Autoimmune thrombocytopenia in non-Hodgkin's lymphomas

Autoimmune thrombocytopenia is a common immunehematologic complication in non-Hodgkin's lymphomas and may complicate the treatment. We analyzed an original series from our institute as well as published cases of non-Hodgkin's lymphomas (excluding chronic lymphocytic leukemia) associated with autoimmune thrombocytopenia with regard to demographic factors, prevalence in non-Hodgkin's lymphoma subtypes and treatment outcome. The male/female ratio is 1.75. Half of the cases occurred prior to diagnosis of lymphoma. Chemotherapy is the best treatment in many non-Hodgkin's lymphomas patients with autoimmune thrombocytopenia compared with standard treatment of autoimmune thrombocytopenia. Splenectomy is effective in splenic marginal zone lymphoma. Autoimmune thrombocytopenia in patients with non-Hodgkin's lymphomas is potentially life-threatening and difficult to treat.     

DNA content of leukaemic cells in non-Hodgkin's lymphomas of low-grade malignancy

Summary The DNA content of blood cells from 17 patients with leukaemic non-Hodgkin's lymphomas of low-grade malignancy according to the Kiel classification [13] was determined by a flow-cytometric assay and compared with cytological findings. The histograms from eight patients with chronic lymphocytic leukaemia (CLL), two patients with prolymphocytic leukaemia (PL), two patients with hairy cell leukaemia (HCL), and one patient with immunocytoma (IC) showed unimodal DNA distributions falling in with a diploid DNA content (2c) of the cells. Bimodal histograms were found in one case of CLL (Rai IV) with marked leukocytosis, in one case of Sézary syndrome with small and some large Lutzner cells, and in one case of IC with prolymphocytoid transformation. In the case of the CLL (Rai IV) the two peaks of the histogram represent a large population of probably diploid cells (88%) and a small one of G2 cells (3%), while 9% of the lymphocytes were found in the DNA synthesis phase. Large Lutzner cells of the patient with Sézary syndrome comprising 4% of the blood cells could be identified as hypotetraploid (3,5 c), whereas small Lutzner cells (44% of all cells) were recorded at 2c. The transformed IC which evolved from a lymphocytic ] type with small, crystalloid immunoglobulin bearing cells was characterized by 84% tetraploid (4c) cells in the blood. Their large and indented nuclei exhibited a relatively dense chromatin pattern and large nucleoli that were easily recognized in semithin and ultrathin sections but not in blood films. Since cells in DNA synthesis phase were absent, the hyperploid elements in the case of the Sé-zary syndrome and the transformed IC had to be regarded as non-proliferating in blood. The tetraploid prolymphocytoid cells of the patient with IC can be interpreted to reflect increased malignancy.     

Prognostic factors in non-Hodgkin's lymphomas

Prognostic factors were investigated in 67 patients with non-Hodgkin's lymphomas, homogeneously staged and treated (COP or CHOP according to low or high malignant histotype). A large number of parameters were scrutinized in order to recognize those exhibiting a prognostic value regarding length of survival. All the parameters that singly appeared to influence survival were entered into a multiple regression factor analysis. The erythrocyte sedimentation rate (ESR), higher or lower than 35 mm at the 1st h, better discriminated the groups of patients surviving or not at a given time. The histologic type, according to the Kiel classification of malignancy, was the second best prognosticator when a short-term prediction was requested (survival or death after no more than 2.5 years), but showed insufficient statistical weight for predicting longer survivals (greater than 4 years). Stage seemed to be the third best prognosticator for the first years of survival, but only the second best for longer survivals. Other parameters had very low prognostic importance when compared with those above. The results were substantially confirmed by 28 other patients, taken as controls. The importance that such a simple and easy test as ESR may be adequate with regard to prognosis is emphasized.     

Autotumour reactive T-cell clones among tumour-infiltrating T lymphocytes in B-cell non-Hodgkin's lymphomas

Summary. Seventy-three T-cell clones (TCC) were established from tumour-infiltrating lymphocytes-T (TIL-T) derived from lymph nodes involved by B-cell non-Hodgkin's lymphomas (B-NHL) in nine patients with different histological subtypes and clinical stages. 40 TCC (55%) expressed the CD25 Ag and were also able to proliferate in the presence of irradiated autologous B-NHL cells. Among them, 23 autotumour (AuTu) proliferative TCC were found not to proliferate to autologous EBV-transformed B-cell lines, indicating that the proliferative reactivity of these TCC was preferentially directed at autologous B-NHL cells. Tested against autologous B-NHL cells, only three AuTu prolifera- tive TCC (CD8 ⁺) showed a significant level of cytotoxicity (specific lysis > 15%). In blocking experiments, the AuTu proliferative reactivity of three TCC from one patient was strongly inhibited by anti-DR and anti-DQ mAbs, whereas that of three TCC from another patient was not affected by either anti-MHC class I or class II (DR., DP, DQ) mAbs. These findings suggest that the recognition of autologous B-NHL cells by AuTu proliferative TCC may occur through MHC-restricted as well as MHC-unrestricted mechanisms.     

