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Biomedical subjects

A Fefer

Publications and source records attributed to A Fefer.

At least 37 records · Page 2Linked to original sources
PubMed1988

Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation.

The purpose of this study was to investigate the effect of dose and duration of infusion of recombinant interleukin-2 (IL-2) on toxicity and immunomodulation. In a phase I/II study, IL-2 was administered intravenously (IV) daily for five consecutive days every other week for 4 weeks of treatment to 23 patients with progressive melanoma, renal, colon, or ovarian cancer by one of four regimens: groups I and II received 3 X 10(5) U/m2/d by two-hour or 24-hour infusion, respectively; groups III and IV received 3 X 10(6) U/m2/d by two-hour or 24-hour infusion, respectively. In a subsequent study, six patients (group V) received a single priming cycle of daily IL-2 for five days at 3 X 10(6) U/m2/d in divided 15-minute infusions every eight hours, before undergoing leukapheresis for lymphokine-activated killer (LAK) cell generation. Toxicity was mild with 3 X 10(5) U/m2/d, but severe chills and fever, moderate hypotension (not requiring IV pressors), and weight gain were observed with 3 X 10(6) U/m2/d. Toxicity was also related to the duration of infusion. In group IV (continuous infusion), fluid retention, weight gain, and azotemia were more frequent and severe than in groups III or V, in which the same total dose was administered by two-hour infusion or in three divided 15-minute infusions. IL-2 induced rebound lymphocytosis, which was directly dose-related and significantly higher in group IV (continuous infusion) than in groups III or V. Dramatic increases in the percentage and absolute number of cells expressing the IL-2 receptor were also most pronounced in group IV. With the higher dose of IL-2, LAK cells appeared in the circulation, and natural killer (NK) cytotoxicity was augmented. The results showed that the toxicity and immunomodulation by IL-2 are dose-dependent and are maximal by continuous infusion compared with two-hour or divided every eight hours infusions.

Adult↗
PubMed1988

Second marrow transplants in patients with leukemia who relapse after allogeneic marrow transplantation.

Twenty-six patients with recurrent leukemia following allogeneic marrow transplantation received a second marrow transplant between 1.5 and 78 months (median 26) after the initial transplant. Preparative regimens for second transplant included multi-agent chemotherapy with total body irradiation, 2.0-10.0 Gy (five patients), dimethylbusulfan alone (one patient), and dimethylbusulfan or busulfan plus cyclophosphamide (20 patients). One patient died before engraftment of infection and 18 died after engraftment from veno-occlusive disease (4), infection (2), idiopathic pneumonia (3), cytomegalovirus pneumonia (3), leukemia (5) and encephalopathy (1). Seven patients (27%) survive 12-38 months (median 26); five (19%) are disease-free and two have recurrent leukemia. Two of the five disease-free survivors have chronic graft-versus-host disease. All of the surviving patients received dimethylbusulfan or busulfan plus cyclophosphamide and six of the seven surviving patients were among 11 patients transplanted more than 2 years after the first transplant whereas only one was among the 15 transplanted in less than 2 years. Those who have second marrow transplants one or more years after their initial transplant are more likely to benefit, while those who are less than 1 year from initial transplant appear to benefit the least.

Adolescent↗
PubMed1988

A prospective randomized trial of alpha 2B-interferon/gamma-interferon or the combination in advanced metastatic renal cell carcinoma.

Eighty-nine patients with advanced measurable metastatic renal cell carcinoma were entered into a prospective randomized trial comparing alpha-interferon to gamma-interferon and to the combination. The trial was performed in order to confirm the activity of gamma-interferon and assess the potential clinical synergism. Response rates were 5, 10, and 5%, respectively. The low response rate may have been due to the inability to raise the doses of the interferons to higher levels. Clinical synergy at this dose, route, and schedule of administration in renal cell carcinoma does not exist.

Carcinoma, Renal Cell↗
PubMed1987

Recombinant interleukin 2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial.

