VA Class:AN200

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Pentostatin

Chemical Name:

• ( R )-3-(2-deoxy-β-D- erythro -pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5- d ][1,3]diazepin-8-ol

Molecular Formula:

• C₁₁H₁₆N₄O₄

Pentostatin is an antineoplastic antibiotic produced by Streptomyces antibioticus .1,2,3,4,5,9,10,11,20

Hairy Cell Leukemia

Pentostatin is used for the treatment of hairy cell leukemia (leukemic reticuloendotheliosis) in previously untreated patients with active disease characterized by clinically relevant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.1,15,59 Pentostatin also is used in patients with active disease that responds inadequately to, or progresses during, interferon alfa therapy.1,15,59 Interferon alfa-refractory hairy cell leukemia is defined as disease that progresses despite at least 3 months of interferon alfa therapy or fails to respond to a minimum of 6 months of therapy.97,110 Pentostatin or cladribine should be considered first-line therapy for most patients with hairy cell leukemia who require treatment because of their apparent greater efficacy (i.e., higher complete response rate).15,59,99,100,101,102,103,104,105,106,107 Of these agents, cladribine may be preferred because of its favorable toxicity profile and ease of administration (i.e., single 7-day course of treatment).99,100,103,105,106,107 (See Cladribine 10:00.) Additional comparative studies and long-term follow-up are required to elucidate optimal therapy for patients with hairy cell leukemia.100,105,106,107

Pentostatin produces clinically important tumor regression or disease stabilization (complete or partial responses) in approximately 80-100% of patients with hairy cell leukemia,1,2,3,4,5,10,12,15 including in previously untreated patients (i.e., those who have not undergone splenectomy or other therapy) as well as in those in whom splenectomy and/or therapy with other agents (e.g., interferons, antineoplastic agents) have failed to control the disease (i.e., those with progressive disease).1,2,3,4,5,7,8,10,12,13,15,97,98,109 A complete response to pentostatin therapy generally has been defined as clearing of peripheral blood and bone marrow of all hairy cells; normalization of organomegaly and lymphadenopathy by physical examination; and recovery of hemoglobin concentration to at least 12 g/dL, platelet count to at least 100,000/mm³, and granulocyte count to at least 1500/mm³.1,4,12 A partial response has been defined as a decrease of greater than 50% in the number of hairy cells in peripheral blood and bone marrow, and a decrease of greater than 50% in organomegaly and lymphadenopathy; hematologic parameters for a partial response were the same as those for a complete response.1,4,12

Currently available evidence suggests that initial response may be more rapid, and complete responses more frequent, with pentostatin therapy than with interferon alfa therapy.1,2,5,10,12,15,97,98,107,109 Results of a randomized, comparative study in previously untreated patients with hairy cell leukemia demonstrate a higher rate of complete and partial responses and longer relapse-free survival in patients receiving pentostatin versus interferon alfa.1,109 Overall complete and partial responses of 84 and 6%, respectively, reportedly were observed in evaluable patients receiving pentostatin 4 mg/m² IV every 2 weeks for 6 months compared with complete and partial responses of 18 and 24%, respectively, in evaluable patients receiving interferon alfa-2a 3 million units subcutaneously 3 times per week for 6 months.1 According to intention-to-treat analysis of the data, complete and partial responses of 68 and 5%, respectively, were observed in patients with hairy cell leukemia receiving initial therapy with pentostatin compared with complete and partial responses of 14 and 18%, respectively, in those receiving interferon alfa.1 The median time to response in patients receiving initial therapy with pentostatin reportedly was 4-6.6 months compared with 6.2-11.5 months in patients receiving interferon alfa.1 After 24 months, 76 and 50% of patients responding to pentostatin therapy maintained complete and partial responses, respectively, whereas 16 and 21% of patients responding to interferon alfa therapy maintained complete and partial responses, respectively.1

In patients with a complete response to pentostatin, 2 additional doses of pentostatin were administered followed by discontinuance of pentostatin therapy.1 In patients with partial response to pentostatin, therapy was continued for an additional 6 months.1 Pentostatin therapy was discontinued in patients with stable disease after 6 months or progressive disease after 2 months of therapy.1 Patients with a complete or partial response to interferon alfa after 6 months of therapy continued to receive interferon therapy for another 6 months.1 Interferon therapy was discontinued in patients with disease that did not respond after 6 months of therapy or progressed after 2 months.1 Patients who were intolerant of interferon alfa therapy or patients with disease refractory to initial treatment with interferon alfa were allowed to cross over to treatment with pentostatin.1 Among patients who received initial therapy with interferon alfa but then crossed over to receive pentostatin therapy, complete and partial responses of 85 and 4%, respectively, were observed.1 At a median follow-up duration of 46 months, there was no difference in survival between the patient groups receiving either pentostatin or interferon alfa as initial therapy for hairy cell leukemia;1 however, no definite conclusions regarding survival may be drawn from these results since most patients who initially received interferon alfa therapy eventually crossed over to receive pentostatin therapy.1 At a median duration of about 9 years, the estimated 5-year survival rate was 90% and and the estimated 10-year survival rate was 81% for patients receiving pentostatin either as initial treatment or as crossover treatment following initial treatment with interferon alfa.112

Nausea and/or vomiting (63 versus 22%), rash (43 versus 30%), and pruritus (21 versus 6%) occurred more frequently in patients receiving pentostatin whereas fever (59 versus 46%), fatigue (55 versus 42%), myalgia (36 versus 19%), chills (34 versus 19%), headache (29 versus 17%), and sweating or increased sweating (21 versus 8%) were more frequent in patients receiving interferon alfa as initial therapy for hairy cell leukemia.1

In phase 2 clinical studies in patients with interferon alfa-refractory hairy cell leukemia, overall complete and partial responses of 58 and 28%, respectively, were observed in a limited number of these patients receiving pentostatin 4 mg/m² IV every other week for 3 months; responding patients continued treatment for another 3-9 months.1 The median time to response in these patients reportedly was 4.2 months.1 The median duration of response to pentostatin therapy in 2 phase 2 clinical studies of patients with hairy cell leukemia reportedly exceeded 7.7 and 15.2 months.1 According to the manufacturer, almost all of the patients in the phase 2 and 3 studies had ECOG performance status of 0-2.1

Current data are insufficient to determine whether pentostatin is curative in hairy cell leukemia.15,105,107 However, long-term follow-up shows that complete responses to pentostatin for hairy cell leukemia are durable.112,122 The drug's role compared with cladribine (also used as initial therapy in patients with hairy cell leukemia) has not been fully elucidated; further comparative studies and long-term follow-up are necessary.2,4,10,15,100,105,106,107

