Anemia interferon alfa

Capsules/Tablets/Oral solution-There are significant adverse events caused by ribavirin capsules/interferon alfa-2b or peginterferon alfa-2b therapy, and ribavirin tablets/peginterferon alfa-2a therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. 

In a phase III trial in 190 patients with metastatic melanoma, sequential chemotherapy with dacarbazine, cisplatin, and vinblastine plus interferon alfa and aldesleukin modestly increased the response rates and produced considerably more frequent and severe adverse effects than chemotherapy alone (128). In particular, severe episodes of anemia and thrombocytopenia that required blood or platelet transfusions were 2-6 times more frequent in the chemotherapy group. 

Hematological toxicity due to interferon alfa commonly includes dose-related leukopenia, neutropenia, and thrombocytopenia, whereas anemia is rare and usually moderate (202). 

Interferon alfa has direct myelosuppressive effects and can also cause hematological disorders by immune blood cell destruction, as suggested by reports of immune-mediated thrombocytopenia, immune hemolytic anemia (205,206), or a positive direct Coombs test, with or without hemolysis (207-209). 

Isolated anemia is not a common feature of the hemotoxic effects of interferon alfa, and pure red cell aplasia has been reported in two patients with chronic leukemia for several months (217,218). Both patients improved progressively after replacement of interferon alfa by hydroxyurea. However, one required erythrocyte transfusions for 14 months. 

Pernicious anemia with a low vitamin B12 concentration and positive intrinsic factor antibodies has been reported in a 54-year-old woman who was receiving interferon alfa as a maintenance treatment for relapsing chronic hepatitis C (219). 

Rapid exacerbation (1-21 days) or delayed (3-38 months) de novo appearance of immune hemolytic anemia has been reported after initiation of interferon alfa treatment in nine patients with lymphoproliferative disorders (220). However, this rare event was identified in only 1% of 581 patients receiving interferon alfa alone or as part of a chemotherapeutic regimen for chronic myelogenous leukemia (221). A mechanism close to that observed with alpha-methyldopa has been thought to be involved (208). The direct antiglobulin test was positive in 32% of 28 chronic myeloid leukemia patients after a median of 1 year of treatment with interferon alfa (222). 

The combination of interferon alfa with ribavirin is one of the most promising treatments for chronic hepatitis C. However, two patients developed rapid and particularly severe anemia within 4 and 6 weeks of combined treatment (415). One patient required erythrocyte transfusions, and both recovered after withdrawal. The combination of pure red cell aplasia due to interferon alfa and hemolytic anemia due to ribavirin was suggested to have accounted for this possible interaction. 

Willson RA. Interferon alfa-induced pernicious anemia in chronic hepatitis C infection. J Clin Gastroenterol 2001 33(5) 426-7. 

Ribavirin 15 mg/kg/day pins interferon alfa in 12 teenagers has been compared with interferon alone in 10 (11). There was no difference in dropont rate, bnt viral clearance was achieved in 50% of the patients who took the combination treatment versns 30% of those who took monotherapy. Adverse events were similar in the two groups. There was mild hemolytic anemia at the end of the first month in most of the children who took ribavirin,... 

Ribavirin accnmnlates in erythrocytes, resnlting in hemolysis by an nnknown mechanism, perhaps related to oxidative damage to the erythrocyte membrane. Time-dependent and dose-dependent hemolytic anemia (eventnaUy associated with hyperbilirubinemia and a high reticnlocyte connt) is the only major toxic effect associated with oral or intravenons ribavirin and is reversible on withdrawal. There was a fall in hemoglobin concentrations below 10.0 g/dl in 9% of patients with hepatitis C treated with ribavirin and interferon alfa (6,7). 

A low pretreatment platelet count, the dose of interferon alfa, and the haptoglobin phenotype are risk factors for ribavirin-induced anemia, and the fall in hemoglobin is independent of dose in the therapeutic range (16). In five patients with chronic hepatitis C on hemodialysis who received subcutaneous interferon alfa-2b and oral ribavirin for 40 weeks, the dose of ribavirin was titrated based on hemoglobin, with bone marrow support by erythropoietin (17). There was significant bone marrow toxicity in all five. A dose of 200 mg/day produced a steady-state AUC comparable to that obtained with 1000-1200 mg/ day in historical controls with normal renal fnnction. More severe anemia was possibly due to chronic renal insufficiency in addition to the prolonged effects of ribavirin. 

Bone marrow toxicity Peginterferon alfa-2a suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including peginterferon alfa-2a. Alpha interferons may be associated with aplastic anemia very rarely. 

Recombinant DNA technology products aldesleukin (IL-2, used in renal cancer) erythropoietin (epoetin alfa, used in anemias) filgrastim (G-CSF, used in neutropenia) interferon alpha (used in hepatitis B and C and in cancer), interferon beta (used in multiple sclerosis) interferon gamma (used in chronic granulomatous disease) oprelvekin (IL-11, used in thrombocytopenia) thrombopoietin (used in thrombocytopenia) and sargramostim (GM-CSF, used in neutropenia). 

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