Folotyn (pralatrexate) / Mundipharma, Aurobindo, CASI, Assertio - LARVOL DELTA

PDX+Romi: Pralatrexate + Romidepsin in Relapsed/Refractory Lymphoid Malignancies (clinicaltrials.gov) - P1/2 | N=57 | Terminated | Sponsor: Jennifer Amengual | Completed ➔ Terminated; Lack of funding and recruitment complications caused by COVID-19

Trial termination • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Design and synthesis of pyrrolo[3,2-d]pyrimidine-based antifolates that mimic 10-formyl tetrahydrofolate | Poster Board #1231 (ACS-Fall 2026) - "The FDA-approved antifolates such as methotrexate, pemetrexed, and pralatrexate target one or more 1C-metabolizing enzymes. From the series of 8 new compounds, we identified AGF420 and analogs as potent, tumor-selective mitochondrial inhibitors of 1C metabolism. The synthesis, structure-activity relationship of these compounds, and the biological activity will be presented and discussed."

MTHFD2 • SHMT1

REAL-WORLD INSIGHTS INTO CLINICAL FEATURES AND OUTCOMES IN EXTRANODAL T-CELL LYMPHOMAS: RESULTS FROM THE INTERNATIONAL T-CELL PROJECT 2.0 PROSPECTIVE COHORT STUDY. (EHA 2026) - "The three most frequent regimes were Gemcitabine-based 17(20%), Asparginase-based 14(16%) and Platinum-based 11(13%). Only 2 patients received BV, and 9 received Pralatrexate...Summary/Conclusion Our findings confirm that extranodal T-cell lymphomas, with the exception of BIA-ALCL, continue to carry a poor prognosis. The low utilization of transplant consolidation and a high rate of primary disease progression highlight a critical need for the integration of novel agents and intensified frontline strategies to improve long-term survival in this heterogeneous group."

Clinical • Real-world • Real-world evidence • Extranodal Natural Killer/T-cell Lymphoma • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • T Cell Non-Hodgkin Lymphoma

Primary Cutaneous Gamma-Delta T-Cell Lymphoma Complicating Long-Standing Immunosuppressed Dermatomyositis. (PubMed, J Cutan Pathol) - "Case 1 is a 47-year-old woman with a 19-year history of DM on azathioprine/prednisone who developed rapidly progressive, painful subcutaneous nodules...She achieved complete remission following pralatrexate and subsequent allogeneic hematopoietic stem cell transplant. Case 2 is a 27-year-old woman with DM on mycophenolate/rituximab who developed subcutaneous nodules with an indolent course and some spontaneous regression...The shared, atypical CD8+ immunophenotype and absence of canonical driver mutations suggest a distinct pathogenic mechanism possibly linked to long-term immune modulation. Unlike classic PCGD-TCL, which is characterized by an aggressive course and < 2-year median survival, the clinical courses in these two cases were variable, with one requiring transplant and the other showing indolent behavior and responsiveness to therapy."

Journal • Bone Marrow Transplantation • Dermatomyositis • Hematological Malignancies • Immune Modulation • Immunology • Inflammatory Arthritis • Lupus • Lymphoma • Myositis • Oncology • Pain • T Cell Non-Hodgkin Lymphoma • Transplantation • CD8

Pasta, a Versatile Transcriptomic Clock, Maps the Chemical and Genetic Determinants of Aging and Rejuvenation. (PubMed, Adv Sci (Weinh)) - "Experimental validation confirmed pralatrexate as a potent senescence inducer and piperlongumine as a rejuvenating agent in human cells. Together, these findings establish Pasta as a versatile and accessible tool for aging research and therapeutic discovery."

Journal • Oncology

Lipocalin 2 as a novel target of pralatrexate mitigating corneal epithelial damage in a mouse model of herpes simplex keratitis. (PubMed, Ocul Surf) - "Mechanistically, PDX suppresses lipocalin-2 (LCN2) expression by reducing P65 phosphorylation and inhibiting its nuclear translocation, which may be involved in HSV-1 replication inhibition and corneal inflammation progression reduction. In conclusion, our work highlights PDX as a promising anti-HSK agent, given its efficacy against viral replication and corneal epithelial damage via inhibiting LCN2 expression."