Chromosome 14: a breakpoint in non-Hodgkin's lymphomas

In non-Hodgkin's lymphoma, chromosome abnormalities are found that are characteristic for the type of the lymphoma. These chromosomal abnormalities provide a tumour-specific marker and seem to play a role in the oncogenesis of the lymphoma. Chromosome 14 is involved in many lymphomas. The immunoglobulin heavy chain gene and the alpha and delta chain genes for the T cell receptor are located on this chromosome, genes which are essential for the function of B or T lymphocytes. These genes are involved in the specific translocations seen in non-Hodgkin's lymphoma. Their role and the role of oncogenes in the oncogenesis of non-Hodgkin's lymphoma are discussed. The oncogene tcl-1 is also located on chromosome 14.     

The role of follicular T helper cells in patients with malignant lymphoid disease

Objectives: To investigate the dynamic change of follicular T helper cells (T_FH) in patients with malignant lymphoid disease (MLD) and to explore its clinical significance.

Methods: The dynamic change of T_FH cells, ICOS⁺- and PD-1⁺ T_FH cells at pretreatment and different treatment periods was determined by flow cytometry in 85 MLD patients. Concentration of interleukin 21 (IL-21) was evaluated by ELISA, and the correlation between clinical prognosis and the ratio of T_FH cells was analyzed.

Results: Significantly increased ICOS⁺- and PD-1⁺ T_FH cells were found in MLD patients at pretreatment compared to healthy controls. Decreased or even close to normal levels of ICOS⁺- and PD-1⁺ T_FH cells were found at the end of treatment. However, in the patients with progressive disease, high levels of ICOS⁺- and PD-1⁺ T_FH cells were found. Moreover, a significantly increased plasma IL-21 level was found in MLD patients. Negative correlation was found between the level of ICOS⁺-, PD-1⁺ T_FH cells, as well as IL-21 and the prognosis of MLD.

Conclusions: Significantly increased T_FH cell ratios were found in patients with MLD, and decreased T_FH cells ratios could be expected in those treatment-effective patients, which could be used as the therapeutic efficacy index.     

Curability of non-Hodgkin's lymphomas.

The relapse rates of patients with malignant lymphoma have been analyzed in relation to the number of patients in complete remission (CR) at yearly intervals after the onset of therapy. Several different patterns of relapse have been identified. Patients in CR from nodular poorly differentiated lymphocytic lymphoma have a low rate of recurrent disease (14%) during the first year of treatment but rates of relapse in succeeding years have not decreased. Patients with diffuse poorly differentiated lymphocytic lymphoma have a significantly higher relapse rate during the first year of treatment (33%). However, remission duration curves suggest that the risk of relapse is decreasing with time. Patients with diffuse histiocytic lymphoma, who initially have the greatest risk of disease recurrence (42%), subsequently showed a significant fall in their rate of relapse. As many as 50% of these patients who attain a CR may have been cured of their disease. An analysis of CR duration curves may be used to determine the effective doubling time of various malignant diseases and to estimate cure rates within a few years after the onset of therapy.     

Prognostic tools in follicular lymphomas

Despite significant improvements in treatment modalities over the 10 years, the clinical course of patients with follicular lymphoma (FL) remains heterogeneous. Thus, prognostic indexes are still required to direct treatment choices and for the design of clinical trials. Investigators have conducted a variety of studies aimed at integrated assessment of biological and clinical features in order to identify novel prognostic factors and scoring systems. Genetic studies focused on tumor cells and the tumor microenvironment represent a step forward in understanding the biology of FL and are likely to provide new prognostic tools for future clinical use. Several prognostic factors have been identified and are currently used in combination to establish prognostic scores and to support therapeutic decisions. The FL International Prognostic Index (FLIPI) is currently used for defining individual risk of death. More recently, FLIPI2 was developed by the same group that built FLIPI as a new model for prognostic definition of patients with FL. The model was defined using prospectively collected data from patients who also received the monoclonal therapeutic antibody rituximab and stratifies patients into three risk categories for disease progression. Since many biological factors are not yet clinically validated or easily assessable, clinical data still represent the major source of prognostic information. The progressive development of new and more effective therapies for the treatment of FL makes the study of prognosis a dynamic and evolving area of clinical research.     

