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Special Alerts
Tumor Necrosis Factor (TNF) Blockers, Azathioprine, and/or Mercaptopurine: Reports of Hepatosplenic T-Cell Lymphoma (HSTCL) (Update)
November 2011
The U.S. Food and Drug Administration (FDA) is reminding healthcare professionals to be alert for possible malignancies in patients being treated with azathioprine, mercaptopurine, and/or tumor necrosis factor (TNF) blockers and to report positive findings to the FDA's MedWatch program (1-800-332-1088 or https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm) or to the manufacturer.
The FDA has previously warned healthcare professionals and the public of continued reports of a rare malignancy, Hepatosplenic T-Cell Lymphoma (HSTCL), occurring in patients receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. HSTCL is an aggressive form of a rare white blood cell cancer that is usually fatal. These reports have occurred predominately in adolescents and young adults being treated with these agents for Crohn's disease or ulcerative colitis; however, some case reports occurred in patients treated for psoriasis (one report) or rheumatoid arthritis (two reports). In addition, most of the reported cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents (including TNF blockers, azathioprine, mercaptopurine), although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy.
The FDA is recommending prescribers discuss with patients the increased risk of HSTCL development, particularly in adolescents and young adults, when prescribing these and other immunosuppressant therapies. Healthcare professionals should monitor for the emergence of malignancies during therapy with TNF blockers, azathioprine, and/or mercaptopurine. Patients should be educated on the signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss) during use. The FDA is also reminding healthcare professionals that patients with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis may be more likely to develop lymphoma compared to the general U.S. population, which can make assessing the additional risk of immunosuppressant use difficult to determine.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm251443.htm
Pronunciation
(mer kap toe PYOOR een)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Maintenance treatment component of acute lymphoblastic leukemia (ALL)
Use: Unlabeled
Steroid-sparing agent for corticosteroid-dependent Crohn's disease (CD) and ulcerative colitis (UC); maintenance of remission in CD; fistulizing Crohn's disease; maintenance treatment in acute promyelocytic leukemia (APL); treatment component for non Hodgkin lymphoma (NHL), treatment of autoimmune hepatitis
Pregnancy Risk Factor
D
Pregnancy Considerations
May cause fetal harm if administered during pregnancy. Case reports of fetal loss have been noted with mercaptopurine administration during the first trimester; adverse effects have also been noted with second and third trimester use. Women of child bearing potential should avoid becoming pregnant during treatment.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
Contraindications
Hypersensitivity to mercaptopurine or any component of the formulation; patients whose disease showed prior resistance to mercaptopurine
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: Dose-related leukopenia, thrombocytopenia, and anemia are common; however, may be indicative of disease progression. Hematologic toxicity may be delayed. Bone marrow may appear hypoplastic (could also appear normal). Monitor for bleeding (due to thrombocytopenia) or infection (due to neutropenia).
• Hepatotoxicity: Hepatotoxicity has been reported, including jaundice, ascites, hepatic necrosis (may be fatal), intrahepatic cholestasis, parenchymal cell necrosis, and/or hepatic encephalopathy; may be due to direct hepatic cell damage or hypersensitivity. While hepatotoxicity or hepatic injury may occur at any dose, dosages >2.5 mg/kg/day are associated with a higher incidence. Signs of jaundice generally appear early in treatment, after ~1-2 months (range: 1 week to 8 years) and may resolve following discontinuation; recurrence with rechallenge has been noted. Monitor liver function tests (monitor more frequently if used in combination with other hepatotoxic drugs or in patients with pre-existing hepatic impairment). Consider a reduced dose in patients with hepatic impairment. Withhold treatment for clinical signs of jaundice (hepatomegaly, anorexia, tenderness), deterioration in liver function tests, toxic hepatitis, or biliary stasis until hepatotoxicity is ruled out.
• Immunosuppression: Mercaptopurine is immunosuppressive; the risk for infection is increased. Common signs of infection, such as fever and leukocytosis may not occur; lethargy and confusion may be more prominent signs of infection.
• Secondary malignancy: May increase the risk for secondary malignancies. Hepatic T-cell lymphoma (HTCL) has been reported with mercaptopurine when used for the treatment of irritable bowel disease (an unlabeled use).
