Enteropathy-Associated T-Cell Lymphoma

Enteropathy-associated T-cell lymphoma is a rare neoplasm with uniformly aggressive features that arises from intestinal T-cells. There is strong evidence supporting its association as a dire complication of celiac disease. The clinical presentation can vary from malabsorption and abdominal pain to an acute abdominal emergency. Originally, it was divided into types I and II in World Health Organization (WHO) classification schemes, reflective of epidemiology and differences in clinicopathologic features. The debate over the degree of separation of the two types is ongoing as new data emerges regarding the pathogenetics. The low incidence and variable patient factors are major barriers in conducting clinical trials and establishing standard treatment regimens. Yet, the collective experience demonstrates favorable outcomes with combination chemotherapy followed by an autologous hematopoietic stem cell transplant in patients who can tolerate such treatment. The prognosis remains dismal; thus, future research studies are warranted to identify effective novel therapies that can improve outcomes in this rare disease entity.     

Novel Interleukin-2 Dependent T-Cell Line Derived from Adult T-Cell Leukemia Not Associated with Human T-Cell Leukemia Virus Type I

A novel interleukin-2 (IL-2)-dependent T-cell line, WHN2, was established from a patient with adult T-cell leukemia (ATL) not associated with human T-cell leukemia virus type I (HTLV-I). Neither the original leukemic cells nor the WHN2 cells showed proviral integration in their cellular DNAs by Southern blot analysis. The surface phenotype showed that both the original leukemic cells and the WHN2 cells had a common phenotype of ATL, i.e., positive for CD2, CD4, human leukocyte antigen DR (HLA-DR) and CD25, but negative for CD8, a characteristic of helper/inducer T-cells. Most of the chromosomal abnormalities of the original leukemic cells were maintained in the WHN2 cell line. Furthermore, Southern blot analysis of the T-cell receptor β -chain gene rearrangement revealed that the original leukemic cells and WHN2 cell line had identical patterns, suggesting that the WHN2 cell line was truly derived from the original leukemic cells. Dose-dependent growth on IL-2 was demonstrated, and at the maximal stimulation, the number of cells doubled within three days. This IL-2-dependent growth was inhibited by the simultaneous existence of anti-IL-2 receptor a and β chain antibodies. These results indicate that the character of the WHN2 cell line is similar to that of the cell lines derived from ATL associated with HTLV-I. Thus, the HTLV-I-negative ATL cell line, WHN2, should be useful in the comparative study of the pathogenesis of ATL associated with or without HTLV-I.     

PET in T-Cell Lymphoma

Most non-Hodgkin lymphomas (NHL) are of B-cell origin; only about 10% are T-cell or NK-cell lymphomas. The clinical features of T/NK-cell lymphomas differ from those of B-cell lymphomas: advanced stage and extranodal disease are more common and the prognosis is worse. Several studies have confirmed that 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18FDG) uptake varies among different subtypes of lymphoma, a disparity that can be explained by the differences in histology, proliferation of tumor cells, and the ratio of viable tumor and reactive cells in the environment. These observations are based on investigation of B-cell lymphomas. Positron emission tomography (PET)/computed tomography (CT) was found to be useful both at staging and at measuring the therapeutic outcome after two to three cycles of chemotherapy (interim PET/CT). Several meta-analyses have confirmed the role of PET in evaluating the viability of the residual tumor mass after treatment. 18FDG-PET has been proved to have an excellent negative predictive value. Conversely, only a few studies have investigated the role of FDG-PET in T/NK-cell lymphomas. This paper summarizes the current information regarding the potential use of PET/CT in patients with T-cell lymphoma.     

Targeting Chemokine Receptor CCR4 in Adult T-Cell Leukemia-Lymphoma and Other T-Cell Lymphomas

Peripheral T-cell lymphoma (PTCL) is a group of lymphoid malignancy that remains difficult to treat, as most PTCL becomes refractory or relapses, and thus there is an unmet medical need for novel treatment modalities. CC chemokine receptor 4 (CCR4) is expressed in various types of PTCL including adult T-cell leukemia-lymphoma (ATL), which has the worst prognosis among them. A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab (KW-0761), yielded an overall response rate of 50?% (13/26) and a median progression-free survival of 5.2?months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy. Mogamulizumab also showed potential efficacy for cutaneous T-cell lymphoma in a US phase I/II study. Further preclinical and clinical investigations are needed to examine whether concomitant use of this novel agent with other agents with different mechanisms of action would be more effective for ATL and other PTCLs.     

