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.     

Lymphosarcoma cell leukemia: the contribution of cell surface study to diagnosis

Cell surface immunoglobulin, complement receptor, and spontaneous rosette formation with sheep erythrocytes were investigated in 43 patients with malignant lymphoma, including 13 with lymphosarcoma cell leukemia, and in 59 patients with chronic lymphocytic leukemia. The quantity of immunoglobulin on the lymphocyte surface was estimated from the intensity of fluorescent staining with fluorescein-conjugated anti- immunoglobulin antisera. At least two, and probably three, B cell species could be recognized by cell surface study. Cells from chronic lymphocytic leukemia and diffuse well-differentiated lymphocytic lymphoma had sparse amounts of surface immunoglobulin, while the cells of diffuse poorly differentiated lymphocytic lymphoma had large quantities of this material. Nodular lymphoma probably represented a third B-cell subtype with intermediate amounts of surface immunoglobulin. The lymphocytes of chronic lymphosarcoma cell leukemia exhibited the intense surface staining, which was characteristic of the underlying poorly differentiated lymphocytic lymphoma (diffuse or nodular), and could be readily distinguished from the faint-staining chronic lymphocytic leukemia cells.     

Combination chemotherapy with VM-26, adriamycin bleomycin, and prednisone as a secondary treatment of malignant lymphoma

Thirty-eight pretreated patients with Hodgkin's disease (HD) and malignant non-Hodgkin's lymphoma were given combination chemotherapy with VM-26, Adriamycin, bleomycin, and prednisone. Four of 15 evaluable patients with HD achieved a partial remission (PR), with a median duration of 8 months. Of 12 patients with diffuse poorly differentiated lymphocytic lymphoma, one achieved a complete remission (30+ months) and five achieved a PR (median, 6 months). One of three patients with histiocytic lymphoma had a PR of 1.5 months. There was one drug-related death. Five patients developed life-threatening hematologic toxicity. Two HD responders died of acute nonlymphocytic leukemia.     

Prognostic significance of lymphocytic surface markers and histology in adult non-Hodgkin's lymphoma.

Neoplastic tissues from 75 adults with non-Hodgkin's malignant lymphoma, histologically classified according to the Rappaport schema, were studied for B- and T-lymphocyte surface markers. All nodular poorly differentiated lymphocytic lymphomas and diffuse well-differentiated lymphocytic lymphomas were B cell. Of 30 diffuse poorly differentiated lymphocytic lymphomas 16 were B, five were T, and nine were "null"; of ten diffuse histiocytic lymphomas, seven were B and three were null. In patients with diffuse lymphoma, those whose malignant cells demonstrated B markers survived significantly longer than those whose malignant cells demonstrated no markers. The prognostic capabilities of the Rappaport histologic classification and surface marker studies were compared. For patients with diffuse lymphomas, classification as B or null more accurately predicted survival than did identification as lymphocytic or histiocytic. However, survival was best predicted by a classification combining the Rappaport histologic scheme with surface marker studies.     

Advanced lymphocytic lymphoma: randomized comparisons of chemotherapy and radiotherapy, alone or in combination.

Ninety-nine previously untreated patients with stage III and IV malignant lymphoma were randomized to receive either cyclic combination chemotherapy (50 patients) or extensive "systemic" radiotherapy (49 patients). Histologic classification included nodular poorly differentiated lymphoma (54 patients), nodular mixed lymphoma (21 patients), and diffuse poorly differentiated lymphoma (24 patients). High overall response rates were seen with either approach (90% for radiotherpy; 86% for chemotherapy) and complete remission were relatively common (60%--80%). Overall median survival of all patients in this trial will exceed 5 years regardless of the induction therapy used; however, disease-free survival is not commonly achieved with either regimen. Relapse-free survival rates at 4-year followup, regardless of induction regimen, are 13% for diffuse lymphomas and 24% for nodular lymphomas. The second prospective trial attempts to use a combined approach and compares cyclic combination chemotherapy with total-body irradiation and combination chemotherapy. Initial results on 34 patients indicate high overall response rates (100%) and similar complete remission rates (64%--67%). With 14 months' median followup no patients in either arm of the trial have died but relatively equal numbers have relapsed.     

