Low-grade Malignant non-Hodgkin Lymphoma Research Articles

Targeted Metabolomics Analysis in Follow-up of Classic and Mild PKU using LC-ESI-MS/MS: Assessment of Metabolic Control through PHE/TYR ratio

MALT lymphoma, also referred to as extra nodal marginal zone B-cell lymphoma, is a low-grade malignant non-Hodgkin lymphoma...

Phase III Intergroup Study of Fludarabine Phosphate Compared With Cyclophosphamide, Vincristine, and Prednisone Chemotherapy in Newly Diagnosed Patients With Stage III and IV Low-Grade Malignant Non-Hodgkin's Lymphoma

To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.

Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen

An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG3 lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (vWF) defect (Ivy bleeding time, &gt; 15 minutes; vWF antigen [vWF:Ag], 0.08 U/mL; ristocetin cofactor activity [vWF:RCoF], &lt; 0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of vWF and inhibitor-vWF complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422–826) and the A3 (aa 909–1112) domain of vWF, but not with the A2 (aa 716–908) or D4 (aa 1183–1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF.

Acquired von Willebrand Disease Caused by an Autoantibody Selectively Inhibiting the Binding of von Willebrand Factor to Collagen

An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG3 lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (vWF) defect (Ivy bleeding time, > 15 minutes; vWF antigen [vWF:Ag], 0.08 U/mL; ristocetin cofactor activity [vWF:RCoF], < 0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of vWF and inhibitor-vWF complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422-826) and the A3 (aa 909-1112) domain of vWF, but not with the A2 (aa 716-908) or D4 (aa 1183-1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF.

First experiences and perspectives for the use of cytokines in the treatment of non-Hodgkin??s lymphoma

Numerous clinical trials have been carried out to investigate the therapeutic potential of cytokines in the management of non-Hodgkin's lymphoma (NHL). Relevant interferon-alpha activity is restricted to low-grade malignant NHL of both B and T cell subtypes, provided the tumor mass is low. Granulocyte-macrophage colony stimulating factor (GM-CSF) accelerates hematopoietic recovery following myelosuppressive therapy, and reduces the risk and severity of infection. Thus, GM-CSF support makes does intensification feasible and may thereby contribute to an improvement of response rates and long-term survival. Among interleukins (IL) studied, IL-2, with or without lymphocyte activated killer cells, so far has only achieved stabilization of refractory NHL but this approach may still require further refinement. IL-3 has already been successfully applied in the treatment of NHL, augmenting neutrophil and platelet recovery after conventional salvage therapy or following autologous bone marrow transplantation. On the basis of these findings promising applications for the use of cytokines in the treatment of NHL can be envisaged.

Prednimustine and mitoxantrone (PmM) in patients with low-grade malignant non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and prolymphocytic leukemia (PLL)

Thirty-five patients with a mean age of 60.6 years (44-78 years, 22 male, 13 female) with advanced low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or prolymphocytic leukemia (PLL) were treated every 4 weeks with prednimustine 100 mg/m2 p.o. d 1-d 5 and mitoxantrone 8 mg/m2 i.v. d 1 and d 2. Seven patients had CLL, one lymphocytic NHL, two PLL, 13 immunocytoma, nine centroblastic/centrocytic NHL, and three centrocytic NHL. Twenty-five patients were pretreated. The subjective toxicity of the treatment was mild, with no WHO grade-3 alopecia, polyneuropathy, cardiotoxicity, mucositis, nausea, or vomiting. Hematologic side effects with WHO grade-4 granulopenia and thrombopenia were experienced by 26% and 23% of the patients, respectively. The overall response rate (CR+PR) was 72% for lymphoma patients and 37% for CLL patients, with a median remission duration of 14.6 months. The maximum response was achieved after a median of two treatment courses. Prednimustine with mitoxantrone is a subjectively well tolerated treatment for low-grade malignant NHL, to be further evaluated in phase-III studies. The regimen may shorten the duration of treatment, saving time-consuming out-patient visits and costs.

