Jacob Zighelboim

Treatment of acute myelogenous leukemia. A prospective controlled trial of bone marrow transplantation versus consolidation chemotherapy.

In a prospective controlled trial, the relative effectiveness of allogeneic bone marrow transplantation and postremission chemotherapy was assessed for adult patients with acute myelogenous leukemia in first complete remission. Twenty-three patients, 15 to 45 years of age, who had an HLA-identical sibling donor were designated to receive bone marrow transplantation. Forty-four patients who either lacked an HLA-identical sibling or were over 45 years of age were designated to receive intensive consolidation chemotherapy. The actuarial rate of leukemia relapse was significantly lower in the transplantation group than in the chemotherapy group (40 +/- 25% [95% confidence interval] compared with 71 +/- 14%, p = 0.01). Actuarial survival at greater than 4 years was not significantly different (40 +/- 21% compared with 27 +/- 14%, p greater than 0.4). These data show that bone marrow transplantation is more effective than consolidation chemotherapy in preventing leukemia relapse, but overall survival was not improved in this study.

Intensive Chemotherapy for Acute Myelogenous Leukemia

A complete remission rate of 82% was obtained in a group of 68 patients with acute myelogenous leukemia treated with a high-dose induction chemotherapy (TAD) consisting of 7-day courses of 6-thioguanine, cytarabine, and daunorubicin. The patients who achieved remission received intensive consolidation chemotherapy and were randomized to receive maintenance chemotherapy with or without immunotherapy. Median remission duration was 13 months and median survival, 21 months. Neither central nervous system prophylaxis nor the addition of immunotherapy to the maintenance regimen prolonged remissions or improved survival. Age, sex, and subclassification of acute myelogenous leukemia had no effect on the remission rate or survival. These data indicate that a large proportion of patients with acute myelogenous leukemia can achieve remission with intensive induction chemotherapy. Attempts to prolong remission have been less successful.

Paraplegia following intrathecal cytosine arabinoside.

Paraplegia following prophylactic intrathecal cytosine arabinoside (Ara‐C) is described in a patient with acute myelogenous leukemia in remission who received doses of 100 mg/m2/d for 5 consecutive days. Cerebrospinal fluid examination prior to the last dosage of cytosine arabinoside revealed a mononuclear pleocytosis and increased protein. The neurological manifestations developed within one week after the last dose of Ara‐C and persisted for over 8 weeks. Administration of intrathecal Ara‐C in the same dose over longer intervals with 3‐5 days between consecutive doses resulted in mild, transient neurological symptoms (paresthesias) in only one of 30 patients so treated.

Comparison of immune derangements in patients with different malignancies

Immune function was evaluated in 109 patients with carcinoma of the breast, bladder, head and neck, and lung. Patients with head and neck cancer showed the most profound derangements of immune function; patients with lung cancer showed no detectable abnormalities. Non‐irradiated patients with disseminated head and neck cancer had significantly depressed lymphocyte counts (mean 1357/mm3, P <.05), E‐rosette forming cells (mean 770/mm3, P <.05), and response to phytohemagglutinin (P <.05) as compared to controls. This immunodeficiency was detected in patients with localized as well as advanced disease. Although significant differences were noted between patients with head and neck cancer and the other tumors, these differences were minimized by radiation therapy. All irradiated patients showed comparable degrees of immune dysfunction. Absolute Fc‐receptor cells were depressed in all irradiated patients and in non‐irradiated patients with disseminated breast cancer.

PROLONGED SURVIVAL IN ACUTE MYELOGENOUS LEUKAEMIA WITHOUT MAINTENANCE CHEMOTHERAPY

46 adults with previously untreated acute myelogenous leukaemia who achieved complete remission with 6-thioguanine, cytarabine, and daunorubicin (TAD) received two courses of intensive consolidation chemotherapy. The first cycle consisted of 5-azacytidine and doxorubicin followed by a second consolidation cycle with TAD. Maintenance chemotherapy was not administered. Median remission duration was 14 months and 26% (95% confidence interval, 11%-41%) remained in continuous remission at 5 years. Actuarial 5 year survival was 31% (+/- 15%). Results were most favourable in patients who achieved complete remission within 60 days of chemotherapy being initiated. These data indicate that prolonged disease-free survival can be achieved in patients treated with intensive induction and consolidation treatment alone without maintenance chemotherapy.

Population immunology: age and immune cell parameters.

Abstract This paper has analyzed the relation of peripheral blood immune cell parameters to age in a population of 200 normal, healthy, working adults. The age range of the population was 21–70 years, and it consisted of an equal number of males and females. The relative and absolute number of E and EA rosettes and the phytohemagglutinin (PHA) reactivity and antibody-dependent cellular cytotoxic activity of peripheral blood mononuclear cells were determined for each individual, and age differences were sought by stratifying the sample population into 5-year age subsets and comparing the groups statistically. No differences were detected between the age groups for any of the parameters examined. These results indicate that T and Fc receptor lymphocyte activity did not vary in the population studied with increasing age. Other investigators examining the same parameters have found evidence of age-related variation in immune status. The discrepancy could indicate that the response of the immune system to age is polymorphic.

