Antipyretic effect of cycloheximide, and inhibitor of protein synthesis, in patients with Hodgkin's disease or other malignant neoplasms.

Infusion of cycloheximide i.v., an antibiotic known to inhibit synthesis of protein, at a rate of 0.2 mg/kg/hr, reliably caused lysis of fever in 15 chronically febrile patients with Hodgkin's disease who did not have detectable bacterial, fungal, or viral infection. Antipyretic effects were also seen in some patients with reticulum cell sarcoma, lymphosarcoma, acute leukemia, histiocytic medullary reticulosis, plasma cell myeloma, carcinoma of the lung, and carcinoma of the cervix. The drug failed to produce defervescence in four patients with normal granulocyte reserves, who were febrile due to bacterial infection. When infused at a rate of 0.2 mg/kg/hr, the drug apparently caused an acute alteration of protein metabolism in man in that plasma amino acid nitrogen rose acutely while plasma levels of muramidase and ribonuclease fell during the period of the infusion. The data suggest that continuing synthesis of protein may be involved in nonbacterial fever of neoplastic disease. Mammalian granulocytes and monocytes are known to elaborate a pyrogenic protein following appropriate stimulation; it is suggested that in some types of neoplastic disease, particularly Hodgkin's disease, tumor cells may produce and release a pyrogenic protein and that drug-induced inhibition of its synthesis is responsible for the observed lysis of fever.

Antileukemic effects of pseudoisocytidine, a new synthetic pyrimidine C-nucleoside.

Pseudoisocytidine, a new synthetic pyrimidine C-nucleoside, which might be considered a more stable analog of 5-azacytidine, is active in vitro and in vivo, i.p. and p.o., against various 1-beta-D-arabinofuranosylcytosine-resistant lines of mouse leukemia. This antileukemic activity is blocked by cytidine but not by deoxycytidine or thymidine.

The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is a malignancy that occurs frequently in the elderly with a median age greater than 60 years. However, most chemotherapy trials have included predominantly patients less than 60 years of age. We treated 157 patients with diffuse aggressive NHL between September 1982 and May 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), procarbazine, bleomycin, vincristine, and prednisone (CAP/BOP). There were no treatment exclusions for age. Patients in this study ranged in age from 15 to 91 years (median, 63) with 112 patients greater than or equal to 60 years of age. The overall complete remission (CR) rate was 65% with no significant difference for age less than 60 (76%) v age greater than or equal to 60 (61%) (P = .18). With a median 36-month follow-up (range, 22 to 65 months), the overall 5-year survival was 42%. The patients less than 60 years old had a 62% 5-year survival in contrast to a 34% 5-year survival in those patients greater than or equal to age 60 (P = .01). The deaths attributed to tumor or treatment-related toxicity were similar above and below age 60. The difference in survival was due to other causes of death not obviously related to the lymphoma or its therapy-occurring in 22% of patients greater than or equal to 60 years of age but only 2% of patients less than 60 years (P = .005). Our data supports the position that aggressive NHL in elderly patients is not significantly less responsive than in younger patients; however, the inclusion of older patients in clinical trials will decrease the overall survival secondary to deaths due to apparently unrelated causes.

CHLVPP chemotherapy with involved-field irradiation for Hodgkin's disease: favorable results with acceptable toxicity.

Patients with Hodgkin's disease who were previously untreated with chemotherapy received the chlorambucil, vinblastine, procarbazine, and prednisone (CHLVPP) regimen plus limited involved-field radiation therapy for treatment of Hodgkin's disease through the Nebraska Lymphoma Study Group. One hundred patients, 87 with newly diagnosed Hodgkin's disease and 13 who relapsed after receiving previous radiation therapy, were treated with this regimen between 1982 and 1989. Complete remissions (CRs) were obtained in 88 of 100 patients (88%), and there have been a total of eight relapses. The overall 3-year failure-free survival was 76%, with good-prognosis patients (ie, Karnofsky performance status greater than or equal to 80) having a 3-year failure-free survival of 87%. Toxicity with this regimen was minimal, with neutropenic fevers reported in 13% of the patient population, moderate alopecia in 5%, and mild to moderate nausea and vomiting in 11% of the patients. As primary induction therapy for Hodgkin's disease, CHLVPP is an effective regimen with a high patient acceptance profile.

