Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma.

Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2-null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10-78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment. SIGNIFICANCE: Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.

The derived neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with angioimmunoblastic T-cell lymphoma.

To determine whether inflammatory markers, derived neutrophil-to-lymphocyte ratio (dNLR), haemoglobin/platelet ratio (HPR) or platelet/lymphocyte ratio (PLR) are predictive for prognosis in angioimmunoblastic T-cell lymphoma (AITL), we derived dNLR, HPR and PLR values for 110 AITL patients and appropriate cut-off point values to define overall survival (OS) and progression-free survival (PFS). dNLR ≥ 2·2, HPR ≥ 0·4 or PLR < 100 were significant factors for shorter OS and PFS. On univariate analysis, these three parameters were significantly associated with worse OS and PFS. On multivariate analysis, only dNLR remained a significant, independent prognostic factor for both OS and PFS.

Immunoglobulinopathies in patients with angioimmunoblastic T-cell lymphoma.

AIM: The aim of the study was to characterize quantitative and qualitative immunoglobulinopathies in patients with AITL at the onset of the disease. MATERIALS AND METHODS: 55 patients with newly diagnosed AITL were enrolled in the study, the male/female ratio was 30/25; median age was 61 (29-81) years. Diagnosis was based on standard WHO criteria. Immunochemical studies of blood serum included serum protein electrophoresis/immunofixation, nephelometric quantification of total immunoglobulins, serum free light chain assay. RESULTS: Quantitative and qualitative immunoglobulinopathies were determined in 49 (89,1%) of 55 pts. Quantitative immunoglobulinopathies were revealed in 47 (85.5%) of 55 cases, qualitative - in 14 (25,5%). Combination quantitative and qualitative immunoglobulinopathies was observed in 12 (21,8%) of 55 pts. The detected immunoglobulinopathies were divided into 4 groups: polyclonal hypergammaglobulinaemia, hypogammaglobulinaemia, oligoclonal gammapathy, and monoclonal gammapathy. Polyclonal hypergammaglobulinaemia was marked in 41 (74.5%) of 55 pts, elevated level of IgG was determined in 27 (49,15%) of 55 cases, IgM - in 18 (32,7%) and IgA - in 21 (38.2%). Interestingly, polyclonal IgE hypergammaglobulinaemia was detected in 12 (48,0%) of 25 cases of performed studies. Hypogammaglobulinaemia was detected in 8 (14,5%) of 55 cases. Oligoclonal gammapathy was determined in 4 (7.3%) of 55 pts. Monoclonal gammapathy was revealed in 11 (20,0%) of 55 cases. The amount of monoclonal immunoglobulin varied from 2.6 to 14.1 g/l. Monoclonal immunoglobulin Gk was detected in 5 of 11 pts, Gλ - in 2, Mλ - in 2, Mk - in 2. Monoclonal gammapathy was accompanied by polyclonal hypergammaglobulinaemia in 9 of 11 cases, hypogammaglobulinaemia - in 2. CONCLUSION: Quantitative and qualitative immunoglobulinopathies are observed in most patients at the onset of AITL. Quantitative abnormalities were determined more often than qualitative. Monoclonal gammapathy can be a manifestation of lymphoproliferation and other concomitant disorders. The prognostic value of immunochemical parameters is still unclear and requires dynamic observation and study.

Clinical characteristics of angioimmunoblastic T-cell lymphoma in China and C-reactive protein as an independent prognostic factor.

Angioimmunoblastic T-cell lymphoma (AITL) is a major subtype of peripheral T-cell lymphoma (PTCL). Due to its low incidence, the characteristics of AITL are still not well understood. The prognostic evaluation of this disease has not been established.We retrospectively analyzed 52 patients with newly diagnosed AITL in China between January 2008 and September 2016.Among these patients, the median age at diagnosis was 62 (40-83) and 58% (30/52) of the patients were older than 60 years. Thirty-five patients were male, accounting for 67.3% of the whole. Among these, 90% (47/52) of the diagnoses were estimated at advanced stage. A total of 25 (48%) patients were scored >1 by the ECOG performance status. Systemic B symptoms were described in 34 (65%) patients. When evaluated by International Prognostic Index (IPI), 81% were scored >2, and 77% got >1 score according to the prognostic index for PTCL (PIT) upon diagnosis. The 3-year progression-free survival (PFS) was 44% and the 3-year overall survival (OS) rate was 52%. IPI and PIT scores could not be effectively applied to stratify those AITL patients into subgroups. Our multivariate analysis results found that the elevated serum C-reactive protein (CRP) level was an independent adverse factor to the OS of the AITL patients.Patients with AITL had a poor outcome. The serum level of CRP may be applied as an independent prognostic factor for AITL.