Central nervous system relapse in malignant lymphomas: risk factors and implications for prophylaxis

The records of 292 patients with malignant lymphoma other than Hodgkin's disease, registered in our protocols from 1967 to 1977, were reviewed to identify those with central nervous system (CNS) involvement. Thirty-one patients were encountered with this complication, an incidence of 11%. Patients with a diffuse histology had a higher frequency of CNS recurences (27/174 = 16%) in contrast to only 4/118 (3%) for those with nodular types. However, if only patients with diffuse histology in CR are considered, the frequency of CNS relapse is 13.5% (13/98). The risk factors that predict for the development of this complication were studied using multivariate analysis. Diffuse poorly differentiated lymphocytic and diffuse undifferentiated lymphomas were found to be associated with a high risk of CNS relapse. Prior chemotherapy, bone marrow involvement, age less than 35, and extranodal disease were also identified as high-risk factors. Using the information generated by a logistic regression model, patients with malignant lymphoma of diffuse type can be classified into three categories when first seen: low-risk group, intermediate, and high-risk group. CNS prophylaxis is recommended for the intermediate and high-risk group, while only close follow-up is advised for the low-risk group patients who have one adverse characteristic.     

Collaborative phase I-II study of recombinant DNA-produced leukocyte interferon (clone A) in metastatic breast cancer,malignant lymphoma,and multiple myeloma

Fifty-two patients with advanced cancer received sequentially escalating doses of 3 to 50 million units of recombinant DNA-produced alpha interferon by daily intramuscular injection. There were 23 patients with metastatic breast cancer, 17 patients with nodular poorly differentiated lymphocytic lymphoma, and 12 patients with multiple myeloma. Complete and partial remissions were obtained in 35 percent of patients with nodular poorly differentiated lymphoma, whereas rare activity was found in breast cancer and multiple myeloma. Dose-limiting toxicity occurred in patients receiving 36 million units or more and consisted of fatigue/asthenia, weight loss, and elevation of transaminase levels, requiring frequent interruption, reduction in dose, or cessation of treatment. Hematologic toxicity was rarely a limiting factor, but myelosuppression was severe in some patients with multiple myeloma. All toxicities were reversible on discontinuation of treatment. Antibodies to recombinant leukocyte A interferon were seen infrequently but may adversely affect therapy.     

Combination chemotherapy ("CHOP-Bleo") in advanced (non-Hodgkin) malignant lymphoma.

Forty-seven adults with advanced malignant lymphoma (the majority in stage IV) were treated with a combination of cyclophosphamide, hydroxyldaunorubicin (Adriamycin), vincristine (Oncovin), prednisone, and bleomycin (CHOP-Bleo). The complete remission (CR) rate was 66%. The overall response (complete + partial remission) was 92%. The CR rate in patients with diffuse histiocytic lymphoma (DHL) was 69%. Only 3 of the 18 patients with DHL in CR have relapsed; the projected median duration of response was calculated to be greater than 2 yr. In patients with nodular poorly differentiated lymphocytic lymphoma (NPDL), the CR rate was 62%. One of the eight patients with NPDL in CR has relapsed; the projected median duration of complete response will be greater than 4 yr. The median survival for all patients entered in this study has not been reached; however, it was estimated that it will be greater than 3 yr. The survival curves became flat at 70 wk for the patients with DHL and at 1 yr for the patients with NPDL. Major complications during chemotherapy with CHOP-Bleo were myelosuppression and alopecia. Only six severe infections occurred during myelosuppression. No hemorrhagic problems were observed. This study indicates that combination chemotherapy with these agents is effective in increasing the CR rate and survival in patients with diffuse histiocytic lymphoma. In patients with NPDL, further observation will be needed to assess the effect of this combination on survival.     

Combination chemotherapy of advanced non-Hodgkin lymphoma with bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP).

