Analysis of Hypochromic Reticulocytes and Ferritin Index as a Rationale for An Effective Therapy of Cancer- and Chemotherapy-Associated Anemia
Authors: Steinmetz H. Tilman , Tsamaloukas Antonis Georg , Schmitz Stephan , Wiegand Jörg , Rohrberg Robert , Eggert Jochen , Eustermann Heidi , Tessen Hans-Werner , Thomas Lothar 
Published: April 2020

Abstract
Introduction: In most cancer patients anemia will be attributable to the mechanisms of chronic disease compounded by the myelotoxic effect of chemotherapy. Nevertheless it is important to exclude alternative explanations such as iron deficiency before starting therapy with erythropoiesis stimulating agents (ESA). Recently Thomas et al. (Clin Chem2002;48:1066-76) combined the reticulocyte hemoglobin (Hb) content (CHr) with the C-reactive protein (CRP)-dependent ferritin (Fer) index (FI: soluble transferrin receptor/ log Fer ratio) in a diagnostic plot (DP). We conducted a prospective phase II trial to analyze the diagnostic value of CHr, FI and the DP in anemic chemotherapy treated cancer patients (pts).
Methods: Informed consenting pts with an indication for ESA therapy as per EORTC guidelines and a ferritin level ≥20ng/ml were screened with the DP in a central laboratory. DP classifies pts in 1 of 4 quadrants (Q1 – Q4). Those with FI values above threshold (FI ≥3.2 if CRP &lt; 5mg/l, or FI &gt; 2.0 if CRP ≥5 mg/l) were assigned to Q2 (CHr &gt; 28 pg) or Q3 (CHr ≤ 28 pg), and those with sub threshold FI values to Q1 (CHr &gt; 28 pg) or Q4 (CHr ≤ 28 pg). Pts in Q1 received Epoetin beta (Epo) 30.000E/wk sc., those in Q4 additionally Fe-saccharat 200mg/wk iv up to 1g. Pts in Q2 + 3 were treated with oral or iv iron only.
Results: 11 centers recruited 303 pts (median age 65 y, male 41%) from 10/04 to 10/06; 230 (76%) had a sub threshold FI (Q1+4), of whom 23 (8%) had a CHr ≤28pg (Q4). 63 pts (21%) fell in Q2+3 with an increased FI, indicating relative iron deficiency, of whom 27 (9%) had a CHr ≤28pg (Q3). There was no correlation between assignment to Q1−4 and age, gender, body-mass-index, type or stage of tumor, measurable metastasis, bonemarrow infiltration, performance status, endogenous epo level, and haematocrit. However, Hb was lower and CRP was higher in Q4. RBC were higher in Q2+3, as leucocytes and thrombocytes were in Q3+4 and transferrin saturation in Q1. In 265 pts. evaluable for response Hb on d1 was 9.8 ± 1.2 g/dl (mean ± SD) and 10.7 ± 1.3 g/dl in 4th week. Mean increase of Hb from d1 to 8th week was 1.4 ± 1.7 g/dl. 36% pts. received a transfusion within 12 weeks and 18% after the 4th week. The table shows response according to Q1−4.
Conclusions: Overall response rate was comparable to other ESA studies. However pre therapeutic analysis of hypochromic reticulocytes and ferritin index in the diagnostic plot identifies about a quarter of pts, which were classified in Q2/3 due to elevated FI and had a good response receiving iron only. 8% pts with hypochromic reticulocytes and a sub threshold FI (Q4) had the best Hb-response with epo + iv iron.
Table: Response to treatment per quadrant in the diagnostic plot
N 265 FI &lt; threshold *&lt;threshold*&lt;=?=” ?=”” ??=”/” span=””&gt;&lt;/threshold*&lt;=?=”&gt; FI ≥ threshold * * FI ≥2.0 if CRP &lt;5 mg/l, or FI &gt;3.2 if CRP ≥5 mg/l CHr &gt;28 pg therapy Hb g/dl mean ± SD d1 4thweek Δ Hb 8th wk-d1 mean ± SD median g/dl (Quartile) % pts. with transfusions within 12 weeks after 4th week Q1 N 194 (73%) Epo only9.9 ± 1 10.7 ± 1.3 1.3 ± 1.5 1.1 (0.3–2.1) 41% 22% Q2 N 31 (12%) Iron only9.6 ± 2 10.4 ± 1.3 1.6 ± 2.4 1.5 (−0.1–2.4) 19% 3% CHr ≤ 28 pg therapy Hb g/dl mean ± SD d1 4thweek ΔHb 8th wk-d1mean ± SD median g/dl (Quartile) % pts. with transfusions within 12 weeks after 4th week Q4 N 21 (8%) Epo + iv iron9.2 ± 1 10.6 ± 1.4 2.3 ± 2 2.2 (0.3–4.1) 33% 19% Q3 N 19 (7%) Iron only 9.2 ± 1.1 10.9 ± 1.1 1.5 ± 1.5 2 (0.1–2.6) 16% 5%