Effectiveness of Imatinib Therapy for a Patient with Sickle Cell Anemia and Chronic Myelocytic Leukemia.

Abstract 2559 Poster Board II-536 Background: To date, hydroxyurea (HU) is the only FDA-approved agent to treat sickle cell anemia (SCA). There is a need to identify alternative agents to prevent the complications of sickle cell disease. Clinical observations of patients receiving medications for other indications may provide insights into new opportunities. We present the clinical course of a patient with SCA and chronic myelocytic leukemia (CML) treated with imatinib. Case Report: A 24 year old woman with hemoglobin (Hb) SS had a variably elevated white blood cell (WBC) count for 3 years. WBC counts ranged from 11–39 × 103/cu mm; differential typically included 65–75% neutrophils, 15–20% lymphocytes, 1–13% metamyelocytes, and 1–3% myelocytes. Consistent with previous values, Hb ranged from 9–11 g/dL, and platelet counts from 250–400 × 103/cu mm. Real-time PCR for BCR-ABL obtained from the peripheral blood was positive. Bone marrow biopsy showed a markedly hypercellular marrow with granulocytic hyperplasia. Blasts were not increased in number. Cytogenetic studies revealed 46 XX, t(9;22)(q34;q11.2) in 20/20 analyzed cells. Further characterization by fluorescence in situ hybridization (FISH) technique demonstrated the loss of chromosome 9 long arm material. BCR-ABL interphase FISH confirmed the presence of 9/22 chromosomal translocation, found in 279/300 interphase nuclei. The patient was diagnosed with SCA in early childhood. Molecular analysis of genomic DNA revealed homozygosity for Hb S and single alpha-globin gene deletion of the rightward type. There was no evidence for typical deletions associated with HPFH or delta-beta zero thalassemia. The C>T polymorphism at nt −158 in the G-gamma-globin gene promoter region and other known HPFH point mutations in the G- or A-gamma globin genes were not identified. Her clinical course has not been complicated by stroke, pulmonary hypertension or acute chest syndrome. Radiographic studies revealed evidence of multiple bony infarcts. She was hospitalized with painful episodes 1-2 times per year, until the age of 16. At that time, her frequency of hospitalizations for painful episodes increased to 3-5 times per year, and showed a temporal relationship to her menses. She was started on oral contraceptives and hydroxyurea (HU) at the age of 18. Subsequently, hospitalizations for painful episodes decreased to 0-2 per year. At the age of 22, hydroxyurea was held during pregnancy. After delivery, HU was reinitiated and continued until the diagnosis of CML. She was hospitalized for painful episodes two times in the 12 months preceding the diagnosis of CML. Imatinib mesylate monotherapy at 400 mg/day was initiated. Two weeks later, a hematologic response was documented. At one year, bone marrow cytogenetic and molecular complete responses were documented. In the 17 months since initiation of imatinib, the patient has had a significant reduction in the frequency of painful episodes. No hospitalizations have been required and the patient has had a reduction in daily pain allowing discontinuation of a transcutaneous electrical nerve stimulation unit. During imatinib therapy Hb levels ranged from 8.0 to 9.2 g/dL, WBC counts from 3.3–6.1 × 103/cu mm, and platelet counts from 114–205 × 103/cu mm. Hemoglobin electrophoresis results are shown in the [table][1]. | | Hb F | Hb S | |:------------------------------- | ---- | ---- | | Pre-HU[*][2] | 26% | 71% | | Post-HU (n=7, mean)[*][2] | 35% | 63% | | Post-imatinib (n=2, mean)[*][2] | 34% | 64% | | Post-imatinib (by HPLC) | 20% | 74% | * [↵][3]* by gel electrophoresis Clinical Implications: To our knowledge, the clinical course of patients with SCA treated with imatinib has not previously been reported. Imatinib targets the BCR-ABL fusion tyrosine kinase, c-kit, and platelet-derived growth factor receptor. Myelosuppression is frequently noted as a side effect of this therapy. The improvement in this patient's sickle cell symptoms may be attributable to a reduction in the neutrophil count, as observed with HU therapy, but it is possible imatinib therapy had a positive effect on release of cytokines or other factors involved in vaso-occlusion. The Hb F level was not significantly increased with imatinib therapy. Evaluation of small molecule tyrosine kinase inhibitors in experimental models of SCA should be considered. Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #fn-1 [3]: #xref-fn-1-1