Seventy-three patients with advanced non-Hodgkin lymphoma were treated with bleomycin, Adriamycin, cyclophosphamide, vincristine (Oncovin) and prednisone (BACOP), administered intensively during a 7-wk induction course followed by intermittent cycles every 3 wk for a total of 28 wk. The objective response in 44 evaluable nonleukemic patients with diffuse histology was 86%, with 66% achieving a complete remission (CR), varying from 80% for diffuse poorly differentiated lymphocytic (DPDL) to 56% for diffuse histiocytic (DH) lymphoma. In patients with nodular histology 89% (8/9) achieved a CR with a projected 75% of patiients in CR at 14 mo. Median follow-up from time of CR for nodular histology was 17 mo. The projected median duration of CR in diffuse histology was 14 mo. with median survival 14 mo. Patients with a partial response survived a median of 7 mo, compared to 3 mo for nonresponders. Of 29 patients with diffuse histology, 17 (59%) have remained disease free for 5-34 mo with a median follow-up of 12 mo. Survival beyond 20 mo has been projected for 42% of patients with diffuse histology (58% with DPDL and 32% with DH). The central nervous system (CNS) was involved in a total of 11/44 (25%) patients with diffuse histology, including 5 with primary CNS relapse. BACOP resulted in a higher CR rate and longer survival than a previous three-drug program (COP), especially in patients with diffuse histology.     

Lymphocyte surface characteristics in malignant lymphoma

The surface of lymphocytes obtained from fresh biopsy specimens from 41 patients with malignant lymphoma and from 30 normal subjects or patients with non-neoplastic lymphadenopathy were investigated. Immunoglobulin on the cell surface was used to identify B cells, whereas T cells were recognized by their reactivity with an antithymocyte antiserum and their ability to form rosettes with sheep erythrocytes. Normal and inflammatory lymph nodes were composed predominantly of T lymphocytes, as were nodes from 14 patients with Hodgkin's disease. Two thymomas were T cell proliferations, whereas a node from a patient with ataxia-telanglectasia was devoid of T lymphocytes. The presence of immunoglobulin on the cell surface indicated that 19 of 21 lymphocytic lymphomas were B cell proliferations, whereas the cells from 3 histiocytic lymphomas (reticulum cell sarcomas) and 1 mixed histiocytic and lymphocytic lymphoma were devoid of surface immunoglobulin. In immunoglobulin-positive tumors, one predominant heavy chain and one predominant light chain could usually be identified, thus establishing the clonal character of the neoplastic proliferation. Ten of 11 diffuse poorly differentiated lymphocytic lymphomas were composed of cells with large amounts of surface immunoglobulin, whereas only 1 of 5 diffuse well differentiated lymphocytic tumors contained such abundant surface immunoglobulin. The surface immunoglobulin data indicate the existence of at least two subspecies of B cell neoplasms. A small lymphocyte with sparse surface immunoglobulin proliferates as diffuse well differentiated lymphocytic lymphoma and chronic lymphocytic leukemia, whereas a larger lymphocyte with abundant surface immunoglobulin proliferates as diffuse poorly differentiated lymphocytic lymphoma and lymphosarcoma cell leukemia.     

Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin's lymphoma

A multicentre phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with refractory or relapsed indolent non-Hodgkin's lymphoma. Thirty-six patients were enrolled onto the study, including 11 cases of mantle cell lymphoma (MCL), 10 cases of chronic lymphocytic leukaemia (CLL)/lymphocytic lymphoma, nine cases of follicular lymphoma, four cases of lymphoplasmacytic lymphoma and two cases of T-cell lymphoma. Gemcitabine 1 g/m(2) was administered as a 30-min infusion on d 1, 8 and 15 of a 28-d schedule, up to a maximum of six cycles. Complete responses were observed in two patients with MCL, and partial responses were observed in seven patients, including three patients with CLL/lymphocytic lymphoma, two patients with T-cell lymphoma, one patient with MCL and one patient with follicular lymphoma. Minor responses were observed in three patients, including two patients with MCL and one patient with CLL. The median duration of response was 150 d and the overall progression-free survival was 342 d. Haematological toxicity was observed as grade 3-4 leucopenia in 12 patients (33%) and grade 3-4 thrombocytopenia in 18 patients (50%). Severe non-haematological toxicity included one case of fatal veno-occlusive disease, one case of thrombotic microangiopathy leading to terminal renal failure, one case of capillary leak syndrome, one case of myocardial infarction and drug-induced fever in two patients. These data suggest that gemcitabine displays activity in patients with MCL and CLL/lymphocytic lymphoma. Haematological toxicity was frequent in these heavily treated patients. Severe non-haematological toxicity was significant and should be taken into account in the design of future trials.     

