mechanism of PDX against VZV infection. The results showed that PDX not only inhibited VZV replication in vitro and in mice corneal tissues but also reduced the inflammatory response and apoptosis induced by viral infection. Furthermore, PDX treatment showed a similar anti-VSV inhibitory effect in both in vitro and in vivo models. Mechanistically, PDX inhibited viral replication by interrupting the substrate supply for de novo purine and thymidine synthesis. In conclusion, this study discovered the potent antiviral activity of PDX with a novel mechanism and presented a new strategy for VZV treatment that targets a cellular metabolic mechanism essential for viral replication. The present study provided a new insight into the development of broad-spectrum antiviral agents.
Topics: Animals; Mice; Herpesvirus 3, Human; Vesicular Stomatitis; Herpes Zoster; Vesicular stomatitis Indiana virus; Vesiculovirus; Antiviral Agents; Virus Replication; Aminopterin
PubMed: 38145756
DOI: 10.1016/j.antiviral.2023.105787 -
Drugs of Today (Barcelona, Spain : 1998) Feb 2010Pralatrexate (PDX, 10-propargyl 10-deazaaminopterin) is an exciting new chemotherapeutic agent with promising activity in T-cell lymphomas and non-small cell lung...
Pralatrexate (PDX, 10-propargyl 10-deazaaminopterin) is an exciting new chemotherapeutic agent with promising activity in T-cell lymphomas and non-small cell lung cancer. It has been granted approval by the Food and Drug administration (FDA) for use in the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). Pralatrexate belongs to a class of antineoplastic agents known as antifolates that also include methotrexate, pemetrexed and ralitrexed. Pralatrexate was rationally designed to have high affinity for the one carbon-reduced folate carrier (RFC-1) which leads to better cellular internalization of the drug and a greater antitumor effect than methotrexate. The following monograph is a story of the development of this drug in a systematic fashion from the bench to the bedside.
Topics: Aminopterin; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Folic Acid Antagonists; Humans; Neoplasms
PubMed: 20393637
DOI: 10.1358/dot.2010.46.2.1439260