Evaluation Of Anemia After Long-Term Treatment With Imatinib In Chronic Myeloid Leukemia In Chronic Phase
Authors: Moura Muriel Silva , Pagnano Katia B. , Benevides Thais , De Souza Carmino A , Lorand-Metze Irene , Delamain Marcia T , Duarte Gislaine O. , Pericole Fernando V , Percout Priscila , Dias Maria , Duarte Bruno , Campos Paula , Assunção Paola , Oliveira Luciene , Paul Pamela , Fernandes Eliana 
Published: October 2019

Abstract
The incidence of Grade 3 (hemoglobin [Hb] level 6.5–8 g/dL) or Grade 4 (Hb level < 6.5 g/dL) anemia was reported to be 3% with imatinib therapy for newly diagnosed CML in the IRIS trial, with a median follow-up of 19 months and 7% for chronic-phase (CP) chronic myeloid leukemia (CML) after IFN-α failure. However, there is few data regarding development of anemia after long-term follow-up and its causes.
The aim of this work was to evaluate the incidence of anemia after at least two years of treatment of CML patients in CP treated with imatinib and to identify other contributing causes of anemia in this population.

Patients and Methods
Between 2006 and 2010 121 patients with CML were treated with imatinib 400-800 mg in our center. Forty-six patients were excluded from the analysis for accelerated phase at diagnosis (n=20), discontinuation of imatinib before 2 years of treatment (n=21) and 5 for other causes. A total of 65 patients were evaluated. Hb levels were analyzed at diagnosis, at imatinib start, and at two years of imatinib. Anemia developed after the second year of imatinib therapy was classified as grade 1 (Hb level < 10.0 g/dL), grade 2 (Hb level of 8.0 to < 10 g/dL), or grade 3 (Hb level of < 8.0 g/dL) for the purpose of treatment evaluation according to National Cancer Institute (NCI) Common Toxicity Criteria - Version 4.0. Other comorbidities were analyzed.

Results
The median age was 53 years (24-86 years), 34 male (52%). 38% of the patients did not present other medical conditions. Comorbidities found in 62% of the patients: systemic arterial hypertension (31%), diabetes mellitus (6.7%), cardiopathy (5%), hypothyroidism (6.1%) and renal failure (only one patient with renal dysfunction in dialysis). Two patients received interferon: one prior imatinib and another during pregnancy, requiring interruption of imatinib in this period. Patient’s responses: 54 (83%) achieved complete cytogenetic response (CCR) and 10 lost response; eight of them developed anemia; 7 had (10.7%) partial response, 1 minor response (1,5%), 1 no response and 1 was not available. Fifty-three patients (81.5%) achieved major molecular response, with loss of response during follow-up in 8 cases (12.5%), seven of these developed anemia.The median Hb (g/dL) level was 12.1, 13 and 13.2 at diagnosis, at imatinib start and at 2 years of treatment respectively. Most of the patients developed Hb bellow the reference level (73.8%; n = 48) during the follow-up, after the second year of treatment. Anemia classification according to NCI criteria: 41 cases presented grade 1, 6 (12.5%) grade 2 and one grade 3. Of these, 68.7% (n = 33) had no etiological causes for the anemia, five patients (10.4%) were resistant, two (4.2%) were not adherent to treatment and in 8 cases (16.7%) the etiology of anemia was identified: hypothyroidism (n=1), erosive gastritis (Helicobacter Pylori positive)(n=1), B12 vitamin deficiency (n=2), HIV/AIDS (n=1), pulmonary tuberculosis (n=1) and renal failure (n=2). Fourteen (29.2%) patients had normalization of Hb levels without medical intervention and the majority (56.2%) still persists with the anemic status until the last follow-up. Four (8.3%) patients had resolution of the anemia after switching to a second generation inhibitor and 3 (6.2%) showed clinical improvement after treatment of the cause.
In summary, several degrees of anemia may occur in patients with CML on long-term imatinib therapy, most of them not severe. Regular hematological follow-up is required to identify causes not CML related that can be corrected or if related to imatinib toxicity, dose modification or change of therapy. It should be emphasized the importance of investigating secondary causes for anemia, especially in patients with good adherence to treatment and satisfactory therapeutic response.

Disclosures:
No relevant conflicts of interest to declare.