Mitoxantrone, etoposide, cytarabine and prednisone as salvage therapy for refractory non‐Hodgkin lymphoma (NHL) and alternated with CHOP in previously untreated patients with NHL

The treatment of relapsing or refractory high-grade malignant non-Hodgkin lymphoma (NHL) following CHOP chemotherapy remains a challenge for the clinician. In this study, 29 patients with relapsing or refractory high- or refractory low-grade malignant NHL received a combination of mitoxantrone 12 mg/m2 i.v. on days 1-2, cytarabine 100 mg/m2 i.v., b.d. d 1-2, etoposide 100 mg/m2 i.v. d 1-3 and prednisone 100 mg/m2 orally d 1-3 (ENAP). An overall response rate of 55% encouraged us to use ENAP alternated with conventional CHOP chemotherapy in 45 previously untreated NHL patients (35 with high-grade and 10 with "aggressive" low-grade malignant NHL). All patients responded with a complete remission rate (CR) of (27%) and a partial remission rate (PR) of 73% after only one course of ENAP. After a median number of 3.5 ENAP/CHOP courses, the CR and PR rate was 69 and 22%, respectively. Myelosuppression was pronounced and fever of unidentified origin and documented infections followed 59% of all cases given ENAP courses. In the last 19 previously untreated patients mitoxantrone was given at a dose of 10 mg/m2 on d 1 and cytarabine 100 mg i.v., b.d. during d 1-2. Nonhematologic toxicity was mild. We conclude that this novel chemotherapy program is effective both as first-line and salvage treatment in patients with high-grade malignant NHL. Furthermore, ENAP appears clinically to be partly non-cross resistant with CHOP chemotherapy. The dose-limiting toxicity is myelosuppression. The combination should be explored as primary therapy in combination with other chemotherapy or radiotherapy programs.

Chronic Lymphocytic Leukemia (B-CLL) and Immunocytoma (LP-IC): Clinical and Prognostic Relevance of this Distinction.

The Kiel classification of non-Hodgkin lymphomas (NHL) has established chronic lymphocytic leukemia (B-CLL) and immunocytoma (LP-IC) as separate entities of low-grade malignant NHL by morphological and immunohistochemical criteria. The clinical and prognostic relevance of this discrimination was evaluated in a prospective multicenter observation study by the Kiel Lymphoma Study Group. From 1975 to 1980, 430 previously untreated patients with B-CLL (n = 217) and LP-IC (n = 213)a were recruited and followed for up to 14 years. While the age and sex distribution and the incidence of clinical stages were quite similar in both entities major differences between initial manifestations in B-CLL and LP-IC became evident, e.g. in the incidence of bone marrow infiltration (99.5 vs. 86%), peripheral blood lymphocytosis (99.5 vs. 60%), or monoclonal gammopathy (1 vs. 30%). A strictly localized tumor (Ann Arbor stage I/IE) was seen in only 1.5% of the LP-IC patients who were successfully treated by local radiotherapy. In all other patients an expectative-palliative treatment concept was pursued. Long-term survival data analysis revealed significant differences between B-CLL and LP-IC and identified the pseudofollicular in B-CLL and the lymphoplasmacytic in LP-IC as the most favorable histological subtypes. The discriminative prognostic potential of clinical stage (Rai or Binet classification) for B-CLL and LP-IC varied and the pattern of prognostic risk factors obtained by multivariate analysis was not identical. Thus, the morphological distinction between B-CLL and LP-IC correlates with characteristic differences between these entities both in their initial clinical presentation and long-term prognosis.

