The combination of chidamide with the CHOEP regimen in previously untreated patients with peripheral T-cell lymphoma: a prospective, multicenter, single arm, phase 1b/2 study

Objective:To assess the efficacy and safety of the novel histone deacetylase inhibitor,chidamide,in combination with cyclophosphamide,doxorubicin,vincristine,etoposide,and prednisone(Chi-CHOEP)for untreated peripheral T-cell lymphoma(PTCL).Methods:A prospective,multicenter,single arm,phase 1 b/2 study was conducted.A total of 128 patients with untreated PTCL(18–70 years of age)were enrolled between March 2016 and November 2019,and treated with up to 6 cycles with the Chi-CHOEP regimen.In the phase 1 b study,3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximumtolerated dose and recommended phase 2 dose(RP2 D).The primary endpoint of the phase 2 study was 2-year progression-free survival(PFS).Results:Fifteen patients were enrolled in the phase 1 b study and the RP2 D for chidamide was determined to be 20 mg,twice a week.A total of 113 patients were treated at the RP2 D in the phase 2 study,and the overall response rate was 60.2%,with a complete response rate of 40.7%.At a median follow-up of 36 months,the median PFS was 10.7 months,with 1-,2-,and 3-year PFS rates of 49.9%,38.0%,and 32.8%,respectively.The Chi-CHOEP regimen was well-tolerated,with grade 3/4 neutropenia occurring in approximately two-thirds of the patients.No unexpected adverse events(AEs)were reported and the observed AEs were manageable.Conclusions:This large cohort phase 1 b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients.

Noncirrhotic portal hypertension due to peripheral T-cell lymphoma,not otherwise specified:A case report

BACKGROUND Peripheral T-cell lymphoma(PTCL),an aggressive and rare disease that belongs to a heterogeneous group of mature T-cell lymphomas,develops rapidly and has a poor prognosis.Early detection and treatment are essential to improve patient cure and survival rates.Here,we report a rare case of PTCL with clinical presentation of noncirrhotic portal hypertension,which provides a basis for early vigilance of lymphomas in the future.CASE SUMMARY A 65-year-old Chinese woman was admitted to our hospital because of abdominal distension for 3 months and pitting oedema of both lower limbs for 2 months.Physical examinations and associated auxiliary examinations showed the presence of hepatosplenomegaly,and her hepatic venous pressure gradient was 10 mmHg.Immunohistochemical analysis of the liver biopsy confirmed the diagnosis of PTCL.The patient underwent combination therapy with dexamethasone,VP-16,and chidamide.Unfortunately,after 41 days of chemotherapy,the patient died of multiple organ failure.CONCLUSION PCTL accompanied by noncirrhotic portal hypertension is rarely reported.This case report discusses the diagnosis of a patient according to the literature.

Secondary peripheral T-cell lymphoma and acute myeloid leukemia after Burkitt lymphoma treatment:A case report

BACKGROUND Multiple primary cancer refers to more than one synchronous or sequential cancer in the same individual.Multiple primary cancer always presents as solid cancer or acute myeloid leukemia(AML)secondary to lymphoma.Here,we report a rare case of secondary peripheral T-cell lymphoma and AML after Burkitt lymphoma treatment.CASE SUMMARY A 54-year-old female patient was admitted to our hospital complaining of edema on her left lower limb.Physical examination revealed multiple superficial lymphadenectasis on her neck and pelvis.Color ultrasonography examination showed multiple uterine fibroids and a solid mass at the lower left side of the abdomen.Pathological biopsy revealed Burkitt lymphoma.After three hyper-CVAD(A+B)regimens,she achieved complete remission.Two years later,lymphadenectasis reoccurred.A relevant biopsy confirmed the diagnosis of peripheral T-cell lymphoma,which was accompanied by gastrointestinal invasion and hemocytopenia.Meanwhile,bone marrow examination revealed AML.On the second day of scheduled treatment,she developed gastrointestinal bleeding,peptic ulcers,and hemorrhagic shock and was critically ill.She was then discharged from the hospital due to financial concerns.CONCLUSION This is the first report of secondary peripheral T-cell lymphoma and AML after Burkitt lymphoma treatment with heterochronous and synchronal multiple primary cancers.

Acute liver failure as a rare initial manifestation of peripheral T-cell lymphoma

Acute liver failure(ALF) is an uncommon disease in the United States,affecting more than 2 000 people each year.Of all the various causes,malignant infiltration is one of the least well known and carries with it a high mortality.We describe a case of ALF as the presenting manifestation of peripheral T-cell lymphoma in an elderly woman.By reporting this case,we hope to increase early recognition of this disease process in order to potentially improve treatment outcomes.

