Refractory Peripheral T-cell Research Articles

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

A Phase II Trial of Brentuximab Vedotin (BV) and Lenalidomide (Len) in Relapsed and Refractory (r/r) Cutaneous (CTCL) and Peripheral (PTCL) T-Cell Lymphomas; Preliminary Results

A Phase II Trial of Brentuximab Vedotin (BV) and Lenalidomide (Len) in Relapsed and Refractory (r/r) Cutaneous (CTCL) and Peripheral (PTCL) T-Cell Lymphomas; Preliminary Results

Potentials of brentuximab vedotin in the treatment of relapse/refractory cutaneous T-cell lymphomas: literature review and authors’ observation

Primary cutaneous T-cell lymphomas encompass a heterogeneous group of T-cell lymphoproliferative disorders developing primarily in the skin and characterized by a number of specific diagnostic, clinical, and therapeutic features. Mycosis fungoides accounts for more than half of all cutaneous lymphoma cases, while CD30+ lymphoproliferative diseases of the skin (primary cutaneous anaplastic large-cell lymphoma and lymphomatoid papulosis) constitute one-fourth of them and the remaining cases are rare tumour types, including primary cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified.Activation antigen СD30 is a cell membrane glycoprotein of the tumour necrosis factor family. More than 75 % of primary cutaneous CD30-positive lymphoma cells express CD30; it may be detected in other diseases as well, but to a lesser extent.Most patients with cutaneous CD30+ lymphoproliferative diseases have indolent disease and a favourable prognosis; resistant disease is observed in approximately 30 % of sufferers, and fatal outcomes occur in 8 % of cases [1].Systemic immunomodulatory therapy or chemotherapy is often used in advanced disease. Monoclonal antibodies were recently introduced into clinical practice for the treatment of cutaneous lymphomas. One of these agents is brentuximab vedotin, a CD30-monoclonal antibody conjugated to monomethyl auristatin E.We present two case reports: one of frequently recurring lymphomatoid papulosis and the other of refractory primary cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified. Targeted therapy with brentuximab vedotin, either alone or in combination with chemotherapy, resulted in a sustained, long-lasting remission in both cases.

An objective based model of published treatment options for relapsed or refractory (R/R) peripheral t-cell lymphoma (PTCL): An evidence-based decision-making approach.

e19048 Background: PTCL are rare diseases with a poor prognosis. Front line therapy achieves CR in 30% to 60% and OS of 25%. Patients with R/R disease have an even worse prognosis. There is no consensus on the management of R/R disease because evidence supporting most treatment approaches is modest. Many approaches are often not supported by literature, and categorizations regarding efficacy and toxicity without attention to details are ignored. Treatments that have achieved regulatory approval with stringent independent assessment of pathology and response are viewed as less established, or equivalent to smaller published experiences. In the effort to take a critical and comprehensive evidence-based approach to available standards in R/R PTCL we developed an objective scoring system for all types of studies published in the literature (eg randomized phase 3, case match control, phase 2, phase 1, case reports and small series) to aid decision-making based on an assessment of all the available data. Methods: An extensive review on PubMed of clinical trials published in literature for R/R PTCL was performed. A rigorous scoring system based on a survey from 100 authorities in the field to quantitate scientific impact of each study based was developed. These include: type of study (randomized phase 3, case match control analysis, phase 2 weighted based on number of PTCL patients [ > 100 vs < 100 patients], phase 1 with > 5 or < 5 PTCL patients enrolled, and retrospective); weighting for use of central pathology or response review; weighting for detailed study metrics (ORR, CR, DoR, PFS). The scoring system included a penalty for omission detail. The proposed scoring system was evaluated by a panel of experts. The scoring system was modified based on recommendations made by 2 or more panel members. Results: We identified 58 publications between 2004 and 2018. The scoring system spanned from 0 to 9. Only 12 of the 58 studies had a score above 5; 15 of 58 had a score between 1 - 5; remaining publications scored 0 - 1. Conclusions: Our analysis suggests practice patterns are based on studies with low priority scores, and underweight robust clinical experiences. This analysis aims to produce an evidenced based approach for R/R PTCL.