2-Chlorodeoxyadenosine activity in patients with untreated, indolent non-Hodgkin's lymphoma

Based on the encouraging results of the use of 2-chlorodeoxyadenosine ([2-CdA], cladribine) in patients with advanced, low-grade lymphomas resistant to conventional therapy and the acceptable toxicity profile encountered, we conducted a phase II trial of 2-CdA in patients with untreated indolent lymphomas. Twenty-eight patients with untreated low- grade lymphomas were given 2-CdA at 0.1 mg/kg/d as a 7-day continuous infusion every 28 to 35 days. A total of 89 courses, median of three courses per patient, of 2-CdA were administered. Seventeen men and 11 women with a median age of 58 years were treated. Fifteen patients had diffuse small lymphocytic (8 with plasmacytoid features), 10 had follicular small cleaved-cell, and there were single patients with monocytoid B-cell, mantle cell and mucosa-associated lymphoid tissue (MALT) lymphoma histologies. All 28 patients were evaluable for toxicity and 26 were evaluable for response. Nine (35%) patients (4 with diffuse small lymphocytic, 3 with follicular small cleaved-cell, 1 with mantle cell, and 1 with MALT lymphoma) achieved a complete response, and 14 (54%) patients (8 with diffuse small lymphocytic, 5 with follicular small cleaved-cell, and 1 with monocytoid B-cell lymphoma) achieved a partial response, for an overall response rate of 88%. The median response duration was 10 months (range, 3 to 44+). Myelosuppression was the principal toxicity. Actuarial survival at 60 months from initial diagnosis was 60% (95% confidence interval, 35% to 82%) and at 48 months from treatment onset was 62% (95% confidence interval, 39% to 83%). These results establish the major activity of 2- CdA in patients with untreated indolent lymphoma, especially those with the diffuse small lymphocytic subtype.     

Abnormal Peripheral Blood Lymphocytes and Bone Marrow Infiltration in Non-Hodgkin''s Lymphoma

The blood lymphocytes of 21 normal blood specimens, 20 patients with various malignant disorders and 63 patients with non-Hodgkin's disease lymphoma, all with lymphocyte counts below 6 x 10(9)/l, were examined by sheep red cell rosetting, fluorescent antisera to surface immunoglobulin and for sensitivity to colchicine. The results were correlated with bone marrow infiltration and lymph node histological findings. The ratio of kappa to lambda light chains in the surface immunglobulin was used to determine if an abnormal clone of lymphocytes was present. In the normals and the non lymphoma controls the expected normal ratio of approximately 2K to 1 lambda was found with a narrow spread. In non-Hodgkin's lymphoma cases there was a wide spread of ratios with half the cases outside the range of the controls. These cases were considered to have a clone of abnormal lymphocytes in the blood although their routine blood and differential counts were usually normal. There was a very significant correlation of the presence of a clone with ultrasensitivity to colchicine and with involvement of the bone marrow. 81% of the cases with a histological diagnosis of well-differentiated diffuse lymphocytic lymphoma, 64% of those with poorly differentiated diffuse but only 22% of those with diffuse histiocytic had an abnormal lymphocyte clone demonstrated by an abnormal K:lambda ratio.     

