Concomitant angioimmunoblastic T‐cell lymphoma and low grade B‐cell lymphoproliferative disorder

The presence of a rearranged immunoglobulin gene, in addition to the expected T‐cell receptor gene rearrangement, is a frequent, albeit poorly understood, finding in the setting of angioimmunoblastic lymphadenopathy. A case of an angioimmunoblastic T‐cell lymphoma is presented, where this apparently paradoxical dual gene rearrangement could be ascribed to the coexistence of an occult B‐cell lymphoproliferative disorder.     

A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection

Adoptive transfer of antigen-specific CD4(+) and CD8(+) T cells is one of the most efficient forms of cancer immunotherapy. However, the isolation of antigen-specific CD4(+) T cells is limited because only few tumor-associated helper epitopes are identified. Here, we used T cell antigen receptor gene transfer to target CD4(+) T cells against an MHC class I-presented epitope of a model tumor antigen. IFN-gamma-producing CD4(+) T cells were unable to expand in vivo and to provide help for tumor rejection. In contrast, CD4(+) T cells producing high levels of IL-2 expanded in vivo, provided help for cytotoxic T lymphocyte-mediated tumor rejection, and developed T cell memory. The data demonstrate in vivo synergy between T cell antigen receptor-transduced CD4(+) and CD8(+) T cells specific for the same epitope resulting in long-term tumor protection.     

Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma

BACKGROUND: Numerous studies have reported on the association between coeliac disease and the otherwise uncommon enteropathy-type T cell lymphoma (ETTL). A systematic risk assessment of more prevalent lymphoma entities, such as B cell and non-intestinal lymphomas, in coeliac disease has not been performed. AIMS: In light of the increasing number of patients diagnosed with coeliac disease and the unknown aetiology of malignant lymphomas, we aimed to estimate the distribution and risk of lymphoma subtypes in coeliac disease. METHODS: We reviewed and reclassified 56 cases of incident malignant lymphomas occurring in a Swedish population based cohort of 11,650 patients hospitalised with coeliac disease. The observed numbers of lymphoma subtypes were compared with those expected in the Swedish population. RESULTS: The majority (n=32, 57%) of lymphomas in the cohort were not intestinal T cell lymphomas. Significantly increased risks were observed for B cell non-Hodgkin lymphoma (NHL) (standardised incidence ratio (SIR) 2.2 (95% confidence interval (CI) 1.2-3.6); 11 non-intestinal and five intestinal) and for lymphomas of non-intestinal origin (SIR 3.6 (95% CI 2.3-5.2), 11 B and 14 T cell). Furthermore, 44% of patients with B cell NHL had a history of other autoimmune/inflammatory diseases. The relative risks for T cell NHL (SIR 51 (95% CI 35-68); n=37) and for primary gastrointestinal lymphomas (SIR 24 (95% CI 16-34); five B and 25 T cell) were markedly increased, as anticipated. CONCLUSION: Most lymphomas complicating coeliac disease are indeed related to the disease and are not of the ETTL-type. There was a remarkable aggregation of autoimmune/inflammatory disorders, female sex, coeliac disease, and B cell lymphoma.     

Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle‐aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL‐like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL‐like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL‐like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL‐like variant of NLPHL as well as THRLBCL (33–38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.     

The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL ‐NOS ) and angioimmunoblastic T‐cell lymphoma (AITL ) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL ‐NOS (n  = 180) or AITL (n  = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS ) and overall survival (OS ) were calculated from the time of first disease progression (FFS 1, OS 1), from second disease progression (FFS 2, OS 2) and from third progression (FFS 3, OS 3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL ‐NOS , 105 AITL ) experienced progression/relapse. In patients with PTCL ‐NOS , the median durations of FFS 1, FFS 2 and FFS 3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL , they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS 1 and OS 1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.     

Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy

Radiotherapy is potentially an important salvage strategy post-chimeric antigen receptor T cell therapy (CART), but limited data exist. We reviewed 14 patients treated with salvage radiation post-CART progression (SRT). Most received SRT for first post-CART relapse (71%) to sites previously PET-avid pre-CART (79%). Median overall survival (OS) post-SRT was 10 months. Post-SRT, six localized relapses achieved 100% response (3 = complete, 3 = partial), with improved freedom from subsequent relapse (P = 0·001) and OS (P = 0·004) compared to advanced stage relapses. Three were bridged to allogeneic transplantation; at analysis, all were alive/NED. SRT has diverse utility and can integrate with novel agents or transplantation to attempt durable remissions.     

