Serum Erythropoietin Dose Not Participate in Anemia That Persists in CML Patients after MMR Achievement by Imatinib Mesylate Therapy
Authors: Ishikawa Maho , Yagasaki Fumiharu , Okamura Daisuke , Maeda Tomoya , Takahashi Naoki , Kawai Nobutaka , Matsuda Akira , Jinnai Itsuro , Bessho Masami 
Published: April 2020

Abstract
Serum Erythropoietin dose not Participate in Anemia that Persists in CML Patients after MMR Achievement by Imatinib Mesylate Therapy
The IRIS study revealed that imatinib mesylate (IM) has resulted in durable responses in patients with CML in early chronic phase. Overall, 86% of patients on IM achieved complete hematologic response (CHR) by 3 months and 78% achieved complete cytogenetic response (CCR) by 18 months.
According to the European LeukemiaNet guidelines, CHR is defined without evaluation of anemia. In the IRIS study, grade 3 or 4 of anemia was reported as 4% after 5 years of therapy, however, we found most patients remain mild to moderate anemia even after achievement of major molecular response (MMR). Persistent anemia sometimes deteriorates patients’ quality of life and is thought to be clinically important.
Here, we investigated frequency and severity of anemia, and participation of serum erythropoietin (EPO) among 23 patients, who have achieved MMR by IM at doses in excess of 300mg for more than 2 years. At diagnosis, the median age was 53 years (range 20–87) and 14 were male. 20 patients were in chronic, and 3 in accelerated phase. Median leukocyte count was 31.6 × 109/L (range 4.1–216.3 × 109), median hemoglobin (Hb) was 13.1 g/dl (range 6.2–16.2), and median platelet count was 629 × 109/L (176–1640). The cumulative rate of CHR by 3 months was 100% and that of CCR by 12 months was 77.3%. Among 18 patients who had MMR, hematologic adverse events were assessed. After reaching MMR, leukocytopenia was observed in 3 (16.6%) patients (grade 2; 2pts, grade 3;1pt), anemia was in 13 (72.2%) patients (grade 1; 10pts, grade 2; 2pts, grade 3; 1pt), and thrombocytopenia was in 3 (16.6%) patients (grade 1; 2pts, grade 2; 1pt). Mild to moderate anemia tends to persist at high rates as compared with other cytopenias. In anemic group, median MCV, MCHC, and reticulocyte was 99.4fL (range 91.6–113.1), 33.3% (range 30.4–35.2), and 53691/micro L (range 30450–72324), respectively, and serum urea and creatinine were normal. To reveal mechanism of persistent anemia, EPO levels were measured by a radioimmunoassay (normal range 9.1–32.8 mIU/ml). For control, we used the formula: log[EPO]=3.436–0.1675[Hb], which was led by 58 iron deficiency anemia (IDA) patients and had been previously reported (Toyoda A, et al. Exp Hematol21:1085, 1993). The EPO corresponding to each Hb level from the formula was defined as the expected value. The median serum EPO level of CML patients with anemia was 46.0 mIU/ml (range 23.9–188.1). Comparison of the observed EPO with the expected EPO levels showed no significant differences (p=0.557). The equation of regression line for the observed EPO was y=−21.07x+284.2 (Figure 1. solid line, r=−0.732, p=0.0008), and that of the expected EPO was y=−22.65x+296.3 (Figure 1. dashed line, r=−0.939, p&lt;0.0001). In addition, serial EPO measurement could be performed in one patient treated with IM. At the diagnosis of CML, Hb was 11.0g/dl and EPO was 47.7mIU/ml. He developed anemia with Hb of 7.8g/dl due to gastrointestinal bleeding, and EPO was 183.6 mIU/ml. After discontinuation of IM for 7days, Hb was 8.4g/dl and EPO was 64.9mIU/ml. These data show that IM has little influence on the serum EPO levels.
In conclusion, grades 1–2 anemia frequently persist in CML patients after MMR achievement. The EPO response does not concern about the condition of persistent anemia, and IM have little influence on the serum levels of EPO.
Figure 1. Correlation between erythropoietin and hemoglobin. Figure 1. Correlation between erythropoietin and hemoglobin.