Update: Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are a group of biologically heterogeneous but typically aggressive diseases. Progress in understanding and developing optimal therapies for PTCLs has been hampered by disease rarity and only relatively recent recognition of the importance of the T-cell phenotype. The International Peripheral T-cell Lymphoma Project was a large collaborative effort to provide a broader understanding of prognosis. Recently, several new therapies have shown promise in the treatment of PTCLs.     

Simultaneous Expression of T-Cell and Myeloid Cell Phenotypes in Eight Newly Established HTLV-I-positive T-Cell Lines

Eight cell lines were established from patients with adult T-cell leukemia, and from normal adults, by cocultivation with human T-cell leukemia virus type I(HTLV-I)-producer cell lines in the presence of interleukin-2. All of these cell lines harbored HTLV-I and showed T-cell markers CD2, CD3 and CD4, hut not B-cell markers. Unexpectedly, all eight cell lines expressed a myeloid marker CD13 and three of the eight lines also expressed another myeloid marker CD33. Dual staining showed the simultaneous expression of CD3 and CD13 on the same cells. Thus, evidence was obtained for the expression of myeloid antigens on HTLV-I-harboring T cells.     

Pathology and Pathogenesis of T-Cell Lymphoma

Peripheral T cell lymphomas (PTCLs) are a heterogeneous and often clinically aggressive group of neoplasms derived from mature post-thymic T lymphocytes. These neoplasms are rare and usually diagnostically challenging. Our understanding of the pathogenesis of PTCL is increasing and this improved knowledge is leading us to better molecular characterization, more objective diagnostic criteria, more effective risk assessment, and potentially to better treatments for these neoplasms.     

Driving CAR-Based T-Cell Therapy to Success

T cells that have been genetically modified, activated, and propagated ex vivo can be infused to control tumor progression in patients who are refractory to conventional treatments. Early-phase clinical trials demonstrate that the tumor-associated antigen (TAA) CD19 can be therapeutically engaged through the enforced expression of a chimeric antigen receptor (CAR) on clinical-grade T cells. Advances in vector design, the architecture of the CAR molecule especially as associated with T-cell co-stimulatory pathways, and understanding of the tumor microenvironment, play significant roles in the successful treatment of medically fragile patients. However, some recipients of CAR⁺ T cells demonstrate incomplete responses. Understanding the potential for treatment failure provides a pathway to improve the potency of adoptive transfer of CAR⁺ T cells. High throughput single-cell analyses to understand the complexity of the inoculum coupled with animal models may provide insight into the therapeutic potential of genetically modified T cells. This review focusses on recent advances regarding the human application of CD19-specific CAR⁺ T cells and explores how their success for hematologic cancers can provide a framework for investigational treatment of solid tumor malignancies.     

Prognostic Markers in Peripheral T-Cell Lymphoma

Based on their own experience and knowledge of the literature, the authors review the pathobiological characteristics of peripheral T-cell lymphomas (PTCLs), focusing on the available prognostic indicators. The International Prognostic Index (IPI), which is based on age, performance status, lactate dehydrogenase [LDH], stage, and extranodal involvement, appears to be efficient as a prognostic index for PTCLs, at least in part and especially for certain PTCL subtypes. However, it is not so satisfactory for the two commonest PTCLs, PTCL not otherwise specified (PTCL/NOS) and angioimmunoblastic T-cell lymphoma (AITL), for which novel scores, possibly based on the biologic features of the tumors, have been explored. An Italian cooperative group proposed a revision of the IPI for PTCL unspecified (PTCL-U), the Prognostic Index for PTCL-U (PIT), which includes age, performance status, LDH, and bone marrow involvement. The PIT apparently offered some advantages, but they were not confirmed in subsequent studies. A clinical-biological score (the Bologna score) was then proposed, including tumor proliferation and clinical features (age, LDH, and performance status). This score appears promising and offers the intriguing advantage of integrating biological and clinical elements, but independent validation on a large series is still warranted. More recently, gene expression profiling has been used to identify novel molecular prognostic factors. In particular, inactivation of the NFκB pathway, high expression of proliferation-associated genes, and cytotoxic molecular phenotype seem to be associated with a worse outcome. So far, however, none of these indicators has been validated in an independent series. Finally, various reports have dealt specifically with the prognostication of NK-derived tumors, including nasal and nasal-type lymphomas. Both the IPI and dedicated models have turned out to be of prognostic relevance for these tumors. In conclusion, although the IPI is somewhat effective for PTCL prognostication, novel scores that are more refined and possibly disease-specific are warranted. The validation process for several models, including clinical-pathological and molecular models, is now ongoing.