Disease-related concerns:
• Renal impairment: Consider dosage modification in patients with renal impairment.
• Thiopurine methyltransferase deficiency: Patients with homozygous genetic defect of thiopurine methyltransferase (TPMT) are more sensitive to myelosuppressive effects; generally associated with rapid myelosuppression. Significant mercaptopurine dose reductions will be necessary (possibly with continued concomitant chemotherapy at normal doses). Patients who are heterozygous for TPMT defects will have intermediate activity; may have increased toxicity (primarily myelosuppression) although will generally tolerate normal mercaptopurine doses. Consider TPMT testing for severe toxicities/excessive myelosuppression.
Concurrent drug therapy issues:
• Azathioprine: Because azathioprine is metabolized to mercaptopurine, concomitant use with azathioprine may result in profound myelosuppression and should be avoided.
• TPMT or xanthine oxidase inhibitors: Patients on concurrent therapy with drugs which may inhibit TPMT (eg, olsalazine) or xanthine oxidase (eg, allopurinol) may be sensitive to myelosuppressive effects.
Other warnings/precautions:
• Error-prone terms: To avoid potentially serious dosage errors, the terms “6-mercaptopurine” or “6-MP” should be avoided; use of these terms has been associated with sixfold overdosages.
• Vaccines: Immune response to vaccines may be diminished.
Adverse Reactions
Frequency not defined.
Central nervous system: Drug fever
Dermatologic: Alopecia, hyperpigmentation, rash
Endocrine & metabolic: Hyperuricemia
Gastrointestinal: Anorexia, diarrhea, intestinal ulcers, mucositis/oral lesions (rare), nausea (minimal), pancreatitis, sprue-like symptoms, stomach pain, vomiting (minimal)
Genitourinary: Oligospermia
Hematologic: Myelosuppression (onset 7-10 days; nadir 14 days; recovery: 21 days); anemia, bleeding, granulocytopenia, leukopenia, marrow hypoplasia, thrombocytopenia
Hepatic: Hepatotoxicity, ascites, biliary stasis, hepatic damage/injury, hepatic encephalopathy, hepatic necrosis, hepatomegaly, intrahepatic cholestasis, jaundice, parenchymal cell necrosis, toxic hepatitis
Renal: Hyperuricosuria, renal toxicity
Miscellaneous: Hepatosplenic T cell lymphoma, immunosuppression, infection, secondary malignancy
Metabolism/Transport Effects
None known.
Drug Interactions
5-ASA Derivatives: May decrease the metabolism of Thiopurine Analogs. Risk C: Monitor therapy
Allopurinol: May decrease the metabolism of Mercaptopurine. Risk D: Consider therapy modification
AzaTHIOprine: May enhance the myelosuppressive effect of Mercaptopurine. Risk X: Avoid combination
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Febuxostat: May increase the serum concentration of Mercaptopurine. Risk X: 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. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Sulfamethoxazole: May enhance the myelosuppressive effect of Mercaptopurine. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Trimethoprim: May enhance the myelosuppressive effect of Mercaptopurine. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Mercaptopurine may enhance the adverse/toxic effect of Vaccines (Live). Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Mercaptopurine may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Absorption is variable with food. Management: Take on an empty stomach at the same time each day 1 hour before or 2 hours after a meal. Maintain adequate hydration, unless instructed to restrict fluid intake.
Storage
Store at room temperature of 15°C to 25°C (59°F to 77°F). Protect from moisture.
