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Frontiers in Medicine 2019Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and... (Review)
Review
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and plaques and the lesions are usually limited to the skin. On the other hand, in some cases, patients show skin tumors or erythroderma followed by lymph node involvement and rarely visceral organ involvement. SS is a rare, aggressive cutaneous T-cell lymphoma marked by exfoliative erythroderma, lymphadenopathy, and leukemic blood involvement. Because patients with relapsed or refractory MF/SS display a poor prognosis and the current treatment options are characterized by high rates of relapse, there is unmet need for the efficient treatment. This review provides a discussion of the recent and future promising therapeutic approaches in the management of advanced MF/SS. These include mogamulizumab, brentuximab vedotin, alemtuzumab, immune checkpoint inhibitors, IPH4102 (anti-KIR3DL2 antibody), histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, belinostat, and resminostat), pralatrexate, forodesine, denileukin diftitox, duvelisib, lenalidomide, and everolimus.
PubMed: 31192214
DOI: 10.3389/fmed.2019.00116 -
Leukemia & Lymphoma Nov 2017It has been nearly 8 years since pralatrexate became the first drug approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory... (Review)
Review
It has been nearly 8 years since pralatrexate became the first drug approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Like most drugs approved for a particular clinical indication, as much or more is learned once it enters mainstream use as in the years leading up to regulatory approval. Over the past several years, many diverse lines of research have shed new insight into both the agent, and the diseases it treats. In this review, we will bring the reader up to date on the many new aspects related to pralatrexate's pharmacology, activity across the panoply of T-cell lymphoproliferative malignancies, as well as some new and emerging guidelines that are likely to improve its safety profile. Finally, the review will close with the many new lines of evidence building a rationale for the combination of these novels: novel combination, and the vision for new platforms in PTCL care.
Topics: Aminopterin; Clinical Trials as Topic; Drug Resistance, Neoplasm; Drug Therapy; Folic Acid Antagonists; Humans; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 28738754
DOI: 10.1080/10428194.2017.1306642 -
ACS Applied Materials & Interfaces Jan 2022Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically...
Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically approved antifolates by the U.S. Food and Drug Administration as chondrogenic-promoting compounds for tonsil-derived mesenchymal stem cells. A poly(ethylene glycol)-poly(l-alanine) thermogelling system was used as a three-dimensional cell culture matrix, where stem cells and antifolates could be incorporated simultaneously during a heat-induced in situ sol-to-gel transition. The antifolates could be supplied over several days by the sustained release of the drug from the thermogel. Initially, seven antifolates were prescreened based on cell viability and expression of a typical chondrogenic biomarker of type II collagen (COL II) at the mRNA level. Then, dapsone, pralatrexate, and trimethoprim were selected as candidate compounds in the second round screening, and detailed studies were carried out on the mRNA and protein expression of various chondrogenic biomarkers including COL II, SRY box transcription factor 9, and aggrecan. Three-dimensional cultures of stem cells in the thermogel in the absence of a chondrogenic promoter compound and in the presence of kartogenin (KGN) were performed as a negative control and positive control, respectively. The chondrogenic biomarkers were significantly increased in the selected antifolate-incorporating systems compared to the negative control system, without an increase in type I collagen (an osteogenic biomarker) expression. Pralatrexate was the best compound for inducing chondrogenic differentiation of the stem cells, even better than the positive control (KGN). Nuclear translocation of the core-binding factor β subunit (CBFβ) and enhanced nuclear runt-related transcription factor 1 (RUNX1) by antifolate treatment suggested that the chondrogenesis-enhancing mechanism is mediated by CBFβ and RUNX1. An in silico modeling study confirmed the mechanism by proving the high binding affinity of pralatrexate to a target protein of filamin A compared with other antifolate candidates. To conclude, pralatrexate was rediscovered as a lead compound, and the polypeptide thermogel incorporating pralatrexate and mesenchymal stem cells can be a very effective system in promoting chondrogenic differentiation of stem cells and might be used in injectable tissue engineering for cartilage repair.
Topics: Aminopterin; Biocompatible Materials; Cell Differentiation; Chondrogenesis; Gels; Humans; Materials Testing; Mesenchymal Stem Cells; Peptides; Temperature
PubMed: 35014790
DOI: 10.1021/acsami.1c20585 -
Blood Jan 2018Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were...
Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m) and romidepsin (12 to 14 mg/m) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m and romidepsin 12 mg/m every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140.
Topics: Adult; Aged; Aminopterin; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Depsipeptides; Female; Folic Acid Antagonists; Humans; Lymphoma, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Young Adult
PubMed: 29141948
DOI: 10.1182/blood-2017-09-806737 -
Spectrochimica Acta. Part A, Molecular... May 2021In this study, a series of green, interference-free fluorimetric detection methods of the excitation-emission matrix coupled with the second-order calibration methods...
