High-grade Malignant non-Hodgkin's Lymphoma Research Articles

Long-term follow-up of CHOP-treated non-Hodgkin lymphoma of high-grade malignancy

The long-term outcome of 116 NHL patients (38 CB, 33 IB, 24 LB, 11 high-grade unclassified, 9 PTCL, 1 Ki-1 lymphoma - see list of abbreviations) treated with an age-adjusted CHOP regimen from 1980-85 was evaluated. The median age was 64 years. Of these patients 28% had significant comorbidity. CB patients had the best outcome; the median survival was not reached after 110 months. However, the differences in survival of all histological entities are not significant (P = 0.08). Fifty-six percent of the patients had clinical stages I-II. The CR rate of all 116 patients was 47%. After a median follow-up of 58 months, 30% of the patients are alive and disease-free. Of 14 relapses 11 occurred within 2 years. The median time period before relapse was 9 months. Salvage therapy failed, as none of the IB and LB patients achieved CR. Five CB patients had CR with second-line therapy, four had PR after induction therapy, one patient relapsed after 30 months. Of the CR patients 15% developed second or third neoplasms. Only one instance of acute myeloblastic leukemia was observed. These results indicate that age-adjusted CHOP is a well-tolerated therapy.

Computer aided cytometry in high grade malignant non-Hodgkin's lymphomas and tonsils.

The aim of the study is to establish quantitative cytological criteria for reliable diagnoses in high grade malignant non-Hodgkin's lymphomas (NHL). For this purpose Pappenheim-stained cytologic imprints from 15 cases of high grade malignant NHL and ten cases of chronic tonsillitis have been analysed using a TV-microscope system, high resolution color scanning (13.3 pixel/microns), and image processing on a computer. The highly reliable computer-extracted cell features can be used to discriminate the different cell types of malignant NHL. Because of a considerable overlap, no feature on its own is sufficient to discriminate all the different cells. Only multivariate analysis of a suitable combination of features allows reliable discrimination. The results show that the different cells defined by subjective morphological criteria in the Kiel-classification of malignant NHL also form distinctive subpopulations with regard to their objective mathematical cell features and show distinctive differences when compared with their benign counterparts derived from reactive lymphatic tissue.

Mitoxantrone and high-dose cytarabine as salvage therapy for refractory non-Hodgkin's lymphoma.

Mitoxantrone (Novantrone, NO) and high-dose cytarabine (Ara-C, AC) have each been shown in monotherapy trials to be active in non-Hodgkin's lymphoma (NHL). In the current study, a combination of the two drugs (NOAC) was administered to 31 patients with advanced NHL refractory to modern sequential chemotherapy regimens. Ara-C was administered at 3 g/m2 as a 3 hour infusion every 12 hours on day 1 (2 doses) and mitoxantrone at 10 mg/m2/day on days 2 and 3. Of the 18 patients with high-grade malignant NHL, six have attained a complete remission (CR) and two, a partial remission (PR). One CR and 5 PRs were achieved among the other 13 patients with intermediate or low-grade NHL. The median time to relapse (TTR) of patients achieving CR was 7 months with a range from 4 to 17 months. Myelosuppression with subsequent infections was the major toxicity of this regimen. The median duration of severe neutropenia (less than 0.5/nl) was 9 days with a range of 0 to 27 days and the median duration of severe thrombocytopenia (less than 20/nl), 5 days with a range of 0 to 35 days. Infectious complications during cytopenia was seen in 45.3% of the courses administered and fever of unidentified origin was seen in 42.3%. About 63% of the patients were hospitalized for intravenous antibiotic or antimycotic treatment. Other side effects were mild and included nausea, stomatitis, and transient tachycardia of greater than 100/min. Thus, this regimen was active in refractory NHL with poor prognosis, and the toxic side effects were not excessive. Evaluation of the activity of this regimen at higher dose levels of Ara-C is warranted.

