Alpha interferons in the treatment of hairy cell leukemia.
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Drug Administration Schedule↗
Biomedical subjects
J R Quesada
Publications and source records attributed to J R Quesada.
Alpha interferons in B-cell neoplasms.
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B-Lymphocytes↗
Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients.
Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.
Adult↗
Clinical toxicity of interferons in cancer patients: a review.
All major types of human interferons (IFNs) have been purified and clinically administered as antitumor agents. We summarize here experience to date with toxicity of IFNs in cancer patients. The acute syndrome consists of fever, chills, myalgias, arthralgias, and headache, with some variation according to type of IFN, route of administration, schedule, and dose. Fatigue, perhaps reflecting CNS toxicity, is the most prevalent nonacute symptom. At high doses, IFNs are neurotoxic; the abnormalities seen by EEG resemble those in diffuse encephalitis. Hematologic toxicity consists mainly of leukopenia, but anemia and thrombocytopenia occur in some patients. Nausea, vomiting, and diarrhea are the main gastrointestinal symptoms. Elevation of serum transaminases seems to reflect liver toxicity. Renal function is well preserved, except for rare instances of acute renal failure. Cardiac toxicity remains questionable, although heart failure and arrhythmias have been associated with the administration of IFNs. Most, if not all, of these effects are reversible or can be ameliorated. With IFN alpha, the type most widely used in clinical studies, doses of 1 million to 9 million units (MU) are generally well tolerated, but doses greater than or equal to 18 MU yield moderate to severe toxicity. Doses greater than or equal to 36 MU can induce severe toxicity and significantly alter the performance status of the patient.
Antibody Formation↗
Phase I study of multiple dose intramuscularly administered recombinant gamma interferon.
We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.
Agranulocytosis↗
Cross-reactive red blood cell antigen-related substances in human leukocyte alpha interferon.
Human leukocyte alpha interferon (IFN alpha) is a blood product. The possible contamination with blood-group antigens was studied using the double-immunodiffusion technique. With the exception of one lot received in 1980, which did not react, all three recent lots received in 1983 and 1984 reacted with 16, 20, and 21 of the 22 erythrocyte group-specific antisera tested. The only antiserum that did not react with any of the IFN alpha lots was anti-N. Preincubation of the IFN alpha with antisera abolished the precipitate lines seen in double immunodiffusion. Recombinant human alpha interferon used as a control did not show any reaction. Our results indicate the presence of red blood cell antigen-related substances in IFN alpha.
Cross Reactions↗
Activation or suppression of the tumoricidal properties of monocytes from cancer patients following treatment with human recombinant gamma-interferon.
The purpose of these studies was to examine the antitumor properties of blood monocytes from patients undergoing phase I trials with recombinant human gamma-interferon (rIFN-gamma). Thirty-one patients with different malignancies were divided into three major treatment groups. The first group of patients received rIFN-gamma by a 6-h i.v. infusion. Activation of blood monocytes was dependent upon the dose of rIFN-gamma administered. The second group of patients received IFN-gamma by a continuous 24-h i.v. infusion. In general, this treatment did not produce antitumor activity in blood monocytes. The third group of patients received daily i.m. injections of rIFN-gamma. Daily i.m. administrations of 0.25-0.5 mg rIFN-gamma/m2/day produced significant activation of antitumor properties in the patients' monocytes, whereas the daily i.m. administrations of 1 mg IFN-gamma/m2/day did not. In fact, the blood monocytes from these patients did not even respond to optimal activating stimuli in vitro. We conclude that the systemic administration of appropriate amounts of IFN-gamma can activate blood monocytes of cancer patients to become tumor cytotoxic. High doses of the same biological should be avoided since it can actually suppress the desired effect. For biologicals with immunostimulatory activity the concept that "more drug is better" may not be operative.
Cytotoxicity, Immunologic↗
Phase I study of i.v. administered recombinant gamma interferon in cancer patients.
We report a phase I study of the biological effects, tolerance, and pharmacokinetics of 6- and 24-hour iv infusions of recombinant interferon-gamma (rIFN-gamma) in cancer patients. Twenty-one patients received the 6-hour iv infusion regimen at doses ranging from 0.016 to 0.65 mg/m2/day. Forty-one patients received the 24-hour iv infusion regimen at doses ranging from 0.01 to 0.05 mg/m2/day. Fever and flu-like symptoms were the most common side effects and were seen at all dose levels. The maximum tolerated dose was 0.16 mg/m2 for the 6-hour regimen and 0.01 mg/m2/day for the 24-hour regimen. A dose-dependent granulocytopenia was observed at doses greater than or equal to 0.05 mg/m2/day. A marked increase in beta2 microglobulin occurred by Day 5 of treatment in almost all patients, regardless of the dose level. Consistent serum levels of rIFN-gamma were achieved only at doses of 0.325 mg/m2/day of the 6-hour infusion. The mean serum concentrations at this dose ranged from 18 to 83 units/ml as measured by bioassay (0.64-2.4 ng/ml by enzyme-linked immunoassay). Antibody against rIFN-gamma did not develop in any patient. During the short period of evaluation of this study, one patient with renal cell carcinoma achieved a partial response, and three patients with renal cell (two) and lung carcinoma (one), respectively, achieved minor responses. This study will form the framework for phase II efficacy trials of iv rIFN-gamma.