Low Grade Malignant Non-Hodgkin's Lymphomas and Peripheral Pleomorphic T-Cell Lymphomas in Childhood - A BFM Study Group Report

Non-Hodgkin's lymphomas (NHL) are classified as low or high grade malignant lymphomas of either B or T cell origin. Cells of low grade malignant NHL (LG-NHL) of B cell type represent either follicular or postfollicular, cells of LG-NHL of T cell type postthymic maturation stages in the lymphoid differentiation pathway. LG-NHL often fail to undergo long-term complete remission or cure in adults, no matter what type of conventional therapy is applied. In three pediatric therapy studies frequency and probability of continuous complete remission (pCCR) were studied for LG-NHL and peripheral pleomorphic T-cell lymphomas (PTCL). Of 432 evaluated patients only six children (1.4%) were qualified as LG-NHL. LG-NHL of T cell type were diagnosed in three children (one T-zone lymphoma, two PTCL of small cell type), LG-NHL of B cell type in another three cases. Two children presented with nodular type of centroblastic/centrocytic lymphoma (CB/CC), one with lymphoplasmocytoid type of immunocytoma (IC). In addition to the two patients with low grade malignant PTCL, there have been also four children with high grade malignant PTCL. The analysis showed that there was not significant difference for event free survival of children with LG-NHL and HG-NHL, respectively (pCCR: 0.63 and 0.82, p = 0.29). In contrast, when comparing high and low grade PTCL versus all other types of childhood NHL (non-PTCL), a significant difference seems to exist (pCCR for PTCL: 0.44, for non-PTCL: 0.83; p = 0.02). However, for further concisive conclusions more patients are needed for evaluation.

Antigenic phenotyping of human follicular dendritic cells isolated from nonmalignant and malignant lymphatic tissue

Follicular dendritic cells (FDC) are located within follicles of secondary lymphoid tissue and in lymph nodes of patients with germinal center cell-derived non-Hodgkin lymphomas. Reliable antigenic phenotyping of FDC within tissue sections has been difficult due to simultaneous labeling of the surrounding germinal center cells. Using an enzyme cocktail to digest human tonsils and cervical lymph nodes with subsequent fractionation by albumin gradient centrifugation, cell isolates containing up to 20% FDC were obtained. This preparation allowed the determination of antigenic phenotype on individual FDC. Molecules expressed by FDC were detected by an isotype-specific immunocytochemical double-labeling procedure, i.e. a monoclonal antibody (mAb) specific for FDC (KiM4 or DRC1) in conjunction with a mAb reactive against an additional antigenic determinant. Nonspecific binding of mAb to immunoglobulin Fc receptors located on FDC membranes was avoided by incubation of cells with human IgG aggregates prior to immunostaining. The results revealed that isolated FDC from these lymphoid tissues express transferrin receptors, the intercellular adhesion molecule 1, class II antigens, the B cell antigens CD20 and CD21, and the myelomonocytic properties CD11b and CD14. Immunoglobulin mu or gamma heavy chains and the B cell antigens CD23 and CD24 are detected on 50% of an isolated FDC population. These FDC are negative for the T helper cell antigen CD4, the B cell cell antigens CD19 and CD22, the immunolobulin alpha and delta chains and the S-100 protein. FDC isolated from lymph nodes of patients with low-grade malignant non-Hodgkin lymphoma, identified by DRC1 or KiM4 mAb, presented the same antigenic profile as seen on FDC from nonmalignant tissue. This suggests that FDC from lymphoma tissue isolated in this manner have the same properties as those found in normal tissue.