The Novel HDAC Inhibitor Chidamide Synergizes with Rituximab to Inhibit DLBCL Tumor Growth in Vitro and In Vivo By up-Regulating CD20 Expression

Background: Histone deacetylases (HDACs) are crucial proteins for supporting tumorigenesis. HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes by removing acetyl groups from histones. HDAC inhibitors are considered as promising anti-cancer drugs, particularly in combination with other standard treatment regimens. Chidamide is the world first oral HDAC inhibitor which selectively inhibits class I HDAC1, HDAC2, and HDAC3 as well as class IIb HDAC10. Chidamide has been approved by China FDA in 2015 for the treatment of relapsed or refractory peripheral T-cell lymphoma.Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of B-cell lymphoma. Treatment with R-CHOP i.e. Rituximab (the anti-CD20 monoclonal antibody) plus CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone) has significantly improved clinical outcome for DLBCL patients. However, treatment-induced deacetylation of CD20 gene and consequently down-regulation of CD20 protein expression causes an acquired resistance to further treatment with R-CHOP.We hypothesize that inhibition of HDACs by Chidamide could overcome Rituximab-mediated down-regulation of CD20 and facilitate Rituximab-induced DLBCL tumor growth inhibition. The aim of this study is to determine the synergistic effect of Chidamide and Rituximab in the treatment of DLBCL in vitro and in vivo.Methods: The levels of CD20 (MS4A1) mRNA expression and clinical outcomes in patients with DLBCL treated either with R-CHOP or CHOP were obtained from the Gene Expression Omnibus (GEO) repository (NCBI GSE 10846). The association of CD20 expression with overall survival (OS) was analyzed by Cox regression analysis and the cut-off point was calculated by the X-tile software. CD20 protein surface expression and Rituximab-induced cell death were analyzed by flow cytometry. The IC50s of Chidamide and the synergisms with Rituximab (10 µg/ml) on five DLBCB cell lines (OCI-LY3, OCI-LY7, Su-DHL6, Su-DHL8, and Su-DLH10) were determined by MTT test after cells were treated with a range of concentrations of Chidamide with or without Rituximab for 24 hours. The synergism was calculated using ComboSyn software to obtain the combination index (CI). For in vivo experiments, the human DLBCL cell line OCI-LY7 were injected to 6 weeks BALB/C nude mice to develop xenograft DLBCL mice models. After tumors were palpable, mice were divided into four groups and injected with NaCl (control), Rituximab, Chidamide and Rituximab plus Chidamide daily for three weeks. The tumor volumes were monitored frequently during the treatment.Results: In R-CHOP treated cohort (n=233), higher expression of CD20 expression (n=137) is significantly associated with superior clinical outcomes compared with lower CD20 expression (n=96) with P=0.0038, HR=0.4753, 95% CI=0.274-0.779. However, the levels of CD20 have no effect on clinical outcome in DLBCL patients treated with CHOP (n=183). The levels of CD20 protein surface expression on five DLBCL cell lines were significantly and positively correlated with the sensitivities of cells to Rituximab-induced cell death (P=0.0018, R=0.88). HDAC1, HDCA2 and HDCA3 proteins were detected in these DLBCL cell lines. Treatment with Rituximab significantly reduced CD20 surface expression but treatment with Chidamide significantly increased CD20 surface expression in DLBCL cells. The CI numbers for combined treatment with Chidamide and Rituximab were either <0.01 (very strong synergism) or <0.3 (strong synergism), indicating that Chidamide significantly synergized Rituximab-induced cell death. For in vivo assay, treatment with either Rituximab or Chidamide alone slightly but not significantly reduced tumor volume. Combination with Chidamide and Rituximab significantly inhibited tumor growth in DLBCL xenograft mice (P<0.0001). Mice with combined treatment showed significantly prolonged survival compared with other groups.Conclusions: our data demonstrate for the first time that inhibition of HDACs by Chidamide significantly synergized Rituximab-induced tumor growth inhibition in vitro and in vivo. We propose that CD20 surface expression should be used clinically to evaluate treatment response in patients with DLBCL. Chidamide is a promising sensitizer for the treatment of DLBCL with R-CHOP. DisclosuresNo relevant conflicts of interest to declare.

