Interleukin 1 enhances growth factor-dependent proliferation of the clonogenic cells in acute myeloblastic leukemia and of normal human primitive hemopoietic precursors.

IL-1 is released by activated monocytes and is thought to be a key mediator of the host immune response. The availability of the purified and, more recently, recombinant IL-1 has allowed the characterization of other biological properties of this molecule. Thus, IL-1 is thought to have the same properties as hemopoietic 1, a growth factor that has been shown to act on primitive murine hemopoietic cells. Here we report that rIL-1 acts synergistically with granulocyte/macrophage CSF (GM-CSF) or granulocyte CSF in the stimulation of clonogenic cells from many patients with acute myeloblastic leukemia (AML). Although IL-1 by itself has no effect on AML blasts, it can support colony formation under conditions where there is detectable production of endogenous GM-CSF. IL-1 also promotes the growth of multipotential progenitors from normal human bone marrow cells in the presence of GM-CSF. These observations support the hypothesis that in the hemopoietic system, IL-1 has a selective effect on primitive precursors.

Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: The National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-one patients with measurable MBC were studied. Three patients were ineligible and were excluded from analysis. The planned dose of docetaxel was 100 mg/m2 intravenously (i.v.) every 3 weeks. Prior adjuvant chemotherapy was allowed if at least 12 months had elapsed from completion of treatment to recurrence. RESULTS: The most severe toxicity was granulocytopenia. Ten patients (20.8%) were hospitalized for febrile neutropenia. The protocol was amended to a starting dose of 75 mg/m2 for the last 16 patients. Sixty percent of patients experienced hypersensitivity reactions (HSRs). After two protocol amendments, the use of a premedication regimen of oral dexamethasone and i.v. H1 and H2 blockers prevented significant HSRs. Edema developed in 62% of patients and was cumulative, was present in 50% who received greater than 400 mg/m2, and was not improved by premedication regimens. Following an independent radiology review, 22 partial remissions and four complete responses in 47 assessable patients were confirmed (response rate, 55%; 95% confidence interval [CI], 40% to 69%). The response rate for 15 assessable patients registered at 75 mg/m2 was 40% (95% CI, 16% to 67%); for 32 assessable patients registered at 100 mg/m2, the response rate was 63%, (95% CI, 43% to 78%). CONCLUSION: Docetaxel is an active agent in MBC. Its activity as a single agent is comparable to many combination chemotherapy regimens and is not affected by prior adjuvant chemotherapy. Studies are ongoing to improve its therapeutic index and to incorporate docetaxel in combination chemotherapy regimens.

A phase II study of recombinant tumor necrosis factor in renal cell carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group.

The National Cancer Institute (NCI) Canada Clinical Trials Group conducted a phase II study of recombinant tumor necrosis factor (rTNF) given intravenously daily for 5 days every other week, in measurable metastatic renal cell carcinoma. Two of 26 patients responded with responses lasting greater than 200 days. Toxicity was severe including rigors, fever, headache, fatigue, hypotension, and localized pain. We conclude that rTNF, given as described, has only modest antitumor activity in renal cell carcinoma and produces considerable toxicity. We plan no further studies of rTNF in this disease.

Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect.

We report a series of 37 consecutive patients with multiple myeloma (MM) who received an allograft between 1990 and 2000 at our institution. Median age was 47 years, and nearly 70% of patients were Durie-Salmon stage III. A median of five cycles of chemotherapy were given before transplant, with a median interval between diagnosis and transplant of 9.3 months. We report a nonrelapse mortality rate of 22% with a median follow-up period of 40 months, whereas complete remission (CR) rate at 12 months is estimated at 57%. Treatment failure rate and overall survival at 40 months are estimated at 52% and 32%, respectively. The number of chemotherapy cycles prior to allotransplantation achieved borderline statistical significance as a poor prognosis factor for overall survival (P = 0.05), while the presence of chronic graft-versus-host disease (cGVHD) was significantly correlated with CR achievement (P = 0.036). Our study confirms that early allografting in MM can yield toxicity rates significantly lower than those associated with historical cohorts, and supports the hypothesis that cumulative chemotoxicity has a negative influence on mortality and survival rates. More importantly, our study clearly demonstrates an association between cGVHD and CR and brings further evidence in favor of a graft-versus-myeloma effect.