A case of angioimmunoblastic T-cell lymphoma with high serum VEGF preceded by RS3PE syndrome.

We report the case of a 76-year-old man diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with high serum vascular endothelial growth factor (VEGF) preceded by Remitting seronegative symmetrical synovitis with pitting edema syndrome. He suffered respiratory discomfort caused by large amounts of pleural effusion. Interestingly, changes in serum VEGF measured over time were similar to changes in pleural effusion. Whether VEGF is related to the pathological condition of AITL is a very important question.

Ultra-high level of serum soluble interleukin-2 receptor at diagnosis predicts poor outcome for angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma and displays an aggressive clinical course with poor outcome. To identify prognostic factors for AITL, we retrospectively analyzed 36 patients with AITL. The median age was 74 years with 83% of the patients having advanced stage. Eighty-three percent received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like chemotherapies, resulting in an overall response rate of 63%. With a median follow-up of 9 years, the estimated overall survival at 5 years was 33.3%. Median serum level of soluble interleukin-2 receptor (sIL-2R) was 5615 U/mL at diagnosis, and over 10 000 U/mL of sIL-2R was identified as a significant poor prognostic factor, independent of the International Prognostic Index, Prognostic Index for peripheral T-cell lymphoma and Prognostic index for AITL (hazard ratio [HR], 4.42; 95% confidence interval [CI], 1.49-13.11; log-rank, p < 0.01). Our study shows that an ultra-high level of serum sIL-2R at diagnosis is a significant poor prognostic biomarker for AITL.

Clinical manifestation of angioimmunoblastic T-cell lymphoma with exuberant plasmacytosis.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma characterized by aggressive symptoms and various abnormal laboratory test results. One of the rare immunologic abnormalities in AITL is exuberant polyclonal plasmacytosis, but its clinical significance has not been evaluated. This report concerns three AITL cases with exuberant polyclonal plasmacytosis and investigates its clinical impact by comparison with 12 patients without plasmacytosis. Our study found that the performance status (PS) of the former was significantly worse and their serum immunoglobulin levels were significantly higher. All other parameters, including B symptoms, various prognostic scores, blood cell counts other than plasmacyte, and serum levels of lactate dehydrogenase, C-reactive protein and soluble interleukin-2 receptor, showed no significant differences. More importantly, although the diagnosis of AITL with plasmacytosis was not straightforward in our series, outcomes of treatment with conventional chemotherapy or immunosuppressive therapy with cyclosporine A were favorable. To conclude, AITL should be considered a candidate underlying disease of exuberant polyclonal plasmacytosis. Provided a correct diagnosis is made early and is followed by adequate treatment, the prognosis for AITL with plasmacytosis may not be worse than that for those without plasmacytosis despite the severe exhaustion at first presentation.

[Angioimmunoblastic T-cell lymphoma with marked polyclonal plasmacytosis in peripheral blood and bone marrow mimicking plasma cell leukemia].

A 70-year-old man was admitted to our hospital with fever, generalized lymphadenopathy and hypoxia in October 2009. Blood examination demonstrated leukocytosis, anemia, thrombocytopenia and hyper γ-globulinemia. Peripheral blood and bone marrow smear showed marked plasma cell proliferation mimicking plasma cell leukemia. However, flow cytometric analysis showed that plasma cells were of polyclonal origin and M-protein was not detected by immunofixation of serum protein. Elevations of soluble interleukin 2 receptor and serum IL-6 were observed. A heavy Epstein-Barr viral load was detected in serum by real-time PCR. Biopsy was obtained from the right inguinal lymph node. The pathological diagnosis was angioimmunoblastic T-cell lymphoma (AITL) and rearrangement of the T-cell receptor Cß1 gene was detected. The patient was treated with CHOP therapy, and all clinical manifestations, including fever, lymphadenopathy, anemia, thrombocytopenia, hyper γ-globulinemia, plasmacytosis and hypoxia, were improved. Only a few reported cases have demonstrated AITL with marked polyclonal plasmacytosis. Although pathological mechanisms of plasmacytosis in AITL patients have not been fully elucidated, it is suggested that IL-6 and IL-10 were involved in its pathogenesis in the present case.

Peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia in patients with angioimmunoblastic T-cell lymphoma: report of 3 cases and review of the literature.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique type of peripheral T-cell lymphoma. Patients with AITL may have occasional reactive plasma cells present in the peripheral circulation. Prominent peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia, however, is distinctly uncommon. Here we describe 3 such cases from two large tertiary medical centers and discuss the role of ancillary studies in the differential diagnosis of peripheral blood plasmacytosis.

[Clinical features and prognostic factors of angioimmunoblastic T cell lymphoma].

OBJECTIVE: To retrospectively analyze the clinical features and prognostic factors of patients with angioimmunoblastic T-cell lymphoma (AITL). METHODS: The clinicopathological and follow-up data of 18 AITL patients undergoing integrated treatment from Feb. 1998 to April 2009 in our department were retrospectively analyzed. All of the patients received CHOP-like regimens as initial chemotherapy, including 4 once treated with radiotherapy and 1 with high dose therapy followed by autologous stem cell transplantation (HDT-ASCT) as upfront consolidation therapy. B-cell, T-cell and NK-cell subgroup proportions in the peripheral blood were tested by flow cytometry in 6 patients. RESULTS: The median age of the 18 patients was 55 years, male and female ratio was 2.6:1. Seventy-two percent of the patients were in an advanced stage. 72% of them had B symptoms, 69% hypergammaglobulinemia, 60% elevated LDH and 47% anemia. Forty-four percent achieved CR after initial treatment with CHOP-like regimens. With the median follow-up of 26 months, the overall 2-year survival and disease free survival (DFS) rates were 62.2% and 44.4%, respectively. In the univariate analysis, only age > 30 years and primary refractory disease adversely affected overall survival (OS); age > 30 years, advanced stage, B symptoms and splenomegaly adversely affected DFS. Four patients suffered from severe pneumonia during treatment, 2 of them died of respiratory failure. Flow cytometry of peripheral blood lymphocytes showed that 5 of the 6 tested cases had decreasing proportion of CD3(+)CD4(+) T cells, B cells and NK cells but elevated CD3(+)CD8(+) T cells. Two heavily treated patients achieved partial and complete response by thalidomide therapy, with a progression free survival (PFS) of 2 and 6+ months, respectively. CONCLUSION: AITL patients do not response well to CHOP-like regimens chemotherapy. Age < 30 years and sensitive to initial chemotherapy are associated with prolonged OS. Effectiveness of thalidomide in the treatment of AITL deserves further investigation. Peripheral blood lymphocytes test indicates that AITL patients suffered from both natural and acquired immune defects.

[Severe systemic edema correlated with serum VEGF titer in a patient with angioimmunoblastic T-cell lymphoma].

A 73-year-old woman was admitted with generalized lymphadenopathy, marked protrusion of the abdomen, severe systemic edema, oliguria, and dyspnea. Histological examination of a cervical lymph node specimen showed a typical structure of angioimmunoblastic T-cell lymphoma. CT scan revealed whole paraaortic lymphadenopathy, marked edematous lesions in the subcutaneous tissues and mesenterium, but small amounts of pleural effusion and ascites. This patient achieved complete remission after 5 courses of chemotherapy, a first course of CHOP followed by 4 courses of hyper CVAD plus high-dose MTX/AraC regimen alternatively. Her body weight was 58 kg on the day of admission and decreased to 41kg after 5 courses of chemotherapy, accompanied with symptomatic improvement. We checked the kinetics of serum Vascular endothelial growth factor (VEGF) concentrations during the 5 courses of chemotherapy. Pretreatment serum level of VEGF was high and declined gradually within the normal range. The serum VEGF value was positively correlated with body weight (r = 0.95). Immunohistochemical study of the biopsy specimen revealed that endothelia of the venules and some dendritic cells were positive for VEGF. We speculated that significant edematous changes in this patient were associated with VEGF, which is known as a vascular permeability factor based on its ability to induce vascular leakage.

