Standard pentostatin dose reductions in renal insufficiency are not adequate: selected patients with steroid-refractory acute graft-versus-host disease.

BACKGROUND AND OBJECTIVE: Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD). PATIENTS AND METHODS: Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m(2)/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m(2) leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m(2) leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated. RESULTS: Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m(2), AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease. CONCLUSION: A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m(2) seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.

Pentostatin in chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a disease that typically afflicts older individuals with a median age of diagnosis in the eighth decade of life for which treatments available now are not curative. Although purine analogue based combinations produce complete responses (CRs) in many patients, the use of these combinations has been limited by toxicity including myelosuppression and an increased risk of infectious complications. OBJECTIVE: To identify the role of pentostatin, a specific inhibitor of adenosine deaminase (ADA), in the treatment of CLL. We compare pentostatin to other purine analogues, most notably fludarabine, with regard to safety and efficacy. Finally, we review the use of pentostatin in other diseases. METHODS: The scope of this review encompasses the history of treatment for CLL as well as the genesis of modern combination chemoimmunotherapy and the advantages of pentostatin within such a treatment program. RESULTS: Combination therapy with pentostatin seems to provide response frequencies comparable to fludarabine based combinations but with less toxicity and with greater ease of administration.

[Pentostatin treatment for a patient with chronic type adult T-cell leukemia undergoing hemodialysis].

This is a preliminary feasibility study to assess the pharmacokinetics and efficacy of pentostatin in a patient undergoing dialysis. Pentostatin is a safe and well-tolerated medication, but a dose reduction is required for patients with renal insufficiency. We present a patient with chronic adult T-cell leukemia, whose white blood cell count exceeded 100 X 10(9)/l, and end-stage renal disease, receiving long-term thrice-weekly dialysis. The initial treatment with oral cyclophosphamide or with oral etoposide resulted in no response. After informed consent was obtained, pentostatin (1, 2, or 3mg/m2) was administered. 1 or 2 hours after injection, the patient received hemodialysis over 4 hours to remove any of the drug remaining in his system. Plasma concentrations of pentostatin were calculated with the known pharmacokinetics parameters. The differential equations describing a 2-compartment open-infusion pharmacokinetic model were fitted to the measured concentration-time data. Tumor lysis syndrome occurred 4 days after the course of the highest dose (3mg/m2), and the patient achieved complete remission. Anorexia, graded as 2 according to the NCI-CTC classification system, occurred and continued for four weeks. Pentostatin therapy consisting of the decreased dose (2mg/m2) was then administered every other week and provided a transient partial response with mild anorexia. Consequently, pentostatin can be considered as one of the chemotherapeutic regimens available for a patient undergoing dialysis.

Pentostatin - pharmacology, immunology, and clinical effects in graft-versus-host disease.

Pentostatin (deoxycoformycin), is one of a number of purine analogues. The drug was originally designed to mimic a form of severe combined immune deficiency, characterised by marked T lymphopenia but variable B cell function. Clinically, the drug has been used primarily to treat a rare type of leukaemia - hairy cell leukaemia. Recently, the drug has seen increasing attention as an immunosuppressant. This review will cover the basic pharmacology and immunological effects of pentostatin. The clinical use of this agent in prevention and treatment of graft-versus-host disease will be examined. Although many of these studies are ongoing, this agent has promise as a novel immunosuppressive agent with a new mechanism of action.

Pentostatin pharmacokinetics and dosing recommendations in patients with mild renal impairment.

