Subcutaneous panniculitis-like T-cell lymphoma: fever and facial swelling with hemophagocytic syndrome.

We report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) in a young man presenting with fever and facial swelling. He had pancytopenia and hemophagocytic syndrome (HPS) on evaluation. The histopathological examination of skin punch biopsy from the face and chest wall showed SPTCL. Given the associated HPS, he was started on steroid and multidrug chemotherapy following which he had symptomatic improvement.

TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Subcutaneous panniculitic-like T-cell lymphoma localized to a site of peginterferon alfa-2a administration.

T cell dyscrasias that demonstrate a proclivity for the subcutaneous fat include atypical lymphocytic lobular panniculitis, lupus profundus, and primary subcutaneous T cell lymphoma, including subcutaneous panniculitis-like T cell lymphoma (SPTCL). We encountered two patients who developed fever and indurated abdominal erythema at their peginterferon alfa-2a injection sites. Biopsies showed an atypical CD8 positive, granzyme positive, CD5 negative, MXA negative lymphocytic lobular panniculitis, diagnostic of SPTCL. Peginterferon alfa-2a was held in both patients. One patient received chemotherapy with an excellent response, while the other continued to have progressive disease. Peginterferon alfa-2a is known to significantly elevate serum MXA, which may induce high levels of MXA expression at the injection site, creating a microenvironment for the development of lupus profundus, which may eventuate into SPTCL. In summation, a potential risk of peginterferon alfa-2a injections is the development of SPTCL potentially arising in a background of an exogenous interferon triggered lymphocytic panniculitis.

Blockade of isoprenoids biosynthesis by simvastatin induces autophagy-mediated cell death via downstream c-Jun N-terminal kinase activation and cell cycle dysregulation in canine T-cell lymphoma cells.

Statins are inhibitors of the mevalonic acid pathway that mediates cellular metabolism by producing cholesterol and isoprenoids and are widely used in treating hypercholesterolaemia in humans. Lipophilic statins, including simvastatin, induce death in various tumour cells. However, the cytotoxic mechanisms of statins in tumour cells remain largely unexplored. This study aimed to elucidate the cytotoxic mechanisms of simvastatin in canine lymphoma cells. Simvastatin induced cell death via c-Jun N-terminal kinase (JNK) activation and autophagy in canine T-cell lymphoma cell lines Ema and UL-1, but not in B-cell lines. Cell death was mediated by induction of caspase-dependent apoptosis in UL-1 cells, but not in Ema cells. Blockade of autophagy by lysosomal inhibitors attenuated simvastatin-induced JNK activation and cell death. Isoprenoids, including farnesyl pyrophosphate and geranylgeranyl pyrophosphate, attenuated simvastatin-induced autophagy, JNK activation, and cell death. In UL-1 cells, simvastatin treatment resulted in the cell cycle arrest at the G2/M phase, which was altered to G0/1 phase cell cycle arrest by treatment with lysosomal inhibitors. These findings demonstrate that depletion of isoprenoids by simvastatin induces autophagy-mediated cell death via downstream JNK activation and cell cycle dysregulation in canine T-cell lymphoma cells.

Nelarabine: when and how to use in the treatment of T-cell acute lymphoblastic leukemia.

ABSTRACT: T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma (T-ALL/LBL) is a rare hematologic malignancy most commonly affecting adolescent and young adult males. Outcomes are dismal for patients who relapse, thus, improvement in treatment is needed. Nelarabine, a prodrug of the deoxyguanosine analog 9-ß-arabinofuranosylguanine, is uniquely toxic to T lymphoblasts, compared with B lymphoblasts and normal lymphocytes, and has been developed for the treatment of T-ALL/LBL. Based on phase 1 and 2 trials in children and adults, single-agent nelarabine is approved for treatment of patients with relapsed or refractory T-ALL/LBL, with the major adverse effect being central and peripheral neurotoxicity. Since its approval in 2005, nelarabine has been studied in combination with other chemotherapy agents for relapsed disease and is also being studied as a component of initial treatment in pediatric and adult patients. Here, we review current data on nelarabine and present our approach to the use of nelarabine in the treatment of patients with T-ALL/LBL.

The combination of brentuximab vedotin and chidamide synergistically suppresses the proliferation of T-cell lymphoma cells through the enhancement of apoptosis.