Chronic Lymphocytic Leukemia

Pentostatin is used alone or in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL)†.22,59

Pentostatin has been used as a single agent for the treatment of CLL.2,6,113 In uncontrolled studies, objective responses ranging from about 18 to 27% (mostly partial responses) have been observed in patients receiving pentostatin for newly diagnosed or previously treated CLL.2,6,113 Objective responses also have been reported in patients receiving pentostatin for aggressive variant forms of CLL, such as B-cell or T-cell prolymphocytic leukemia†.76,114

Higher rates of objective response have been reported in patients receiving pentostatin in combination regimens for the treatment of CLL.115,116,117 In a phase 2 study, a response rate of 75% (25% complete responses) was reported in 32 patients receiving pentostatin, cyclophosphamide, and rituximab for previously treated CLL.116 In another phase 2 study, a response rate of 91% (41% complete responses) was reported in 64 evaluable patients receiving pentostatin, cyclophosphamide, and rituximab as initial treatment for CLL.117 Subgroup analysis suggests that geriatric patients (70 years of age or older) and patients with moderate renal impairment (creatinine clearance less than 70 mL/minute) experience similar efficacy and tolerance as other patients receiving this regimen for CLL, but patients with reduced renal function were more likely to require dosage reduction.118 Further studies are needed to compare the efficacy and toxicity of pentostatin-based regimens with other regimens for the treatment of CLL.116,117

Because chronic lymphocytic leukemia generally is not curable, occurs principally in geriatric patients, and often progresses slowly, the disease generally is treated conservatively unless there is a clear indication for immediate, aggressive therapy.22,60,63,64,65,66,68,69 Therefore, antineoplastic chemotherapy usually is reserved for patients with progressive, symptomatic disease (e.g., those with disease-related symptoms such as fever, night sweats, or weight loss; progressive bone marrow failure; acquired autoimmune hemolytic anemia or thrombocytopenia; enlarged or painful lymph nodes or spleen; disease-related recurrent infections; or progressive lymphocytosis).22,60,63,65,66,68,69,70,71

Cutaneous T-cell Lymphoma

Pentostatin is used in the treatment of cutaneous T-cell lymphoma†.59 Objective responses to pentostatin have been reported in the treatment of cutaneous T-cell lymphoma, such as mycosis fungoides and Sézary syndrome.2,76,77,85,119

Reconstitution and Administration

Pentostatin is administered by IV infusion or direct IV injection.1 It is recommended that patients be adequately hydrated (e.g., with 500-1000 mL of 5% dextrose and 0.45% sodium chloride injection or a similar infusion solution) prior to and immediately after (with an additional 500 mL of 5% dextrose or a similar infusion solution) administration of pentostatin to minimize the risk of adverse renal effects.1,3,11,97

Pentostatin powder for injection is reconstituted by adding 5 mL of sterile water for injection to a vial labeled as containing 10 mg of the drug to produce a solution containing 2 mg/mL.1 Before withdrawing a dose of pentostatin, the powder and diluent should be shaken thoroughly to ensure complete dissolution of the drug.1,97 For direct IV injection, the appropriate dose of reconstituted pentostatin should then be withdrawn from the vial and injected over a period of 5 minutes.1,9,97

Alternatively, for intermittent IV infusion, the appropriate dose of reconstituted pentostatin can be diluted with 25 or 50 mL of either 5% dextrose injection or 0.9% sodium chloride injection.1,97 The manufacturer states that dilution of the entire contents of a 10-mg vial of pentostatin that has been reconstituted to a final concentration of 2 mg/mL will result in solutions containing 0.33 or 0.18 mg/mL of drug when 25 or 50 mL, respectively, of diluent is used.1 The drug usually is infused IV over 20-30 minutes.1,97

The manufacturer recommends that procedures for proper handling and disposal of antineoplastic drugs (e.g., use of protective clothing, including polyethylene gloves) be used to avoid exposure to pentostatin during preparation of IV solutions.1 The manufacturer recommends that spills and wastes be treated with 5% sodium hypochlorite solution prior to disposal.1,97

Reconstituted and diluted solutions of pentostatin contain no preservatives and should be used within 8 hours of preparation.1 (See Chemistry and Stability: Stability.) Parenteral solutions of pentostatin should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit.1

Dosage

Hairy Cell Leukemia

For the treatment of hairy cell leukemia in adults with creatinine clearances of 60 mL/minute or greater, the usual initial IV dosage of pentostatin is 4 mg/m² administered as single doses every other week.1,3,4 Higher dosages (e.g., 20-50 mg/m2 administered in divided doses over 5 days) have been associated with an increased risk of severe toxicity (e.g., renal, hepatic, pulmonary, CNS) and currently are not recommended .1,2,97,98

The optimum duration of pentostatin therapy in patients with hairy cell leukemia has not been determined.1 If continued clinical improvement is observed in the absence of any major toxicity, the patient should be treated until a complete response is observed.1 Although not necessarily established as required, it has been suggested that patients receive 2 additional doses of pentostatin following achievement of a complete response.1,97,98 Therapy with pentostatin should be discontinued in patients who have not achieved a complete or partial response after 6 months of therapy and in those in whom the optimum response achieved following 12 months of therapy is a partial response.1

Dosage Modification for Toxicity

Withholding or discontinuing one or more individual doses may be required in patients who experience severe adverse reactions with pentostatin therapy.1

Dermatologic Toxicity

Pentostatin should be withheld in patients with severe rash.1

Neurologic Toxicity

Pentostatin should be withheld or discontinued in patients with evidence of nervous system toxicity.1

Infectious Complications

Pentostatin should be withheld in patients with an active underlying infection; however, treatment may be resumed once the infection is controlled.1

Renal Toxicity

Individual doses of pentostatin should be withheld and creatinine clearance determined in any patient in whom a predose serum creatinine concentration is found to be increased.1 (See Dosage and Administration: Dosage in Renal Impairment.)