Twenty-two patients with refractory malignancies were treated with four escalating weekly doses of recombinant interleukin 2 (IL2), given either i.v. by 2- or 24-h infusion, or s.c. A 1-wk washout period between each dose of IL2 was provided for the evaluation for pharmacokinetic and immunomodulatory effects. The maximum i.v. dose was 30 X 10(6) units; the dose-limiting toxicities were fever, flu-like symptoms, and hypotension. The maximum s.c. dose was 3 X 10(6) because of volume limitations with s.c. injection. No tumor regression was seen. During infusions of 3 X 10(6) units over 2 h or 24 h, serum IL2 levels greater than or equal to 223 units/ml or 16 units/ml were maintained, respectively; with s.c. injection of 3 X 10(6) units, levels greater than 20 units/ml were maintained for 9 h. Marked lymphopenia was observed 24 h after the initiation of IL2 doses which was completely reversible when measured prior to the next dose. The lymphopenia was nonselective; T- and B-lymphocytes decreased in an IL2 dose-dependent manner, without consistent change in the OKT4:OKT8 ratio. No change was detected in monocyte expression of HLA-Dr or T-cell expression of the IL2 receptor. The in vitro generation of lymphokine-activated killer cytotoxicity decreased sharply and transiently shortly after i.v. doses. Mitogen responsiveness, delayed-type hypersensitivity, natural killer cytotoxicity, and mixed-lymphocyte reactivity were unchanged or decreased transiently shortly after IL2 doses. These studies help define the bioavailability of IL2 by i.v. or s.c. routes, and they will aid in the design of studies utilizing daily doses of IL2.

Antibodies↗
PubMed1987

Interferon in the treatment of hairy cell leukemia.

An ongoing multicenter study has confirmed earlier observations that interferon alfa-2b (Intron A, Schering Corp., Kenilworth, NJ) is effective in the treatment of hairy cell leukemia (HCL). The 212 evaluable subjects in this trial received 2 X 10(6) U/m2 of interferon alfa-2b subcutaneously, on an outpatient basis, three times a week for 1 year. Of this group, 166 had previously undergone splenectomy, and 94 had received chemotherapy; 96% had more than 50% hairy cells in the bone marrow. Objective responses (complete, partial, and minor) were recorded in 89% of the study group and were characterized by a marked reduction in infections as well as in the need for transfusions. Complete response, defined as a normal complete blood count (CBC) and less than 5% hairy cells in the marrow, was achieved in 4% of the subjects. Partial responses (normal CBC) were attained in 74%, and minor responses (normalization of subnormal hematocrits or granulocyte or platelet counts) in 11%. Normalization of CBC usually did not occur until after 2 to 5 months of therapy. Results were comparable in splenectomized and nonsplenectomized patients. After 1 year of treatment, the responders were randomized to continue therapy for 6 months or to stop treatment and remain under observation. Preliminary findings have shown no significant differences in the incidence or time to progression of disease in the two groups, but additional data will be required before conclusions can be reached with regard to the need for maintenance therapy. Overall, the results of this study indicate that interferon alfa-2b is well tolerated, produces durable responses, and dramatically improves the quality of life in a high percentage of patients with progressive HCL.

Clinical Trials as Topic↗
PubMed1987

Subcutaneous recombinant gamma interferon in cancer patients: toxicity, pharmacokinetics, and immunomodulatory effects.

Recombinant gamma interferon (r gamma-IFN) was administered s.c. daily to 26 patients with advanced cancer. Patients were assigned to one of six doses: 0.5, 1, 2, 4, 6, or 8 million units (MU)/m2 per d. The major toxicities were an influenza-like syndrome and fever, seen in all patients. Dose limiting toxicity occurred in 4 of 4 patients treated at 8 MU/m2. One patient with nodular poorly differentiated lymphocytic lymphoma had a mixed response, and two patients with renal cell cancer have had stabilization of disease for greater than 10 and greater than 12 months. Pharmacokinetic analysis, by radioimmunoassay, revealed mean serum r gamma-IFN concentrations up to 17 ng/ml, with maximal serum levels noted 6 to 13 h after injection. In vivo immunomodulation was assessed by natural killer (NK) cytotoxicity, monocyte activation as determined by cell surface expression of HLA-Dr, and peripheral blood mononuclear cell phenotype analysis by flow cytometry. The mean T4/T8 ratio increased from 2.1 pretreatment to 4.1 after 24 h of treatment, but returned to baseline after 7 and 28 days of treatment. Augmentation of NK function was noted after 7 days of treatment. Monocyte cell surface expression of HLA-Dr increased after 28 days of treatment at the three lowest doses. In conclusion, daily s.c. r gamma-IFN can be easily administered on an outpatient basis with minimal local skin toxicity, results in prolonged serum levels, and is associated with immunological changes of potential antitumor significance. Further study of the in vivo immunomodulatory effects induced by r gamma-IFN is indicated to help define the optimal treatment regimen.

Adult↗
PubMed1987

The treatment of hairy cell leukemia with recombinant alfa interferon: a multi-institutional study.

This report expands on previous work with interferon alfa-2b (Intron A; Schering-Plough) in the treatment of hairy cell leukemia (HCL). Sixty-four patients were treated, with 89% achieving a response (either CR, PR or MR). The percentage of hairy cells in the peripheral blood decreased dramatically within one month and in the marrow, progressively over nine months. Normalization of blood counts was associated with a marked decline in serious infections and in the need for red cell or platelet transfusions. Preliminary results with a further group of patients confirm these satisfactory results.