Copanlisib: First Global Approval.

Bayer are developing copanlisib (Aliqopa™)-a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor-as a treatment for various haematological and solid malignancies. The US FDA has granted copanlisib accelerated approval for the treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies based on the results of a phase II trial. Phase III trials are underway evaluating copanlisib as treatment for relapsed/refractory diffuse large B-cell lymphoma and in combination with rituximab or rituximab-based chemotherapy or standard immunochemotherapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma. Phase I/II studies are underway in relapsed or refractory peripheral T-cell or NK/T-cell lymphoma, advanced cholangiocarcinoma, hormone receptor-positive HER2-negative stage I-IV breast cancer, HER2-positive breast cancer and recurrent and/or metastatic head and neck squamous cell carcinomas harbouring a PI3KCA mutation/amplification and/or a PTEN loss. This article summarizes the milestones in the development of copanlisib leading to this first approval for relapsed follicular lymphoma.

Pilot trial of chidamide, an oral histone deacetylase (HDAC) inhibitor, in combination with exemestane in hormone receptor-positive advanced breast cancer.

e12543 Background: Chidamide (CHI) is a novel benzamide type of subtype-selective histone deacetylase inhibitor approved in China for refractory and relapsed peripheral T-cell lymphoma with a dosage of 30 mg PO twice a week. A randomized, double blind and placebo-controlled phase 3 clinical trial of CHI plus exemestane (EXE) is currently ongoing in patients (pts) with hormone receptor-positive (HR+) advanced breast cancer (ABC). This abstract reports the results from the pilot study preceded the phase 3 trial. Methods: Eligible pts were postmenopausal women recurrent or progressed to at least one endocrine therapy. In the run-in period for pharmacokinetic (PK) analysis, pts received EXE 25 mg on day (D) 1 and CHI 30 mg on D 2. From D 5 pts started combination treatment having EXE 25 mg daily and CHI 30 mg twice a week until progression of disease (PD) or intolerable toxicities. A treatment cycle was defined as 28 days. Safety, PK parameters and preliminary efficacy were assessed. Results: 20 pts with HR+ and HER-2 negative were enrolled between Jul and Dec, 2015. Median duration of treatment was 5 cycles (range 0-16), with 4 pts still on treatment. 3 pts discontinued due to adverse events (AE). Drug-related AEs ≥ grade 3 in 2 or more pts were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). Similar plasma exposure of EXE was observed in the absence and presence of CHI ( 73 ± 27 vs. 80 ± 29 ng·hr/mL). A potential increased plasma exposure of CHI was noted in the presence of EXE compared with CHI alone ( 2232 ± 973 vs 1787 ± 946 ng·hr/mL), apparently related to the inter-patient variations in CHI plasma concentrations. Best response in 18 pts was assessed by RECIST, including 3 pts with partial response, 12 pts with stable disease and 3 pts with PD. Median progression free survival was 7.6 months. Conclusions: The combination of CHI and EXE was generally well tolerated. Most AEs were related to the CHI single-agent treatment that are generally manageable. Encouraging antitumor activity was observed. The overall results from this pilot trial enabled the next-stage clinical development of this combination regimen in HR+ ABC pts. Clinical trial information: NCT02482753.

Brentuximab Vedotin in refractory or relapsed Peripheral T-cell Lymphoma: The French name patient program experience in 66 patients

Brentuximab Vedotin in refractory or relapsed Peripheral T-cell Lymphoma: The French name patient program experience in 66 patients

Dexabeam versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T-cell lymphoma: A retrospective evaluation of parallel patient cohorts of one center.

8548 Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.