Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib.

The tyrosine kinase inhibitor (TKI) imatinib (Gleevec; Novartis, Basel, Switzerland) is standard therapy for patients with chronic myeloid leukemia (CML).1 Therapy with imatinib is generally well tolerated, and the most common side effects include nausea, diarrhea, fatigue, muscle cramps, rashes, fluid retention, liver enzymes abnormalities, and myelo-suppression.2,3 Myelosuppression is the most common grade 3–4 toxicity, occurring in 35% to 45% of patients treated with imatinib after interferon (IFN)-α failure and in 15% of patients with previously untreated CML.3–5 Anemia has been reported in 45% to 68% of patients in chronic phase treated with imatinib, and is grade 3-4 in 7% of patients after IFN-α failure and in 3% to 7% of those receiving imatinib as initial CML therapy.3–5 The development of myelosuppression, including anemia, in patients with CML has been associated with an inferior outcome.2,5,6 The use of growth factors such as erythropoietic-stimulating agents (recombinant human erythropoietin [EPO] or darbepoietin-α) and granulocyte-colony stimulating factor during therapy with TKI in CML can improve cytopenias and decrease the frequency of interruptions and dose reductions.6,7 Among patients with chronic phase CML receiving therapy with imatinib, erythropoietic-stimulating agents improved hemoglobin (Hb) levels by at least 2 g/dL in 68% of patients.6 Recently, concerns have been raised regarding the safety of erythropoietic-stimulating agents in patients with cancer.8 A meta-analysis showed that the use of erythropoietic-stimulating agents for prophylaxis or treatment of anemia in patients with cancer increases mortality (hazard ratio [HR], 1.17) and decreases overall survival (OS) (HR, 1.06).9 Another meta-analysis reported that erythropoietic-stimulating agents increase the risk for venous thromboembolic events (relative risk, 1.57) and decrease survival (HR, 1.10) in patients with cancer.10 In addition, a randomized trial showed that use of darbepoietin-α was associated with worse survival in patients with cancer-related anemia not receiving chemotherapy.11 Erythropoietic-stimulating agents shortened time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when it was administered to target an Hb of >12 g/dL.12 Similarly, use of erythropoietic-stimulating agents decreased OS in patients with metastatic breast cancer and nonsmall cell lung cancer.13,14 This evidence led to a revision in the US Food and Drug Administration product labels for erythropoietic-stimulating agents, issuing a black box warning indicating the possibility of shortened survival and cancer progression in cancer patients treated with erythropoietic-stimulating agents when targeting a Hb level of 10 to 12 g/dL.8 For patients with CML and imatinib-induced anemia, there are few treatment options. The American Society of Hematology/American Society of Clinical Oncology guidelines on the use of erythropoietic-stimulating agents in patients with cancer recommends that for patients with chemotherapy-associated anemia and low-risk myelodysplastic syndrome, erythropoietic-stimulating agents should be initiated as Hb approaches or falls below 10 g/dL to increase Hb and decrease transfusions.8 The dose should be decreased by 25% to 40% when Hb reaches the level needed to avoid transfusion or if the rate of Hb increase is >1 g/dL in 2 weeks.8 However, erythropoietic-stimulating agent are frequently used in patients with CML to treat anemia associated with TKI therapy, but the long-term safety of their use in this setting is unknown.6 We thus conducted this analysis to investigate the prognostic impact of erythropoietic-stimulating agent use among patients with CML in chronic phase treated with imatinib and to define the incidence of cardiovascular, cerebrovascular, or thromboembolic episodes in this patient population.