Salvage therapy for relapsed or refractory non-Hodgkin's lymphoma utilizing autologous bone marrow transplantation.

PURPOSE: Our objective was to evaluate the impact of high-dose therapy and autologous bone marrow transplantation as salvage treatment for recurrent non-Hodgkin's lymphoma in a defined group of patients from the Nebraska Lymphoma Study Group. DESIGN: Patients treated initially by oncologists from the Nebraska Lymphoma Study Group between January 1983 and July 1987 who subsequently underwent autologous bone marrow transplantation for recurrent or refractory disease were evaluated for treatment outcome. PATIENTS: Twenty-five patients with relapsed or refractory non-Hodgkin's lymphoma underwent high-dose therapy and autologous stem cell infusion in the time period reviewed. An initial doxorubicin (Adriamycin)-containing chemotherapy regimen had failed in all patients. The most favorable subgroup included 17 patients who were less then 60 years of age and had received no chemotherapy beyond their initial doxorubicin-containing regimen when referred for bone marrow transplantation. RESULTS: The complete response rate to the high-dose therapy was 52%, with an actuarial five-year disease-free survival of all patients treated of 40%. The overall survival at five years was 46%. CONCLUSIONS: High-dose chemo-radiotherapy, followed by infusion of autologous hematopoietic stem cells, can effectively function as salvage therapy in a significant number of patients in whom primary chemotherapy regimens for non-Hodgkin's lymphoma fail. This treatment approach appears to offer superior results when compared with the reported outcome for patients treated with salvage chemotherapy administered at conventional doses.

Studies of cellular proliferation in human leukemia. VIII. The generation time and growth fraction in lymphosarcoma in a leukemic phase during advanced and early relapsing disease.

The kinetics of cell proliferation were studied in a patient with lymphosarcoma in a leukemic phase both before treatment when the disease was very advanced and again at the earliest sign of bone marrow relapse following a drug-induced remission. During advanced disease, the pulse 3H-TdR labeling index (LI) was 11%, the mitotic index (MI) was 0.4% the growth fraction (GF) was 0.6, and the generation time (TG), as measured by the median grain count halving time, was estimated to be 160 hours. The patient went into remission for 25 days after a short course of therapy with prednisolone and arabinosylcytosine (Ara-C). During early relapsing disease, the LI was 17%; MI, 1.1%; GF, 1.0; and TG, 85 hours. The results of this study suggest that the rate of cell proliferation slows in leukemia as the tumor mass increases in volume, and that the slower growth is due to an increase in cell generation time, a decrease in the growth fraction, and an increased rate of spontaneous cell loss.

The L-5 protocol: intensive treatment for patients with chronic myeloid leukemia.

An aggressive treatment program combining splenic irradiation, splenectomy and intensive cytotoxic combination chemotherapy was used in 37 patients with Ph1 chromosome positive chronic myelogenous leukemia. Cytogenetic Ph1 chromosome determination on marrow cells revealed a significant but transient decrease in the Ph1 positive cell population in 12/37 (32%) cases. Survival duration appears longer in patients who show a reduction in the Ph1 positive population. Blastic transformation occurred in 18/37 (49%) cases, not different from our historical control.

Relationship of a T-lymphocyte marker to phase of cell cycle and morphology of leukemic cells.

Spontaneous rosette formation with sheep erythrocytes (SRBC) was studied in the peripheral blood and bone marrow lymphoid cells from a patient whose leukemic cells appeared to be T-lymphocytes. Simultaneous morphological examination of the peripheral blood white cells indicated that they consisted of 21% lymphoblast; 26% prolymphocytes and 48% mature lymphocytes. The distribution of bone marrow cells within the cell cycle was determined by flow microfluorometry and 7 hours after treatment with vincristine consisted of 69% in G1, 21% in S, and 9% in mitosis. Since virtually all the cells both in marrow and blood formed rosettes with SRBC this implies that the expression of this T cell marker is independent both of the morphological appearance of these cells and their position within the cell cycle.

Acute lymphoblastic leukemia in adults and children. Differences in response with similar therapeutic regimens.