Adult↗
Treatment of hairy cell leukemia with recombinant alpha-interferon.
Thirty patients with hairy cell leukemia were treated with recombinant interferon alpha-A (rIFN alpha A; Roferon-A); seven were previously untreated. Nine complete and 17 partial remissions were documented by bone marrow core biopsies. All patients' peripheral blood hematologic indexes either improved or normalized. Twelve of 13 patients with retroperitoneal or mediastinal adenopathy obtained remissions of tumor masses. All seven patients with splenomegaly showed prompt reduction in the size of the spleen to normal size. The incidence of complete remissions was significantly higher (P = .02) in previously untreated patients (5 of 7) than in those in whom splenectomy had been performed (4 of 23), a result presumed to be related to the pretreatment tumor burden. rIFN alpha A was well tolerated; mild fatigue was the most frequent complaint. In most patients, tumor remissions resulted in an improved quality of life: they eliminated the need for transfusing blood products and reduced the incidence of infections, and immune deficits were apparently restored in some of the patients. We conclude that rIFN alpha A is an effective therapy for all stages of hairy cell leukemia including previously untreated or newly diagnosed patients.
Adult↗
Treatment of multiple myeloma with recombinant alpha-interferon.
Thirty-two patients with multiple myeloma were treated with recombinant alpha-interferon clone A (rIFN alpha A) daily by intramuscular injection with an initial dose of 12 X 10(6) U/m2. Of 27 patients evaluable for response, tumor responses were obtained in seven of 14 previously untreated patients (50%) and two of 13 who had relapsed or failed prior chemotherapy (15%). In all patients who had tumor response, there was restoration from subnormal levels of serum immunoglobulins, an effect infrequently observed with chemotherapy. The median duration of tumor responses exceeded 14 months (range, 6 to 20). Moderate-to-severe fatigue was the predominant side effect and necessitated dose reductions in all patients. We conclude that treatment of early stages of multiple myeloma with rIFN alpha A is beneficial because of the substantial response rate and the improvement in the synthesis of serum immunoglobulins. rIFN alpha A has a potential role in combination with other agents in the treatment of multiple myeloma.
Female↗
Immune thrombocytopenia following alpha-interferon therapy in patients with cancer.
Immune thrombocytopenia occurred in five patients with cancer receiving alpha-interferon. The median pretreatment platelet count was 217,000/cu mm, which fell to a median of 12,000/cu mm after a median of 25 days of interferon therapy. All had normal numbers of megakaryocytes, with dysplasia noted in three; all four who were tested had platelet-associated immunoglobulin. All had normalization of platelet counts with prednisone therapy. Four tolerated re-treatment with interferon, two with concurrent prednisone administration and two others following splenectomy. Immune thrombocytopenia should be considered in patients who become thrombocytopenic during interferon therapy.
Adult↗
Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma.
Fifty-six patients with metastatic renal cell carcinoma (RCC) were treated with recombinant DNA-derived interferon alpha (rIFN alpha A). The first 30 patients were randomized between doses of 2 X 10(6) U/m2 and 20 X 10(6) U/m2 intramuscularly daily. No complete (CR) or partial (PR) remissions were achieved in 15 patients receiving the low dose. In contrast, 27% of those receiving the high dose achieved CR or PR. Subsequently, 26 additional patients were given the high dose and achieved a 31% response rate. Remissions lasted from 1 to more than 12 months (median, 3 months). Responses occurred predominantly in lung parenchyma or mediastinal node metastases. Toxicity of the high dose required dose reduction in 50% of the patients. Neutralizing antibodies to rIFN alpha A developed in seven of 12 responsive (58%) and nine of 29 (31%) nonresponsive patients (P = greater than .5). The median duration of remission among the antibody-positive and antibody-negative patients were 2 and 10 months, respectively (P = .009). The clinical significance of the antibodies to rIFN alpha A remains unclear, but the coincidence between the detection of antibodies and the early relapse of the disease in some responsive patients suggests that these antibodies may abrogate the biologic activity of rIFN alpha A. This effect, however, was not associated with adverse clinical sequelae.