Random suppression of T cells that bear specific T cell receptor Vβ sequences in adult T cell leukemia/lymphoma (ATLL) patients at each clinical stage: Carrier,smoldering, chronic,and acute

Human T cell leukemia virus type I (HTLV-I) is associated with adult T cell leukemia/lymphoma (ATLL), which is well known as a T cell malignancy. In order to clarify whether HTLV-I plays a role as a virus-encoded superantigen in the neoplastic process, we examined the TCR Vβ families in the peripheral blood at four different clinical stages: carrier, smoldering leukemia, chronic leukemia, and acute leukemia. An increased number of CD4 T cells was found in each of the four clinical stages. However, we found neither uniform specific losses nor uniform clonal expansion of particular TCR Vβ gene families in any case from the four clinical stages. However, a suppression of the random TCR Vβ families was found. Our data did not therefore directly suggest the existence of a common superantigen model of HTLV-I which induces an increase in CD4 T cells. The random suppression in the TCR Vβ repertoire is most likely caused by the influence of HTLV-I neoplastic pathogenesis rather than by virus-encoded superantigens. In the patients with acute leukemia, one or two families of the Vβ repertoires were very strongly expressed, while in chronic leukemia, no such repertoire of strong expression was observed. The immunological reaction of the hosts might thus be different between the above described groups. © 1996 Wiley-Liss, Inc.     

Regression of gastric T cell lymphoma with eradication of Helicobacter pylori

Helicobacter pylori is thought to be important in the pathogenesis of chronic active gastritis, peptic ulceration, gastric adenocarcinoma, and gastric B cell lymphoma of mucosa associated lymphoid tissue. The mechanism of evolution from chronic gastritis to monoclonal B cell proliferation is not known but is thought to be dependent on antigen specific T cells to H pylori and its products. Here, we report a case of gastric T cell lymphoma associated with chronic H pylori gastritis which regressed with eradication of the organism. This is the first report of a gastric T cell lymphoma regressing with H pylori eradication, and suggests a causal link between primary gastric T cell lymphoma and this organism.     

Changes in intraepithelial lymphocyte subpopulations in coeliac disease and enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine).

Studies of the morphologic and phenotypic diversity of intraepithelial T cells in human small intestine have shown them to be heterogeneous, yet distinct from most extra intestinal T cells. In this study sequential immunoenzymatic staining was used to define new intraepithelial lymphocyte subpopulations in man. In normal human jejunum approximately 6% of the intraepithelial T cells expressing CD3 (an antigen associated with the T cell receptor) do not express the T cell subset antigens CD4 or CD8. Approximately 20% of CD7+ cells (T cells and null cells) do not express CD4 or CD8 and 14% of the CD7+ cells do not express CD3 and are therefore not T cells. The CD7+, CD3+/-, CD4-, CD8- population is concentrated in the tips of the villi. In coeliac disease, the ratios of the subsets change significantly. The percentage of CD3+, 4-, 8- cells increases to 28%, the proportion of CD7+, 4-, 8- cells remains unchanged and the CD7+, CD3- (non-T cell) population is reduced to 1.4% of the CD7+ cells. In contrast, in patients with villous atrophy of uncertain aetiology, all CD4-, CD8- lymphocyte subsets are decreased compared with normal biopsies. Finally, in enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine) in which the 'uninvolved mucosa' is histologically similar to untreated coeliac disease, the changes in the intraepithelial T cell sub-sets are indistinguishable from those in coeliac disease, suggesting that the lymphoma is a complication of coeliac disease.     