[Diagnostic and prognostic value of interleukin-6 in malignant non-Hodgkin's lymphomas]. / Diagnosticheskoe i prognosticheskoe znachenie interleikina-6 pri zlokachestvennykh nekhodzhkinskikh limfomakh.

Sixty six patients with non-Hodgkin's lymphomas (NHL) were studied, interleukin-6 (IL-6) was revealed in the blood sera of 33 patients. IL-6 was revealed more frequently in patients with high-grade malignant (p < 0.05) than in those with low-grade malignancy. The largest group of IL-6 positive patients included NHL patients with diffuse large B-cell lymphoma and angioimmunoblastic lymphoma. The marked relationship was found between the serum IL-6 levels and the stage of disease: the serum IL-6 level was significantly lower in untreated patients with Stages II and III disease than in those with end-stage (IV) NHL. IL-6 significantly decreased upon remission, comparable with its level before the initiation of treatment. Analysing the association of prognosis of disease with the serum IL-6 showed that in the group of patients with good (The SNLG index < 2) and intermediate (2 < SNLG index < by 2.6) prognosis, the concentration of this cytokine was significantly lower than in those with poor prognosis (SNLG index > 2.6). There was a significant decrease of the total survival rates of NHL with serum IL-6 found. Therefore, IL-6 is a good prognostic marker in NHL and associated with the activity of a malignant process. Additionally, the increased serum IL-6 levels correlated with NK activities positively and with serum IL-4 levels negatively.

Angioimmunoblastic lymphadenopathy with dysproteinemia--lack of a prognostic value of clear cell morphology.

It has been suggested that angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is closely related to peripheral T cell lymphoma (PTCL). However, the clinical course of AILD-like PTCL is notoriously unpredictable. A minor portion of patients enjoyed prolonged remission with steroid-only treatments (indolent AILD) while most others died rapidly despite the use of intensive chemotherapy (aggressive AILD). Recently, it has been suggested that histological features such as the presence or absence of clear cells and convoluted cells are of high prognostic value. The validity of this observation was addressed in this study. Eighteen patients who presented between 1977 and 1994 at the National Taiwan University Hospital were retrospectively studied. There were 11 men and 7 women, with a median age of 47 years. Twelve patients had received various regimens of systemic chemotherapy, and the other 3 patients had been treated with steroids alone. Eight patients had indolent AILD and 6 aggressive AILD. The follow-up period in 4 patients was too short to be analyzed. The histopathology of these cases was divided, according to the criteria of Aozasa et al., into group I (neither cells), 4 patients; group II (only convoluted cells), 1 patient, and group III (clear cells with or without convoluted cells), 13 patients. Contrary to others, our data revealed that group III patients were doing better than group I patients. Univariate analysis of other pertinent clinical features, including sex, age, lymphadenopathy, B symptoms, hepatosplenomegaly, hypergammaglobulinemia, elevated serum lactate dehydrogenase, and treatment regimens, revealed none of them to be prognostically relevant. However, patients who had achieved complete remission by steroids or other systemic chemotherapy had a significantly better prognosis than those who had not. Together, these preliminary data suggested that (1) the presence or absence of clear cells and convoluted cells failed to predict the clinical behavior, and (2) induction of complete remission by steroids or other chemotherapeutic agents is an important prognostic index.

Detection of clonally rearranged T-cell-receptor gamma chain genes from T-cell malignancies and acute inflammatory rheumatic disease using PCR amplification, PAGE, and automated analysis.