Primary sino-orbital peripheral T-cell lymphoma presenting as unilateral periorbital swelling: a case report

Dear Editor,My name is Ahmad Al Omari and I am currently working as an otorhinolaryngology assistant professor at Jordan University of Science and Technology. I am writing this letter to present a case of a primary sino-orbital peripheral T-cell

Primary hepatic peripheral T-cell lymphoma associated with Epstein-Barr viral infection

Primary hepatic peripheral T-cell lymphoma(H-PTCL) is one of the rarest forms of non-Hodgkin lymphoma. We report a patient who presented with worsening jaundice, abdominal pain, and vomiting. Laboratory values were significant for elevated total bilirubin, alkaline phosphatase, and liver aminotransferases. Following a liver biopsy, histopathology revealed several large dense clusters of atypical T-lymphocytes which were CD2+, CD3+, CD5+, CD7-, CD4+, CD8-, CD56-, CD57-, CD30+ by immunohistochemistry. The proliferation index was approximately 70% by labeling for ki67/mib1. The above histological profile was consistent with peripheral T-cell lymphoma of the liver. Epstein-Barr viral serology indicated a remote infection, a likely risk factor for PTCL. Bone marrow biopsy was negative for malignancy, further supporting hepatic origin.

Peripheral T-Cell Lymphoma of Cervical Spine

Peripheral T-cell lymphoma is a rather uncommon non-Hodgkin’s lymphoma with the initial manifestation of spinal cord compression. Herein, we reported a 74-year-old woman with sustained neck pain radiating into the right shoulder and arm and weakness of the right upper extremity. A mass that had invaded the C5 and C6 vertebral bodies, causing a kyphotic curvature and compressing the spinal cord, was discovered with magnetic resonance imaging. The patient then underwent anterior corpectomy at C5 and C6, and reconstruction with a titanic rod and bone cement. The pathology confirmed a diagnosis of peripheral T-cell lymphoma after serial H & E and immunohistochemical staining. She recovered well from her profound neurological deficit. Both chemotherapy and radiotherapy were used postoperatively. Surgical intervention is indicated in these cases to decompress the cord, remove the majority of the tumor mass, stabilize the spine and obtain tissue for pathological diagnosis.

Identification of Hub Genes and Key Pathways Associated with Peripheral T-cell Lymphoma

Peripheral T-cell lymphoma(PTCL)is a very aggressive and heterogeneous hematological malignancy and has no effective targeted therapy.The molecular pathogenesis of PTCL remains unknown.In this study,we chose the gene expression profile of GSE6338 from the Gene Expression Omnibus(GEO)database to identify hub genes and key pathways and explore possible molecular pathogenesis of PTCL by bioinformatic analysis.Diferentially expressed gencs(DEGs)between PTCL and normal T cells were selected using GEO2R tool.Gene ontology(GO)analysis and Kyoto Encyclopedia of Gene and Genome(KEGG)pathway analysis were performed using Database for Annotation,Visualization and Integrated Discovery(DAVID).Moreover,the Search Tool for the Retrieval of Interacting Genes(STRING)and Molecular Complex Detection(MCODE)were utilized to construct protein-protein interaction(PPI)network and perform module analysis of these DEGs.A total of 518 DEGs were identifed,including 413 down-regulated and 105 up-regulated gencs.The down-regulated genes were enriched in osteoclast differentiation,Chagas disease and mitogen-activated protein kinase(MAPK)signaling pathway.The up-regulated genes were mainly associated with extracellular matrix(ECM)-receptor interaction,focal adhesion and pertussis.F our important modules were detected from the PPI network by using MCODE software.Fifteen hub genes with a high degree of connectivity were selected.Our study identifed DEGs,hub genes and pathways associated with PTCL by bioinformatic analysis.Results provide a basis for further study on the pathogenesis of PTCL.