Mechanism of Action
Purine antagonist which inhibits DNA and RNA synthesis; acts as false metabolite and is incorporated into DNA and RNA, eventually inhibiting their synthesis; specific for the S phase of the cell cycle
Pharmacodynamics/Kinetics
Absorption: Variable and incomplete (~50%)
Distribution: Vd > total body water; CNS penetration is poor
Protein binding: ~19%
Metabolism: Hepatic and in GI mucosa; hepatically via xanthine oxidase and methylation via TPMT to sulfate conjugates, 6-thiouric acid, and other inactive compounds; first-pass effect
Half-life elimination (age dependent): Children: 21 minutes; Adults: 47 minutes
Time to peak, serum: ~2 hours
Excretion: Urine (46% as mercaptopurine and metabolites)
Dosage
Oral (also consult details concerning dosing in combination regimens):
Children:
ALL: Maintenance: 1.5-2.5 mg/kg/day or
Unlabeled ALL dosing (combination chemotherapy; refer to specific reference for combinations): Adolescents ≥15 years:
Consolidation phase: 60 mg/m2/day days 0-27 days (5-week course) (Stock, 2008) or 60 mg/m2/day days 0-13 and days 28-41 (9-week course) (Stock, 2008)
Early intensification (two 4-week courses): 60 mg/m2/day days 1-14 (Larson, 1995; Larson, 1998; Stock, 2008)
Interim maintenance: 60 mg/m2/day days 0-41 (8-week course) (Stock, 2008) or 60 mg/m2/day days 1-70 (12-week course) (Larson, 1995; Larson, 1998; Stock, 2008)
Maintenance (prolonged): 50 mg 3 times/day for 2 years (Kantarjian, 2000; Thomas, 2004) or 60 mg/m2/day for 2 years from diagnosis (Larson, 1995; Larson, 1998; Stock, 2008) or 75 mg/m2/day for 2 years (girls) or 3 years (boys) from first interim maintenance (Stock, 2008)
APL maintenance (unlabeled use): Adolescents ≥15 years: 60 mg/m2/day for 1 year (in combination with tretinoin and methotrexate) (Powell, 2010)
Autoimmune hepatitis (unlabeled use): 1.5 mg/kg/day (in combination with prednisone) (Manns, 2010)
Dosage adjustment with concurrent allopurinol: Reduce mercaptopurine dosage to 25% to 33% of the usual dose.
Dosage adjustment in TPMT-deficiency: Not always established; substantial reductions are generally required only in homozygous deficiency.
Adults:
ALL: Maintenance: 1.5-2.5 mg/kg/day or
Unlabeled ALL dosing (combination chemotherapy; refer to specific reference for combinations):
Early intensification (two 4 week courses): 60 mg/m2/day days 1-14 (Larson, 1995; Larson, 1998)
Interim maintenance (12-week course): 60 mg/m2/day days 1-70 (Larson, 1995; Larson, 1998)
Maintenance (prolonged): 50 mg 3 times/day for 2 years (Kantarjian, 2000; Thomas, 2004) or 60 mg/m2/day for 2 years from diagnosis (Larson, 1995; Larson, 1998)
APL maintenance (unlabeled use): 60 mg/mm2/day for 1 year (in combination with tretinoin and methotrexate) (Powell, 2010)
Crohn's disease, remission maintenance or reduction of steroid use (unlabeled use): 1-1.5 mg/kg/day (Lichtenstein, 2009)
Ulcerative colitis (unlabeled use):
Initial: 50 mg once daily; titrate dose up if clinical remission not achieved or down if leukopenia occurs (Lobel, 2004) or
Initial: 50 mg (25 mg if heterozygous for TPMT activity) once daily; titrate up to goal of 1.5 mg/kg (0.75 mg/kg if heterozygous for TPMT activity) if WBC >4000/mm3 (and at least 50% of baseline) and LFTs and amylase are stable (Siegel, 2005) or
Maintenance: 1-1.5 mg/kg/day (Carter, 2004) or
Remission maintenance: 1.5 mg/kg/day (Danese, 2011)
Dosage adjustment with concurrent allopurinol: Reduce mercaptopurine dosage to 25% to 33% of the usual dose.
Dosage adjustment in TPMT-deficiency: Not always established; substantial reductions are generally required only in homozygous deficiency.
Elderly: Due to renal decline with age, initiate treatment at the low end of recommended dose range
Dosing adjustment in renal impairment: The manufacturer's labeling recommends starting with reduced doses in patients with renal impairment to avoid accumulation; however, no specific dosage adjustment is provided. The following adjustments have been used by some clinicians (Aronoff, 2007): Children:
Clcr <50 mL/minute/1.73 m2: Administer every 48 hours
Hemodialysis: Administer every 48 hours
Continuous ambulatory peritoneal dialysis (CAPD): Administer every 48 hours
Continuous renal replacement therapy (CRRT): Administer every 48 hours
Dosing adjustment in hepatic impairment: The manufacturer's labeling recommends considering a reduced dose in patients with hepatic impairment; however, no specific dosage adjustment is provided.