Sequential Combination Chemotherapy (Caboppivim) for the Treatment of High-Grade Malignant Non-Hodgkin Lymphoma

In 42 patients with high-grade malignant non-Hodgkin lymphomas, a new treatment program was used in an attempt to improve results without increasing toxicity. Two effective but relatively well tolerated and non-cross resistant drug combinations were given sequentially according to the response of disease. Therapy was started with a combination consisting of cyclophosphamide, doxorubicin, bleomycin, vincristine, procarbazine and prednisone (CABOPP). In patients with complete remission after a maximum of 4 cycles of CABOPP, this regimen was continued for a total of 6 cycles. In patients with progressive disease or with only a partial remission after 4 cycles of CABOPP, therapy was switched to a combination consisting of etoposide, ifosfamide and methotrexate (VIM). Complete remission (CR) was achieved in 86% of patients. Sixty-nine percent achieved CR with CA-BOPP alone and 17% after changing to VIM. The CR rate was 100% in patients with stage I or II and 78% in those with stage III or IV of disease. The projected survival at 2 years is 66%. Fifty-six percent of patients with CR are predicted to have continued CR at 2 years. Thus, CABOPP/VIM appears to be an effective and well tolerated program for the treatment of aggressive lymphomas. The value of this program, however, can only be established comparing it with other newly developed protocols in randomized studies.

Klinefelter's syndrome and malignant lymphoma

The high risk for malignancy for carriers of several congenital chromosomal abnormalities is discussed. We report herein a patient with Klinefelter's syndrome associated with a high grade malignant non-Hodgkin lymphoma. Chromosome analysis of PHA-stimulated lymphocytes showed a mosaic of 46,XXY (90%) and normal 46,XY (10%) metaphases. To our knowledge, this is the third reported case of a malignant non-Hodgkin lymphoma in a patient with Klinefelter's syndrome in the literature.

A clinicopathological study of seven cases of primary high-grade malignant non-Hodgkin's lymphoma of the central nervous system.

Seven cases of primary non-Hodgkin's lymphomas of the central nervous system are described. Six cases were diagnosed after pathologic examination of surgical material; in one case, a patient with acquired immunodeficiency syndrome, the diagnosis was made at autopsy. The mean age of the patients was 52 years. The lesions were supratentorial in all cases, and unifocal in 6: the autopsy case had multicentric lesions. The cytologic examination of the cerebrospinal fluid was performed in 3 cases and was negative. The most common histologic type was immunoblastic lymphoma. The mean postoperative survival time was 12 months; in 2 cases, surgery combined with radiotherapy prolonged the survival for more than 2 years. Leptomeningeal involvement was considered to indicate a poor prognosis.

Relation between enzymatic activities and the degree of malignancy of human lymphomas

The relationship between the intracellular levels of DNA polymerase alpha (DP-alpha), adenosine deaminase (ADA) and lactate dehydrogenase (LDH) and the degree of malignancy of human lymphomas was investigated. Twelve non-neoplastic lymph nodes and 88 malignant lymphomas were examined. For non-Hodgkin's lymphomas (NHL) the low or high grade of malignancy was established according to three classifications: the Rappaport, the Kiel and the Working Formulation for Clinical Usage, with the latter also recognizing an intermediate grade group. Non-neoplastic lymph nodes had significantly lower levels of all the three enzymes than those found in high-grade malignant NHL (the P value ranged from < 0.02 to < 0.001). Hodgkin's disease, a slowly evolving neoplasia, showed lower levels of DP-alpha ( P < 0.001) and ADA ( P < 0.001), but not of LDH, than high-grade NHL. Among NHL, whatever classification was used, the low-grade malignant lymphomas had significantly lower levels than the high-grade ones for all the three enzymes ( P < 0.005 or P < 0.001). The intermediate-grade group of the Working Formulation different from the high-grade group for DP-alpha ( P < 0.01) and ADA ( P < 0.02) but not for LDH. It differed from the low-grade group only for ADA ( P < 0.005). Lymphoblastic and Burkitt's lymphomas were the groups with the highest levels of the three enzymes. Among low-grade lymphomas very low values were found in the histological entities defined as DLWD in the Rappaport classification, CLL and lymphoplasmacytoid immunocytoma in the Kiel classification and small lymphocytic (group A) in the WF. The levels of all enzymes in these histotypes were always significantly different from the other low-grade histotypes, and from the intermediate-grade ones of the WF. In the Kiel classification polymorphous lymphoplasmacytoid lymphoma, recently recognized as a group with a quite aggressive clinical course, was characterized by high levels of all three enzymes. Moreover, among centroblastic-centrocytic (Cb-Cc) lymphomas those associated with a better prognosis (Cb-Cc follicular, with small centrocytes) had lower levels of DP-alpha ( P < 0.05) than those with a mixed cellular population. Taken together, these data suggest that intracellular enzyme values may have a role in better defining the prognosis of NHL.