Treatment of Peripheral T-cell Lymphoma by Chidamide and Literature Analysis

[Objectives] To analyze the dosage,curative effect,and adverse effect of Chidamide in treating peripheral T-cell lymphoma( PTCL). [Methods]A case of treating peripheral T-cell lymphoma by Chidamide was reported,including the treatment process,dosage,curative effect,and adverse effect. Literature review was made and searched in Wanfang Digital Database,China National Knowledge Infrastructure( CNKI),and Pubmed database,using the key word chidamide in Chinese and English separately. Disease and case number of patients,Chidamide observation indicator,curative effect,and adverse effects were recorded in detail. The search was carried out as of September,2016. [Results] It searched 3 articles related to clinical application and 111 cases of patients. [Conclusions] Chidamide has excellent curative effect in treating peripheral T-cell lymphoma and is suitable for clinical application.

Peripheral T-cell Lymphomas： Updates in AIIogeneic Hematopoietic Stem Cell Transplantation

Objective： Peripheral T-cell lymphomas （PTCLs） confer dismal prognosis and no consensus has been established on the role of allogeneic hematopoietic stem cell transplantation （allo-HSCT） due to its rarity and heterogeneity. The purpose was to review key points ofallo-HSCT for PTCLs, including indication, times of transplantation, conditioning regimen, graft versus host disease prophylaxis, and treatment of relapse.Data Sources： A comprehensive search in PubMed and Cochrane up to February 28, 2018, with the keywords ＂Peripheral＂, ＂T＂, ＂Lymphoma＂, and ＂Transplantation＂ was done. Study Selection： Relevant articles including HSCT for PTCLs were carefully reviewed. Results： Promising data have been reported from advances in transplant technology and more and more PTCLs patients with poor prognosis could benefit from allo-HSCT. Conclusion： Allo-HSCT is a useful choice for patients with refractory/relapsed PTCLs or high-risk new diagnosed PTCLs.

A multicenter retrospective study on the real-world outcomes of autologous vs. allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphoma in China

Background:There were few studies on real-world data about autologous hematopoietic stem cell transplantation(auto-HSCT)or allogeneic HSCT(allo-HSCT)in peripheral T-cell lymphoma(PTCL).This study aimed to investigate the clinical outcomes of patients who received auto-HSCT or allo-HSCT in China.Methods:From July 2007 to June 2017,a total of 128 patients who received auto-HSCT(n=72)or allo-HSCT(n=56)at eight medical centers across China were included in this study.We retrospectively collected their demographic and clinical data and compared the clinical outcomes between groups.Results:Patients receiving allo-HSCT were more likely to be diagnosed with stage III or IV disease(95%vs.82%,P=0.027),bone marrow involvement(42%vs.15%,P=0.001),chemotherapy-resistant disease(41%vs.8%,P=0.001),and progression disease(32%vs.4%,P<0.001)at transplantation than those receiving auto-HSCT.With a median follow-up of 30(2–143)months,3-year overall survival(OS)and progression-free survival(PFS)in the auto-HSCT group were 70%(48/63)and 59%(42/63),respectively.Three-year OS and PFS for allo-HSCT recipients were 46%(27/54)and 44%(29/54),respectively.There was no difference in relapse rate(34%[17/63]in auto-HSCT vs.29%[15/54]in allo-HSCT,P=0.840).Three-year non-relapse mortality rate in auto-HSCT recipients was 6%(4/63)compared with 27%(14/54)for allo-HSCT recipients(P=0.004).Subanalyses showed that patients with lower prognostic index scores for PTCL(PIT)who received auto-HSCT in an upfront setting had a better outcome than patients with higher PIT scores(3-year OS:85%vs.40%,P=0.003).Patients with complete remission(CR)undergoing auto-HSCT had better survival(3-year OS:88%vs.48%in allo-HSCT,P=0.008).For patients beyond CR,the outcome of patients who received allo-HSCT was similar to that in the atuo-HSCT group(3-year OS:51%vs.46%,P=0.300).Conclusions:Our study provided real-world data about auto-HSCT and allo-HSCT in China.Auto-HSCT seemed to be associated with better survival for patients in good condition(lower PIT score and/or better disease control).For patients possessing unfavorable characteristics,the survival of patients receiving allo-HSCT group was similar to that in the auto-HSCT group.