Journal • Preclinical • Corneal Abrasion • Herpes Simplex • Infectious Disease • Keratitis • Ocular Infections • Ocular Inflammation • Oncology • Ophthalmology • LCN2 • RELA

Beyond Romidepsin: Novel Therapeutic Targets and Emerging Strategies for Relapsed and Refractory Peripheral T-Cell Lymphoma. (PubMed, Clin Lymphoma Myeloma Leuk) - "Following romidepsin's withdrawal from the R/R PTCL indication in 2021, the only FDA-approved agents are belinostat and pralatrexate, and Brentuximab Vedotin...EZH2 inhibitors represent a mechanistically novel class: valemetostat produced an ORR of 43.7% with a median duration of response of 11.9 months. JAK/STAT inhibitors, including golidocitinib (ORR 44.3%) and cerdulatinib (ORR 51.9% in AITL/TFH), show subtype-selective activity. Rational combinations yield superior efficacy: duvelisib plus romidepsin achieved ORR of 56% (CR 44%), while azacitidine combined with romidepsin produced ORR of 61% (CR 48%), particularly in TFH-phenotype disease (ORR 80%)...The Ro-CHOP trial's failure in unselected populations, contrasted with efficacy signals in nTFHL subsets, underscores a critical lesson: PTCL is not one disease, and future trial designs must incorporate biomarker-driven enrichment strategies to advance precision therapeutics. Improved outcomes can be expected..."

Journal • Review • Gene Therapies • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • DNMT3A • KLRD1 • RHOA • TET2

Belinostat in Combination With Azacitidine or Pralatrexate for the Treatment of Relapse or Refractory T-cell Lymphoma (clinicaltrials.gov) - P1 | N=40 | Not yet recruiting | Sponsor: City of Hope Medical Center

New P1 trial • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CD8

A MULTICENTER, OPEN-LABEL, PHASE 3, RANDOMIZED TRIAL OF DUVELISIB VS INVESTIGATOR'S CHOICE (GEMCITABINE OR BENDAMUSTINE) IN RELAPSED/REFRACTORY NODAL T-CELL LYMPHOMA WITH T-FOLLICULAR HELPER PHENOTYPE (EHA 2026) - P2, P3 | "Currently, the only agent approved in the EU/UK for treatment of R/R PTCL is brentuximab vedotin for anaplastic large-cell lymphoma. Novel agents such as romidepsin, belinostat, and pralatrexate have received accelerated approvals outside the EU/UK, but to date, none have received full approval...TERZO will test the hypothesis that DUV monotherapy is associated with improved outcomes versus GEM or BEN in patients with R/R nTFHL. TERZO is the only phase 3 study dedicated to nTFHL in the EU/UK, designed to address this serious unmet need."

Clinical • P3 data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma

Single-agent gemcitabine enabling successful bridging to allogeneic haematopoietic stem-cell transplantation in refractory peripheral T-cell lymphoma, not otherwise specified. (PubMed, BMJ Case Rep) - "The disease was refractory to brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisone, SMILE and pralatrexate. Throughout the course, serial leucocyte-to-lymphocyte ratio (LLR) measurements appeared to parallel disease activity, with elevation during refractory disease and normalisation in remission. This case suggests that single-agent gemcitabine may provide a feasible low-toxicity bridge to transplantation in selected refractory PTCL-NOS and that serial LLR measurements may represent a simple adjunctive marker of disease dynamics."

Journal • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Transplantation

MECHANISM-GUIDED HDAC INHIBITION INDUCES COMPLETE RESPONSE IN PRIMARY REFRACTORY GATA3-POSITIVE PTCL-NOS: A BIOLOGICALLY INFORMED THERAPEUTIC STRATEGY (EHA 2026) - "Third-line Pralatrexate had to be truncated before completing the first cycle due to intolerable Grade IV mucositis, severe cytopenias, and recurrent bacteremia. (B) Progression (November 2024): Disease progression after first-line CHOEP-TIT, demonstrating increased metabolic activity in right iliac (SUV max 5.83) and inguinal nodes (SUV max 7.0), alongside new bilateral laterocervical involvement (SUV max 5.12). (C) Complete Response (September 2025): Metabolic complete response after 4 cycles of 4th-line Belinostat, with reduction of splenomegaly to 17 cm and minimal residual right inguinal uptake (SUV max 1.87; Deauville Score 2)."