Bone involvement in pediatric non-Hodgkin's lymphomas

Abstract

Data pertaining to primary and secondary osseous involvement in pediatric non-Hodgkin's lymphoma (NHL) are scarce in English literature. Fifty-nine cases of childhood NHL over a period of 3·5 years were reviewed out of which eight had bone involvement, the incidence of skeletal involvement being 13·6%. There were seven males (87·5%) and mean age was 9·9 years (range: 1–15 years). Two patients (25%) had primary bone lymphoma and six cases (75%) were classified as secondary bone lymphoma. Six patients who opted for treatment received chemotherapy; 4/6 (67%) patients are in complete remission at a median follow-up of 41 months (range 19–44 months). Bone involvement was more common in relapsed cases in comparison to de novo presentations.     

Pathohistology of non-Hodgkin's lymphomas: recent progress]

After the recognition of the various phase of the physiologic differentiation and transformation of lymphocytes (from the stem cells over T-prolymphoblasts and lymphoblasts to the effector-T-cells and over the B-lymphoblasts, B1-lymphocytes to the lymphatic plasma cells and, respectively, over centroblasts, centrocytes, B2-lymphocytes to the Marschalko plasma cells) it became clear that the non-Hodgkin-lymphomas correspond to the individual, apparently blocked phases of the differentiation and transformation. The classification after Kiel distinguishes non-Hodgkin-lymphomas of a malignity of low degree (CLL, centrocytoma, centroblastic-centrocytic lymphoma, immunocytomas) and of high degree (T-lymphoblastoma, centroblastoma, immunoblastoma). An essential part of these tumours may be diagnosed with the help of the usual light-microscopic methods. When several supplementing cytochemical and immunocytological methods are used, nearly all non-Hodgkin-lymphomas are to be characterized, though border-line cases and non-classifiable non-Hodgkin-lymphomas rarely appear, but they appear.     

Treatment of follicular non-Hodgkin's lymphoma

Follicular non-Hodgkin's lymphoma (NHL) represents the most common indolent lymphoma with a median survival of 10 years. A new prognostic index (FLIPI) provides prognostic information at diagnosis and at relapse. Initial treatments combining monoclonal antibody therapy using rituximab with chemotherapy appear to increase the response rate and decrease the risk of relapse with little increase in toxicity. Promising phase III trial results demonstrating improvements in outcome using rituximab have recently been reported. A number of phase II trials have also demonstrated encouraging activity combining radiolabeled antibodies in sequence with chemotherapy. The role of high-dose therapy and autologous transplantation is becoming more defined, with improvements in progression-free survival observed in the upfront and relapsed setting. The application of allogeneic transplantation, once restricted to young otherwise healthy patients has shown encouraging activity in older, relapsed, and refractory patients using nonmyeloablative conditioning regimens. These new treatment options make the management of newly diagnosed patients both exciting and a challenge.     

Differentiation of anti-tumour cytotoxic T lymphocytes from autologous peripheral blood lymphocytes in non-Hodgkin's lymphomas

We have previously reported that specific anti-tumour cytotoxic T cells (CTL) can be differentiated from tumour-infiltrating lymphocytes (TIL) in non-Hodgkin's lymphoma. We found that the combination of interleukin (IL)-1, IL-2 and IL-12 was very efficient for expansion of CD8+ T-cell receptor (TCR)alphabeta+ T cells and for development of their ability to specifically lyse tumour cells. In this study, we investigated whether anti-tumour T cells could be generated from the peripheral blood of patients using the culture protocol developed for TIL. Autologous T cells and tumour B cells from five patients were included in this study. It was found that polyclonal anti-tumour cytotoxic effector cells were generated when cultured in the presence of IL-1beta, IL-2 and IL-12. Interestingly, tumour cells were lysed by perforin/granzyme-mediated cytolysis and not by CD95-mediated apoptosis. By performing inhibition experiments, it was observed that both CD8+ and CD4+ T cells were responsible for the cytotoxic effect and that they were able to recognize malignant B cells by either a major histocompatibility complex (MHC)-restricted or MHC-non-restricted mechanism. Intriguingly, in addition to interferon-gamma and tumour necrosis factor-alpha, IL-10 was secreted continuously during culture. The source of patient T cells used for the generation of anti-tumour CTL should be based on the results obtained with peripheral blood lymphocytes and TIL.