Primary mediastinal lymphoma in adults

The incidence of primary mediastinal lymphoma in adults was investigated in 184 patients with non-Hodgkin's lymphoma. This entity was defined as disease within the mediastinum in patients who presented with symptoms due to an enlarging mediastinal mass. Of 184 patients, 17 presented with primary mediastinal lymphoma. All had a diffuse histologic pattern. The most common pathologic type was poorly differentiated lymphocytic lymphoma, diffuse (PDL-D), (11 cases). In nine of these 11 cases the patients had tumors of convoluted lymphocytes. The presentation was rapid in onset, with heart failure, pericarditis, dyspnea and superior vena caval syndrome predominating. Eleven of the 17 were clinical stage I or II, but eight of these had widespread disease on pathologic staging or rapid dissemination soon after diagnosis. In conclusion (1) primary mediastinal lymphoma is always diffuse in histology. (2) The most frequent pathologic type is PDL-D, with convoluted morphology. (3) Compression of vital intra-thoracic structures is common. (4) Although seemingly localized at presentation, this entity usually implies disseminated disease.     

NON-HODGKIN'S LYMPHOMA INVOLVING THE CENTRAL NERVOUS SYSTEM

Abstract: :In 44 out of 758 patients (5.8%) with non-Hodgkin's lymphoma presenting between 1971 and 1982, the central nervous system (CNS) was involved. Patients with a diffuse histology had a 7.6% (34/449) incidence of CNS involvement compared to 3.9% (10/257) for patients with nodular lymphoma. In 63% of patients there was evidence of progressive systemic lymphoma at the time of diagnosis of CNS disease and in 23% CNS relapse occurred in clinical remission. Bone marrow was involved in 34% of patients at diagnosis and in 52% at some time prior to the onset of CNS complications. Cerebrospinal fluid cytology was positive in 63% and an elevated protein level was found in 95% of patients. The median length of survival of the 44 patients was only 3.2 months, but patients who responded to treatment of CNS lymphoma survived significantly longer than those who showed no response or progressed on therapy. Complete response to CNS treatment was achieved in five patients, of whom none relapsed in the CNS and two are long-term disease-free survivors. CNS prophylaxis appears justified for patients with lymphoblastic lymphoma, Burkitt's tumour, and diffuse undifferentiated lymphoma, who are at high risk of developing CNS complications. Patients with diffuse histiocytic, and diffuse poorly differentiated lymphocytic, lymphoma who have bone marrow involvement may also benefit from CNS prophylaxis.     

Treatment of non-Hodgkin's lymphoma with marrow transplantation in identical twins

Eight patients with disseminated non-Hodgkin's lymphoma who failed conventional combination chemotherapy were treated with high-dose chemotherapy, a supralethal dose of total-body irradiation, and a bone marrow transplant from a normal identical twin. Seven patients experienced complete remission. Four of the seven patients (two with diffuse poorly differentiated lymphocytic lymphoma, one with composite lymphoma, and one with diffuse moderately well differentiated lymphocytic lymphoma) remain in complete unmaintained remission 12-126 mo from transplantation. One patient relapsed after 10 mo but was retreated and is alive in unmaintained complete remission 73 mo from transplantation. One patient died of Pseudomonas pneumonia while in complete remission and one patient relapsed and died of progressive lymphoma. These results demonstrate that intensive chemoradiotherapy and twin marrow transplantation can induce frequent and enduring remissions in patients with disseminated non-Hodgkin's lymphoma who have failed conventional therapy.     

Acute dilation of the colon in malignant lymphoma.

Acute dilatation of the colon with signs of systemic toxicity developed in an elderly man with malignant lymphoma. Although barium contrast X-rays taken previously were interpreted as consistent with granulomatous colitis, rectal biopsy had revealed features characteristic of malignant lymphoma, poorly differentiated lymphocytic type. Bone marrow and lymph nodes were also involved. The onset of dilatation was temporally related to therapy with opiates and anticholinergics, and the acute episode was resolved with nasogastric suction, intravenous fluids, albumin, and antibiotics.     

Terminal deoxynucleotidyl transferase in the diagnosis of leukemia and malignant lymphoma.