Adult↗
PubMed1987

Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0 X 10(6) IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table. Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.

Acute Kidney Injury↗
PubMed1987

Marrow transplantation for acute nonlymphocytic leukemia following therapy for Hodgkin's disease.

Seven patients with acute nonlymphocytic leukemia (ANL) following therapy for Hodgkin's disease (HD) were treated with cyclophosphamide (Cy) alone or combined with 10.00 to 15.75 Gy total body irradiation (TBI) and marrow transplantation. Five patients were transplanted without an attempt at prior remission induction, one patient following failure of remission induction and one patient in first remission following successful induction. Four patients died of multiorgan failure, 15 to 70 days after transplant. Three patients died of progressive or recurrent leukemia 56, 120, and 280 days after transplant. These results illustrate the difficulty of treating patients for secondary leukemia with marrow transplantation and suggest that transplantation in the preleukemic phase should be studied.

Acute Disease↗
PubMed1987

Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation.

Between July 1970 and January 1985, 100 patients with malignant lymphoma were treated with high-dose chemoradiotherapy and bone marrow transplantation. Twenty-eight of the 100 are alive and the actuarial probability of disease-free survival 5 years from transplantation is 22%. The most common reason for treatment failure was disease recurrence, with an actuarial probability of 60%. A proportional hazards regression analysis showed that the likelihood of disease-free survival was less in those patients transplanted in resistant relapse and in those previously treated with chest radiotherapy. Neither disease histology (Hodgkin's disease, high-grade lymphoma or intermediate-grade lymphoma), nor source of marrow (syngeneic, allogeneic, or autologous) significantly influenced either disease-free survival or probability of relapse. The use of high-dose chemoradiotherapy and marrow transplantation appears to offer a better chance for long-term survival than any other form of therapy for young patients with disseminated malignant lymphoma whose disease has progressed after initial combination chemotherapy. The best results with marrow transplantation were obtained in patients transplanted in early relapse or second remission who had not received prior chest radiotherapy.

Adolescent↗
PubMed1987

Graft-versus-leukemia in man: relationship of acute and chronic graft-versus-host disease to relapse of acute leukemia following allogeneic bone marrow transplantation.

To study the effect of acute and chronic graft-versus-host disease (GVHD) on recurrent leukemia, we analysed data on patients with acute leukemia receiving allogeneic marrow transplants in Seattle between 1970 and 1986. Four hundred fifty-four patients survived in remission 150 days after HLA-identical transplant and 114 currently survive five to fifteen years after marrow grafting. At the time of transplant, 252 patients had acute nonlymphocytic leukemia in remission or relapse and 202 had acute lymphocytic leukemia in remission or relapse. According to Kaplan-Meier estimates, recurrence of leukemia following transplantation was observed in 28% of patients developing moderate to severe (grade II-IV) acute GVHD and 48% of patients with no or mild (grade O-I) acute GVHD (p = 0.0028). Relapse was observed in 34% of patients developing clinical extensive chronic GVHD and 45% of patients free of chronic GVHD (p = 0.0001). The incidence of recurrent leukemia was 28% in recipients developing both acute and chronic GVHD and 52% in patients free of both acute and chronic GVHD (p = 0.0001). These data confirm an apparent graft-versus-leukemia effect in patients developing GVHD after allogeneic marrow grafting. Current studies are aimed at determining the influence of such apparent adoptive immunotherapy within the different categories of leukemia and methods to manipulate and augment the clinical benefit of this observation.

Acute Disease↗
PubMed1987

Graft versus leukemia effect in man: the relapse rate of acute leukemia is lower after allogeneic than after syngeneic marrow transplantation.

To determine whether allogeneic bone marrow transplantation (BMT) is associated with a graft vs leukemia (GVL) effect in man, the relapse rate of acute leukemia after allogeneic BMT was compared with that occurring after syngeneic (genetically identical twin) BMT. The patients had ALL or ANL in second or subsequent complete remission (CR) or in relapse. The allogeneic and syngeneic marrow recipients were comparable in diagnosis, age, and interval from diagnosis to BMT and received comparable chemoradiotherapy regimens. Allogeneic marrow recipients, however, received, in addition, GVH disease prophylaxis, most often methotrexate and, more recently, cyclosporine or both. All patients treated by the Seattle team from 1970-1986 are included. Leukemic recurrence was observed in 62% of 785 allogeneic recipients and 75% of 53 syngeneic recipients (p less than 0.0001). The results confirm the circumstantial evidence for a GVL effect exerted by allogeneic marrow. Analyses are in progress to determine whether a GVL effect exists in subsets of patients as a function of their particular diagnosis or status at the time of BMT.