Absence of enhancement in a lesion does not preclude primary central nervous system T-cell lymphoma:A case report

BACKGROUND Primary central nervous system lymphoma(PCNSL)is a non-Hodgkin lymphoma that originates in the central nervous system(CNS)and is exclusively limited to the CNS.Although most PCNSLs are diffuse large B-cell lymphomas,primary CNS T-cell lymphomas(PCNSTLs)are rare.PCNSTLs typically demonstrate some degree of enhancement on contrast-enhanced magnetic resonance imaging(MRI).To the best of our knowledge,non-enhancing PCNSTL has not been reported previously.CASE SUMMARY A 69-year-old male presented to the neurology department with complaints of mild cognitive impairment and gradual onset of left lower leg weakness over a span of two weeks.Initial MRI showed asymmetric T2-hyperintense lesions within the brain.No enhancement was observed on the contrast-enhanced T1 image.The initial diagnosis was neuro-Behçet’s disease.Despite high-dose steroid therapy,no alterations in the lesions were identified on initial MRI.The patient’s symptoms deteriorated further.An MRI performed one month after the initial scan revealed an increased lesion extent.Subsequently,brain biopsy confirmed the diagnosis of PCNSTL.The patient underwent definitive combined chemoradiotherapy.However,the patient developed bacteremia and died of septic shock approximately three months after diagnosis.CONCLUSION The absence of enhancement in the lesion did not rule out PCNSTL.A biopsy approach is advisable for pathological confirmation.

Plasmacytosis mimicking multiple myeloma in angioimmunoblastic T-cell lymphoma:A case report and review of literature

BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL)is a common subtype of peripheral T-cell lymphoma.Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia.Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis.These tumors mimic plasma cell myelomas,hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.CASE SUMMARY A 78-year-old woman experienced poor appetite,weight loss of 5 kg,fatigue 2 months before presentation,and shortness of breath 2 d before presentation,but no fever or night sweats.Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions,approximately>2 cm in size,with rubbery consistency and no tenderness.Blood tests revealed anemia and thrombocytopenia,lactate dehydrogenase level of 153 U/L,total protein level of 10.9 g/dL,albumin to globulin ratio of 0.2,and immunoglobulin G level more than the upper limit of 3000 mg/dL.The free kappa and lambda light chain concentrations were 451 and 614 mg/L,respectively.A pathological examination confirmed the diagnosis of AITL.The initial treatment was the cyclophosphamide,epirubicin,vincristine,and prednisolone regimen.Following this treatment,pleural effusion was controlled,and the patient was discharged in a stable condition and followed up in our outpatient department.CONCLUSION This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia.A precise diagnosis of AITL requires a comprehensive evaluation,involving clinical,immunophenotypic,and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.

Monomorphic epitheliotropic intestinal T-cell lymphoma with bone marrow involved: A case report

BACKGROUND Monomorphic epithelial intestinal T-cell lymphoma(MEITL)is a rare type of peripheral T-cell lymphoma.The clinical manifestations are diarrhea,abdominal pain,perforation and an abdominal mass.CASE SUMMARY We present a 52-year-old female patient who was diagnosed with MEITL.Further disease progression was observed after multiline chemotherapy.Eventually,the patient died of a severe infection.CONCLUSION MEITL is a rare intestinal primary T-cell lymphoma with aggressive behavior,a high risk of severe life-threatening complications,and a poor prognosis.

The peripheral T-cell lymphoma:can we pivot from the chemotherapy-predicated paradigm?

Peripheral T-cell lymphomas(PTCL)are uncommon and aggressive diseases that are difficult to study.Combination chemotherapy such as cyclophosphamide,doxorubicin,vincristine,and prednisone has been the mainstay of treatment for almost 30 years,but outcomes remain poor.The development of new targeted therapies is changing the landscape of how we treat patients with these difficult diseases.For instance,the addition of brentuximab vedotin to combination chemotherapy enhanced the outcomes in patients with CD30-positive anaplastic large cell lymphomas,but there is still a need for better therapies in the other numerous subtypes.Here we discuss the data for the existing treatment paradigm of PTCL as well as the merits of shifting toward a chemotherapy-free approach.

Therapeutic Efficacy of L-asparaginase in the Treatment of Refractory Midfacial Peripheral T-Cell Non-Hodgkin’s Lymphoma

Objective: To improve the efficacy of refractory midfacial peripheral T-cell non-Hodgkin’s lymphoma (MPTC-NHL) with L-asparaginase (L-ASP) based salvage chemotherapy. Methods: 21 patients with refractory MPTC-NHL were analyzed. 11patients (L-ASP group) received L-asparaginase based salvage chemotherapy consisting of L-asparaginase, vincristine and dexame-thosone. 10 patients (control group) received salvage combination chemotherapy without L-asparaginase. Results: Complete remission rates were 45.6% for L-ASP group and 0.0% for control group (p<0.05). Overall response rates (CR+PR) were 63.6% for L-ASP group and 10.0% for control group, respectively (p<0.05). 2-year survival rates were 45.5% for L-ASP group and 0.0% for control group (p<0.05). The major adverse effects of L-ASP were leukopenia, elevation of serum bilirubin and hyperglycemia. Conclusion: The preliminary clinical study shows that the L-ASP based salvage chemotherapy may improve the response rate and 2-year survival rate of the patients with refractory MPTC-NHL. It is necessary to continue the study further.

