Marked improvement of cardiac function early after non-myeloablative BMT in a heavily transfused patient with severe aplastic anemia and heart failure

Allogeneic stem cell transplantation (allo-SCT) is one of the curative treatment options for patients with severe aplastic anemia (SAA). However, since multiple transfusions can cause organ damage such as heart failure, diabetes mellitus and liver dysfunction due to iron overload, the majority of heavily transfused patients with SAA would not tolerate the intensive conditioning regimens followed by allo-SCT. In addition, multiple transfusions also can sensitize the patients with alloantigens, resulting in the high risk of graft rejection. Non-myeloablative SCT (NST) has been developed to reduce regimen-related toxicities (RRT), especially for patients with poor organ function or advanced age, but it may be more frequently associated with graft rejection. Recently, several trials have utilized an NST regimen to reduce RRT and overcome graft rejection in the heavily transfused and allo-immunized SAA patients, using fludarabine in combination with melphalan1, 2 or cyclophosphamide.3, 4

A 32-year-old man had suffered from SAA for 16 years. He had received several treatments with prednisolone, anabolic steroids, cyclosporine, ATG and G-CSF, without appreciable effects. The patient had no HLA-identical donors among his family or unrelated donor banks. Therefore, a large number of transfusions were required to keep him alive for 16 years. Owing to hemochromatosis secondary to the numerous RBC transfusions, he had developed cardiac failure, diabetes mellitus and hypothyroidism. An HLA-matched donor search had continued, and finally allo-BMT from an unrelated donor with HLA matched at A, B, C and DR loci was conducted in February 2004. On admission, the hemoglobin concentration was 6.0 g/dl; platelet count, 5.0 × 109/l; WBC, 1.6 × 109/l with 27% neutrophils. He presented with hepatosplenomegaly and congestive heart failure due to the hemochromatosis with a serum ferritin concentration of 11 506 ng/ml. Ultrasound cardiography (UCG) disclosed that the left ventricular EF (LVEF) was 20.9%, LV internal diameter in diastole (LVDd) 64.9 mm, LVD in systole (LVDs) 58.6 mm and LV wall motion was globally reduced, resembling a dilated cardiomyopathy (Figure 1). The serum concentration of brain natriuretic peptide (BNP) was increased up to 975 pg/ml (normal, <58.4 pg/ml). He was treated with metildigoxin, furosemide, spironolactone and losartan. The patient would not tolerate the standard conditioning regimen, including high-dose cyclophosphamide. