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Pentostatin

Pronunciation

(pen toe STAT in)

Index Terms

  • 2′-Deoxycoformycin
  • Co-Vidarabine
  • dCF
  • Deoxycoformycin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Nipent: 10 mg (1 ea)

Brand Names: U.S.

  • Nipent

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Purine Analog)

Pharmacology

Pentostatin is a purine antimetabolite that inhibits adenosine deaminase, preventing the deamination of adenosine to inosine. Accumulation of deoxyadenosine (dAdo) and deoxyadenosine 5′-triphosphate (dATP) results in a reduction of purine metabolism which blocks DNA synthesis and leads to cell death.

Distribution

Vd: IV: 20 L/m2 (Lathia, 2002)

Excretion

Urine (~50% to 96%) within 24 hours (30% to 90% as unchanged drug)

Clearance: Adults: 68 mL/minute/m2 (mean)

Half-Life Elimination

Terminal: ~6 hours; Renal impairment (CrCl <50 mL/minute): 18 hours (range: 11 to 23 hours [Lathia, 2002])

Protein Binding

~4%

Use: Labeled Indications

Hairy cell leukemia: Treatment (as a single-agent) of untreated and interferon-refractory hairy cell leukemia in patients with active disease (clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms)

Use: Unlabeled

Treatment of acute and chronic steroid-refractory graft-versus-host disease (GVHD), chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (Mycosis fungoides), and T-cell prolymphocytic leukemia

Contraindications

Hypersensitivity to pentostatin or any component of the formulation

Dosing: Adult

Hairy cell leukemia: IV: 4 mg/m2 every 2 weeks. Note: The optimal duration has not been determined; in the absence of unacceptable toxicity, may continue until complete response is achieved or until 2 doses after complete response. Discontinue after 6 months if partial or complete response is not achieved.

Acute graft-versus-host disease (GVHD), steroid-refractory (off-label use): IV:

Initial therapy: 1.5 mg/m2 days 1 to 3 and days 15 to 17 (in combination with corticosteroids) (Alousi, 2009)

Steroid-refractory disease: 1.5 mg/m2 daily for 3 days; may repeat after 2 weeks if needed (Bolanos-Meade, 2005)

Chronic graft-versus-host disease (GVHD), steroid-refractory (off-label use): IV: 4 mg/m2 once every 2 weeks; discontinue after 6 months for sustained objective response, or continue every 2 to 4 weeks for up to 12 months if still improving (Jacobsohn, 2007; Jacobsohn, 2009) or 4 mg/m2 once every 2 weeks for 3 months (Wolff, 2011)

Chronic lymphocytic leukemia (CLL; off-label use): IV:

Previously treated: 4 mg/m2 once every 3 weeks (in combination with cyclophosphamide and rituximab) for 6 cycles (Lamanna, 2006)

Previously untreated: 2 mg/m2 once every 3 weeks (in combination with cyclophosphamide and rituximab) for 6 cycles (Kay, 2007)

Cutaneous T-cell lymphoma, mycosis fungoides/Sezary syndrome (off-label use): IV: 4 mg/m2 once weekly for 3 weeks, then every 2 weeks for 6 weeks, then once monthly for a maximum of 6 months (Ho, 1999)

T-cell prolymphocytic leukemia, refractory (off-label use): IV: 4 mg/m2 once weekly for 4 weeks then every 2 weeks until optimum response is achieved (Mercieca, 1994) or 4 mg/m2 once weekly for 4 weeks then every 2 weeks (in combination with alemtuzumab) until complete or best response or up to a total of 14 doses (Ravandi, 2009)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic graft-versus-host disease (GVHD), steroid-refractory: IV: 4 mg/m2 once every 2 weeks; discontinue after 6 months for sustained objective response, or continue every 2 to 4 weeks for up to 12 months if still improving (Jacobsohn, 2007; Jacobsohn, 2009) or 4 mg/m2 once every 2 weeks for 3 months (Wolff, 2011)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; although not adequately studied, two patients with CrCl 50 to 60 mL/minute achieved responses when treated with 2 mg/m2/dose. For renal toxicity during treatment, withhold for elevated serum creatinine and determine creatinine clearance. The following adjustments have also been recommended:

Kintzel, 1995:

CrCl 46 to 60 mL/minute: Administer 70% of dose

CrCl 31 to 45 mL/minute: Administer 60% of dose

CrCl <30 mL/minute: Consider use of alternative drug

Lathia, 2002:

CrCl ≥60 mL/minute: Administer 4 mg/m2/dose

CrCl 40 to 59 mL/minute: Administer 3 mg/m2/dose

CrCl 20 to 39 mL/minute: Administer 2 mg/m2/dose

Alousi, 2009; Jacobsohn, 2009; Poi, 2013 (for GVHD treatment):

CrCl 30 to 50 mL/minute/1.73 m2: Reduce dose by 50%

CrCl <30 mL/minute/1.73 m2: Withhold dose

Lamanna, 2006 (for previously treated CLL): Serum creatinine >2 mg/dL or 20% above patient’s baseline: Withhold treatment until serum creatinine ≤2 mg/dL or returns to baseline, or until CrCl ≥50 mL/minute

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

ANC <200/mm3 (with baseline ANC >500/mm3): Temporarily interrupt treatment until ANC returns to pre-dose levels.