PURPOSE: The purpose of this study was to determine the pharmacokinetic parameters of pentostatin in renally impaired patients in order to establish dosing guidelines for this population. METHODS: Pentostatin doses were administered as 15-min intravenous infusions to patients based on their measured creatinine clearance (CLcr) as follows. Patients with normal renal function (NRF), defined as CLcr >60 ml/min, received 4 mg/m(2) repeated every14 days. Patients with impaired renal function (IRF) included those with CLcr 41-60 ml/min who received 3 mg/m(2) and those with CLcr 21-40 ml/min who received 2 mg/m(2), also repeated every 14 days. Heparinized plasma samples were collected during drug infusion and out through 96 h after dosing, except in two patients in whom sampling was extended to 144 h after dosing. Urine sampling extended to 96 h after dosing, and all samples were analyzed by a validated enzyme immunoassay for pentostatin concentrations. RESULTS: Enrolled in the study were 13 patients (7 IRF and 6 NRF), of whom 12 contributed samples for pharmacokinetic analysis. Median baseline CLcr values were 71.5 ml/min for NRF patients and 44 ml/min for IRF patients. Following the end of intravenous infusion, pentostatin plasma concentrations declined biexponentially with time. In some patients there was a transient increase in pentostatin equivalents 2 to 4 h after dosing. There was a good correlation between measured CLcr and pentostatin total plasma clearance. The AUC(0- infinity ) values seen in IRF patients, at lower doses, were within the range of the AUC(0- infinity ) values seen in patients with normal CLcr. Toxicities observed in the two groups of patients were similar. CONCLUSIONS: The pentostatin doses used in the study appear to be appropriate for administration to cancer patients with varying degrees of renal impairment.

Pharmacology of purine nucleoside analogues.

Three new purine nucleoside analogues, pentostatin, cladribine and fludarabine, have demonstrated remarkable clinical activity in a variety of hematologic malignancies. Although they share structural similarities, their plasma pharmacology, metabolism, and mechanisms of action differ qualitatively and quantitatively. The plasma pharmacokinetics and the cellular pharmacodynamics are reviewed to provide a basis for dose schedules and rationales for combinations with other anticancer drugs.

Pentostatin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders.

Pentostatin, a potent inhibitor of adenosine deaminase, is an antineoplastic agent which has been studied in the treatment of a variety of lymphoproliferative disorders. It is particularly effective in the treatment of hairy cell leukaemia, achieving complete remissions in 33 to 92% of patients, and has useful activity in treating B cell chronic lymphocytic leukaemia, prolymphocytic leukaemia, adult T cell leukaemia/lymphoma and cutaneous T cell lymphoma refractory to conventional chemotherapy. Initial results suggest that in the treatment of hairy cell leukaemia pentostatin achieves a more rapid response and higher frequency of complete remission with longer duration than interferon-alpha 2a, although it is still not known if some patients experiencing complete remission have been cured. The drug has yet to be directly compared with other promising purine analogues such as cladribine and fludarabine, and results of such comparisons are required before the ultimate role of pentostatin in the treatment of hairy cell leukaemia can be clearly established. However, pentostatin does produce a substantial response in a difficult therapeutic area and should be considered for initial treatment of hairy cell leukaemia.

Pentostatin: an adenosine deaminase inhibitor for the treatment of hairy cell leukemia.

OBJECTIVE: To review the pharmacology, pharmacokinetics, adverse effects, and various dosage regimens of pentostatin, and to evaluate the role of pentostatin in the treatment of hairy cell leukemia (HCL). DATA IDENTIFICATION: Articles were identified via an English-language literature search of MEDLINE (1966-91) and an extensive search of bibliographies from identified articles. STUDY SELECTION: Human clinical trials and case reports were selected for evaluation. DATA EXTRACTION: The literature was assessed for quality, methodology, and outcome information. DATA SYNTHESIS: At dosages of 4 mg/m2 administered every other week for 6-9 months, pentostatin has been shown to successfully induce a complete response in 58-90 percent of patients and to produce a partial response in up to 30 percent of patients with HCL. The median time to achieve a response is 4.7 months. Long-term remissions of at least 14 months' duration have occurred in some patients. Compared with interferon alfa alone, total response rates are not significantly different when pentostatin and interferon alfa are used in combination. When dosed appropriately, pentostatin is generally well tolerated. Common adverse effects include nausea, vomiting, myelosuppression, fever, and infection. CONCLUSIONS: Pentostatin is a purine analog that inhibits adenosine deaminase, a key enzyme necessary for purine salvage. Pentostatin has received labeling approval for the treatment of HCL refractory to a minimum of three to six months of treatment with interferon alfa. Based on current data, pentostatin will be a useful addition to the therapeutic agents presently available to patients with HCL. Ongoing trials are evaluating the effectiveness of pentostatin as first-line therapy for patients with HCL.