Functional Iron Deficiency Effectively Overcome by Adjuvant IV Iron during Epoetin Treatment.

Background: 30–40% of anemic cancer patients don’t respond to epoetin treatment. New insights in iron regulation have indicated that one reason for lack of response may be functional iron deficiency (FID), in which an upregulation of hepcidin by imflammatory cytokines impairs the ferroportin-mediated iron export from macrophages.

Aims: To assess whether adjuvant IV iron therapy would overcome the iron restriction of FID as well as that of exhaustion of iron stores during epoetin treatment of anemia in patients with lymphoproliferative disorders (LPD) and proven iron presence in the bone marrow.

Methods: 67 patients with indolent lymphoid malignancy (19 NHL, 23 CLL and 25 MM), Hb ≥9 to ≤11 g/dl and a positive bone marrow iron staining were randomized to receive epoetin-beta, (NeoRecormon^®) 30 000 IU QW or this treatment plus IV iron sucrose, (Venofer^®) 100 mg QW, during week 0–6, 100 mg Q2W week 7–16 with dose modifications of epoetin according to the label.

60 patients completed the study. Three patients received transfusion and/or chemotherapy and thus 57 were evaluable.

Results:

The Hb response rate was superior in the iron-treated group, 91% vs 54%, the time to response (>2 g/dL) half as long, 6 w vs 12 w and the Hb level was 1.2 g/dL higher at the end of study(1).

In both groups, the mean transferrin saturation (Tsat) was low at baseline, 22%, and the mean S-ferritin was around 200 ug/L. During treatment, several indicators showed that iron availability was superior in the iron-treated group. In the non-iron group Tsat declined from baseline to <20% in 26 out of 30 patients for the duration of the study, and S-ferritin fell rapidly during the first week and then steadily declined from a baseline value of 191 to 112 ug/L at the end of study. (EOS). The mean soluble transferrin receptor (sTfR) level increased from normal to a maximum of 3.7 mg/L in week 8.

In the iron-treated group (n=27) Tsat increased from baseline and stabilized at 30%. S-Ferritin showed no initial fall and continued to increase from 210 at baseline to 398 ug/L at EOS.

Discussion.

Iron restriction may be present in epoetin treatment of cancer anaemia by two different mechanisms. Iron deposits may be small and become depleted, and secondly iron may be trapped in the macrophages due to FID. In these patients, FID was common, as indicated by the presence of bone marrow iron and the low mean Tsat at baseline. In some patients, small iron deposits were exhausted by the increased erythropoiesis in the non-iron group, as shown by subnormal S-ferritin levels. The fact that the mean Tsat and S-ferritin increased in the iron-treated group indicated that iron availability was constantly better in this group and the reason for the superior Hb response.

Conclusions

• - Functional iron deficiency (low Tsat and iron-restricted erytropoiesis in spite of proven iron stores) is common in patients with anaemia of haematological malignancies.

• - FID is a common and important reason for lack fo response to epoetin treatment

• - IV iron treatment improves epoetin response both by overcoming FID and by avoiding iron depletion casued by increased erythropoiesis.