Three efficient chemometrics assisted fluorimetric detection methods for interference-free, rapid, and simultaneous determination of ibrutinib and pralatrexate in various complicated biological fluids.
In this study, a series of green, interference-free fluorimetric detection methods of the excitation-emission matrix coupled with the second-order calibration methods were proposed for the determination of ibrutinib and pralatrexate in various complicated biological fluids. The second-order advantage of the proposed method can overcome the problem of poor selectivity caused by the wide spectra of the fluorescence method. Even in the presence of uncalibrated interferences and severe peak overlap, the signal of pure substance and accurate quantitative results were still obtained. The average recoveries of the three methods were 94.5-104.9% for Alternating Trilinear Decomposition (ATLD) algorithm, 95.5-105.8% for Alternating Normalization Weighted Error (ANWE) algorithm and 94.4-105.7% for Parallel Factor Analysis (PARAFAC) algorithm, respectively. For ATLD, ANWE and PARAFAC, the relative standard deviations (RSD) were lower than 9.2%, 6.8% and 9.2%, and the RMSEPs were less than 8.1, 8.4 and 8.6 ng mL, respectively. In addition, the elliptic joint confidence region (EJCR) was adopted to further prove the accuracy of the three methods. The results showed that the three methods can accurately be quantified without significant difference. Good figures of merit parameters were also obtained. Among them, the limit of detection (LOD) and limit of quantification (LOQ) of ibrutinib and pralatrexate were in the range of 0.11-0.76 ng mL and 0.21-1.12 ng mL, respectively, which were lower than the corresponding blood concentrations. These results indicate that the proposed method provides a promising, alternative and universal analysis strategy for clinical drug monitoring.
Topics: Adenine; Algorithms; Aminopterin; Calibration; Fluorometry; Limit of Detection; Piperidines; Spectrometry, Fluorescence
PubMed: 33524816
DOI: 10.1016/j.saa.2020.119419 -
Analytical Methods : Advancing Methods... Feb 2023An attempt was made to develop a new sensitive biosensor for pralatrexate, as an anticancer drug, based on its interaction with the guanine of fish sperm DNA anchored on...
An attempt was made to develop a new sensitive biosensor for pralatrexate, as an anticancer drug, based on its interaction with the guanine of fish sperm DNA anchored on a screen-printed electrode (SPE) modified with polypyrrole (PP)/octahedral Pd-doped CoO composite (Oh-Pd-doped CoO C). Electrochemical techniques like differential pulse voltammetry verified the mechanism of such an interaction on the dsDNA/PP/Oh-Pd-doped CoO C/SPE surface. A reduction in the peak current of guanine oxidation elucidated the interaction in acetate buffer with pH = 4.8. The optimization of response was performed for the interaction method according to potential, accumulation time, reproducibility and drug content. The linear dynamic range was estimated at 1.0 nM to 150.0 μM as well as a limit of detection as low as 0.61 nM for the DNA and pralatrexate concentrations. The practical potential of the proposed sensor was verified by determining pralatrexate in its pharmaceutical matrices.
Topics: Animals; Male; Polymers; Reproducibility of Results; Pyrroles; Semen; Biosensing Techniques; DNA; Guanine
PubMed: 36651313
DOI: 10.1039/d2ay01909d -
Clinical Lymphoma, Myeloma & Leukemia Aug 2014This study aimed to assess the long-term tolerability of pralatrexate alone or in combination with oral bexarotene for relapsed or refractory mycosis fungoides (MF).
BACKGROUND
This study aimed to assess the long-term tolerability of pralatrexate alone or in combination with oral bexarotene for relapsed or refractory mycosis fungoides (MF).
PATIENTS AND METHODS
Patients with MF in this report were participants in 1 of 2 multicenter trials. During the dose-ranging phase I/II study, participants were treated with pralatrexate alone for 3 of 4 weeks. During a second phase I/II dose-ranging combination trial, participants were treated with pralatrexate at 15 mg/m(2)/wk for 3 of 4 weeks combined with 150 to 300 mg/m(2) of daily oral bexarotene.
RESULTS
Twenty-six patients were enrolled at our center, including 12 receiving pralatrexate and 14 receiving pralatrexate plus bexarotene. Four of 12 patients (33%) treated with pralatrexate alone responded. Of 14 patients treated with bexarotene plus pralatrexate, 7 (50%) responded. Ten participants, with a median age of 71 years (range, 41-82 years), received more than 9 cycles of pralatrexate, including 3 receiving pralatrexate and 7 receiving combination therapy. Median time to response was 15.75 weeks (range, 4-24 weeks), and the median duration of response was 26.75 weeks (range, 8.5-49.5 weeks). The most common adverse event (AE) was mucositis in 8 (80%) patients. Other AEs of any grade included arthralgias (n = 1), headache (n = 1), neutropenia (n = 5), and skin necrosis (n = 2). Two patients initially had lower leg tumors that responded to therapy, leaving residual chronic leg ulcers.
