Anemia When Taking Interferon + Ribavirin and EPO Therapy for Anemia

This study suggests that EPO may be helpful in preventing anemia for patients receiving HCV therapy (IFN/RBV). Preventing anemia ought to improve a patient’s ability to tolerate therapy, to adhere to therapy and to remain on therapy. Interferon+ribavirin can result in significantly reduced hemoglobin (anemia) in the first few weeks of therapy. Doug Dieterich (Cabrini Hospital, NYC & NYU) reported data from a study showing that Epoetin alfa (EPO) once weekly increased hemoglobin levels significantly after they had fallen on HCV therapy(abstract 340). Also, patients were able to maintain taking a higher dose of ribavirin (lower hemoglobin can lead to reducing RBV dose), which should translate to a better virologic response. And the data suggested patients benefiting from EPO had less depression (which is a side effect of interferon and ribavirin therapy) and patients reported a better quality of life. This suggests that depression experienced on RBV/IFN may be due to at least in part to fatigue and anemia. Another study reviewed below shows less anemia was experienced by patients taking Pegasys alone (without ribavirin) compared to patients taking standard interferon with ribavirin.

As background information, Dieterich reported a major toxicity of ribavirin (RBV) is reversible hemolytic anemia. Often hemoglobin (Hb) decreases within the first 4 weeks of treatment with IFN+RBV. Hb level decreases of 3 or more g/dL occur in 60% of men and 44% of women receiving RBV/IFN alfa-2b. Ordinarily, this is managed by RBV dose reduction or discontinuation. RBV dose reduction may decrease sustained virologic response to therapy.

Although I don’t think there have been studies of this, it appears as if EPO is also being used before HCV therapy in the hopes of preventing decline in Hb or a RBV dose reduction.

At DDW, Mark Sulkowski reported (abstract 2896) women are 4.4 times more likely than men (20% vs 4.5%) to experience a Hb <10 g/dL. Men were at a greater risk (40%) than women to experience a decrease in Hb of 3 or more g/dL from baseline. Sulkowski also reported that daily IFN therapy was not associated with a greater decline in Hb than IFN three times per week by week 4 of treatment. In a subset of anemic patients with a mean Hb of 10.7 g/dL who had RBV dose reduced to 600 mg daily, Hb levels increased by a mean 1.1 g/dL at 4-8 weeks after the dose decrease. Sulkowski retrospectively analyzed treatment-related changes in Hb in about 600 participants in 2 studies (IFN naïve and experienced) randomized to receive RBV 1000 mg daily or 1000-1200 mg daily (based on weight) plus IFNa 3 MIU daily or three times per week for 48 weeks, or IFN 3 MIU daily or 3 times per week for 4 weeks followed by 3 times per week dosing. More than 80% of women at baseline had Hb 13 g/dL or greater, and more than 90% of men had 14 or more g/dl Hb. As expected, 10.3% (57/551) of patients had a Hb <10 g/dL. Hb decreased 3 or more g/dL in 54% of all patients. About 27% of men & women reached a nadir (lowest point) of 11-11.9 Hb, while many more men were able to maintain Hb 12-12.9 (25% vs 17%) and 13 or more (30% vs 10%). Sulkowski also reported that in a univariate analysis, increased age, higher baseling Hb and platelet counts, and CrCl (decreases in creatinine clearance) were significantly (P<0.5) associated with the largest Hb decreases.

Getting back to the Dieterich study. The study was an open-label, randomized, parallel-group study involving 7 centers nationwide. Patients with Hb 12 or less g/dL after starting treatment with IFN/RBV were randomized to EPO or standard of care management of anemia. The primary endpoint of the study was to follow patients for 16 weeks. Patients were HCV treatment naïve or experienced. Patients were excluded for anemia due to iron, folate or B12 deficiencies, serum ferritin <50 ng/mL, uncontrolled hypertension, primary hematologic disease such as sickle cell anemia, uncontrolled seizure dosorder, known sensitivity to human serum albumin, and known sensitivity to mammalian cell derived product.

The initial dose of EPO was 40,000 Units subcutaneously once weekly. Patients with an increase in Hb of 1 or more g/dl continued EPO. Patients with less than 1 increase stopped EPO. If HB increased to >14 g/dL for women or 16 for men, EPO was withheld. When HB subsequently decreased to 13 g/dL for women or <15 g/dl for men, EPO was resumed at 30,000 Units once weekly. I think Dieterich said he titrated (incrementally increased doses) by 5,000-10,000 to a maximum of 40,000 Units once weekly.

Primary endpoints were change in Hb, secondary endpoints were change in RBV dose, and change in quality of life measured by SF-12. The ITT analysis was at week 16, including all patients receiving at least one dose of EPO. At study entry there were 36 patients (24 men, 12 women) receiving EPO and 28 standard of care (20 men, 8 women). Age was 50 in EPO arm, and 48 in SOC arm. Weight (kg) was 88 in EPO arm, and 78 in SOC. The RBV dose (mg/day) was 953 mg/day in EPO arm (200-1200) and 951 In SOC (600-1200) arm (total dose received to that point I think).

