Central venous device-related infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2.

BACKGROUND: This study was performed to determine the incidence of central venous device-related blood stream infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2 (IL-2). METHODS: The records of 160 consecutive patients treated at the University of Wisconsin Hospital and Clinics, between June 1990 and June 1997, with moderate dose continuous-infusion IL-2 (IL-2 [1.5-3.0 x 10(6) U/m(2)/day] Hoffman-LaRoche, Nutley, NJ or IL-2 [4.5 x 10(6) U/m(2)/day] Chiron Corporation, Berkley, CA) were reviewed retrospectively. The majority of patients had metastatic melanoma (78 patients) or renal cell carcinoma (70 patients). All of the patients had a surgically implanted central venous device placed before starting IL-2 therapy; 89% of these were cuffed Hickman catheters. Eighty-four patients received 1 mg of warfarin per day as prophylaxis against device-related thrombosis; none received periinsertion prophylactic antibiotics. RESULTS: Twenty-one patients (13%) developed central venous device-related bloodstream infection (DRBSI) during the study period, a rate of 2 DRBSI per 1000 device-days. DRBSIs were associated with the type of immunotherapy given with IL-2 (P = 0.01) and with thrombosis (odds ratio, 4.1; 95% confidence interval, 1.5-11.4; P = 0.008) but not with patient gender, type of cancer, duration of the central device, or site of device placement. Twenty-six patients (16%) developed central venous device-related thrombosis (DRT) during immunotherapy. Low dose warfarin did not appear to prevent thrombosis. Device-related thrombosis was associated with DRBSI but not with patient gender, type of cancer, type of device, duration or location of device, or concomitant immunotherapy. CONCLUSIONS: Central venous DRBSI and DRT are significant complications that can occur during moderate dose continuous-infusion IL-2 therapy. The risk of DRBSI appears lower than the risk reported with high dose IL-2 therapy by previous investigators. The risk of DRT appears to be higher than the risk reported for patients with similar devices but not given IL-2. Low dose warfarin did not prevent DRT when started after device placement.

A phase Ib/II trial of granulocyte-macrophage-colony stimulating factor and interleukin-2 for renal cell carcinoma patients with pulmonary metastases: a case of fatal central nervous system thrombosis.

BACKGROUND: Interleukin-2 (IL-2) and granulocyte-macrophage-colony stimulating factor (GM-CSF) are cytokines with nonoverlapping pleiotropic effects. In a prior Phase Ib study, this combination of agents exhibited antitumor effects in the lungs of four of eight patients with renal cell carcinoma and pulmonary metastases. We conducted this Phase Ib/II trial to determine the response rate of renal cell carcinoma patients with pulmonary metastases treated with continuous infusion IL-2 plus GM-CSF. METHODS: Patients with renal cell carcinoma and pulmonary metastases were treated with 1.5, 2.25, or 4.5 x 10(6) IU/m(2)/day 96-hour continuous infusion IL-2 on Days 1-4, 8-11, and 15-18, and 1.25, 2.25, or 2.5 microg/kg/day GM-CSF on Days 8-19. RESULTS: Sixteen patients were treated per protocol, 14 of whom could be evaluated for disease progression. None of these 14 patients had >50% shrinkage of either total tumor burden or pulmonary metastasis. One patient developed Grade 5 neurotoxicity. Autopsy revealed acute multifocal cerebral venous thrombosis as well as acute subdural and subarachnoid hemorrhage. CONCLUSIONS: The combination of IL-2 and GM-CSF may be associated with marked morbidity and, as in one case in this study, mortality. No significant antitumor activity was appreciated. Thus, the combination of IL-2 and GM-CSF, when administered at this dose and according to this schedule, does not appear to be active in renal cell carcinoma and is associated with significant toxicities. Further studies using this combination of agents should only be undertaken with extreme caution and particular attention to neurotoxicity.