Dosage: Combination Regimens
Leukemia, acute lymphocytic:
Hyper-CVAD (Leukemia, Acute Lymphocytic)
Larson Regimen (ALL)
MTX/6-MP/VP (Maintenance)
POMP
PVA (POG 8602)
Leukemia, acute promyelocytic:
Tretinoin-Daunorubicin (APL)
Tretinoin-Daunorubicin-Cytarabine (APL)
Tretinoin-Idarubicin (APL)
Administration: Oral
Preferably on an empty stomach (1 hour before or 2 hours after meals)
For the treatment of ALL in children (Schmiegelow, 1997): Administration in the evening has demonstration superior outcome; administration with food did not significantly affect outcome.
Monitoring Parameters
CBC with differential (weekly initially, although clinical status may require increased frequency), bone marrow exam (to evaluate marrow status), liver function tests (weekly initially, then monthly; monitor more frequently if on concomitant hepatotoxic agents), renal function, urinalysis; consider TPMT genotyping to identify TPMT defect (if severe toxicity occurs)
For use as immunomodulatory therapy in CD or UC, monitor CBC with differential weekly for 1 month, then biweekly for 1 month, followed by monitoring every 1-2 months throughout the course of therapy. LFTs should be assessed every 3 months. Monitor for signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Test Interactions
TPMT testing: Recent transfusions may result in a misinterpretation of the actual TPMT activity. Concomitant drugs may influence TPMT activity in the blood.
Dietary Considerations
Should not be administered with meals.
Patient Education
Take daily dose at the same time each day. Preferable to take an on empty stomach, 1 hour before or 2 hours after meals. Maintain adequate hydration unless instructed to restrict fluid intake. You may be more susceptible to infection. May cause nausea, vomiting, diarrhea, loss of appetite, weakness or lethargy, mouth sores, or headache. Report signs of persistent fever, opportunistic infection (eg, fever, chills, sore throat, burning urination, fatigue), bleeding (eg, tarry stools, easy bruising), unresolved mouth sores, nausea or vomiting, swelling of extremities, respiratory difficulty, unusual weight gain, signs of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss), or changes in urinary pattern.
Geriatric Considerations
Toxicity to immunosuppressives is increased in the elderly. Start with lowest recommended adult doses. Signs of infection, such as fever and WBC rise, may not occur. Lethargy and confusion may be more prominent signs of infection.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis and mucositis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia; use caution with clozapine or carbamazepine
Nursing: Physical Assessment/Monitoring
Do not use the terms "6-mercaptopurine" or "6-MP" when writing prescriptions; use of these terms has been associated with sixfold overdosage. Assess hepatic function; jaundice, ascites, and encephalopathy can occur some time during or following therapy. Monitor nutritional status and renal status. Monitor for dehydration, myelosuppression, anemia, and leukopenia on a regular basis. Teach patient importance of adequate hydration. Monitor for signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 50 mg
Purinethol®: 50 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Mercaptopurine)
50 mg (30): $92.99
Tablets (Purinethol)
50 mg (30): $207.99
Extemporaneously Prepared
Hazardous agent: Use appropriate precautions for handling and disposal.
A 50 mg/mL oral suspension may be prepared in a vertical flow hood with tablets and a 1:1 mixture of methylcellulose 1% and simple syrup. Crush thirty 50 mg tablets in a mortar and reduce to a fine powder. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to a final volume of 30 mL; transfer to a calibrated bottle. Note: May use ultrasonication dispersal. Label "shake well" and "caution chemotherapy". Stable for 35 days at room temperature.
Dressman JB and Poust RI, "Stability of Allopurinol and of Five Antineoplastics in Suspension," Am J Hosp Pharm, 1983, 40(4):616-8.
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 173.
Carter MJ, Lobo AJ and Travis SP, “Guidelines for the Management of Inflammatory Bowel Disease in Adults,” Gut, 2004, 53(Suppl 5):1-16.
Danese M and Fiocchi C, “Ulcerative Colitis,” New Engl J Med, 2011, 365(18):1713-25.
Gremse DA and Crissinger KD, “Ulcerative Colitis in Children: Medical Management,” Paediatr Drugs, 2002, 4(12):807-15.