CNS toxicity: Withhold treatment or discontinue.

Infection, active: Interrupt treatment until infection is controlled.

Rash: Severe rashes may require treatment interruption or discontinuation.

Other severe adverse reactions: Withhold treatment or discontinue.

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in pentostatin dosing for hematopoietic stem cell transplant conditioning regimens in adults (Bubalo, 2014).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitute with 5 mL SWFI to a concentration of 2 mg/mL. The solution may be further diluted in 25 to 50 mL NS or D5W for infusion. When diluted for infusion in D5W or NS at concentrations of 0.18 to 0.33 mg/mL, pentostatin is compatible with PVC containing infusion bags and infusion sets.

Administration

Administer IV over 20 to 30 minutes or as a bolus infusion. Hydrate with 500 to 1,000 mL fluid prior to infusion and 500 mL after infusion.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in LR, NS.

Storage

Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Reconstituted vials and solutions diluted for infusion (in D5W or NS) may be stored at room temperature for 8 hours.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Cyclophosphamide: Pentostatin may enhance the cardiotoxic effect of Cyclophosphamide. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fludarabine: May enhance the adverse/toxic effect of Pentostatin. Pentostatin may enhance the adverse/toxic effect of Fludarabine. Pulmonary toxicity is of specific concern. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nelarabine: Pentostatin may diminish the antineoplastic effect of Nelarabine. Conversion of nelarabine, a pro-drug, to its active form may be inhibited by pentostatin. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pegademase Bovine: May diminish the therapeutic effect of Pentostatin. Pentostatin may diminish the therapeutic effect of Pegademase Bovine. Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fever (42% to 46%), fatigue (29% to 42%), pain (8% to 20%), chills (11% to 19%), headache (13% to 17%), CNS toxicity (1% to 11%)

Dermatologic: Rash (26% to 43%), pruritus (10% to 21%), skin disorder (4% to 17%)

Gastrointestinal: Nausea/vomiting (22% to 63%), diarrhea (15% to 17%), anorexia (13% to 16%), abdominal pain (4% to 16%), stomatitis (5% to 12%)

Hematologic: Myelosuppression (nadir: 7 days; recovery: 10-14 days), leukopenia (22% to 60%), anemia (8% to 35%), thrombocytopenia (6% to 32%)

Hepatic: Transaminases increased (2% to 19%)

Neuromuscular & skeletal: Myalgia (11% to 19%), weakness (10% to 12%)

Respiratory: Cough (17% to 20%), upper respiratory infection (13% to 16%), rhinitis (10% to 11%), dyspnea (8% to 11%)

Miscellaneous: Infection (7% to 36%), allergic reaction (2% to 11%)

1% to 10%:

Cardiovascular: Chest pain (3% to 10%), facial edema (3% to 10%), hypotension (3% to 10%), peripheral edema (3% to 10%), angina (<3%), arrhythmia (<3%), AV block (<3%), bradycardia (<3%), cardiac arrest (<3%), deep thrombophlebitis (<3%), heart failure (<3%), hypertension (<3%), pericardial effusion (<3%), sinus arrest (<3%), syncope (<3%), tachycardia (<3%), vasculitis (<3%), ventricular extrasystoles (<3%)

Central nervous system: Anxiety (3% to 10%), confusion (3% to 10%), depression (3% to 10%), dizziness (3% to 10%), insomnia (3% to 10%), nervousness (3% to 10%), somnolence (3% to 10%), abnormal dreams/thinking (<3%), amnesia (<3%), ataxia (<3%), emotional lability (<3%), encephalitis (<3%), hallucination (<3%), hostility (<3%), meningism (<3%), neuritis (<3%), neurosis (<3%), seizure (<3%), vertigo (<3%)

Dermatologic: Cellulitis (6%), furunculosis (4%), dry skin (3% to 10%), urticaria (3% to 10%), acne (<3%), alopecia (<3%), eczema (<3%), petechial rash (<3%), photosensitivity (<3%), abscess (2%)

Endocrine & metabolic: Amenorrhea (<3%), hypercalcemia (<3%), hyponatremia (<3%), gout (<3%), libido decreased/loss (<3%)

Gastrointestinal: Dyspepsia (3% to 10%) flatulence (3% to 10%), gingivitis (3% to 10%), constipation (<3%), dysphagia (<3%), glossitis (<3%), ileus (<3%), taste perversion (<3%), oral moniliasis (2%)

Genitourinary: Urinary tract infection (3%), impotence (<3%)

Hematologic: Agranulocytosis (3% to 10%), hemorrhage (3% to 10%), acute leukemia (<3%), aplastic anemia (<3%), hemolytic anemia (<3%)

Local: Phlebitis (<3%)