Hematologic Toxicity

No dosage adjustments are necessary at the start of therapy in patients with anemia, neutropenia, or thrombocytopenia; in addition, dosage adjustments are not necessary during a treatment course in patients with thrombocytopenia or anemia that otherwise can be managed with appropriate hematologic monitoring and/or therapy.1 However, pentostatin should be withheld temporarily if the absolute neutrophil count declines from a baseline value exceeding 500/mm³ prior to therapy to a value less than 200/mm³ during therapy; the drug can be resumed when the absolute neutrophil count returns to pretreatment levels.1

Dosage in Renal Impairment

In patients with an elevated predose serum creatinine concentration, the dose of pentostatin should be withheld and creatinine clearance determined.1 The manufacturer states that there are insufficient data to recommend an initial or subsequent dose of pentostatin in patients with impaired renal function (i.e., creatinine clearance less than 60 mL/minute).1 Since patients with renal failure may be at increased risk for toxicity,2,9,32,85 they should receive pentostatin only when the potential benefits justify the possible risks; 2 patients with creatinine clearances of 50-60 mL/minute achieved complete responses without unusual toxicity when treated with 2 mg/m² of pentostatin.1

Pentostatin is a toxic drug.1,2,7,8,9,10,32,105,107 Many toxic effects of the drug appear to be dose dependent,1,2,8,75,78,79,105,107 and the risk of severe and potentially irreversible or fatal toxicity is increased at relatively high dosages.1,9,10,105,107 However, dosage alone cannot predict the likelihood of pentostatin toxicity, and other factors such as patient age, underlying disease, renal function, and performance status contribute to individual risk.2,9,10,32,85,107 Because the relationship of such factors is complex, interindividual risk varies considerably and may be unpredictable.2,46 During clinical studies, 3-10% of patients receiving pentostatin (either as initial therapy for hairy cell leukemia or as second-line therapy for interferon alfa-refractory disease) died.1,110

In early studies in which pentostatin was used in relatively high dosages (e.g., up to 10 mg/m² daily for 5 days) for a variety of neoplasms, severe, sometimes fatal adverse effects occurred frequently.2,7,9,10,16,32,82,83,105,107 In contrast, serious toxicity generally has been minimal with use of relatively low dosages of the drug (e.g., 4 mg/m²every other week) in patients with hairy cell leukemia that was refractory to interferon alfa.1,2,9,10,97,98,107 Most adverse effects in these patients reportedly were either mild or moderate in severity and generally diminished in frequency with continued therapy.1,3,4,5,6,11,12,107 However, even at relatively low dosages, patients with impaired renal function or poor performance status and certain others may be at substantially increased risk of toxicity.2,9,10,32,85 In addition, some evidence suggests that the risk of toxicity may depend partly on the dosage schedule.2,78

The most severe adverse effects associated with currently recommended dosages of pentostatin involve principally the kidneys (e.g., acute renal failure) and nervous system (e.g., seizures, lethargy).2,10,32,59,75,107 Adverse effects reportedly resulted in discontinuance of pentostatin therapy in 11% of patients with interferon alfa-refractory hairy cell leukemia in phase 2 clinical studies.1 In a phase 3 multicenter study comparing initial therapy with pentostatin versus interferon alfa in patients with hairy cell leukemia, adverse effects reportedly resulted in discontinuance of therapy in 19 (5%) patients: 9 during initial therapy with pentostatin, 4 during crossover to pentostatin therapy, 5 during initial therapy with interferon alfa, and 1 during both initial therapy with interferon alfa and crossover to pentostatin therapy.1 Some evidence suggests that children may tolerate the drug better than adults.2,75,98 (See Cautions: Pediatric Precautions.)

Incidence data for adverse effects of pentostatin are based principally on data from a randomized trial comparing pentostatin with interferon alfa as initial therapy for hairy cell leukemia.1 As noted, selected information is included on frequent adverse effects and additional toxicities reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia in phase 2 studies.1

Hematologic Effects

The frequency and severity of pentostatin-induced myelosuppression appear to be related principally to the underlying disease type and tumor mass.2,10,46,85,97,98,105,107 In patients whose malignancy includes bone marrow involvement (e.g., in hairy cell leukemia), myelosuppression associated with the drug generally is more frequent and more severe than in those without such involvement (e.g., in mycosis fungoides); thus, even at low dosages, substantial myelosuppression can occur in certain patients.2,10,105,107 Patients with good marrow reserve generally exhibit minimal myelosuppression.105

Leukopenia,1,11,12,46,75,80,107 anemia,1,8,46,107 and thrombocytopenia1,80,107 have been reported in 60, 35, and 32%, respectively, of patients receiving pentostatin therapy for interferon alfa-refractory hairy cell leukemia.1 However, in patients receiving pentostatin as initial therapy for neoplasm, such myelosuppressive effects were less common, with leukopenia occurring in 22%, anemia in 8%, and thrombocytopenia in 6% of patients.1 Hemorrhage and agranulocytosis have been reported in 3-10% of patients receiving the drug as initial therapy for hairy cell leukemia.1 Myelosuppression appears to be particularly likely during the first several courses of therapy with the drug.1 Assessing the myelosuppressive effect of pentostatin can be difficult because many patients with hairy cell leukemia have preexisting disease-related myelosuppression.2,5,10,107 The initial decrease in leukocytes observed in patients with hairy cell leukemia receiving the drug results principally from a reduction in lymphocytes (including hairy cells).107 As response to pentostatin therapy occurs, a corresponding improvement in marrow status also may be observed, and each subsequent treatment course may be associated with a lesser degree of marrow suppression.2,105

Hemolytic anemia and aplastic anemia each was reported in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Other adverse hematologic effects, which were reported in less than 3% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included abnormal erythrocytes, leukocytosis, pancytopenia, eosinophilia, unspecified hematologic disorder, hemolysis, lymphoma-like reaction, and thrombocythemia.110

Nervous System Effects

Severe CNS toxicity was observed in patients receiving pentostatin in phase 1 studies in which high dosages were used.1 Pentostatin appears to cause dosage schedule-dependent nervous system toxicity, even in patients with normal renal function.2,8,32,75 Increasing lethargy with successive doses of pentostatin has been reported in some patients receiving the drug weekly, and most clinicians recommend that the drug generally not be administered more frequently than every 2 weeks.2,97,98 If weekly therapy is used, some clinicians recommend that no more than 3 successive weekly doses be given.2 It has been suggested that CNS effects may be related to intracerebral accumulation of deoxyadenosine and/or adenosine; such cumulative toxicity has not been reported with the currently recommended every-other-week dosage schedule for pentostatin.2,8 CNS toxicity of the drug can range in severity from lethargy and somnolence to coma.2,32,97,98,107 However, in patients receiving currently recommended, relatively low dosages, adverse CNS effects generally are limited to fatigue, headache, malaise, and depression and only occasionally manifest as severe neurologic toxicity.1,107 Pentostatin-induced nervous system toxicity (e.g., seizures, coma) rarely can be fatal,2,32 and therapy with the drug should be withheld or discontinued in patients exhibiting evidence of nervous system toxicity.1,97,98

