Abstract
For patients with chemotherapy-induced anemia (CIA) and functional iron deficiency (FID) who are treated with an erythropoiesis-stimulating agent (ESA), guidelines recommend intravenous (IV) iron supplementation and resolution of iron deficiency (ID) before ESA use to reduce blood transfusions and ESA doses (both linked to safety concerns). This prospective, randomized phase II study evaluated ferric carboxymaltose (FCM, Vifor Pharma) without additional ESA for correction of anemia and FID in patients with lymphoid malignancies receiving antineoplastic therapy.
Patients with indolent lymphoid malignancies (non-Hodgkin lymphoma, multiple myeloma or chronic lymphocytic leukemia), anemia (Hb 8.5-10.5 g/dL) and FID (transferrin saturation [TSAT] ≤20% and stainable bone marrow iron or serum ferritin >30 ng/mL [women] to >40 ng/mL [men]), who had been on chemotherapy (CT) for at least 8 weeks or two cycles were randomized to FCM (1000 mg iron) or no anemia treatment (control). Iron was administered within 24 hours before or after the next chemotherapy cycle's first treatment. The primary endpoint was the mean Hb change from baseline to Weeks 4, 6 and 8 without use of blood transfusions or ESA. Secondary endpoints included Hb response (increase ≥1.0 g/dL) or Hb correction (Hb ≥11.0 g/dL) at any week and changes in hematologic variables, endogenous erythropoietin (EPO), hepcidin and interleukin (IL)-6 over time. Data are shown as median [range]. Enrollment was stopped after 19 of planned 40 patients due to low recruitment.
Of 19 randomized patients, 17 (8 FCM, 9 control; 11 males, age 71 y [26-88 y]) were analyzed for the primary endpoint (full analysis set, FAS). FCM-treated patients had a significant Hb increase vs. baseline at any week (Table). Mean Hb increase at Week 8 was significantly higher in the FCM than the control group (FAS, Fig. A, Table). In the per protocol population (PPS; 5 FCM, 7 control), mean Hb increase in the FCM group was significantly higher from Week 4 onwards (Fig. B). All FCM-treated patients in the FAS achieved Hb response (time to response 2.3 [0.6-6.0] weeks) compared to only 6 of 9 (66.7%) control patients (time to response 4.4 weeks). Hb was corrected in 87.5% (7 of 8) FCM-treated and 55.6% (5 of 9) control patients. In the FCM group, median Hb was >11.0 g/dL from Week 6 and TSAT was >20% from Week 2 onwards, whereas in the control group, none exceeded these cut-offs. EPO, hepcidin and IL-6 levels did not show any significant variations (Table). No blood transfusion or ESA treatment was given in either group, and no treatment-related adverse events (AEs) were recorded during the study. Five (62.5%) patients in the FCM and one (9.1%) in the control group reported 12 and 2 unrelated AEs, respectively, in this open-label study. All AEs except one unrelated, fatal post-study injury were mild or moderate.