Twenty-three adult patients (ages greater than 15 years) and 75 children with acute lymphoblastic leukemia were treated with similar intensive, sequential cytotoxic protocols (L-2). The adult patients have lower remission rate (78%) than the children (98%). The duration of remission and the length of survival are also shorter in adults. The incidence of central nervous system (CNS) relapse in adults (27.7%) is higher than in children (7.1%) suggesting that prolonged prophylactic intrathecal methotrexate as given to the children is more effective than the schedule used for adults where intrathecal methotrexate was given only in the first 2 months of therapy. The low incidence of CNS involvement in children on the L-2 protocol compares favorably with other series reported using a combination of cranial irradiation and intrathecal methotrexate. In both adults and children there seemed to be a higher incidence of CNS involvement in patients with initial white blood cell counts greater than 25,000 cells/mm3.

Prophylactic heparin therapy in acute promyelocytic leukemia.

Twenty-four patients with acute promyelocytic leukemia were reviewed. Group I, treated between July 1970 and September 1973, received arabinosylcytosine and 6-thioguanine, and there was one complete remission, with 4/7 dying during induction with intracerebral hemorrhages, and 2/7 dying within one month. Group II, treated between May 1974 and March 1975, received daunomycin and arabinosylcytosine without heparin and 2/8 went into remission, with 6/8 dying during induction, 5 with intracerebral hemorrhages. Group III, treated between March 1975 and November 1976, received the identical chemotherapy as group II but with the addition of prophylactic heparin and there were 7/9 complete remissions, with 2/9 dying with intracerebral hemorrhages. In Group III there was an increased incidence of remission induction when compared to Group II (p less than .05) or when compared to Groups I and II combined (p less than .05). There was also a decreased incidence of fatal hemorrhage in Group III. This suggests that prophylactic heparin is useful during remission induction in acute promyelocytic leukemia.

Treatment of acute leukemia in adults.

Improvement in the management of acute leukemia in adults has not progressed nearly so rapidly as has the treatment of childhood leukemia. One important difference is that most adults have myeloblastic or related forms of the disease (AML), whereas the majority of children have lymphoblastic leukemia (ALL). However, even adults with ALL fail to respond as well to a similar regimen as do children with the same type of leukemia. In a recent series of patients with ALL who were treated with the complex multiple drug "L-2" protocol, the incidence of complete remission in adults was 78% vs. 99% in children, and the median duration of remission was only 24 months in the adults, whereas it has not yet been reached in the children and is projected to be over 4 years. In AML and the related nonlymphoblastic forms of acute leukemia, therapy is still unsatisfactory in both adults and children. With the best current drug treatment schedules, the incidence of complete remission is now better than 50%, but it is often difficult to compare the exact remission rates in different series because of differences in reporting results. In adults treated with the multiple drug "L-6" protocol, the incidence of remission in previously untreated patients was 56% and the median duration of remission was 10 months. The median survival of all patients (responders and non-responders) was 1 year whereas that of responders only was 2 years. It is encouraging that a significant proportion of those patients with AML who have complete remissions now remain in remission for extended periods; about 45% of patients responding to the "L-6" protocol remained in remission over 1 year, and 18% have been in continuous remission for 2 to over 4 years. Even after discontinuing treatment, some patients with AML stay in remission for long periods, and it is possible that some of them may have been cured. If this proves to be true, it becomes of great importance to determine what is different about the patients who do exceptionally well as compared to the majority who continue to die within a year. However, no consistent nor distinctive favorable prognostic features have yet been identified.

Cyclophosphamide L2 protocol: a combination chemotherapeutic regimen for advanced non-hodgkin's lymphoma.

A group of 49 patients with advanced non-Hodgkin's lymphoma were entered in a combination-chemotherapy protocol (cyclophosphamide L2). Of 14 patients with diffuse poorly differentiated lymphocytic lymphoma (DPDL), 64% responded with two partial remissions (PR) and seven complete remissions (CR). Both PRs are stable at 17+ months while six of the CR group are free of disease at 3+-23+ months. Fifty-three percent of 30 patients with diffuse histiocyctic lymphoma (DHL) responded with 23% attaining CR status. Of the nine PR patients, six are stable at 11+-23+ months while six of the seven CR group are without disease at 9+-27+ months. The major toxic effect was bone marrow suppression with two deaths during periods of neutropenia; one of these deaths was definitely drug related. The encouraging results in the DPDL category have led to a continuation of this protocol for patients with this histologic type. In patients with DHL other approaches are being explored.