Among patients receiving pentostatin as initial therapy for hairy cell leukemia, fatigue occurred in 42%, headache in 17%, asthenia in 12%, and unspecified CNS disorder/toxicity in 1% of patients.1 Among patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, fatigue occurred in 29%, headache in 13%, unspecified CNS disorder/toxicity in 11%, and asthenia in 10% of patients.1 Anxiety, confusion, depression, dizziness, insomnia, nervousness, paresthesia, and somnolence each was reported in 3-10% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Abnormal dreams, abnormal thinking, amnesia, ataxia, decreased libido or loss of libido, dysarthria, emotional lability, encephalitis, hallucination, hostility, hyperkinesia, meningism, neuralgia, neuritis, neuropathy, neurosis, paralysis, seizures, syncope, twitching, and vertigo each was reported in less than 3% of these patients.1

Other adverse nervous system effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included malaise (in 3-10% of patients) and abnormal gait, agitation, apathy, CNS depression, coma, decreased reflexes, depersonalization, facial paralysis, hyperesthesia, hypesthesia, hypertonia, incoordination, postural dizziness, stupor, unusual or perverted taste, and tremor (each in less than 3% of patients).110 Multiple, small, nonhemorrhagic cerebral infarcts were found in one patient receiving the currently recommended dosage of pentostatin who developed a change in mental status and arm weakness; however, the CNS deficit subsequently improved, and the role of pentostatin in the development of these infarcts is unclear.7

GI Effects

Nausea and/or vomiting1,2,3,4,5,9,11,12,59,75,80,107 in patients receiving pentostatin usually is mild to moderate in severity3,4,98 but can be life-threatening.107 Among patients receiving pentostatin as initial therapy for hairy cell leukemia, nausea and/or vomiting occurred in 63%, diarrhea in 17%, abdominal pain in 16%, anorexia in 13%, and stomatitis in 12% of patients.1 Among patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, nausea and vomiting occurred in 53%, nausea only in 22%, anorexia in 16%, diarrhea in 15%, stomatitis in 5%, and abdominal pain in 4% of patients.1 In some cases, nausea and/or vomiting may develop despite antiemetic prophylaxis and may increase in frequency and severity with successive courses; the onset of vomiting usually is delayed for 15-24 hours after pentostatin administration.107

Dental abnormalities, gingivitis, dyspepsia, and flatulence each was reported in 3-10% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Glossitis, dysphagia, ileus, and constipation each was reported in less than 3% of these patients, and oral candidiasis (moniliasis) was reported in 2% of these patients.1 Other adverse GI effects, which were reported in less than 3% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included gum hemorrhage, oral leukoplakia, periodontal abscess, unspecified mouth disorder, unspecified mucous membrane disorder, eructation, esophagitis, gastritis, GI hemorrhage, hernia, colitis, intestinal obstruction, proctitis, abnormal stools, and melena.110

Hepatic Effects

Severe hepatic toxicity was observed in patients receiving pentostatin in phase 1 studies in which high dosages were used.1 Unspecified hepatic disorder and/or elevated liver function test results occurred in 2% of patients receiving pentostatin as initial therapy for hairy cell leukemia and in 19% of patients receiving the drug for interferon alfa-refractory hairy cell leukemia.1 Other adverse hepatic effects, which were reported in less than 3% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included jaundice, hepatitis, hepatomegaly, and hepatic failure.110

Dermatologic Effects

Among patients receiving pentostatin as initial therapy for hairy cell leukemia, rash occurred in 43%, pruritus in 21%, and unspecified skin disorder in 4% of patients.1 Among patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, rash occurred in 26%, pruritus in 10%, and unspecified skin disorder in 17% of patients.1

Rash (including erythematous, papular, and vesiculobullous),1,3,4,5,8,12,80,107 which occasionally may be severe and worsen during continued therapy, has been reported in patients receiving pentostatin for hairy cell leukemia. Rash occasionally is associated with keratoconjunctivitis and may occur during early pentostatin therapy without recurrence during continued therapy with the drug.107 Fatal erythroderma was reported in a patient receiving pentostatin for T-cell chronic prolymphocytic leukemia.123 Therapy with the drug should be withheld in patients developing severe rash.1

Dry skin and urticaria each was reported in 3-10%, and acne, alopecia, eczema, petechial rash, and photosensitivity reaction each was reported in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Skin abscess was reported in 2% and mycotic skin infection in less than 1% of these patients.1 Other adverse dermatologic effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included ecchymosis, maculopapular rash, seborrhea, skin discoloration, sweating, and vesicobullous rash (each in 3-10% of patients) and contact dermatitis, exfoliative dermatitis, fungal dermatitis, psoriasis, purpura, benign skin neoplasm, subcutaneous nodule, and skin hypertrophy (each in less than 3% of patients).110

Sensitivity Reactions

Allergic reactions have been reported in 11% of patients with interferon alfa-refractory hairy cell leukemia receiving pentostatin and in 2% of patients with this neoplasm receiving pentostatin as initial therapy.1 Anaphylactoid reactions were reported in less than 3% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia.110

Musculoskeletal Effects

Among patients receiving pentostatin as initial therapy for hairy cell leukemia, myalgia occurred in 19% and arthralgia in 6% of patients.1 Among patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, myalgia occurred in 11% and arthralgia in 3% of patients.1 Arthritis and gout each was reported in less than 3%, and osteomyelitis was reported in 1% of patients receiving first-line therapy with pentostatin for hairy cell leukemia.1 Other adverse musculoskeletal effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included back pain (in 3-10% of patients) and bone pain, neck rigidity, neck pain, and pathological fracture (each in less than 3% of patients).110

Renal Effects

Hemolytic-uremic syndrome has been described in case reports of patients receiving high dosages of pentostatin for cutaneous T-cell lymphoma.120,121 Fatal hemolytic-uremic syndrome was reported in a patient receiving pentostatin and interferon alfa for mycosis fungoides.121 Another patient receiving pentostatin for Sézary syndrome developed thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, hallucinations, confusion, disorientation, oliguric acute renal failure requiring hemodialysis, and fever.120 The syndrome resolved with plasma exchange and glucocorticoid therapy.120

Severe renal toxicity was observed in patients receiving pentostatin for hairy cell leukemia in phase 1 studies in which high dosages were used.1,9,98,105 In patients treated with the currently recommended dosage (4 mg/m²) and adequate hydration, increases in serum creatinine generally are minor and reversible.1,9,98,107 Some patients with normal renal function prior to pentostatin therapy were reported to have evidence of mild to moderate renal toxicity following therapy.1,7,46