Progress in the management of high risk non-Hodgkin's lymphomas. 10 years of experience of the 3rd Medical Department of Hanusch Hospital, Vienna.

An analysis of 173 cases of non-Hodgkin's lymphoma (NHL) admitted to our hospital from January 1973 to January 1983 is presented. Of the 173 cases, 124 patients suffered from NHL of high grade malignancy according to the Kiel classification (37 centroblastic lymphoma (CB), 30 immunoblastic lymphoma (IB), 43 lymphoblastic lymphoma (LB), 14 NHL high grade malignancy unclassifiable). In addition, 26 patients with secondary high grade malignant NHL were included in the analysis (14 secondary CB, 10 secondary IB, 2 secondary LB). Also investigated were 23 patients with anaplastic centrocytic lymphoma (CC) (20 primary CC, 3 secondary CC), an entity originally classified as low grade malignant lymphoma, but showing a poor outcome and need for aggressive therapy. Symptoms at presentation of all patients are described. Of the 173 patients, 71% had an advanced stage of the disease at the time of diagnosis (Ann Arbor stage III or IV). B-symptoms were observed in 81%. Extranodal involvement, (exceptive bone marrow involvement), determined by clinical examination was seen in 55%. Survival of patients changed significantly after replacing initial radiotherapy with aggressive chemotherapy (P less than 0.001). Improvement of survival statistics was due to the better outcome of patients with localized stages (Ann Arbor stages I and II) as compared to those with generalized disease (P less than 0.002). Prognostic factors influencing survival were elevation of lactic dehydrogenase (P less than 0.0001) and response to therapy (P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Intensive cytotoxic therapy followed by autologous bone marrow transplantation for non-Hodgkin's lymphoma of high-grade malignancy

Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.

Intensive Cytotoxic Therapy Followed by Autologous Bone Marrow Transplantation for Non-Hodgkin's Lymphoma of High-Grade Malignancy

Abstract Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.

HNK-1+ cells in non-Hodgkin's lymphoma: lack of relation with transferrin receptor expression on malignant cells.

It has been proposed that Natural Killer (NK) cell activity is involved in host defence against neoplasia, and that NK cells react with or recognize the transferrin receptor (TrR) on target cells. HNK-1 expression has been related to NK cell function. Therefore, in 118 cases of non-Hodgkin's lymphoma (NHL) we studied the occurrence and distribution of HNK-1+ cells by immunohistochemistry, and simultaneously assessed the expression of TrR on malignant cells. In NHL of intermediate or high grade malignancy there was uniform expression of TrR on malignant cells. In low grade malignancy NHL, only lymphocytic and lymphoplasmacytoid lymphomas were TrR negative, except for faint staining of proliferation centres. In 23 cases of follicular lymphoma, 9 showed the absence of HNK-1+ cells in neoplastic follicles. In 16/23 cases HNK-1+ cells were present around follicles or in interfollicular areas: 8 of these cases revealed a higher density of HNK-1+ cells at this site than inside the follicles. In 22/26 cases with high grade malignancy NHL, HNK-1+ cells were absent or present in small density, which is different from the presence in higher density in low grade malignancy NHL. We conclude that (i) TrR expression on NHL cells is not obligatory related with histological class or malignancy grade of the tumour, and that (ii) HNK-1+ cells are not universally present in areas of malignant cells, in particular in follicular lymphoma and in NHL of high grade malignancy.