Analysis of the Expression of the TRBC1 in T lymphocyte tumors

T cell therapy represents a new class of immunotherapies garnering considerable attention. T cell receptor beta chain constant region 1 (TRBC1) is partially expressed in subsets of normal T cells. However, the immunotherapy of T lymphocyte tumors is rarely validated in clinical trials. Here, we aim to explore whether TRBC1 is a promising target for the immunotherapy of T lymphocyte tumors. This study examined TRBC1 expression in 25 healthy bone marrow samples, 39 patients with T-lineage acute lymphocytic leukemia (T-ALL), 4 patients with mature T cell neoplasms, and 5 patients suspected with mature T cell neoplasms with evidence of T cell neoplasia. Moreover, the expression of TRBC1 was evaluated by flow cytometry and through PCR detection of TCR gene rearrangements. The expression of monophasic TRBC1 was identified in all 25 normal bone marrows (23.83% ± 2.74% positive rate). The expression of TRBC1 was positive in 5 patients (12.8%) among the 39 T-ALL patients. TRBC1 was partially expressed in 1 patient (25%) with T cell non-Hodgkin''s lymphoma (T-NHL) and in 1 patient (20%) suspected to have T-NHL. Healthy donors showed a pattern of partial expression and patients with T-lymphocyte tumors showed a polytypic TRBC1 expression pattern. Thus, TRBC1 may be a diagnostic and therapeutic marker for T lymphocyte tumors.     

T cell receptor and immunoglobulin gene rearrangement analysis as a laboratory aid in the diagnosis of human malignant lymphoproliferative diseases

The identification of clonal rearrangements of the immunoglobulin heavy chain and T cell receptor beta chain gene loci by Southern blot analysis has led to advances in the diagnosis and classification of lymphoproliferative disorders. This paper reviews our experience with this technique over a three and a half year period. Specimens from 99 patients with suspected haemato-logical malignancy were tested for leucocyte immunophenotype and immunoglobulin or T cell receptor gene rearrangement. Genotyping provided evidence of clonality in malignancies from 28 patients and demonstrated malignant cell lineage in eight patients not formally deduced from immunophenotyping alone. Our findings suggest that this technique can be employed in conjunction with immunophenotyping to aid in the determination of malignant cell lineage derivation and identification of malignant cell clonality, as well as potentially estimating the extent of disease, detecting relapse, and monitoring disease progression.     

Imbalance of T cell subpopulations in peripheral blood of children with non-Hodgkin malignant lymphoma

Peripheral blood lymphocytes from 13 children with newly diagnosed untreated non-Hodgkin malignant lymphoma were investigated for the proportion of Tμ and Tγ cells. Tumor involvement was classified as stage II in two patients, stage III in five patients, and stage IV in six patients. Diffuse poorly differentiated lymphoblastic histological-type lymphomas, as defined by the Rappaport classification, were found in eight patients. The proportion of Tγ cells was found to be increased and that of Tμ cells decreased in the patient group as compared to levels in healthy controls. A marked imbalance of the Tμ/Tγ ratio was observed in ten of 13 patients. There was no correlation between Tμ/Tγ ratios and stage of the disease. Imbalances of Tμ and Tγ cell proportions are discussed in relation to humoral and cellular immunodeficiencies observed in patients with non-Hodgkin malignant lymphoma.     

Clinical experience of CAR T cell therapy in lymphomas

Non-Hodgkin lymphoma in relapse portends a poor prognosis due to resistance to cytotoxic chemotherapy and monoclonal antibodies. Chimeric Antigen receptor (CAR) T cell therapy has been tested in many lymphomas in the relapse refractory setting and has resulted in durable responses despite some peculiar side effects including cytokine release syndrome (CRS), neurological events (NE), prolonged cytopenias and hypogammaglobulinemia. This review summarizes the registration trials conducted in lymphomas. All products showed response rates that were far better than obtainable by salvage chemotherapy and most patients recovered from side effects including CRS and NEs. The impact of CAR T in the real world setting was discussed as well as how to approach the use of CAR T in special circumstances such as CNS involvement, management of post CAR relapses and outpatient therapy.     

Efficacy of R-BAC in relapsed,refractory mantle cell lymphoma post BTK inhibitor therapy

Patients with mantle cell lymphoma progressing on Bruton’s tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort study, patients progressing on BTKi received R-BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression-free survival was 10.1 months (95% confidence interval (CI) 6·9–13·3) and median overall survival was 12·5 months (95% CI 11·0–14·0). In those consolidated with alloSCT only one patient relapsed. R-BAC demonstrates a high response rate in the post-BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.