Kantarjian HM, O'Brien S, Smith TL, et al, “Results of Treatment With Hyper-CVAD, A Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia,” J Clin Oncol, 2000, 18(3): 547-61.
Kornbluth A and Sachar DB, “Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee,” Am J Gastroenterol, 2010, 105(3):501-23.
Larson RA, Dodge RK, Burns CP, et al, “A Five-Drug Remission Induction Regimen With Intensive Consolidation for Adults With Acute Lymphoblastic Leukemia: Cancer and Leukemia Group B Study 8811,” Blood, 1995, 85(8):2025-37.
Larson RA, Dodge RK, Linker CA, et al, "A Randomized Controlled Trial of Filgrastim During Remission Induction and Consolidation Chemotherapy for Adults With Acute Lymphoblastic Leukemia: CALGB Study 9111," Blood, 1998, 92(5):1556-64.
Lichtenstein GR, Abreu MT, Cohen R, et al, “American Gastroenterological Association Institute Medical Position Statement on Corticosteroids, Immunomodulators, and Infliximab in Inflammatory Bowel Disease,” Gastroenterology, 2006, 130(3):935-9.
Lichtenstein GR, Hanauer SB, and Sandborn WJ, “Management of Crohn's Disease in Adults,” Am J Gastroenterol, 2009, 104(2):465-83.
Lobel EZ, Korelitz BI, Xuereb MA, et al, “A Search for the Optimal Duration of Treatment With 6-Mercaptopurine for Ulcerative Colitis,” Am J Gastroenterol, 2004, 99(3):462-5.
Manns MP, Czaja AJ, Gorham JD, et al, “Diagnosis and Management of Autoimmune Hepatitis,” Hepatology, 2010, 51(6):2193-213.
Markowitz J, Grancher K, Kohn N, et al, “A Multicenter Trial of 6-Mercaptopurine and Prednisone in Children With Newly Diagnosed Crohn's Disease,” Gastroenterology, 2000, 119(4):895-902.
Mosesso P and Palitti F, "The Genetic Toxicology of 6-Mercaptopurine," Mutat Res, 1993, 296(3):279-94.
Parakkal D, Sifuentes H, Semer R, et al, “Hepatosplenic T-Cell Lymphoma in Patients Receiving TNF-α Inhibitor Therapy: Expanding the Groups at Risk,” Eur J Gastroenterol Hepatol, 2011, 23(12):1150-6.
Powell BL, Moser B, Stock W, et al, “Arsenic Trioxide Improves Event-Free and Over-All Survival for Adults With Acute Promyelocytic Leukemia: North American Leukemia Intergroup Study C9710,” Blood, 2010, 116(19):3751-7.
Sandborn WJ, “A Review of Immune Modifier Therapy for Inflammatory Bowel Disease: Azathioprine, 6-mercaptopurine, Cyclosporine, and Methotrexate,” Am J Gastroenterol, 1996, 91(3):423-33.
Schmiegelow K, Glomstein A, Kristinsson J, et al, “Impact of Morning versus Evening Schedule for Oral Methotrexate and 6-Mercaptopurine on Relapse Risk for Children With Acute Lymphoblastic Leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO),” J Pediatr Hematol Oncol, 1997, 19(2):102-9.
Siegel CA and Sands BE, “Review Article: Practical Management of Inflammatory Bowel Disease Patients Taking Immunomodulators,” Aliment Pharmacol Ther, 2005, 22(1):1-16.
Stock W, La M, Sanford B, et al, “What Determines the Outcomes for Adolescents and Young Adults With Acute Lymphoblastic Leukemia Treated on Cooperative Group Protocols? A Comparison of Children's Cancer Group and Cancer and Leukemia Group B Studies,” Blood, 2008, 112(5):1646-54.
Thomas DA, O'Brien S, Cortes J, et al, “Outcome With the Hyper-CVAD Regimens in Lymphoblastic Lymphoma,” Blood, 2004, 104(6):1624-30.
Zimm S, Ettinger LJ, Holcenberg JS, et al, “Phase I and Clinical Pharmacological Study of Mercaptopurine Administered as a Prolonged Intravenous Infusion,” Cancer Res, 1988, 45(4):1869-73.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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