Among patients receiving pentostatin as initial therapy for hairy cell leukemia, elevated serum creatinine concentrations occurred in 3-10% of patients, and abnormal kidney function, nephropathy, renal failure, renal insufficiency, and renal stone each occurred in less than 3% of patients.1 Other adverse renal effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included increased BUN (in 3-10% of patients) and hydronephrosis and toxic nephropathy (each in less than 3% of patients).110

Genitourinary Effects

Unspecified genitourinary disorder has been reported in 15% of patients receiving pentostatin for the treatment of interferon alfa-refractory hairy cell leukemia.1 Urinary tract infection occurred in 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Amenorrhea, breast lump, and impotence each was reported in less than 3% of these patients.1 Other adverse genitourinary effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included hematuria and dysuria (each in 3-10% of patients) and pelvic pain, albuminuria, fibrocystic breast, glycosuria, gynecomastia, oliguria, polyuria, pyuria, urinary frequency, urinary retention, urinary urgency, impaired urination, urolithiasis, and vaginitis (each in less than 3% of patients).110

Cardiovascular Effects

Hypotension and peripheral edema each was reported in 3-10%, and angina pectoris, arrhythmia, A-V block, bradycardia, cardiac arrest, deep thrombophlebitis, heart failure, hypertension, pericardial effusion, phlebitis, pulmonary embolus, sinus arrest, tachycardia, vasculitis, and ventricular extrasystoles each was reported in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Other adverse cardiovascular effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included abnormal ECG (in 3-10% of patients) and aortic stenosis, arterial anomaly, cardiomegaly, congestive heart failure, flushing, myocardial infarction, palpitation, shock, and varicose vein (each in less than 3% of patients.110

Hypotension, contributing to death, has been reported in patients receiving pentostatin with carmustine, etoposide, and high-dose cyclophosphamide in an ablative regimen as preparation for a bone marrow transplant.1

Respiratory Effects

Severe pulmonary toxicity was observed in patients receiving pentostatin in phase 1 studies in which high dosages were used.1 Among patients receiving pentostatin as initial therapy for hairy cell leukemia, coughing or increased cough occurred in 20%, upper respiratory infection in 13%, dyspnea and rhinitis each in 11%, pharyngitis in 8%, sinusitis in 6%, pneumonia in 5%, and bronchitis in 3% of patients.1 Among patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, unspecified lung disorder or disease was reported in 12% of patients.1

Asthma was reported in 3-10%, and bronchospasm and laryngeal edema each was reported in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Lung edema occurred in 3-10% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia.110 Other adverse respiratory effects, which were reported in less than 3% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included atelectasis, hemoptysis, hyperventilation, hypoventilation, laryngitis, lung fibrosis, pleural effusion, pneumothorax, pulmonary embolus, and increased sputum.110

Patients receiving concomitant therapy with pentostatin and fludarabine have shown an increase in severe pulmonary toxicity, including fatal pulmonary toxicity.1 (See Drug Interactions: Fludarabine.) Acute pulmonary edema, contributing to death, has been reported in patients receiving pentostatin with carmustine, etoposide, and high-dose cyclophosphamide in an ablative regimen as preparation for a bone marrow transplant.1

Infectious Complications

Among patients receiving pentostatin as initial therapy for hairy cell leukemia, fever occurred in 46% of patients.1 In a randomized trial, infections occurred in 38% of patients receiving pentostatin and 34% of patients receiving interferon alfa as initial treatment for hairy cell leukemia.1 On average, patients receiving pentostatin experienced 2.4 documented infections while patients receiving interferon alfa experienced 1.9 documented infections during treatment.1 The types of infections reported in patients receiving pentostatin as initial therapy for hairy cell leukemia included upper respiratory infection in 13%; rhinitis in 11%; herpes zoster, pharyngitis, and unspecified viral infection each in 8%; unspecified infection in 7%; sinusitis and cellulitis each in 6%; bacterial infection and pneumonia each in 5%; conjunctivitis, furunculosis, and herpes simplex each in 4%; bronchitis, sepsis, and urinary tract infection each in 3%; skin abscess and oral candidiasis (moniliasis) each in 2%; osteomyelitis in 1%; and mycotic skin infection in less than 1% of patients.1 Except for herpes zoster (8% in pentostatin-treated patients versus 1% in interferon alfa-treated patients), these types of infections occurred at similar rates among patients receiving initial therapy with interferon alfa for hairy cell leukemia.1

In some cases, patients with preexisting infections experienced exacerbations of their condition, some of which were fatal, during pentostatin therapy.1 Temporary depression of both T and B cells, with prolonged depression of the helper/inducer (CD4⁺, T4⁺) T-cell subset, was observed in one study in patients receiving pentostatin therapy;3,10 persistent decrease in CD4⁺and CD8⁺ lymphocyte counts (particularly in T-cell subsets) has been reported in another study.105,111 The clinical importance of this effect is unknown, but it potentially may increase the risk of opportunistic infections in patients receiving the drug.3,10,111 Prompt evaluation of patients with evidence of infection and early initiation of antimicrobial therapy, as in the treatment of febrile neutropenic patients, is recommended in patients receiving pentostatin.1,2

Ocular Effects

Conjunctivitis occurred in 4% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Abnormal vision, amblyopia, dry eyes, lacrimation disorder, nonreactive eye, photophobia, retinopathy, and watery eyes each was reported in less than 3% of these patients.1 Other adverse ocular effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included eye pain (in 3-10% of patients) and blepharitis, cataract, diplopia, exophthalmos, optic neuritis, and retinal detachment (each in less than 3% of patients).110 A patient receiving pentostatin for hairy cell leukemia in another clinical study developed unilateral uveitis with loss of vision.1

Otic Effects

Deafness, earache, labyrinthitis, and tinnitus each was reported in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 Other adverse otic effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included ear pain (in 3-10% of patients) and otitis media (in less than 3% of patients).110

Metabolic Effects

Among patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, weight loss was reported in 3-10% of patients, and diabetes mellitus, hypocholesterolemia, and weight gain each was reported in less than 3% of patients.110

Local Effects

Hemorrhage and/or inflammation at the injection site was reported in less than 3% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia.110 No injuries from extravasation of pentostatin were reported in clinical studies for hairy cell leukemia.1

Other Adverse Effects

Among patients receiving pentostatin as initial therapy for hairy cell leukemia, chills occurred in 19%, pain in 8%, and sweating or increased sweating in 8% of patients.1 Pain occurred in 20% of patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia.110 Chest pain and facial edema each occurred in 3-10% of patients, and flulike symptoms, hangover effect, hypercalcemia, and hyponatremia each occurred in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1