CONCLUSION
Pralatrexate alone or in combination with low-dose oral bexarotene is well tolerated and capable of providing long-term responses in patients of advanced age with advanced-stage MF.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Neoplasm Recurrence, Local; Retrospective Studies; Tetrahydronaphthalenes; Treatment Outcome
PubMed: 24589156
DOI: 10.1016/j.clml.2014.01.010 -
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 -
Cancer Nov 2016The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive...
BACKGROUND
The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer.
METHODS
In phase 1, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the maximum-tolerated dose (MTD) of pralatrexate was achieved. The primary endpoint was the response rate. Additional endpoints were safety, response duration, progression-free survival, overall survival, and pharmacokinetics.
RESULTS
Thirty patients were enrolled in phase 1, and 20 were enrolled in phase 2. Of all 50 patients, 49 completed the study. The mean patient age was 59 years, and patients completed a median of 6 cycles. The MTD for pralatrexate was 105 mg/m . The clinical benefit rate (complete responses plus partial responses plus stable disease) was 86%. Of 26 patients who received the MTD, 12 had a partial response, 11 had stable disease, and 2 had disease progression. The progression-free survival rate at 3 and 6 months was 87% and 79%, respectively; and the overall survival rate was 98% at 6 and 12 months and 66% at 24 months. Of 30 patients, 18 (60%) in phase 1 experienced an adverse event of any grade; and, of those, 4 patients (13%) had a grade 3 or greater adverse event. In phase 2, 12 patients (60%) had an adverse event of any grade, and 4 (20%) had grade 3 or greater toxicity. There was a significant reduction in the total body clearance of pralatrexate when it was received concurrently with carboplatin.
CONCLUSIONS
Most patients responded to carboplatin-pralatrexate combination. This regimen is well tolerated and effective in this patient population. Cancer 2016;122:3297-3306. © 2016 American Cancer Society.
Topics: Adult; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Carcinosarcoma; Cystadenocarcinoma, Serous; Endometrial Neoplasms; Fallopian Tube Neoplasms; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Peritoneal Neoplasms; Prognosis; Survival Rate; Tissue Distribution
PubMed: 27421044
DOI: 10.1002/cncr.30196 -
Scientific Reports Dec 2019Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas with poor clinical outcomes. Pralatrexate showed efficacy and safety in recurrent...
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas with poor clinical outcomes. Pralatrexate showed efficacy and safety in recurrent or refractory PTCLs. The purpose or this study was to investigate the efficacy and safety of pralatrexate in relapsed or refractory PTCLs in real-world practice. This was an observational, multicenter, retrospective analysis. Between December 2012 and December 2016, a total of 38 patients with relapsed or refractory PTCLs were treated with pralatrexate at 10 tertiary hospitals in Korea. Patients received an intravenous infusion of pralatrexate at a dose of 30 mg/m/week for 6 weeks on a 7-week schedule. Modified dosing and/or scheduling was allowed according to institutional protocols. Median patient age was 58 years (range, 29-80 years) and the most common subtype was peripheral T-cell lymphoma, not otherwise specified (n = 23, 60.5%). The median dosage of pralatrexate per administration was 25.6 mg/m/wk (range, 15.0-33.0 mg/m/wk). In intention-to-treat analysis, 3 patients (7.9%) showed a complete response and 5 patients (13.2%) showed a partial response, resulting in an overall response rate (ORR) of 21.1%. The median duration of response was 7.6 months (range, 1.6-24.3 months). The median progression-free survival (PFS) was 1.8 months (95% confidence interval [CI], 1.7-1.8 months) and the median overall survival was 7.7 months (95% CI, 4.4-9.0 months). The most common grade 3/4 adverse events were thrombocytopenia (n = 13, 34.2%), neutropenia (n = 7, 23.7%), and anemia (n = 7, 18.4%). Our study showed relatively lower ORR and shorter PFS in patients with recurrent or refractory PTCLs treated with pralatrexate in real-world practice. The toxicity profile was acceptable and manageable. We also observed significantly lower dose intensity of pralatrexate in real-world practice.
Topics: Aged; Aged, 80 and over; Aminopterin; Antineoplastic Agents; Disease Management; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Staging; Prognosis; Recurrence; Retreatment; Retrospective Studies; Treatment Outcome
PubMed: 31889144
DOI: 10.1038/s41598-019-56891-0