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.

The "clostridial effect" of selective decontamination of the human gut with trimethoprim/sulphamethoxazole in neutropenic patients.

During 59 periods of hospitalisation, 39 patients with either acute myeloid leukemia (22), acute lymphatic leukemia (9), acute undifferentiated leukemia (1), blastic crisis of chronic myeloid leukemia (6) or high-grade malignant non-Hodgkin lymphoma (1) were subjected to aggressive polychemotherapy after selective decontamination of the gut. The patients were given an amphotericin B suspension in a dosage of 1.2 g/day for two days, after which one tablet of trimethoprim/sulphamethoxazole (TMP/SMZ) (160 mg TMP and 800 mg SMZ) t.i.d. was added to prevent endogenous infections by gram-negative aerobic bacteria or moulds and to maintain the "colonisation resistance" endowed by the anaerobes. During 16 of the 59 periods of hospitalisation, no potentially pathogenic aerobic bacteria were isolated. TMP/SMZ-resistant Escherichia coli were the etiological agent of septicemia in two patients, and resistant Klebsiella pneumoniae and Pseudomonas aeruginosa in two other patients. These bacteria were cultured from the patients' fecal samples prior to the development of septicemia. We observed that long-term prophylaxis with TMP/SMZ modified the normal aspect of the fecal biotop culture, not only by suppressing the aerobic gram-negative bacteria, but also by allowing certain clostridia to appear. We differentiated 207 clostridia from the fecal samples of 29 patients and observed a predominance of TMP/SMZ-resistant Clostridium difficile, Clostridium innocuum and Clostridium clostridiiforme. C. difficile was also isolated from the blood culture of a neutropenic patient treated with TMP/SMZ and proved to be very toxic in the Verocell culture.

B-cell lymphomas (non-Hodgkin's lymphomas of B type) in children--morphologic and immunologic spectrum

The non-Hodgkin's lymphomas (NHL) occurring in children are described on the basis of the Kiel classification. As a rule, the NHL in children are of high-grade malignancy. The morphologic and immunologic features of all types of high-grade malignant B-cell lymphoma are described. The most frequent type of B-NHL in children is B-lymphoblastic lymphoma, including Burkitt and non-Burkitt types. Centroblastic lymphoma, immunoblastic lymphoma and unclassified high-grade malignant NHL are less common in children. The difference between the morphologic term "unclassified" and the immunologic definition "non-B/non-T" or "null" (or "unclassified") is explained. The equivalents of the various lymphoma types in the Lukes-Collins and Rappaport classifications are given.

Germinal center cell lymphomas: prognostic significance of their histopathological differentiation.

Clinical data of 48 patients with centrocytic, 83 patients with centroblastic/centrocytic and 64 patients with centroblastic lymphoma who had entered a prospective multicenter study of the Kiel Lymphoma Study Group since October 1975 were compared. Advanced (stage IV) disease at time of diagnosis, predominantly due to bone marrow infiltration, was most frequent in centrocytic (69% of patients) and in centroblastic/centrocytic (51% of patients) lymphomas as compared to only 28% of patients with centroblastic lymphoma. High survival probability of patients with localized centrocytic and centroblastic/centrocytic lymphomas after radiotherapy, contrasting with a worse prognosis of corresponding patients with centroblastic lymphoma, is compatible with the classification of these lymphoma entities as neoplasias of low-grade malignancy. However, as shown by this prospective and previous retrospective trials overall survival probability of patients with advanced centrocytic lymphoma was inferior to that observed in corresponding patients with centroblastic/centrocytic lymphoma. These findings suggest the possibility that patients with advanced centrocytic lymphoma occupy an intermediate position between typical low-grade and typical high-grade malignant non-Hodgkin lymphomas.