Other adverse effects, which were reported in patients receiving pentostatin for interferon alfa-refractory hairy cell leukemia, included epistaxis, increased serum lactate dehydrogenase concentration, and lymphadenopathy (each in 3-10% of patients) and abnormal healing, abscess, acidosis, ascites, cyst, dehydration, enlarged abdomen, fibrosis, granuloma, increased creatine phosphokinase concentration, increased gamma globulin concentrations, parosmia, splenomegaly, and unspecified immune system disorder (each in less than 3% of patients).110

Precautions and Contraindications

Pentostatin is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity.1,2 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.1 Most, but not all, adverse effects of pentostatin are reversible if detected promptly.1,2 When severe adverse effects occur during pentostatin therapy, the drug should be discontinued or dosage reduced and appropriate measures instituted.1,9 Pentostatin should be reinstituted with caution if at all, with adequate consideration of further need for the drug, and with awareness of possible recurrence of toxicity.9,97,98

Patients with poor performance status appear to experience greater toxicity with pentostatin and should be treated with the drug only when the anticipated benefits outweigh the potential risks.1,2,10

Hematologic function must be frequently and carefully monitored during and after pentostatin therapy, particularly during the first several courses of therapy in patients at increased risk of myelosuppression (e.g., those with hairy cell leukemia).1,2,9,10 Initiation of pentostatin therapy in such patients can result in severe myelosuppression.1,2,10 (See Cautions: Hematologic Effects.) If severe neutropenia continues beyond the initial cycles of pentostatin therapy, patients should be examined, including bone marrow examination, to determine the status of their disease.1 In addition, periodic monitoring for evidence of peripheral hairy cells should be performed in patients with this leukemia to evaluate the patient's response to therapy.1 Bone marrow aspirations and biopsies also may be required at 2- to 3-month intervals.1,3

Patients receiving pentostatin should be observed closely for signs of nonhematologic (e.g., neurologic) toxicity.1,9 If severe adverse reactions occur, the drug should be withheld and appropriate corrective measures taken as indicated.1,9 Therapy with pentostatin should be temporarily withheld or discontinued in patients who develop evidence of neurologic toxicity.1,9

There currently are inadequate data regarding the use of pentostatin in patients with impaired renal function.1 Patients with abnormal renal function prior to receiving pentostatin appear to be at higher risk for pentostatin-induced toxicity, even when receiving low dosages of the drug, and should be treated with pentostatin (including initial and subsequent doses) only when the anticipated benefits outweigh the potential risks.1,2,98 Prior to initiating pentostatin therapy, renal function should be assessed with a serum creatinine concentration and/or creatinine clearance determination.1,9 Serum creatinine concentration also should be assessed prior to each pentostatin dose and at other appropriate periods during therapy; if an elevated serum creatinine concentration is observed, the dose should be withheld pending creatinine clearance determination.1,9

Patients with infection in whom pentostatin therapy is contemplated should be treated with the drug only when the benefits of such therapy outweigh the potential risks.1,10 Patients with infection prior to initiation of pentostatin therapy have, in some cases, developed worsening of their condition leading to death during the course of therapy.1 If infection develops during therapy with the drug, pentostatin preferably should be temporarily withheld; control of the infection should be attempted before initiating or resuming therapy with the drug.1,9

Although elevations in liver function test results have been reported in patients receiving pentostatin, these changes generally were reversible.1,5,7,9,11,12,75 Regular monitoring of blood chemistry values in patients receiving pentostatin is recommended.1,9,97,98

Patients should be advised of the usual signs and symptoms of adverse effects associated with pentostatin therapy.1

Pentostatin is contraindicated in patients with known hypersensitivity to the drug and/or any ingredient in the formulation.1

Pediatric Precautions

Safety and efficacy of pentostatin in children and adolescents have not been established.1,97 Pentostatin has been studied in the treatment of acute leukemia in a limited number of pediatric patients,2,17 and some evidence suggests that the drug may be better tolerated in this age group than in adults.2,75,98

Geriatric Precautions

Safety and efficacy of pentostatin in geriatric patients have not been studied specifically to date,98 and clinical studies of the drug did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients;1 however, the drug has been used in the treatment of chronic lymphocytic leukemia,2,6,10,14,32,47,59,78,80 which occurs principally in patients older than 50 years of age.60,63,71 Because geriatric patients may have decreased renal function84 and because patients with renal impairment appear to be at increased risk of pentostatin-induced toxicity,1,2 assessment of renal function should be performed in any patient for whom pentostatin therapy is contemplated, and appropriate precautions initiated accordingly.1 (See Cautions: Precautions and Contraindications.) While other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.1

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when pentostatin was tested in several strains of Salmonella typhimurium ; however, when tested in strain TA-100 with or without metabolic activation, a reproducible mutagenic response was observed.1 The mutagenic response was approximately twofold higher than the standard at the maximum drug concentration tested (10 mg/plate).1 The commercially available formulation of pentostatin was clastogenic in vivo when tested in the mouse bone marrow micronucleus assay at concentrations of 20, 120, and 240 mg/kg.1 Pentostatin with or without metabolic activation was not mutagenic nor did it increase chromosomal aberrations in Chinese hamster lung cells exposed to the drug at concentrations of 1-3 mg/mL for 3 hours.1

Acute leukemia and neoplasm each has been reported in less than 3% of patients receiving pentostatin as initial therapy for hairy cell leukemia.1 No studies evaluating the carcinogenicity of pentostatin in animals have been performed to date.1

Pregnancy, Fertility, and Lactation

Pregnancy

Pentostatin can cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.1 There are no adequate and controlled studies of the drug in pregnant women; however, pentostatin produced both maternal and fetal (teratogenic) toxicity in animal studies at dosages approximating those currently recommended in humans.1 Women of childbearing potential should be advised to avoid becoming pregnant while receiving pentostatin,1 and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.97,98 If pentostatin is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1

Fertility

No studies evaluating the effects of pentostatin on fertility in animals have been performed to date; however, mild seminiferous tubular degeneration was observed in animals during an IV toxicity study of the drug at doses of 1 and 4 mg/kg.1 The possible effects of pentostatin on fertility in humans have not been determined to date.1

Lactation

It is not known whether pentostatin is distributed into milk.1 Because of the potential for serious adverse reactions to pentostatin in nursing infants if the drug were distributed into milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Fludarabine