Neoplastic cells from 253 patients with leukemia and 46 patients with malignant lymphoma were studied for the presence of terminal deoxynucleotidyl transferase (TdT) by biochemical and fluorescent antibody technics. TdT was detected in circulating blast cells from 73 of 77 patients with acute lymphoblastic leukemia, 24 of 72 patients with chronic myelogenous leukemia examined during the blastic phase of the disorder and in cell suspensions of lymph nodes from nine of nine patients with diffuse lymphoblastic lymphoma. Blast cells from six of 10 patients with acute undifferentiated leukemia were TdT positive, but the enzyme was found in only two of 55 patients with acute myeloblastic leukemia. TdT was not detected in other lymphocytic or granulocytic leukemias or in other types of malignant lymphomas. The fluorescent antibody assay for TdT permits rapid and specific identification of the enzyme in single cells. The TdT assay is clinically useful in confirming the diagnosis of acute lymphoblastic leukemia, evaluating patients with blastic chronic myelogenous leukemia, and distinguishing patients with lymphoblastic lymphoma, whose natural history includes rapid extranodal dissemination, from patients with other poorly differentiated malignant lymphomas.     

Primary Gastrointestinal Tract Lymphoma–A Clinico–pathological Study of 28 Cases

Abstract: Primary gastrointestinal tract lymphoma . K. S. Crowley, G. Don, G. E. Gibson, C. A. Juttner and JR. Miliauskas, Aust. N.Z. J. Med., 1982, 12, pp. 135–142.
A retrospective study of 28 patients with primary gastrointestinal tract lymphoma is presented. There were 27 cases of non–Hodgkin's lymphoma and one case of Hodgkin's disease. The patients with non–Hodgkin's lymphoma of the gastrointestinal tract represented 10% of all non–Hodgkin's lymphoma cases seen at the Royal Adelaide Hospital/Institute of Medical and Veterinary Science complex over the six year survey period, 1972–1977.
Of the patients with non–Hodgkin's lymphoma, 26 cases were diffuse type, and one case was nodular type. There was a M/F sex preponderance of 2–811, and 70% of cases were aged between 40 and 69 years. The commonest site was the stomach (19 cases), followed by small intestine (7 cases), and one case involved large intestine. At initial presentation, the disease was confined to the affected viscus (Stage IE) in seven patients (25%), and in 12 patients (43%) the disease involved viscus and regional lymph nodes (Stage HE). The one patient with Hodgkin's disease had involvement of the large intestine, abdominal lymph nodes and bone marrow (Stage IV).
This study was retrospective, and a management protocol was not employed. However, of the seven patients presenting with Stage IE disease, six cases had diffuse poorly differentiated lymphocytic lymphoma. Five of these patients were treated by surgical resection alone, and were in complete remission at follow–up of 66 to 103 months.
In order to compare realistically the survival of different groups of patients with primary gastrointestinal lymphoma, we consider that a prospective multicentre clinical trial with comprehensive staging procedures, uniform histological classification and accepted management protocol is warranted.     

Protected environment-prophylactic antibiotic program for malignant lymphoma. Randomized trial during chemotherapy to induce remission.

Fifty-eight patients with malignant lymphoma were randomly allocated to receive three courses of chemotherapy to induce remission with CHOP-Bleo on the protected environment-prophylactic antibiotic (PEPA) program (30 patients) or as controls (28 patients). The complete remission rate for all patients was 74 per cent, for patients with diffuse histiocytic lymphoma 78 per cent and for patients with nodular poorly differentiated lymphocytic lymphoma 65 per cent. There were no significant differences in response rates and duration of responses between those on the PEPA program and control patients. The frequency of infection was significantly lower among the patients on the PEPA program, and dosage escalation of the chemotherapeutic agents was accomplished more often among these patients. Dosage escalation did not increase the complete remission rate, but it did reduce the relapse rate and signficantly reduced the fatality rate. The duration of remission and survival was significantly longer for those patients who received dosage escalation.