Baseline hematologic variables and changes vs. baseline (FAS)
| Median change vs. baseline | ||||||
|---|---|---|---|---|---|---|
| Parameters | Group | Baseline | Week 2 | Week 4 | Week 6 | Week 8 |
| Hb (g/dL) | FCM | 9.5 9.0–10.5 | 0.9* -0.3–2.9 | 1.2* -0.1–4.7 | 2.0* 0.1–3.9 | 2.1*,† 0.2–3.5 |
| Co. | 10.1 8.4–10.6 | 0.7 -2.5–1.0 | 0.5 -2.1–2.0 | 0.6 -1.4–2.6 | 0.9* -0.1–2.2 | |
| TSAT (%) | FCM | 16 3–35 | 12† -6–24 | 9† 0–27 | 7 -4–19 | 9 3–23 |
| Co. | 17 0–20 | -1 -7–11 | 6 -1–14 | 2 -5–50 | 6 -3–14 | |
| Ferritin (ng/mL) | FCM | 216 65–800 | 425† 128–913 | 399† 135–899 | 328† -216–780 | 213† -20–1113 |
| Co. | 225 8–707 | 0 -180–240 | -132 -589–64 | -127 -321–60 | -108 -405–260 | |
| EPO (IU/L) | FCM | 44 24–314 | -4 -105–5 | -17 -205–(-5) | -22 -144–(-9) | -23 -148–(-8) |
| Co. | 34 9–176 | 5 -24–109 | -10 -161–1 | -19 -68–6 | -10 -140–16 | |
| Hepcidin-25 (nmol/L) | FCM | 6.6 0.5–34.6 | 3.3 -12.1–11.4 | 0.3 -9.4–7.7 | 0.4 -11.8–2.6 | -0.1 -9.4–3.4 |
| Co. | 3.9 0–38.7 | 1.3 -38.5–4.8 | -0.8 -38.4–0.8 | -0.1 -34.1–42.9 | -1.7 -30.1–4.1 | |
| IL-6 | FCM | 9.2† 0.7–36.6 | -1.3 -12.3–4.9 | -5.2 -18.7–3.3 | -2.6 -24.8–6.1 | 0.9 -31.6–10.3 |
| Co. | 13.4 5–300 | -2.5 -285–51 | -4.7 -270–0 | -2.0 -262–21 | -3.9 -199–11 | |
| Median change vs. baseline | ||||||
|---|---|---|---|---|---|---|
| Parameters | Group | Baseline | Week 2 | Week 4 | Week 6 | Week 8 |
| Hb (g/dL) | FCM | 9.5 9.0–10.5 | 0.9* -0.3–2.9 | 1.2* -0.1–4.7 | 2.0* 0.1–3.9 | 2.1*,† 0.2–3.5 |
| Co. | 10.1 8.4–10.6 | 0.7 -2.5–1.0 | 0.5 -2.1–2.0 | 0.6 -1.4–2.6 | 0.9* -0.1–2.2 | |
| TSAT (%) | FCM | 16 3–35 | 12† -6–24 | 9† 0–27 | 7 -4–19 | 9 3–23 |
| Co. | 17 0–20 | -1 -7–11 | 6 -1–14 | 2 -5–50 | 6 -3–14 | |
| Ferritin (ng/mL) | FCM | 216 65–800 | 425† 128–913 | 399† 135–899 | 328† -216–780 | 213† -20–1113 |
| Co. | 225 8–707 | 0 -180–240 | -132 -589–64 | -127 -321–60 | -108 -405–260 | |
| EPO (IU/L) | FCM | 44 24–314 | -4 -105–5 | -17 -205–(-5) | -22 -144–(-9) | -23 -148–(-8) |
| Co. | 34 9–176 | 5 -24–109 | -10 -161–1 | -19 -68–6 | -10 -140–16 | |
| Hepcidin-25 (nmol/L) | FCM | 6.6 0.5–34.6 | 3.3 -12.1–11.4 | 0.3 -9.4–7.7 | 0.4 -11.8–2.6 | -0.1 -9.4–3.4 |
| Co. | 3.9 0–38.7 | 1.3 -38.5–4.8 | -0.8 -38.4–0.8 | -0.1 -34.1–42.9 | -1.7 -30.1–4.1 | |
| IL-6 | FCM | 9.2† 0.7–36.6 | -1.3 -12.3–4.9 | -5.2 -18.7–3.3 | -2.6 -24.8–6.1 | 0.9 -31.6–10.3 |
| Co. | 13.4 5–300 | -2.5 -285–51 | -4.7 -270–0 | -2.0 -262–21 | -3.9 -199–11 | |
Median [range], Co. control, *p<0.05 vs. baseline, †p<0.05 FCM vs. control
A (FAS)
B (PPS)
This pilot study indicates that ferric carboxymaltose without additional ESA may effectively increase and correct Hb levels and is well tolerated in patients with lymphoid malignancies, CIA and FID. Hb improvement is supported by resolution of ID from the first post-treatment visit onwards. A larger phase 3 study in a representative patient population is warranted to confirm the results of this study.
Hedenus:Vifor Pharma: Consultancy, Honoraria. Ludwig:Vifor Pharma: Honoraria. Felder:Vifor Pharma: Employment. Roubert:Vifor Pharma: Employment. Birgegard:Vifor Pharma: Honoraria.