Bone Marrow Transplantation↗
PubMed1987

Allogeneic and syngeneic marrow transplantation following high dose dimethylbusulfan, cyclophosphamide and total body irradiation.

Fifty-eight patients received an allogeneic or syngeneic marrow transplant following conditioning with high doses of dimethylbusulfan (DMB), cyclophosphamide (CY) and total body irradiation (TBI). Thirty-two patients had either chronic myeloid leukemia (CML) in accelerated phase or blast transformation, or acute leukemia after first relapse. The actuarial survival of these 32 patients at 3 years was 12% compared with 25% for a group of 206 patients with similar diagnoses prepared for transplantation with CY and TBI alone. This reduced survival was associated with a greater incidence of early non-leukemic deaths, in particular as a result of severe hepatic veno-occlusive disease. The incidence of leukemic relapse was not different in the two groups. Of 13 patients with CML in chronic phase who received syngeneic transplants following DMB, CY and TBI, nine are alive in hematologic and cytogenetic remission from 3.9 to 9.4 (median 6.2) years post-transplant.

Adolescent↗
PubMed1987

Treatment of preleukemic syndromes with marrow transplantation.

Thirty patients with advanced preleukemic syndromes were treated with marrow transplantation. Most cases were diagnosed by the presence of peripheral pancytopenia and a diagnostic marrow examination but in 6 of the 30 patients pretransplant chromosome studies were instrumental in establishing the diagnosis. Three patients prepared for transplantation with cyclophosphamide alone recurred with their disease within 6 months of transplantation. The other 27 patients were treated with cyclophosphamide and total body irradiation. Twenty of these 27 patients had preleukemia not associated with prior therapy or severe marrow fibrosis. Thirteen of these 20 are alive and well 9 to 56 months from transplant and 7 died, 4 of interstitial pneumonia, 2 of candida septicemia, and 1 of disseminated zoster. There have been no disease recurrences in this group. The remaining preleukemic patients, which include 3 patients transplanted for preleukemia secondary to prior therapy and 4 patients transplanted for preleukemia associated with severe marrow fibrosis, have all died. Major problems in these patients included disease recurrence (2 cases) and, in those with severe marrow fibrosis, graft failure (2 cases). These results suggest that for patients with life-threatening pancytopenia due to spontaneous preleukemia without severe marrow fibrosis, marrow transplantation can prolong disease-free survival and may result in cure of the disease.

Bone Marrow Transplantation↗
PubMed1987

Sequential evaluation of alpha-2b-interferon treatment in 128 patients with hairy cell leukemia.

This multicenter study reports on 128 patients with hairy cell leukemia (HCL) who were treated subcutaneously with alfa-2b interferon (Intron A, Schering Corp, Kenilworth, NJ), three times a week at a dosage of 2 megaunits/m2. Five patients (4%) had a complete response (CR) with virtual eradication of hairy cells from the bone marrow, 98 (77%) showed a partial response (PR), defined as hematologic normalization of all three blood counts associated with decreased hairy cells in the bone marrow, and nine (7%) showed a minor response (MR) that included improvement in at least one measurement of the blood count. Sixteen persons (12%) did not respond. Thirteen of the 128 had had neither a splenectomy nor a CR. Responders who completed 12 months of interferon therapy were randomized to either an additional 6 months of therapy or to observation only. Relapses occurred in six of 35 (18%) randomized to observation alone and in two of 29 (7%) who continued interferon therapy. The relapses are too few to draw conclusions; however, 27 responders have remained off interferon treatment for greater than 6 months; cessation of interferon therapy does not result in a rapid deterioration of peripheral blood counts. In HCL, interferon therapy produced a large percentage of durable objective responses in the majority of patients. The exact duration of this response and the results of retreatment are yet undetermined.

Adult↗
PubMed1987

Magnetic resonance imaging of bone marrow in hairy cell leukemia: correlation with clinical response to alpha-interferon.

Five patients with progressive hairy cell leukemia were treated with recombinant alpha 2-interferon and examined prospectively at 3-month intervals using serial bone marrow biopsies and magnetic resonance (MR) imaging. Pretreatment iliac crest marrow biopsies demonstrated hairy cell infiltration involving 30-90% of marrow cellularity. Concurrent pretreatment coronal images of the proximal femurs and pelvis using MR revealed extensive marrow involvement that varied in distribution from patchy to diffuse. At 6 months, all patients had responded to alpha 2-interferon with improvement in peripheral blood counts and decrease in lymphoid infiltration on marrow biopsy to 15-40%. Six-month follow-up MR scans demonstrated decreasing marrow leukemia infiltration and increasing marrow fat. MR bone marrow imaging appears useful in the initial diagnosis of hairy cell leukemia, for monitoring the response to treatment, and possibly for predicting relapse.

Bone Marrow↗