Distinct clinical and laboratory activity of two recombinant interleukin-2 preparations.

Interleukin-2 (IL-2) is a potent lymphokine that activates natural killer cells, T cells, and other cells of the immune system. Several distinct recombinant human IL-2 preparations have shown antitumor activity, particularly for renal cell cancer and melanoma. Somewhat distinct immune and clinical effects have been noted when different IL-2 preparations have been tested clinically; however, the regimens and doses used were not identical. To compare these more directly, we have evaluated two clinical recombinant IL-2 preparations in vitro and in vivo using similar regimens and similar IUs of IL-2. We used the Food and Drug Administration-approved, commercially available Chiron IL-2 and the Hoffmann LaRoche (HLR) IL-2 supplied by the National Cancer Institute. Using equivalent IUs of IL-2, we noted quantitative differences in vitro and in vivo in the IL-2 activity of these two preparations. In patients receiving comparable IUs of the two preparations, HLR IL-2 induced the release of more soluble IL-2 receptor alpha into the serum than Chiron IL-2. In addition, more toxicities were noted in patients receiving 1.5 x 10(6) IU of HLR IL-2 than were seen in patients treated with 1.5 x 10(6) or even 4.5 x 10(6) IU of Chiron IL-2. These toxicities included fever, nausea and vomiting, and hepatic toxicity. In vitro proliferative assays using IL-2-dependent human and murine cell lines indicated that the IU of HLR IL-2 was more effective than Chiron IL-2 at inducing tritiated thymidine incorporation. Using flow cytometry, we also found quantitative differences in the ability of these two preparations to bind to IL-2 receptors. These findings indicate that approximately 3-6 IU of Chiron IL-2 are required to induce the same biological effect as 1 IU of HLR IL-2.

Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients.

We conducted a Phase IB trial of antidisialoganglioside chimeric 14. 18 (ch14.18) antibody and interleukin 2 (IL-2) to determine the maximal tolerated dose (MTD), immunological effects, antitumor effects, and toxicity of this treatment combination. Twenty-four melanoma patients received immunotherapy with ch14.18 antibody and a continuous infusion of Roche IL-2 (1.5 x 10(6) units/m2/day) given 4 days/week for 3 weeks. The ch14.18 antibody (dose level, 2-10 mg/m2/day) was scheduled to be given for 5 days, before, during, or following initial systemic IL-2 treatment. The ch14.18 MTD was 7.5 mg/m2/day, and 15 patients were treated with the ch14.18 MTD. Immunological effects included the induction of lymphokine-activated killer activity and antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells. In addition, serum samples obtained following ch14.18 infusions were able to facilitate in vitro antibody-dependent cellular cytotoxicity. Antitumor activity included one complete response, one partial response, eight patients with stable disease, and one patient with >50% decrease of hepatic metastases in the face of recurrence of a s.c. lesion. Dose-limiting toxicities were a severe allergic reaction and weakness, pericardial effusion, and decreased performance status. Most patients treated at the MTD had abdominal, chest, or extremity pain requiring i.v. morphine. One patient had an objective peripheral neuropathy. This IL-2 and ch14.18 treatment combination induces immune activation in all patients and antitumor activity in some melanoma patients. We are attempting to enhance this treatment approach by addition of the anti-GD3 R24 antibody to this IL-2 and ch14.18 regimen.

Phase II trial of oral piritrexim in advanced, previously treated transitional cell cancer of bladder.