Methyl-Gag, Ifosfamide, Methotrexate and Etoposide (Mime) as Salvage Therapy for Hodgkin's Disease and Non-Hodgkin's Lymphoma

One hundred and three patients with recurrent or refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) treated with MIME (methyl-GAG, ifosfamide, methotrexate, etoposide) were retrospectively studied. Thirty-seven of the 44 patients with HD, 34/47 with high-grade malignant and 9/12 with low-grade malignant NHL were evaluable for response. Of the 37 evaluable patients with HD, 16 (43%) achieved complete remission (CR) and 4 partial remission (PR), giving a total response rate of 54%. Of the 34 evaluable patients with high-grade NHL, 5 achieved CR and 8 PR, giving a response rate of 38%. Of 9 evaluable patients with low-grade NHL, 2 achieved CR. The main toxicity was leukopenia, thrombocytopenia and infections. Twenty-six per cent of the patients developed septicaemia, which was fatal in 6 cases (6%). We conclude that MIME as salvage regimen can induce complete remissions in lymphoma patients, particularly in HD with previous heavy treatment, and that it is relatively well tolerated.

Primary non-Hodgkin's lymphomas of the central nervous system

Thirty-five primary non-Hodgkin's lymphomas (NHL) of the central nervous system (CNS) were examined in a retrospective study and classified according to the Kiel classification. Diagnosis was made on surgical biopsies in 28 cases and on autopsy specimens in seven cases. The tumors were predominantly located in the frontal lobe and were unifocal in all but two cases. Patients ranged in age from seven to 74 years, with a male-female ratio of 1.3:1. The lymphomas were probably all of B cell type. In contrast to NHLs of the lymph nodes, the NHLs of the CNS we encountered were more often high grade (immunoblastic, lymphoblastic) than low grade malignant. All but one low grade malignant NHL found in our study were lymphoplasmacytoid (LP) immunocytomas.

Non-Hodgkin's lymphomas in Osaka, Japan

Six hundred and eighty-four cases with non-Hodgkin's lymphomas (NHL) in Osaka, Japan were reviewed, using current histopathological classification to obtain a general feature of Japanese lymphomas. There were no remarkable differences in the distribution of age, sex and the location of primary tumors between Japanese NHL and the disease in Western races. Histologically, however, several differences were present; in particular, the lower frequencies of nodular lymphomas of nodal origin and lymphocytic type of nodal and extranodal origin in the present cases. About 10% of the cases show a peculiar histology characteristic for adult T cell lymphomas. From this study, it appears that the ratio of low-grade malignant NHL in Japan is much lower than in the Western countries.

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas results of a prospective multicenter study by the Kiel Lymphoma Study Group.

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas (NHL) was investigated in 1127 patients entering a prospective multicenter observation study. Survival of the 782 (69.4 per cent) patients with low-grade malignant NHL (lymphocytic lymphomas, predominantly B-CLL, LP immunocytoma, centrocytic lymphoma, centroblastic-centrocytic lymphoma) exceeded that of the 341 patients (30.2 per cent) with high-grade malignant NHL (centroblastic, immunoblastic, lymphoblastic lymphomas). Prognosis was best in centroblastic-centrocytic lymphoma and in B-CLL and least favorable in immunoblastic and lymphoblastic lymphomas. Survival of LP immunocytoma and centrocytic lymphoma patients was intermediate after 2 to 2.5 years of follow-up. Corresponding to histopathology, pattern of survival curves of low-grade malignant NHL (slow decline, no plateauing) differed from that of high-grade malignant NHL (rapid decline, subsequent plateauing). Prognosis of B-CLL was superior to that of LP immunocytoma. Stages I and II were more frequent in centroblastic-centrocytic lymphoma (21 per cent) than in LP immunocytoma (2.5 per cent) and centrocytic lymphoma (11 per cent). Ability of radiotherapy to induce stable complete remissions in stage III of centroblastic-centrocytic lymphoma indicates prolonged restriction of lymphoma to the lymphatic system. In immunoblastic and centroblastic lymphomas, stages I and II were diagnosed in 34 and 38 per cent of cases, respectively, but only in stage I/IE of centroblastic lymphoma prolonged remissions were achieved by radiotherapy. In advanced high-grade malignant NHL marked improvement of prognosis was solely possible by induction of complete remissions whereas in corresponding low-grade malignant lymphomas also partial remissions were prognostically relevant.