PURPOSE: Peripheral T-cell lymphoma (PTCL) is an aggressive disease with a poor prognosis. Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody linked to a microtubule-disrupting agent, has been approved for the treatment of PTCL. We evaluated a new effective combination partner of BV using non-clinical approaches that could potentially identify agents capable of improving survival times for patients with PTCL. METHODS: A high-throughput screening test was used to select the most synergistic partner of BV from 14 candidate drugs that were under development or available in clinical practice for PTCL. HH cells, originating from an aggressive cutaneous T-cell lymphoma, were used as an experimental model of PTCL. Apoptotic effects of the synergistic partner of BV were further investigated in vitro and in vivo using HH-cell xenograft mice. RESULTS: Chidamide (tucidinostat), a novel histone deacetylase inhibitor, was found to have the greatest synergistic effect with BV on HH cells. The combined effects of chidamide and BV were demonstrated in a study of HH-cell xenograft mice; mean tumor size following combined treatment was 22% of that observed in the control group, compared with 71% and 58% following chidamide and BV monotherapy, respectively. Further investigations in vitro and in vivo revealed that the levels of an anti-apoptotic protein, Bcl-2, and a rate-limiting factor of DNA replication, CDC45, were reduced in HH cells treated with chidamide combined with BV compared with the control group. CONCLUSION: The use of chidamide in conjunction with BV may positively affect and enhance T-cellular apoptotic pathways without offsetting each other.

Selinexor With Anti-PD-1 Antibody as a Potentially Effective Regimen for Patients With Natural Killer/T-Cell Lymphoma Failing Prior L-Asparaginase and PD-1 Blockade.

BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a rare and heterogeneous tumor type of non-Hodgkin's lymphoma (NHL) with a poor clinical outcome. There is no standardized salvage treatment failing l-asparaginase-based regimens. Here we report our retrospective results of the combined use of selinexor and PD-1 blockade (tislelizumab) in 5 patients with NKTCL who had exhausted almost all available treatments. PATIENTS AND METHODS: A total of 5 patients with relapsed/refractory(R/R) NK/T-cell lymphomas failing prior l-asparaginase and anti-PD-1 antibody were retrospectively collected. They were treated with at least one cycle of XPO1 inhibitor plus the same anti-PD-1 antibody. Anti-PD-1 antibody (Tislelizumab) was administrated at 200 mg on day 1 every 3 weeks and selinexor doses and schedules ranged from 40 mg weekly for 2 weeks per 21-day cycle to 60 mg weekly per cycle. RESULTS: Five patients with relapsed NKTCL with extensive organ involvement including 4 central nervous system (CNS) infiltration patients were included. Four patients achieved objective responses including 3 complete responses (CR) and 1 partial response (PR). After a median follow-up time of 14.5 (range, 5-22) months, 1 patient was still in remission with CR, and the other 4 patients discontinued due to disease progression with a median progression-free survival (PFS) of 6 months and median overall survival (OS) of 12 months. Four patients with CNS involvement achieved a median OS of 8 months. Our data suggest that selinexor in combination with an anti-PD-1 antibody is a promising small molecule and immunotherapy combination regimen for patients with relapsed or refractory NKTCL.

Safety and efficacy of tenalisib in combination with romidepsin in patients with relapsed/refractory T-cell lymphoma: results from a phase I/II open-label multicenter study.

Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).

Gemcitabine and liposomal doxorubicin (GemDox) for the treatment of relapsed and refractory T-cell lymphomas.

Aggressive T-cell lymphomas (TCL) account for 10-15% of non-Hodgkin lymphomas (NHL) with weaker responses and shorter durations to chemotherapy than other types of NHL. Current therapies for patients with relapsed/refractory Cutaneous T-cell lymphoma (CTCL) have limited efficacy, and short durations of response. Gemcitabine and liposomal doxorubicin have shown single-agent activity in TCL and combined have activity in relapsed B-cell lymphomas. We evaluated outcomes of 18 patients with relapsed/refractory aggressive TCL (13 CTCL, 5 PTCL) treated with a gemcitabine plus liposomal doxorubicin (GemDox) combination and evaluated outcomes with a specific focus on CTCL patients. Significant responses were observed in CTCL patients with an overall response rate of over 80%. In all patients, objective responses were seen in eight patients (50%), with six patients (5 CTCL) able to proceed to allogeneic stem cell transplant. Given limited treatment options for r/r CTCL, GemDox should be considered a therapeutic option in relapsed/refractory CTCL.

Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas.

ABSTRACT: Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.