Limited data suggest that concomitant therapy with pentostatin (4 mg/m² every 2 weeks) and fludarabine (principally 10 mg/m² daily for 4 days at 28-day intervals), a synthetic purine nucleoside, may be associated with severe and/or fatal pulmonary toxicity (e.g., pneumonitis).1,98 In one study, 4 of 6 patients receiving the drugs concomitantly for treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.1,98 While the mechanism of this increased toxicity has not been determined, concomitant therapy with these drugs is not recommended.1,98

Allopurinol

Although therapy with either pentostatin or allopurinol alone has been associated with the development of skin rash, limited evidence suggests that concomitant use of the drugs, compared with pentostatin therapy alone, in patients with refractory hairy cell leukemia is not associated with an increased incidence of rash.1,11 However, other toxicities, including abnormalities in renal or hepatic function, have been observed in a few patients receiving concomitant pentostatin and allopurinol.8 Although such abnormalities resolved following discontinuance of allopurinol but continuance of pentostatin therapy, some clinicians suggest that pentostatin and allopurinol not be used concurrently.8 One patient reportedly developed a fatal hypersensitivity vasculitis while receiving pentostatin and allopurinol concurrently; however, a causal relationship to the drugs has not been established.1

Vidarabine

Pentostatin inhibits the degradation of vidarabine and enhances its cytotoxicity in cell culture and in animals with experimentally induced leukemia.1,2,18,86,87,88,89,90 In addition, limited data in patients with acute leukemia suggest that combined therapy with the drugs may be associated with increased plasma vidarabine concentrations and/or half-life18,52,58,63,91 and greater toxicity compared with pentostatin therapy alone.58 Although improvement and/or remission has been reported in a few patients with acute T-cell lymphocytic leukemia who received vidarabine and pentostatin concomitantly,58,63,92 the potential therapeutic benefit versus possible risk of such combined therapy remains to be fully elucidated.1,2,18,58,63,97,98

Other Antineoplastic Agents

Acute pulmonary edema and hypotension, resulting in death, have been reported in patients receiving pentostatin with carmustine, etoposide, and high-dose cyclophosphamide in an ablative regimen as preparation for a bone marrow transplant.1

Acute Toxicity

No specific antidote for pentostatin overdosage is known.1 Administration of pentostatin in dosages higher than those currently recommended (20-50 mg/m² over 5 days as compared with 4 mg/m² every other week, respectively) has been associated with severe renal, hepatic, pulmonary, and CNS toxicity, which was unpredictable and occasionally fatal.1,2 In case of overdosage, management should include discontinuance of the drug and initiation of supportive measures appropriate to the type of toxicity observed.1

Pharmacology

The precise mechanism(s) of action of pentostatin in hairy cell leukemia and other lymphoid malignancies has not been fully elucidated.1,4,5,10,29,50,52,53 Pentostatin is a potent transition-state (tight-binding) inhibitor of adenosine deaminase, an enzyme involved in purine metabolism.1,2,9,10,11,18,20,29,49,52,53,55,56,57 This enzyme appears to regulate intracellular adenosine concentrations via irreversible deamination of adenosine and deoxyadenosine.2,18,53,55,56,57 Although adenosine deaminase is widely distributed in mammalian tissues,2,20,34,35,36,37 highest levels are found in lymphoid tissue; levels in circulating T cells (particularly in T-cell lymphocytic leukemia)1,2,11,20,36 are higher than those in B cells.1,2,10,11,20,36,49 While the level of enzyme activity is low in healthy bone marrow, it is high in myeloid leukemic blast cells.20,34,35,51

Inhibition of adenosine deaminase by pentostatin results in intracellular accumulation of toxic levels of adenine deoxynucleotides (e.g., deoxyadenosine triphosphate [dATP]), which in the presence of deoxyadenosine can lead to cell death.1,2,10,27,28,29,30,49,52,53,54,55,57,97,98 Pentostatin alone, even in concentrations high enough to inhibit adenosine deaminase completely, is not cytotoxic to lymphoid cells cultured in the absence of cytotoxic nucleosides (e.g., deoxyadenosine).2,58 Thus, unlike many other nucleoside-analog antineoplastic agents, the cytotoxic effects of pentostatin do not appear to be attributable directly to the drug or its metabolites but instead appear to result indirectly from the effects of the substrates for adenosine deaminase (adenosine and deoxyadenosine) and/or their metabolites.26,49,52,58,97,98 Although elevated dATP concentrations in the cell can block DNA synthesis via inhibition of ribonucleotide reductase,1,2,4,5,8,10,27,29,30,49,52 the precise role of high dATP concentrations in pentostatin-induced cytotoxicity is controversial.2,4,5,27 Pentostatin also can inhibit RNA synthesis, cause DNA strand breaks, disrupt ATP-dependent cellular processes, and inhibit adenosylhomocysteinase ( S -adenosylhomocysteine hydrolase), all of which also may contribute to the drug's lymphocytotoxic effects.1,2,5,27,29,49,52,53

The degree to which pentostatin inhibits adenosine deaminase varies among cell types, possibly because of differences in enzyme-inhibitor dissociation constants in different cells as well as differences in cellular accumulation of the drug.2,32,34,35,36,37,43,44 There generally has been no clear relation between adenosine deaminase inhibition and pentostatin-induced cytotoxicity in clinical studies.2,47,75 However, the cytotoxic and growth-inhibitory effects of adenosine deaminase inhibition appear to be greater in T cells than in B cells.2,48,57 Although conflicting data exist, some evidence suggests that T cells accumulate more dATP than B cells and thus may be more susceptible to the effects of adenosine deaminase inhibition; dATP concentrations in B cells may be lower because these cells possess higher membrane-associated ecto-5'-nucleotidase activity, which promotes the hydrolysis of higher phosphate compounds to more freely diffusible nucleosides.2,57 Differences in the sensitivity of B and T cells to pentostatin's effects also may be artifactual as a result of testing procedure variables (e.g., cell source, culture media conditions).2 The time course of adenosine deaminase inhibition appears to differ in erythrocytes and lymphocytes and depends on the intrinsic activity of the enzyme in the cell as well as cell-specific pharmacodynamics (e.g., protein synthesis, rate of cellular proliferation).2,18,32,43,44,45 In some cells, inhibition by a single dose of pentostatin may persist for 1 week or longer.2 It is not known whether recovery from adenosine deaminase inhibition occurs as a result of slow efflux of pentostatin from the cell or regeneration of adenosine deaminase;2 however, recovery of blood adenosine deaminase activity may result from replenishment of enzyme from newly formed erythrocytes in that such recovery in animals has been reported to coincide with the life span of erythrocytes in circulation (e.g., 40-60 days).18,81