Clinical • Acute Kidney Injury • Cardiovascular • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Lymphoma • Mucositis • Obesity • Peripheral T-cell Lymphoma • Renal Disease • Septic Shock • T Cell Non-Hodgkin Lymphoma • GATA3

Functional genomics and proteomics identify Folate Carrier SLC19A1 as a predictor of pralatrexate sensitivity in diverse T-cell lymphoma models. (PubMed, Mol Cancer Ther) - "Simulated clinical trials predicted that biomarker-guided patient selection could improve the power to detect significant benefit of adding pralatrexate to frontline chemotherapy in PTCL. These findings illustrate how functional genetic screens can augment correlative studies to identify candidate biomarkers of drug response, and suggest the potential for precise use of pralatrexate for PTCL."

Journal • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Fusion-positive rhabdomyosarcoma oncofusions share a common interactome. (PubMed, Nat Commun) - "Accordingly, the antifolate pralatrexate suppressed growth across all seven oncofusions, in multiple human FP-RMS cell lines, and a patient-derived xenograft. These findings demonstrate that divergent FP-RMS oncofusions are functionally fungible through a shared interactome that defines common vulnerabilities."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • PAX3 • TYMS

Pralatrexate is a potent pan-serotype human adenovirus inhibitor through suppression of dihydrofolate reductase. (PubMed, Antimicrob Agents Chemother) - "In this study, three folate antagonists aminopterin (AMT), pralatrexate (PDX), and methotrexate (MTX) with potent antiviral activity against HAdV infection have been identified through a drug repurposing screening strategy. Mechanistic studies revealed that PDX achieved its antiviral activity through suppression of dihydrofolate reductase (DHFR). These findings support the potential of folate antagonists as repurposed therapeutic agents against HAdV infection and provide a rationale for the development of host-directed antiviral strategies."

Journal • Infectious Disease • DHFR

Pembrolizumab and Pralatrexate in Treating Patients With Relapsed or Refractory Peripheral T-Cell Lymphomas (clinicaltrials.gov) - P1/2 | N=13 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Feb 2026 ➔ Feb 2027

Trial completion date • Cutaneous T-cell Lymphoma • Dermatology • Follicular Lymphoma • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Lymphoma • Mycosis Fungoides • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK

In silico discovery of novel small-molecule PD-L1 inhibitors through a multi-stage computational workflow integrating machine learning and molecular dynamics. (PubMed, J Comput Aided Mol Des) - "Through virtual screening of FDA-approved drugs, Pralatrexate was subsequently identified as a promising repurposing candidate, demonstrating a higher predicted binding affinity than the reference inhibitors...This multi-stage computational workflow effectively integrates machine learning predictions with atomic-level binding analyses, providing a robust platform for accelerated drug discovery. The optimized derivative D1 thus represents a promising candidate for experimental validation and further development as a potential cancer immunotherapeutic agent."

Journal • Oncology

Real-world pharmacovigilance analysis of pralatrexate using the FDA adverse event reporting system database. (PubMed, Front Pharmacol) - "Our findings suggest that clinicians should implement personalized monitoring on the basis of patient sex and age, with a particular emphasis on mucosal toxicity and metabolism-related AEs in patients ≥65 years old. Furthermore, the adverse reaction spectrum of pralatrexate may be broader than previously recognized, necessitating further investigation to optimize medication safety management."

Adverse events • Journal • Real-world evidence • Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Metabolic Disorders • Mucositis • Oncology • Peripheral T-cell Lymphoma • Steven-Johnson Syndrome • T Cell Non-Hodgkin Lymphoma

Pralatrexate With Bendamustine and Total-Body Irradiation Followed by Donor Stem Cell Transplant for the Treatment of Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1/2 | N=50 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Transplantation • CD33 • HLA-B • HLA-C • HLA-DQB1 • HLA-DRB1

Repurposing of pralatrexate in gastric cancer: Inducing cell death via SMO inhibition and GLI1 suppression (AACR 2025) - "Structural predictions using AI modeling indicated that Pralatrexate binds to a site similar to the SMO antagonist ANTA-XV, distinct from Cyclopamine's binding pocket. In summary, Pralatrexate canonically regulates Hh signaling by inhibiting SMO and suppressing GLI1, ultimately reducing cell proliferation and causing apoptosis in GC. Our findings uncover a novel anticancer mechanism of Pralatrexate in GC, providing a potential basis for its clinical application in GC therapy."

Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Peripheral T-cell Lymphoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • GLI1

ATR inhibitors synergize with DHFR inhibitors in rhabdomyosarcoma cells by disrupting DNA damage checkpoint (AACR 2024) - "In this study, we aimed to explore a potential synergistic interaction using a combination treatment of ATR inhibitors (elimusertib and ceralasertib) and DHFR inhibitors (pralatrexate, methotrexate, and raltitrexated) in multiple RMS cell lines. Our findings warrant further research into identifying genomic regions where the DNA damage is enriched in combination treatment by using END-sequencing and synthesis-associated with repair sequencing (SAR-seq). In conclusion, this study provides promising rationale for the combination treatment of ATR and DHFR inhibitors to treat RMS patients, including those with advanced, relapsed, and metastatic states."

Late-breaking abstract • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CHEK1 • DHFR

Soquelitinib vs Standard of Care in Participants With Relapsed/Refractory Peripheral T-cell Lymphoma Not Otherwise Specified, Follicular Helper T-cell Lymphomas, or Systemic Anaplastic Large-cell Lymphoma (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Corvus Pharmaceuticals, Inc. | Trial completion date: Jul 2028 ➔ Dec 2028 | Trial primary completion date: Nov 2026 ➔ Nov 2027

Trial completion date • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Systemic Anaplastic Large Cell Lymphoma • T Cell Non-Hodgkin Lymphoma

ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANT AS SALVAGE THERAPY FOR MATURE T CELL LYMPHOMA: CLINICAL EXPERIENCE AND OUTCOMES (EBMT 2026) - "Following salvage with pralatrexate, she proceeded to haploidentical HCT with FLU-CY-TBI conditioning, achieving engraftment on day 13 and a durable remission of 4 years. Finally, Case 3, pre-treated with four prior lines (including CHOP, radiotherapy, and brentuximab vedotin), underwent a matched sibling donor transplant utilising FLU-BU conditioning post-chemotherapy salvage... This case series confirms the feasibility and curative efficacy of AlloHCT as a salvage strategy for Filipino patients with high-risk MTCL. The study demonstrates that the graft-versus-lymphoma effect can induce sustained survival even in patients with chemo-refractory disease or prior autologous transplant failure. Furthermore, the successful implementation of haploidentical platforms highlights that donor availability need not be a barrier to life-saving therapy in this region."

Clinical • Acute Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Transplantation

Current Practice and Research in T-cell and NK/T-cell Lymphoma in Japan (ICKSH 2026) - "For patients with major subtypes of peripheral T -cell lymphoma (PTCL), including PTCL not otherwise specified, angioimmunoblastic T -cell lymphoma (AITL), and anaplastic large cell lymphoma, the 2024 Japanese Society of Hematology (JSH) guidelines recommend the use of brentuximab vedotin (BV) -CHP for CD30 -positive tumors and CHOP -like regimens for CD30 -negative tumors as the first -line treatment...For patients with relapsed /refractory T-cell and NK/T -cell lymphoma, many therapeutic drugs (mogamulizumab, BV , pralatrexate, forodesine, romidepsin, alectinib, denileukin diftitox, tucidinostat, darinaparsin, and valemetostat) are approved and available in Japan...However, among immune checkpoint inhibitors, only atezolizumab was approved for the treatment of ENKL in 2025, and little experience is available with its use. Patients with ENKL in Japan account for less than 1% of all lymphoma patients, which is as low as in Western countries. To fill these gaps, an..."

Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • TNFRSF8

Pembrolizumab and pralatrexate for relapsed or refractory peripheral T-cell lymphomas. (PubMed, Br J Haematol) - No abstract available

Journal • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

CASI Pharmaceuticals, Inc. reported that China’s National Medical Products Administration formally rejected its renewal application for the Import Drug Registration License for FOLOTYN in China. (StockTitan.net) - " The company had already stopped selling FOLOTYN in China after the prior license expired, in line with applicable regulations, so sales had ceased before this formal rejection....CASI highlights its focus on developing CID-103 and notes ongoing disputes and legal proceedings related to EVOMELA and CNCT-19, suggesting a portfolio in transition toward pipeline assets."

Pipeline update • Regulatory • Immunology • Oncology