Hepatosplenic T-cell lymphoma and inflammatory bowel disease

A 48-year-old man with a diagnosis of ulcerative colitis 18 years ago, under immunosuppressive treatment with azathioprine in the last 6 years due to corticosteroid dependence, was admitted to the Emergency Department due to fever of one week’s evolution. Blood tests showed thrombocytopenia, CRP 96.9mg/L, ferritin 3021ng/mL and hypertriglyceridemia. Blood and urine cultures were negative. Viral serologies (hepatitis B and C, HIV, parvovirus, CMV, HSV), atypical bacteria (Borrelia, Chlamydia, Coxiella) and screening for latent tuberculosis were also negative. Thoracoabdominal CT scan only showed splenomegaly. The bone marrow aspirate revealed immature lymphoid cells and a hemophagocyte figure, fulfilling the criteria for hemophagocytic syndrome, starting corticosteroid therapy at a dose of 1mg/Kg. Subsequently, the existence of an intrasinusoidal CD3 + CD5- lymphoid infiltrate and a FISH study with isochromosome 7q was reported, a characteristic pattern of hepatosplenic T-cell lymphoma (HSTCL). The study was completed with liver biopsy appreciating a 70% infiltration of T lymphocytes (50% gamma-delta) therefore the diagnosis was confirmed. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide) was started with the aim of considering hematopoietic stem cell transplantation. Unfortunately, the patient died 6 months later. (AU)

Clinical and histological study of follicular helper T-cell lymphomas with indolent evolution.

INTRODUCTION: Follicular helper T-cell lymphomas (TFHL) have an aggressive course with a poor outcome. European and US guidelines recommend anthracycline-based chemotherapy as a first-line treatment, but the 5-year overall survival rate is still approximately 30%. We describe here the features of a cohort of TFHL patients who experienced prolonged survival despite the absence of specific treatment or the initiation of steroid-based therapy. PATIENTS AND METHODS: In our study, we describe 15 adult patients who suffered from TFHL and had not received intensive chemotherapy at diagnosis for any reason. Biopsies of these cases were centrally reviewed, and the mutational pattern was determined using next-generation sequencing. RESULTS: These 15 patients had the classic clinical, biological and pathological features of TFHL, angioimmunoblastic-type. TET2 mutations were found in 83% of patients; RHOA G17V, IDH2 R172 and DNMT3A mutations were found in 67%, 42% and 33% of the patients, respectively. Among the 15 patients, 8 did not receive any treatment, and 7 received steroid-based treatment. Ten patients had progression (5 in each group). Four patients died (3 of them from the progression of their lymphoma). The median follow-up in our cohort was 53 months. The 5-year OS was 66%, 100% for untreated patients and 29% for the others. In those 2 groups, the median time to treatment initiation was 22 months from diagnosis. CONCLUSION: We described a series of 15 well-characterized TFHL patients with an indolent outcome, suggesting that a watch-and-wait approach can be proposed in selected patients. Identifying factors predicting such evolution is warranted.

Case report: Successful treatment of Chidamide in a refractory/recurrent SPTCL with ARID1A mutation on the basis of CHOP plus auto-HSCT.

RATIONALE: Subcutaneous panniculitis like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma that belongs to peripheral T cell lymphomas, of which the overall prognosis is poor. Chidamide, a deacetylase inhibitor, has been approved for the treatment of peripheral T cell lymphomas. However, due to the rare occurrence of SPTCL, it is currently unknown whether Chidamide is effective for all SPTCL patients and whether there are molecular markers that can predict its therapeutic effect on SPTCL. PATIENT CONCERNS AND DIAGNOSES: The patient was a sixteen-year-old male and underwent subcutaneous nodule biopsy which showed SPTCL. Next-generation sequencing revealed AT-rich interaction domain 1A (ARID1A) mutation, and positron emission tomography/computed tomography showed scattered subcutaneous fluorodeoxyglucose metabolic lesions throughout the body. INTERVENTIONS AND OUTCOMES: During the first 3 CHOP (cyclophosphamide, doxorubicin, vindesine, and prednisone) treatment, the patient relapsed again after remission, and the successive addition of methotrexate and cyclosporine did not make the patient relapsing again. Then, after adding Chidamide to the last 3 CHOP treatment, the patient was relieved again. The patient underwent autologous hematopoietic stem cell transplantation (auto-HSCT) after completing a total of 8 cycles of chemotherapy, and continued maintenance therapy with Chidamide after auto-HSCT. Currently, the patient has been in continuous remission for 35 months. LESSONS SUBSECTIONS: This case is the first report of a refractory/recurrent SPTCL with ARID1A mutation treated with Chidamide. The treatment of Chidamide on the basis of CHOP plus auto-HSCT therapy achieved good results, suggesting that ARID1A may act as a molecular marker to predict the therapeutic effect of Chidamide on SPTCL patients, which helps to improve the precision of SPTCL treatment and the overall prognosis of SPTCL patients.

CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma.

T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.

Composite B-cell and T-cell lymphomas: clinical, pathological, and molecular features of three cases and literature review. / 三例复合性B细胞和Tç»†èƒžæ·‹å·´ç˜¤æ‚£è€ çš„ä¸´åºŠã€ç— ç†å’Œåˆ†å­å­¦ç‰¹å¾çš„åˆ†æžåŠæ–‡çŒ®å›žé¡¾.

Composite lymphoma (CL) involving B-cell lymphoma and T-cell lymphoma is extremely rare. Herein, we report three such cases using immunohistochemistry, flow cytometry, and the next-generation sequencing (NGS) to identify the pathological and molecular characteristics of CL. In the first case, the patient was admitted to hospital for generalized pruritic maculopapular rash over the whole body. An excisional biopsy of the skin lesions showed T-cell lymphoma. At the same time, the staging bone marrow (BM) biopsy revealed a diffuse large B-cell lymphoma (DLBCL). After R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapies, the patient produced a good response with substantial dissipation of the rashes and relief of skin. The other two patients were admitted to hospital due to lymphadenopathy and were diagnosed with DLBCL and follicular lymphoma (FL) after core needle biopsy of lymph nodes, BM biopsy, BM aspiration, and flow cytometry. Following R-CHOP and R-COP (rituximab, cyclophosphamide, vincristine, and prednisone) therapies, they achieved complete remission unconfirmed (CRu) and complete remission (CR). However, one or two years later, they suffered a relapse of lymphadenopathy. The shocking fact was that re-biopsy of lymphadenopathy revealed peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T-cell lymphoma (AITL). NGS findings identified DNA methyltransferase 3a (DNMT3a), isocitrate dehydrogenase 2 (IDH2), Ras homolog gene family, member A (RHOA), splicing factor 3B subunit 1 (SF3B1), and tumor protein p53 (TP53) mutations. After immunochemotherapy, these patients achieved CRu and CR again. Nevertheless, they suffered a second relapse of T-cell lymphoma. Finally, they died due to progression of disease. We found that the occurrence of CL is associated with Epstein-Barr virus infection and DNMT3a, IDH2, and TP53 mutations, and the prognosis of the disease is closely related to the T-cell lymphoma components.

Long-term survival after salvage pemetrexed for refractory primary T-cell lymphoma of the CNS.

Primary T-cell CNS lymphoma is a rare and aggressive malignancy. High-dose methotrexate (MTX) based chemotherapy regimens are used as standard first-line treatment, followed by consolidative strategies to improve the duration of response. Although MTX-based therapy has been shown to be efficacious, treatment options for MTX-refractory disease are not well-defined. Here, we report a case of a 38-year-old man with refractory primary T-cell CNS lymphoma who demonstrated a complete response to pemetrexed treatment. He subsequently received conditioning chemotherapy consisting of thiotepa, busulfan and cyclophosphamide followed by autologous stem cell transplantation. The patient continues to remain recurrence-free to date at 9 years post-treatment.

Rapid T-cell lymphoma progression associated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are widely used for multiple types of malignancies and are considered the fourth pillar in cancer treatment. Anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab are approved for relapsed/refractory classical Hodgkin lymphoma. Nonetheless, two phase 2 trials for T-cell lymphoma were terminated because of hyperprogression after a single dose in some patients. AREAS COVERED: In this review, we summarize available information on the rapid progression of peripheral T-cell lymphoma including adult T-cell leukemia/lymphoma (ATLL). EXPERT OPINION: In the abovementioned two trials, disease subtypes in patients who experienced hyperprogression were mostly ATLL or angioimmunoblastic T-cell lymphoma. Possible hyperprogression mechanisms induced by PD-1 blockade are the compensatory upregulation of the expression of other checkpoints, altered expression of lymphoma-promoting growth factors, functional blockade of stromal PD-ligand 1 acting as a tumor suppressor, and unique immune environment in indolent ATLL. The differentiation between hyperprogression and pseudoprogression is practically essential. There are no established methods to predict hyperprogression before administration of an ICI. In the future, the progress of novel diagnostic modalities such as positron emission tomography with computed tomography and circulating tumor DNA is expected to facilitate early cancer detection.