Role of lenalidomide in the treatment of peripheral T-cell non-Hodgkin lymphomas

T-cell lymphomas(TCLs)represent a group of lymphoid neoplasms characterized by an aggressive clinical course,even after an anthracycline-containing regimen.Novel agents for patients with relapsed/refractory TCL are urgently needed.Lenalidomide is an oral drug with immunomodulatory,antiangiogenic and direct antineoplastic effects.These peculiar mechanisms of action make TCL an attractive target for lenalidomide.We have identified five clinical trials in which lenalidomide monotherapy was investigated to treat TCL,including cutaneous TCL(CTCL)and adult T-cell lymphoma/leukemia(ATLL).In the ATLL-002 study,the overall response rate(ORR)was 42%and median progression-free survival(PFS)and overall survival were 3.8 mo and 20.3 mo,respectively.In a phase II trial for CTCL,ORR was 28%and median PFS and overall survival were 8 mo and 43 mo,respectively.For nodal peripheral TCL,ORR was between 10%and 43%in three clinical trials,with a median PFS of about 4 mo,even if some patients had a durable response.Overall toxicity is manageable and grade 3-4 events are mainly hematological and reversible.Combination strategies did not improve PFS.In conclusion,lenalidomide could represent a suitable treatment option for relapsed/refractory TCL,especially for neoplasms with a T-follicular helper origin,such as angioimmunoblastic TCL.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Transcriptome sequencing analysis of ursolic acid-mediated proliferation suppression on cutaneous T-cell lymphoma cells

Background:Ursolic acid is a triterpenoid compound found in natural plants that exhibits antiproliferative effects in various cancer cells.Our study is the first to demonstrate the strong inhibitory effects of ursolic acid on the proliferation of cutaneous T-cell lymphoma(CTCL)cells.We aimed to further investigate the underlying mechanism of the proliferation inhibition induced by ursolic acid in CTCL cells using transcriptome sequencing.Methods:Cell counting kit-8 assays were used to observe the effects of six traditional medicine monomers on the proliferation of CTCL cells.Transcriptome sequencing was used to identify differentially expressed genes after ursolic acid treatment.Bioinformatics analysis was performed to determine the potential mechanism.Real-time quantitative PCR and western blotting analyses were performed to confirm the sequencing results and verify the possible mechanisms of ursolic acid-mediated proliferation inhibition in CTCL cells.Results:Ursolic acid exhibited the strongest inhibitory effect on the proliferation of CTCL cells among the six traditional medicine monomers.Transcriptome sequencing analysis showed that 2,466 genes were significantly altered.Combined with Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction network analysis,the interaction of various pathways and signaling molecules,such as tumor necrosis factor-α,NLR family pyrin domain containing 1,c-Jun N-terminal kinase,and melanoma differentiation-associated gene 5,accounted for the anti-tumor effects of ursolic acid in CTCL cells.Conclusion:Ursolic acid significantly inhibited the proliferation of CTCL cells,and our study laid a theoretical foundation for the future treatment of CTCL using ursolic acid.

Angioimmunoblastic T-cell lymphoma induced hemophagocytic lymphohistiocytosis and disseminated intravascular coagulopathy: A case report

BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL) is a subtype of peripheral T-cell lymphoma, with heterogenous clinical manifestations and poor prognosis. Here,we report a case of AITL induced hemophagocytic lymphohistiocytosis(HLH)and disseminated intravascular coagulopathy(DIC).CASE SUMMARY An 83-year-old man presented with fever and purpura of both lower limbs for one month. Groin lymph node puncture and flow cytometry indicated a diagnosis of AITL. Bone marrow examination and other laboratory related indexes indicated DIC and HLH. The patient rapidly succumbed to gastrointestinal bleeding and septic shock.CONCLUSION This is the first reported case of AITL induced HLH and DIC. AITL is more aggressive in older adults. In addition to male gender, mediastinal lymphadenopathy, anaemia, and sustained high level of neutrophil-to-lymphocyte ratio may indicate a greater risk of death. Early diagnosis, early detection of severe complications, and prompt and effective treatment are vital.