Response to pentostatin varies according to the type and sensitivity of the neoplasm being treated.2,10,46,47 Conditions associated with relatively low adenosine deaminase activity (e.g., hairy cell and chronic lymphocytic leukemias) manifest prolonged and complete adenosine deaminase inhibition in response to relatively low dosages of pentostatin, whereas conditions associated with high adenosine deaminase activity (e.g., acute leukemias) are less sensitive to the drug, requiring higher doses that produce relatively incomplete inhibition of adenosine deaminase activity.2,10,47

Pharmacokinetics

Limited data are available on the pharmacokinetics of pentostatin.97,98

Absorption

Plasma concentrations of pentostatin following direct IV injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/mL.2,20 Plasma concentrations appear to increase linearly with dose;2,17,21 in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30-minute IV infusion averaged approximately 0.4 or 1.26 mcg/mL, respectively.21

No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin;2,21,31 however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts.2,26,27,28,30,54 In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts,53,55 and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.2,32,33,55

Distribution

Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species.1,2,73,74 Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen.18,73 In dogs, pentostatin tissue concentrations following IV administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum.18,74 Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion;2,18,72 efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (i.e., adenosine deaminase inhibition) varies among different types of cells (e.g., lymphocytes, erythrocytes).2,32,43,44,45

Limited data in animals and humans indicate that pentostatin distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations.1,16,17,18 In a 6-year-old leukemia patient receiving pentostatin 0.25 mg/kg daily for 3 successive days by direct IV injection, serum and CSF (via lumbar puncture) pentostatin concentrations 4 hours after the initial dose were approximately 147 and 19 ng/mL, respectively, using an enzyme-inhibition titration assay; one hour after the third dose, corresponding serum and CSF concentrations were approximately 241 and 35 ng/mL, respectively.17

The mean apparent volume of distribution (V_d) of pentostatin has been reported to be 41.7 L,9 and the volume of distribution at steady state (V_ss) has been reported to be approximately 36 L (20.1 L/m²).2,9 Pentostatin reportedly is approximately 4% bound to plasma proteins.1

Elimination

Limited data indicate that plasma pentostatin concentrations decline in a biphasic manner following IV administration of the drug.2,9,18,19 Following IV administration of 4 mg/m² of pentostatin as a single dose over 5 minutes in healthy individuals, the distribution half-life (t_½α) and terminal elimination half-life (t_½β) reportedly averaged 11 minutes and 5.7 hours, respectively.1,97 In a multiple-dose study in a limited number of patients receiving 36 courses of pentostatin at a dosage of 4 mg/m² IV, t_½α and t_½β reportedly averaged 9.6 minutes (range: 3.1-48.5 minutes) and 4.9 hours, respectively,9 In other studies in a limited number of patients with advanced cancer, the distribution half-life averaged 17-85 minutes and the terminal elimination half-life averaged 2.6-15 hours following single IV doses of 0.1 or 0.25 mg/kg of pentostatin.2,18,19,20

The plasma clearance of pentostatin reportedly averages 68 mL/minute per m².1 Available data suggest that 30-90% or more of a dose of pentostatin is excreted in urine unchanged and/or as active metabolite(s), as evidenced by adenosine deaminase inhibitory activity.1,2,18,19 A correlation has been observed between creatinine clearance and pentostatin clearance in patients with creatinine clearances of 60-130 mL/minute.1,2,9 In patients with renal impairment (creatinine clearance less than 60 mL/minute), the half-life pentostatin averages approximately 18 hours.1,2

Chemistry and Stability

Chemistry

Pentostatin, a structural analog of deoxyadenosine, is an antineoplastic antibiotic produced by Streptomyces antibioticus .2,3,4,5,9,10,11,20 Pentostatin differs from the physiologic nucleosides, adenosine and deoxyadenosine, by the interposition of a methylene group between N-1 and C-6 of the purine ring, resulting in a 7-membered (imidazobenzopin) rather than a 6-membered ring, and by the deletion of an amino group from, and the addition of a hydroxyl group to, the ring; the sugar moiety, deoxyribose, is common to both pentostatin and deoxyadenosine, while adenosine contains ribose.18 The resultant stereochemical and tautomeric differences in the compounds provide an increased binding affinity of pentostatin for the catalytic center of adenosine deaminase compared with the affinities of these physiologic substrates for the enzyme.2,18 Pentostatin is thought to resemble closely the transition-state intermediates of the adenosine deaminase reaction involving these nucleosides (i.e., the intermediaries formed during the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively).2,18,20 The drug is a purine antagonist antimetabolite that acts as an adenosine deaminase inhibitor.2,18 (See Pharmacology.)

Pentostatin is commercially available as the base.1 The drug occurs as a white to off-white solid that is freely soluble in water, having an aqueous solubility exceeding 100 mg/mL.1,97 The pK_a of pentostatin is 5.4.97 Pentostatin for injection is commercially available as a sterile, lyophilized powder; sodium hydroxide and/or hydrochloric acid have been added to adjust final pH.1 Following reconstitution of the drug with sterile water for injection to a concentration of 2 mg/mL, the resultant solution has a pH of approximately 7-8.5.1

Stability

Commercially available pentostatin powder for injection should be stored at 2-8°C.1,25 Although the powder for injection previously distributed by the National Cancer Institute (NCI) was described as being stable for at least 4 years after the date of manufacture when stored at 2-8°C,25 the manufacturer states that currently available pentostatin powder for injection is stable for 18 months after the date of manufacture when stored as directed.97 The manufacturer currently does not recommend storage of pentostatin powder for injection at room temperature; however, the powder previously available from NCI was shown to be stable for at least 3 years when stored at temperatures of 22-25°C.25

Pentostatin is compatible with 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's.1,25 When reconstituted with 0.9% sodium chloride injection to a final concentration of 2 mg/mL, pentostatin solutions are physically and chemically stable for at least 72 hours at room temperature (22-25°C).25 When diluted to a final concentration of 20 mcg/mL, the drug is chemically compatible at room temperature with 0.9% sodium chloride or lactated Ringer's injection for at least 48 hours and with 5% dextrose injection for at least 24 hours.25 Up to an 8-10% loss in potency has been reported to occur within 48 hours in such solutions diluted in 5% dextrose.25 However, because such reconstituted and/or diluted pentostatin solutions contain no preservatives, the manufacturer recommends that they be used within 8 hours when stored at room temperature in ambient light, and that unused portions be discarded.1

When diluted in 5% dextrose or 0.9% sodium chloride injection to concentrations of 0.18-0.33 mg/mL, pentostatin reportedly does not interact with polyvinyl chloride (PVC) infusion containers or administration sets,1 as evidenced by both visual and chemical analysis.97

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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