Coordinate secretion of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor by the blast cells of acute myeloblastic leukemia: role of interleukin-1 as an endogenous inducer.

Acute myeloblastic leukemia (AML) blasts have been shown to produce a variety of cytokines in culture such as interleukin-1 (IL-1), IL-6, granulocyte-, macrophage-, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF alpha). Using two sensitive and specific enzyme-linked immunosorbent assays for IL-1 beta and GM-CSF, we document in the present study that the production of the two cytokines by AML blasts in culture is coordinated. First, we observe a striking correlation between the levels of GM-CSF and IL-1 beta released by the cells. Thus, a high production of IL-1 beta is always concordant with a high production of GM-CSF and, conversely, low production of IL-1 beta is concordant with low levels of GM-CSF. Second, neutralization of intrinsic IL-1 using antibodies that are specific for IL-1 alpha and -1 beta suppresses the release of GM-CSF by the cells. Third, neutralization of the endogenous source of IL-1 also results in an abrogation of GM-CSF mRNA. Fourth, the production of both IL-1 beta and GM-CSF is up-regulated by exposing AML blasts to an exogenous source of IL-1, suggesting a positive regulation of autocrine growth factor production. Taken together, our results indicate that GM-CSF production by AML blasts is mediated by endogenously produced IL-1. Both IL-1 beta and -1 alpha are produced by AML blasts, although IL-1 beta appears to be more abundant. Spontaneous colony formation by AML blasts is abrogated by the addition of neutralizing antibodies against IL-1 beta and GM-CSF, whereas each antibody alone has little effect on blast proliferation. Taken together, our results are consistent with the view that the production of IL-1 beta by AML blasts supports autocrine growth in culture, through induction of CSFs or other cytokines that stimulate blast proliferation.

Phase II study of elsamitrucin in non-small cell lung cancer.

Elsamitrucin (BMY-28090) a novel fermentation product has demonstrated pre-clinical anti-tumour activity against a number of cell lines. The dose limiting toxicity in phase I studies was a reversible increase in hepatic transaminase. This study was initiated to determine the activity of elsamitrucin in patients with previously untreated, bi-dimensionally measurable, cytologically or histologically proven, non-small cell lung cancer who were not curable by surgery. Elsamitrucin at a dose of 25 mg/m2 was administered intravenously over 5-10 min weekly for a minimum of 6 weeks. Seventeen patients were entered on study, 15 were evaluable for toxicity and 14 evaluable for response. No responses were documented in the 14 patients evaluable for response. Both hematological and non-hematological toxicities were mild to moderate in severity. The commonest being nausea, vomiting, lethargy and local skin reactions at the site of the infusion. These results indicate that elsamitrucin when given in this dose and schedule to patients with surgically incurable non-small cell lung cancer has no activity.

Acute and delayed emesis after cisplatin-based regimen: description and prevention.

Lorazepam, dexamethasone and high-dose metoclopramide were given to 54 patients to prevent emesis induced by cisplatin (50-120 mg/m2) on day 1, while prochlorperazine and dexamethasone were administered on days 2 and 3 for control of delayed emesis. Nausea and emesis were recorded from day 1 to day 8. This combination was well tolerated. Prevention on day 1 was complete for 72% of patients and satisfactory (less than or equal to 2 emeses on day 1) in 85%. From days 2 to 8, no emesis, less than or equal to 2 and greater than 2 episodes occurred in 70, 11 and 19%, respectively. Overall control (days 1-8) was complete in 55.5% and satisfactory (less than or equal to 2 emeses on day 1 and/or less than or equal to 2 emeses from days 2 to 8) in 74%. Delayed emesis started on days 2-5. Mean duration was 2.6 days. Delayed nausea or emesis were more frequent when emesis occurred on day 1. Based on data previously reported and on these observations, better ways to prevent delayed events are discussed. Further trials must record systematically delayed side effects.

A large multisite cancer family is linked to BRCA2.

We identified a large French-Canadian family with 21 cases of breast cancer, including two affected brothers. Segregation of markers from chromosome 13q in this family showed linkage to the BRCA2 gene locus (lod = 3.67 at D13S289). A number of cancers of other types occurred in this family, including three cases of prostate cancer and two cases of lymphoma. The penetrance of breast cancer among BRCA2 carriers is estimated to be 75% to the age of 70.