Neuromuscular & skeletal: Arthralgia (3% to 10%), paresthesia (3% to 10%), arthritis (<3%), dysarthria (<3%), hyperkinesia (<3%), neuralgia (<3%), neuropathy (<3%), paralysis (<3%), twitching (<3%), osteomyelitis (1%)

Ocular: Conjunctivitis (4%), amblyopia (<3%), eyes nonreactive (<3%), lacrimation disorder (<3%), photophobia (<3%), retinopathy (<3%), vision abnormal (<3%), watery eyes (<3%), xerophthalmia (<3%)

Otic: Deafness (<3%), earache (<3%), labyrinthitis (<3%), tinnitus (<3%)

Renal: Creatinine increased (3% to 10%), nephropathy (<3%), renal failure (<3%), renal insufficiency (<3%), renal function abnormal (<3%), renal stone (<3%)

Respiratory: Pharyngitis (8% to 10%), sinusitis (6%), pneumonia (5%), asthma (3% to 10%), bronchitis (3%), bronchospasm (<3%), laryngeal edema (<3%), pulmonary embolus (<3%)

Miscellaneous: Diaphoresis (8% to 10%), herpes zoster (8%), viral infection (≤8%), bacterial infection (5%), herpes simplex (4%), sepsis (3%), flu-like syndrome (<3%)

<1% (Limited to important or life-threatening): Dysuria, fungal infection (skin), hematuria, lethargy, pulmonary edema, pulmonary toxicity (fatal; in combination with fludarabine), uveitis/vision loss

ALERT: U.S. Boxed Warning

Experienced physician:

Pentostatin should be administered under the supervision of a physician qualified and experienced in the use of cancer chemotherapeutic agents.

Drug toxicities:

The use of higher doses than those specified is not recommended. Dose-limiting severe renal, liver, pulmonary, and CNS toxicities occurred in Phase 1 studies that used pentostatin at higher doses (20 to 50 mg/m2 in divided doses over 5 days) than recommended.

In a clinical investigation in patients with refractory chronic lymphocytic leukemia using pentostatin at the recommended dose in combination with fludarabine phosphate, 4 of 6 patients entered in the study had severe or fatal pulmonary toxicity. The use of pentostatin in combination with fludarabine phosphate is not recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Myelosuppression may occur, primarily early in treatment (first few courses). Neutropenia may worsen during initial courses for the treatment of hairy cell leukemia. If severe neutropenia persists beyond early cycles, evaluate for disease status. Monitor blood counts during treatment (more frequently in the initial cycles).

• CNS toxicity: [U.S. Boxed Warnings]: Severe CNS toxicities have occurred with doses higher than recommended; do not exceed the recommended dose. Withhold treatment or discontinue for CNS toxicity.

• Hepatotoxicity: [U.S. Boxed Warnings]: Severe liver toxicities have occurred with doses higher than recommended; do not exceed the recommended dose. May cause elevations (usually reversible) in liver function tests.

• Pulmonary toxicity: [U.S. Boxed Warnings]: Severe pulmonary toxicities have occurred with doses higher than recommended; do not exceed the recommended dose. Do not administer concurrently with fludarabine; concomitant use has resulted in serious or fatal pulmonary toxicity.

• Rash: Severe rashes may occur and worsen with therapy continuation; may require treatment interruption or discontinuation.

• Renal toxicity: [U.S. Boxed Warnings]: Severe renal toxicities have occurred with doses higher than recommended; do not exceed the recommended dose. Serum creatinine elevations occurring at recommended doses are usually minor and reversible. Withhold treatment for elevated serum creatinine and determine creatinine clearance. May require dosage adjustment or therapy discontinuation.

Disease-related concerns:

• Infections: In patients who present with infections prior to treatment, infections should be resolved, if possible, prior to initiation of treatment; preexisting infections may worsen with pentostatin treatment. Treatment should be temporarily withheld for active infections during therapy. Use in patients with infections only if the potential benefit justifies the potential risk.

• Renal impairment: Use with caution in patients with renal dysfunction (CrCl <60 mL/minute); the terminal half-life is prolonged; may require dosage adjustment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Concurrent use with fludarabine has resulted in severe or fatal pulmonary toxicity and is not recommended. Fatal pulmonary edema and hypotension have been reported in patients treated with pentostatin in combination with carmustine, etoposide, or high-dose cyclophosphamide as part of a myeloablative regimen for bone marrow transplant.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

CBC with differential and platelet count (prior to each dose; more frequently during initial cycles), peripheral blood smears (periodically for hairy cells and to assess treatment response), liver function, serum uric acid, renal function (serum creatinine and/or creatinine clearance at baseline, and serum creatinine prior to each dose), bone marrow evaluation, signs/symptoms of pulmonary and CNS toxicity

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Women of childbearing potential should be advised to avoid becoming pregnant during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, headache, diarrhea, abdominal pain, lack of appetite, rhinorrhea, itching, mouth sores, muscle pain, joint pain, or sweating a lot. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), severe fatigue, seizures, severe weakness, numbness or tingling of feet or hands, angina, tachycardia, illogical thinking, depression, anxiety, severe dizziness, passing out, bruising, bleeding, loss of strength and energy, or swelling of arms of legs (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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