Adult↗
Phase II study of interferon alpha in metastatic renal-cell carcinoma: a progress report.
Partially purified interferon alpha (IFN alpha) was administered to 50 patients with metastatic renal-cell carcinoma (RCC) studied for more than two years. Complete or partial remissions were observed in 26% of the patients. Duration of remissions range from two to 16 months (median, six months). No distinct prognostic factors were clearly identified in the responsive patients, but responses occurred more frequently in men with optimal performance status who had undergone nephrectomy and in whom the metastatic disease was confined to the lungs, pleura, or mediastinum. Leukopenia and granulocytopenia were useful markers of biological activity but did not predict tumor response. Side effects and toxicity at the dosage used (3 X 10(6) units intramuscularly daily) were well-tolerated and consisted predominantly of fatigue and asthenia. We concluded that IFN alpha is useful for palliating metastatic RCC, but no impact on survival was demonstrated. Further studies are required to determine the optimal dose, routes of administration, and treatment schedules.
Adult↗
Pharmacokinetics, single-dose tolerance, and biological activity of recombinant gamma-interferon in cancer patients.
We report a clinical study of the pharmacokinetics, toxicity, and biological activity of i.v.- and i.m.-administered recombinant gamma-interferon (rIFN-gamma) consisting of 143 amino acids. Ten patients with metastatic cancer were given rIFN-gamma at doses of 0.01 to 2.5 mg/sq m by alternating i.m. and i.v. bolus injections with a minimum intervening period of 72 h. After i.v. administration, rIFN-gamma was cleared monoexponentially with a short half-life of 25 to 35 min as determined by bioassay and enzyme immunoassay. After i.m. injection, a longer half-life of 227 to 462 min was measured by enzyme immunoassay. Serum titers were detected by bioassay only at high doses, suggesting partial loss of antiviral activity at the i.m. site. However, other biological effects were retained as evidenced by fever, chills, and fatigue after both routes of administration and granulocytopenia after i.m., but not i.v., doses. Two of ten patients showed objective evidence of tumor regression. These data suggest that further studies with i.m. as well as prolonged i.v. infusions of rIFN-gamma are indicated.
Half-Life↗
Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer.
The conditions of ten patients with metastatic renal cell carcinoma were serially evaluated by neuropsychiatric examination to determine the nature of the fatigue-asthenia symptoms resulting from human leukocyte interferon alpha therapy. The majority of the patients had moderate to severe behavioral changes and mild to moderate cognitive, affective, and personality changes within the first week of daily intramuscular administration of 3 X 10(6) units of interferon. This descriptive clinical study suggests that the intense fatigue may be a manifestation of a complex neurotoxicity, most suggestive of frontal lobe changes, and resulting in neurasthenia syndrome with reversible impairment of some higher mental functions.
Adenocarcinoma↗
Alpha interferon for induction of remission in hairy-cell leukemia.
We treated seven patients who had progressive hairy-cell leukemia with daily doses of 3 million units of partially pure alpha (leukocyte) interferon by the intramuscular route. Three patients had a complete remission, and four had a partial remission, according to strict criteria for a response. After treatment, bone-marrow aspirates showed an absence of leukemia cells in three patients and 5 per cent or fewer in three others. Normalization of subnormal peripheral-blood values occurred in six of six patients with anemia, in seven of seven with granulocytopenia, and in four of four with thrombocytopenia. Remissions have been maintained for over 6 to over 10 months. Alpha interferon appears to be highly effective in patients with hairy-cell leukemia.
Adult↗
Collaborative phase I-II study of recombinant DNA-produced leukocyte interferon (clone A) in metastatic breast cancer, malignant lymphoma, and multiple myeloma.
Fifty-two patients with advanced cancer received sequentially escalating doses of 3 to 50 million units of recombinant DNA-produced alpha interferon by daily intramuscular injection. There were 23 patients with metastatic breast cancer, 17 patients with nodular poorly differentiated lymphocytic lymphoma, and 12 patients with multiple myeloma. Complete and partial remissions were obtained in 35 percent of patients with nodular poorly differentiated lymphoma, whereas rare activity was found in breast cancer and multiple myeloma. Dose-limiting toxicity occurred in patients receiving 36 million units or more and consisted of fatigue/asthenia, weight loss, and elevation of transaminase levels, requiring frequent interruption, reduction in dose, or cessation of treatment. Hematologic toxicity was rarely a limiting factor, but myelosuppression was severe in some patients with multiple myeloma. All toxicities were reversible on discontinuation of treatment. Antibodies to recombinant leukocyte A interferon were seen infrequently but may adversely affect therapy.
Adult↗
Interferons and cell growth regulation.
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Animals↗