UNLABELLED: Oral piritrexim (PTX), a second generation antimetabolite, has been shown to be an active agent against methotrexate refractory transitional cell cancer (TCC) of the bladder in phase I trials. We conducted a phase II trial of this drug in patients with TCC of the bladder who failed a first line chemotherapy regimen. METHODS: Oral PTX was started at the dose of 25 mg three times per day for 5 days weekly for 3 weeks followed by one week of rest. If this was tolerated the dose was increased to 50 mg three times a day. Patients were monitored for response rate and toxicity. RESULTS: Seventeen patients were entered into the trial. Two patients did not complete the required 2 courses of treatment to be evaluable. There were 13 evaluable patients. Among the 13 no one achieved a complete response (CR), however, there were 3 partial responses (PRs = RR: 23%) and 5 stable diseases (SDs). The responses lasted 2, 8 and 14 months. The major dose-limiting toxicity was myelosuppression. Two patients died on treatment. One death was due to neutropenic fever and the cause of death in the second patient is thought to be a cerebral vascular accident (CVA). CONCLUSION: PTX is an active drug in the treatment of TCC of the bladder. Bone marrow suppression is the most common dose-limiting toxicity. In view of the observed responses and toxicities in this study and other studies, we suggest that the role of PTX be further investigated in the following clinical settings: 1. Palliative initial treatment in patients with TCC of the bladder who are not candidates for more aggressive chemotherapy. 2. As first line chemotherapy in combination with other active drugs.

Multiple cerebral lesions complicating therapy with interleukin-2.

We reviewed the records and radiologic studies of eight patients who developed new focal neurologic abnormalities while receiving interleukin-2 (IL2)-based immunotherapy for malignancy or HIV infection. Initial confusion and delirium in the patients evolved into coma, ataxia, hemiparesis, seizures, and cortical syndromes including aphasia, apraxia, and cortical blindness. Imaging studies showed multiple white and gray matter lesions with a predilection for the occipital poles, centrum semiovale, and cerebellum. After cessation of IL2 treatment, seven patients improved to normal or near-normal neurologic function paralleled by resolution of the lesions on scans. One patient improved only minimally. Possible etiologies for the lesions include an IL2-induced cerebral vasculopathy, a direct toxic effect of IL2, or immunologically mediated damage.

Clinical and immunological effects of granulocyte-macrophage colony-stimulating factor coadministered with interleukin 2: a phase IB study.

Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects of the combination. Thirty-four patients with incurable cancers received 2.5, 5, or 10 microgram/kg GM-CSF s.c. either before or concurrently with 1.5 or 3.0 million units/m2/day IL-2. The most common laboratory and clinical side effects included an elevation of the total WBC or eosinophil count due to GM-CSF, and constitutional symptoms due to IL-2. Grade 3 or 4 toxicities included hypotension, thrombocytopenia, elevations in aspartate aminotransferase or bilirubin, renal toxicity, gastrointestinal hemorrhage, arrhythmia, and constitutional symptoms. Two patients receiving 5.0 microgram/kg GM-CSF plus concurrent 3.0 million units IL-2 experienced dose-limiting grade 3 or 4 neurological toxicity, which reversed almost completely. An increase in the serum-soluble IL-2 alpha chain receptor was observed with administration of GM-CSF, IL-2, or the combination. IL-2 therapy enhanced lymphokine-activated killer activity, antibody-dependent cellular cytotoxicity, and lymphocyte activation, with increased CD16 and CD56 expression. GM-CSF increased expression of human leukocyte antigen DR on peripheral blood monocytes and decreased surface expression of CD16 on circulating monocytes and polymorphonuclear cells. Lymphokine-activated killer activity and CD16 expression on monocytes and lymphocytes and CD56 expression on lymphocytes were significantly lower in patients receiving GM-CSF simultaneously with IL-2 than in patients receiving the sequential treatment. Antitumor activity was observed in the lungs of four of eight renal cell carcinoma patients with pulmonary metastases treated with concurrent GM-CSF and IL-2. Although no or minimal shrinkage was observed in the patients' large primary tumors, these results warrant further study. The recommended initial Phase II dose and schedule is 1.25 microgram/kg/day GM-CSF, given concurrently with 1.5 million Roche units/m2/day (4.5 x 10(6) international units/m2/day) IL-2, with subsequent escalation of GM-CSF to 2.5 microgram/kg/day after careful observation for toxicities.