pentostatin and Nausea

Pentostatin (Nipent; SuperGen, San Ramon, CA) is a safe and well-tolerated medication but, like all chemotherapeutic agents, it may be associated with some toxicity. The toxicity seen with pentostatin is dose and schedule dependent and can be minimized by appropriate dosing. The dose of pentostatin should never exceed 4 mg/m2. A dose reduction is required for patients with renal insufficiency. Renal and neurological toxicities may occur, yet are uncommon with appropriate dosing. Nausea and vomiting also occur; however, they are usually controlled with antiemetic therapy. Like the other purine nucleoside analogs, pentostatin is an immunosuppressive drug that may increase the risk of infection, especially with opportunistic organisms. Prophylactic antibiotics should be considered when treating patients with pentostatin.

Topics: Antibiotic Prophylaxis; Antibiotics, Antineoplastic; Antiemetics; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Immunosuppressive Agents; Kidney; Nausea; Nervous System; Opportunistic Infections; Pentostatin; Vomiting

Hairy cell leukemia (HCL) is a chronic lymphoproliferative disease of B-cell origin manifested by pancytopenia and splenomegaly. Before 1980 the only effective treatment for HCL was splenectomy, which resolved the cytopenia but did not eliminate the disease from the bone marrow. In addition, the majority of patients progressed after splenectomy and required further treatment. Pentostatin (Nipent; SuperGen, San Ramon, CA) is a purine antimetabolite that was found in phase I studies to induce profound lymphocytopenia Although in vitro studies suggested that T lymphocytes were most sensitive to pentostatin, patients with B-cell chronic lymphatic leukemia and low-grade non-Hodgkin's lymphoma responded to treatment in the initial phase I trials. Due to evidence that the drug was effective in lymphoproliferative disease, patients with HCL were treated with pentostatin. The promising initial results led to phase II studies in both untreated and previously treated patients. These studies demonstrated that pentostatin was highly effective as a single agent, with complete responses seen in 60% to 90% of patients. These responses were durable without maintenance chemotherapy and were seen in patients previously treated with interferon or chemotherapy. Toxicity was usually mild, with nausea and skin rashes predominating. When seen, infections resulting from neutropenia occurred early in treatment. The high response rates and low toxicity suggest that pentostatin should be considered as one of the standard treatments for HCL.

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Disease Progression; Drug Eruptions; Enzyme Inhibitors; Exanthema; Humans; Immunosuppressive Agents; Leukemia, B-Cell; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Nausea; Neutropenia; Pancytopenia; Pentostatin; Remission Induction; Splenomegaly

Pentostatin (Nipent; SuperGen, San Ramon, CA), which is highly lymphocytotoxic, is an active agent in hairy cell leukemia. We therefore initiated a trial of this agent in T-cell lymphomas. Pentostatin was administered at a dose of 3.75 or 5.0 mg/m2/d intravenously for 3 days every 3 weeks to heavily pretreated patients with cutaneous and peripheral T-cell lymphomas. To date, there are 24 evaluable patients in the trial. Seventeen of these individuals have responded (complete or partial remission). The most common toxicities included granulocytopenia, nausea, renal insufficiency, CD4 suppression, and delayed herpes zoster. Pentostatin is an active agent in this group of diseases and merits further exploration.

Topics: Adult; Aged; Agranulocytosis; Antibiotics, Antineoplastic; CD4-Positive T-Lymphocytes; Female; Herpes Zoster; Humans; Immunosuppressive Agents; Injections, Intravenous; Lymphoma, T-Cell; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Nausea; Pentostatin; Remission Induction; Renal Insufficiency; Skin Neoplasms

YK-176 is a newly isolated 2'-deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase, produced by Aspergillus nidulans. In a cooperative phase I study, YK-176 was administered to 22 patients, comprising 18 with adult T-cell leukemia-lymphoma (ATL), two with cutaneous T-cell lymphoma (CTCL), one with lymphoblastic lymphoma of T-cell type and one with carcinoma of the uterine cervix. Doses of YK-176 ranged from 3.0 to 9.0 mg/m2 and were given intravenously for three consecutive days. General malaise, anorexia, nausea, vomiting and low grade fever were frequently encountered, but were transient and not dose-related. At all dose levels hematological toxicities were mild. Two of seven patients receiving 7.0 mg/m2 for three consecutive days developed hepatocellular enzyme elevations (grade 2) and one patient, proteinuria (grade 2). One of two patients given 9.0 mg/m2 for three consecutive days manifested a life-threatening (grade 4) disturbance of consciousness and dyspnea, presumably ascribable to the drug-related toxicity of YK-176. The results suggest that 7.0 mg/m2 i.v. for three consecutive days is the maximum acceptable dose of YK-176. Central nervous system, pulmonary and possibly renal toxicities appeared to be dose-limiting. Out of the 20 patients evaluable for therapeutic response, partial remissions were observed in four, three with ATL and one with CTCL, who received less than 7.0 mg/m2 for three consecutive days. We conclude that YK-176 is an active agent against ATL at doses that may not be associated with prohibitive toxicity. A starting dose of 5.0 mg/m2 for three consecutive days is recommended for further phase II studies on ATL.

Topics: Adult; Aged; Appetite; Drug Evaluation; Female; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Nausea; Pentostatin; Remission Induction; Vomiting

2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2'-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2'-dCF which were not associated with limiting toxicities. These results suggest that 2'-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.

Topics: Adenosine Deaminase Inhibitors; Adolescent; Adult; Child; Child, Preschool; Coformycin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Liver; Lymphopenia; Male; Nausea; Pentostatin; Prognosis; Ribonucleosides; Vomiting

2'-deoxycoformycin (2'-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2'-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kg X 1 to 0.25 mg/kg/day X 5; ado deaminase and 2'-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential (alpha and beta t 1/2 values about 1 and 10 h respectively). Recovery of unchanged 2'-dCF from urine (48 h) was 32%--48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2'-dCF/kg/day X 5.

Topics: Adenosine Deaminase Inhibitors; Adult; Aged; Animals; Coformycin; Dogs; Female; Humans; Kinetics; Leukemia, Lymphoid; Lymphocytes; Male; Middle Aged; Nausea; Neoplasms; Nucleoside Deaminases; Pentostatin; Ribonucleosides; Uric Acid