Antibody dependent cellular cytotoxicity: cytotoxicity mediated by non t-lymphocytes.

Abstract The cytotoxic capacity of human lymphocytes in antibody dependent cellular cytotoxicity (ADCC) is mediated by non T-lymphocytes. Evidence is presented that purified peripheral blood T-lymphocytes as well as human thymus cells are inefective in ADCC. By contrast, lymphocytes bearing a receptor for immunoglobulin (Ig) effectively mediated this function.

Acute Leukemia: Biology and Treatment

A fundamental abnormality in acute myeloid leukemia is a block in cell differentiation with resultant accumulation of immature leukocytes. This abnormality can be studied in continuously growing leukemic cell lines that differentiate with simple chemical signals. Surface antigenic modulation occurring with cell differentiation can be monitored by specific antisera. These antisera have great potential as diagnostic and therapeutic reagents. More than 90% of patients with acute lymphoblastic leukemia and more than 70% of patients with acute myeloid leukemia can achieve remission of disease with aggressive multiagent chemotherapy. Long-term, disease-free survival is obtainable in about one half of patients with acute lymphoblastic leukemia but in less than 15% of patients with acute myeloid leukemia. The future directions of research for achieving cure of acute leukemia seem to be well defined.

Intraperitoneal immunotherapy of epithelial ovarian carcinoma with Corynebacterium parvum

Corynebacterium parvum was administered intraperitoneally to 21 patients with epithelial ovarian cancer. Nineteen patients had surgically measurable disease and two received adjuvant therapy. Surgically confirmed responses were documented in six of 19 patients (31.6%), with two complete responses (10.5%) and four partial responses (21.1%). Three patients (15.8%) had stable disease, and 10 patients (52.6%) had disease progression. The mean survival of the patients who had a complete response was 35.5 months; the four patients who had a partial response the mean survival was 26.6 months, and of the nonresponders the mean survival was 12.6 months (p less than 0.02). The mean survival of the entire group was 18.2 months. Initial response and patient survival correlated with the amount of disease pretreatment. Thus six responding patients had less than or equal to 5 mm maximum diameter tumors, that is, minimal residual disease. Toxicity in the 86 courses of therapy included abdominal pain in 78% of cases, fever in 56%, nausea in 40%, and vomiting in 22%. Stimulation of cytotoxic lymphocytes resulted from the administration of C. parvum, which induced a significant increase of both intraperitoneal natural killer lymphocyte cytotoxicity and antibody-dependent cell-mediated cytotoxicity in six of nine patients tested; these two types of cytotoxicity correlated with response to therapy and may be partially responsible for the surgically documented tumor regression. While the clinical usefulness of intraperitoneal C. parvum is limited because of its toxicity, intraperitoneal immunotherapy may prove useful in patients with minimal residual ovarian cancer when more refined agents become available.

Synergy is documented in vitro with low-dose recombinant tumor necrosis factor, cisplatin, and doxorubicin in ovarian cancer cells

Abstract Ovarian carcinomas have been shown to be sensitive or insensitive to the in vitro exposure of several cytotoxic drugs and cytokines. Because of the potential for cytokines to enhance the efficacy of chemotherapeutic agents and to improve their therapeutic index, the optimal dose and schedule of the combination of these agents have been studied. We examined the cytotoxic effect of a combined modality using a variety of concentrations of recombinant tumor necrosis factor (rTNF) (a cytotoxic cytokine) with Adriamycin (ADR) and cisplatin (CDDP) on human ovarian carcinoma cell lines. Cytotoxicity was determined in a 24-hr 51 Cr-release assay and confirmed in a 5-day viability culture assay. Five cell lines were used: PA-1, 222, OVCAR-3, SKOV-3, and OVCAR-8. Doses of rTNF that were minimally cytotoxic resulted in significant cytotoxicity and synergy when used with optimal or suboptimal concentrations of ADR or CDDP. This synergy was observed in four cell lines. Interestingly, the rTNF-and drug-resistant SKOV-3 cell line was sensitive to the synergistic effect of Adriamycin and rTNF. The synergistic effect that was obtained was specific to rTNF, while the combined use of ADR and CDDP or recombinant interleukin-2 and cytotoxic drugs had no synergistic effect on tumor cell lysis. Further, the addition of anti-TNF antibody abrogated the synergistic effect seen with rTNF and the cytotoxic drugs. These studies demonstrate clearly that significant synergistic antitumor cytotoxic activity against human ovarian carcinoma cell lines can be achieved with combinations of low doses of rTNF and ADR or CDDP, suggesting their possible adaptation in vivo for cancer therapy. Further, the studies suggest that rTNF and the cytotoxic drugs tested may share a common lytic pathway. Since rTNF used alone has been relatively inactive in clinical trials, its potential activity may be apparent only when combined with conventional cytotoxic chemotherapeutic agents and when administered in relatively low concentration.