pentostatin and Herpes-Zoster

Pentostatin is a highly lymphocytotoxic agent active in hairy cell leukemia. Several studies also suggest significant activity in T cell lymphomas manifested in the skin. Herein, we will review the studies of pentostatin in these lymphomas and our most recent trial of this agent in heavily pretreated patients with cutaneous and peripheral T cell lymphomas. Overall, the data suggest that pentostatin has significant antitumor activity in these patients, with response rates ranging from 33% to over 70%. Approximately one-third of the responses are complete. The most common side effects include granulocytopenia, nausea, and renal insufficiency. CD4 suppression occurs and may result in an increased risk of herpes zoster infection. Although prolonged remissions have been seen, most responses are short-lived. These observations suggest that further exploration of this agent, in combination with other drugs active in T cell lymphomas, is warranted in this group of diseases.

Topics: Antibiotics, Antineoplastic; Female; Herpes Zoster; Humans; Lymphoma, T-Cell, Cutaneous; Male; Pentostatin; Skin Neoplasms; Treatment Outcome

Purine analogs and alkylating agents are the most active drugs in the treatment of patients with chronic lymphocytic leukemia (CLL). Although fludarabine is the most widely tested purine analog in CLL, myelosuppression has limited its use in combination chemotherapy regimens. Because pentostatin (Nipent; SuperGen, San Ramon, CA), a related purine analog with proven activity in CLL, has less myelosuppression, we postulated that it would prove advantageous and could be more readily combined with alkylating agents. We are conducting a phase I/II trial of combination chemotherapy with pentostatin and cyclophosphamide for previously treated patients with CLL. Patients need to have Rai high-risk disease or "active" intermediate-risk disease. The treatment regimen consists of a fixed dose of pentostatin (4 mg/m2) combined with an increasing dose of cyclophosphamide. We plan to treat cohorts of three patients each at cyclophosphamide dose levels of 600, 900, 1,200, 1,500, and 2,000 mg/m2. Cycles will be repeated every 21 days. If unacceptable toxicity is encountered at one dose level, then three additional patients (total of six patients) will be accrued to that dose level before further dose escalations will be permitted. A second instance of unacceptable toxicity will close that dose level and identify the preceding level as the phase II dose. Additional patients will be accrued to the phase II dose level to better assess response. Supportive measures include the use of granulocyte colony-stimulating factor (5 microg/kg/d) to limit neutropenia. Sulfamethoxazole/trimethoprim will be given as prophylaxis against Pneumocystis carinii pneumonia and acyclovir will be administered as prophylaxis for herpes zoster. Response will be assessed according to standard criteria, and flow cytometry and fluorescent in situ hybridization will be used to assess for minimal residual disease in patients with trisomy 12.

Topics: Acyclovir; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemoprevention; Chromosomes, Human, Pair 12; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cohort Studies; Cyclophosphamide; Dose-Response Relationship, Drug; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Herpes Zoster; Humans; Immunosuppressive Agents; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Patient Selection; Pentostatin; Pneumonia, Pneumocystis; Remission Induction; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Trisomy

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

Managing the infectious complications associated with pentostatin (Nipent), used alone or in combination with other agents in patients with low-grade lymphomas, poses a significant problem for clinicians. Since there is limited experience with these therapies, definitive treatment recommendations concerning prophylaxis cannot be made. The panel members discussed the use of valacyclovir (Valtrex) to provide prophylaxis for herpes zoster, trimethoprim/sulfamethoxazole for Pneumocystis, and acyclovir (Zovirax) for varicella zoster. They also considered combinations of pentostatin with agents such as interferon, rituximab (Rituxan), and chlorambucil (Leukeran) and their effect on the immune system. The biology of B and T cells was discussed, with an emphasis on clinical application.