RESULTS:

The Hb values before RBV/IFN treatment was 14.5 (10.6-16.9 range) for the 36 patients receiving EPO, and 14.6 for the SOC arm, so it was about the same before treatment.

--Prior to week 16 there were 15 (42%) discontinuations in the EPO arm vs 14 (50%) in the SOC arm.

--At the start of receiving EPO the mean HB levels were 11.0 in the EPO arm vs 11.0 in the SOC arm.

--At week 16, the mean Hb was 13.9 in the EPO arm vs 11.3 in the SOC arm.

--So, the mean change in Hb was a 2.9 g/dL increase for patients receiving EPO vs a 0.3 mean increase in the SOC arm, in other words there was no change.

--By ITT (strictest) analysis 88% (30/34) in the EPO arm had 1 g/dL or more increase in Hb compared to 28% (8/28) in the SOC arm

--Using an On-Treatment Analysis, at week 16 the mean Hb g/dL was 14.2 in EPO (n=21) arm vs 11.2 in the SOC arm (n=14)

--Perhaps more important, RBV dose was higher in the EPO arm at week 16 (ITT). Patients may be helped to tolerate adequate RBV dose by taking EPO. At study entry the mean RBV dose was 956 in the EPO vs 961 in the SOC arm. At week 16 the EPO arm dose 926 mg/day vs 782 in the SOC arm. The mean change was –179 in the SOC arm vs –31 in the EPO arm (P<0.5)

--By on treatment analysis at week 16, the RBV dose was 900 (± 238) mg/day (n=20) vs 707 (± 217) mg/day

--By ITT analysis a higher percentage of patients receiving EPO (85%, 29/34) were able to take 800 mg or more RBV per day vs 61% (17/28) in the SOC arm. Only 15% receiving EPO were taking <800 mg/day vs 39% not receiving EPO (P<0.5)

--A greater percentage of patients were able to achieve a higher weight based RBV dosing (>10.6 mg/kg) in the EPO arm compared to the SOC arm, but this was not statistically significant. This 10.6 mg/kg level was suggested by Schering as the level of RBV dosing based on weight that patients should be above to achieve a maximum virologic response using PegIntron+RBV. This has been controversial as Roche suggests RBV weight based is not necessary for Pegasys+RBV, and Roche is collecting data now to report on this question

--In both the physical and mental components of the Quality of Life Test SF-12, the patients receiving EPO had better scores than those not receiving EPO

--In total, 29 patients were treated with 40,000 Units once weekly of EPO. 5 patients were dose reduced to 30,000, 20,000 or 10,000

--Safety & tolerability: Dieterich reported EPO was well tolerated, that adverse events were similar to those expected with RBV/IFN, and adverse events wee not significantly different across the study groups (including ALT &HCV-RNA). He reported more patients had headaches in the EPO arm (26% vs 11%), and nausea (23% vs 7%), and pain (20% vs 14%). Interestingly, only 17% reported depression in the EPO arm compared to 32% in the SOC arm suggesting that fatigue may be related to depression experienced on RBV/IFN.

Less Anemia with Pegasys Alone vs Standard IFN a-2b+Ribavirin

Kenneth Rothstein (albert Einstein Med Ctr, Philadelphia) reported on a safety, tolerability, efficacy, and quality of life study comparing Pegasys alone to standard IFN a-2b+ribivarin therapy. About 200 patients in each arm received either Pegasys (IFN a-2a) 180 ug once weekly or IFN a-2b 3 MIU three times per week plus RBV 1000-1200 mg/day. Preliminary virologic response at week 24 showed the same response (56% in Peg alone arm vs 57% in the IFN/RBV arm).

The incidence of adverse events were reported as less in the Pegasys arm: less rigors, nausea, insomnia, myalgia, pyrexia, depression and pruritus (itching). Of interest to this discussion on anemia, 2% were reported to experience anemia in the Pegasys arm vs 32% in the IFN/RBV arm. About 60% in the IFN/RBV arm vs 10% in the Pegasys arm had 10 or less g/dL Hb or a drop of 3 or more in Hb. 33% vs 2% (Peg vs IFN/RBV, respectively) had 10 g/dL or less Hb or a drop of 4 or more in Hb. There was also a wide disparity when looking at drops of 5 or 6 or more in Hb or 10 or less in Hb

Patients reported better physical functioning scores, mental health, and better overall health & well-being at weeks 4 and 12 using Pegasys compared to standrard IFN/RBV. Patients also reported better distress scores and positive well being scores. Patients also reported less work and activity impairment and impairment while working due to health when receiving Pegasys compared to RBV/IFN. Less patients taking Pegasys went from employed to unemployed at week 4 or 12 (7% vs 18%). Anecdotal and study reports suggest that the severity and incidence of side effects with Pegasys+ribavirin is less compared to standard IFN a-2b 3 times per week plus RBV. Most notably less depression was reported in one study.