Clonal expansions of T cells carrying identical T-cell-receptor (TCR) genes are the hallmark of T-cell malignancies, but they can also result from a strong immune reaction to a dominant epitope. The basis for the molecular detection of clonal T cells is amplification of the V-(D)-N-J region of the TCR gene. We evaluated PCR amplification of the rearranged gamma TCR from genomic DNA extracted from peripheral blood and subsequent polyacrylamide gel electrophoresis (PAGE) in an automated DNA sequencer. We determined the sensitivity for the detection of clonal T cells and propose a standardized evaluation procedure for the electrophoretic profiles generated by the DNA sequencer. The sensitivity of our method was 0.6-1.25% of clonal T cells within a polyclonal background. Sixteen patients with T-cell malignancies, ten with acute inflammatory rheumatic diseases, and twelve healthy controls were examined. Among the systemic T-cell malignancies, all but one patient with T-PLL (8/ 9) revealed a clonal PCR signal. No clonal signal was detectable in any patient in clinical complete remission (5/5) or in either of the two patients with lymphomas limited to cutaneous sites. However, clonal T cells were detected in one patient with polymyalgia rheumatica and in one with reactive arthritis. A polyclonal signal was found in the remaining eight patients with acute inflammatory rheumatic diseases and in 12 healthy controls. Taking our results together, the PCR/PAGE assay is able to reliably distinguish clonal from polyclonal T-cell populations. However, although the sensitivity is limited to approximately 1%, clonal T cells can be found in the peripheral blood of some patients with autoimmune diseases and not only in T-cell malignancies.

Clonal identification of trisomies 3, 5 and X in angioimmunoblastic lymphadenopathy with dysproteinemia by fluorescence in situ hybridization.

Trisomies 3, 5 and X in six Japanese patients with AILD were detected by fluorescence in situ hybridization (FISH). Trisomies 3 and X were detected using centromeric probes. Cosmid probes locating on 5q31.1, the commonly deleted region, was used to detect trisomy 5. FISH detected three patients with trisomy 3 alone, one with trisomy 5 alone and one with all the three trisomies analysed. The sample that showed all three aberrations was further analysed by dual color FISH. The three trisomies were present on different cells. The AILD cells with trisomy 5 tended to replicate slowly, whereas those with trisomy 3 seem to have a proliferative advantage. An increase in the histopathological stage was reflected in the increase in the percentage of trisomy 3 cells in one patient.

Treatment of angioimmunoblastic lymphadenopathy with dysproteinemia using 2-chlorodeoxyadenosine.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is an atypical lympho-proliferative disorder with borderline features that often constitute a diagnostic challenge for the hematopathologist and a therapeutic dilemma for the treating clinician. Morphologically, the involved lymph nodes in this disorder are characterized by abnormal infilitration by immunoblasts and plasma cells, often in clusters or sheets. Regressed follicles may be seen; these are referred to as "burned out." Neovascularization is prominent, and a background of inflammatory cells is usually present. AILD was originally thought to represent an exaggerated autoimmune response. Because of the short median survival of the patients and the demonstration of T-cell clonality, AILD now is considered an aggressive lymphoma and is recognized as a subset of peripheral T-cell lymphoma by the REAL classification. In this article we present a patient with AILD who achieved durable partial remission after treatment with one cycle of 2-chlorodeoxyadenosine.

Increased levels of interleukin-6 (IL-6) in serum and spontaneous in vitro production of IL-6 by lymph node mononuclear cells of patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD), and clinical effectiveness of cyclosporin A.

Serum levels of cytokines and in vitro cytokine production by lymph node mononuclear cells (LNMC) were studied in four patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD) or AILD-type T cell lymphoma. An increased level of serum interleukin-6 (IL-6) was detected on initial diagnosis in both of two patients examined. Spontaneous production of IL-6 by LNMC was detected in all four patients studied. Immunosuppressive therapy with cyclosporin A (CsA) was attempted in a 68-year-old man, who was refractory to intensive combination chemotherapy. The increased level of IL-6 in this patient decreased to normal within 3 weeks of CsA administration and the patient became symptom-free. One and a half months later, the IL-6 level gradually increased along with clinical exacerbation. We also measured serum levels of IL-1 alpha, IL-2, IL-4, IFN-alpha, gamma and TNF-alpha in parallel with IL-6, but these factors were only sporadically detected. IL-6 production by LNMC was stimulated by IL-2 but inhibited by CsA. These observations suggest that IL-6 is one of the important cytokines to be involved in the pathophysiology of AILD and CsA is a useful reagent for relieving symptoms.