Topics: Acyclovir; Anti-Infective Agents; Anti-Infective Agents, Urinary; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chlorambucil; Encephalitis, Varicella Zoster; Herpes Zoster; Humans; Interferons; Lymphoma; Pentostatin; Pneumocystis Infections; Rituximab; Sulfamethoxazole; Trimethoprim; Valacyclovir; Valine

Immune function in patients with hairy cell leukemia (HCL) was examined serially during treatment with alternating monthly cycles of recombinant interferon alpha-2a and 2'-deoxycoformycin (dCF). At presentation, most patients had normal numbers of T lymphocytes and their cells had normal proliferative responses to mitogens [phytohemagglutinin (PHA) and concanavalin A (Con A)] and alloantigens. Patients had severe monocytopenia, decreased delayed-type hypersensitivity (DTH) reactions, and decreased peripheral blood natural killer (NK) activity. Treatment caused a profound decrease in all lymphocyte subpopulations. T cells were more affected than B cells or NK cells. Numbers of CD4+ and CD8+ lymphocytes decreased to levels less than 200 cells/microliters in all patients during treatment. This decrease in T cell number was associated with a marked decrease in proliferative responsiveness to PHA, Con A, and alloantigens. These abnormalities persisted throughout the 14 months of treatment and have continued for up to 6 months beyond discontinuation of treatment. NK cell activity increased during treatment, but cycled depending on the phase of treatment; highest activities were observed after interferon (IFN)-alpha and lower levels of activity were observed after dCF. DTH responses generally did not improve during therapy. Levels of IgM, IgG, IgA, and IgD did not change during treatment, but IgE levels rose in most patients. All immunosuppressive effects were attributable to dCF since patients receiving IFN-alpha 2a alone did not exhibit these same immunosuppressive effects, and patients receiving dCF alone after IFN failure exhibited similar abnormalities. Despite this severe immunosuppression from dCF, life-threatening opportunistic infections have not been observed in our patient population. Six patients developed localized Herpes zoster infection among 21 patients who had received dCF. Pending the results of long-term follow-up, we recommend that dCF be reserved for patients who have failed splenectomy and IFN therapy.

Topics: Coformycin; Drug Therapy, Combination; Female; Herpes Zoster; Humans; Immunosuppressive Agents; Interferon Type I; Leukemia, Hairy Cell; Leukocyte Count; Lymphocyte Activation; Male; Pentostatin; Recombinant Proteins; Ribonucleosides; T-Lymphocytes

Pentostatin (dCF), an inhibitor of adenosine deaminase, has shown activity in the treatment of several lymphoid malignancies, even in the earliest phase I trials. An analysis of the first 300 patients treated in such trials shows a high incidence of severe infection (8%) during the relatively brief period of treatment. Of 24 patients in whom infection was diagnosed, 17 had no evidence of myelosuppression. The causative organisms included viruses, fungi, and bacteria of both high and low pathogenicity. Two-thirds of the infections were fatal. It is suggested that dCF may cause a syndrome similar to severe combined immunodeficiency during the course of treatment. Patients treated with dCF who show evidence of infection, even in the absence of neutropenia, should receive vigorous and rapid diagnostic evaluation to establish the cause of their infection, and aggressive treatment of suspected organisms.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Coformycin; Drug Evaluation; Female; Herpes Zoster; Humans; Leukemia; Lymphoma; Male; Middle Aged; Mycoses; Neoplasms; Pentostatin; Ribonucleosides

Pentostatin (2'-deoxycoformycin, DCF) was administered to 17 patients with a variety of lymphoid neoplasms, both T- and B-cell, that were refractory to conventional treatments. Several responses and 2 complete remissions occurred. Toxic effects were less severe than previously described: this may be attributable to relatively low doses of DCF or to precautions taken to prevent tumour lysis syndrome. DCF appears valuable as a second-line treatment in non-Hodgkin's lymphomas and as initial treatment in T-cell chronic lymphocytic leukaemia and mycosis fungoides. Although myelosuppression is mild, immunosuppression and superinfection are potential hazards of treatment with DCF. The ocular toxicity of DCF, previously described as conjunctivitis, appears to be a keratitis of moderate severity which requires further study.

Topics: Adult; Coformycin; Female; Herpes Zoster; Humans; Keratitis; Lymphoma; Male; Pentostatin; Ribonucleosides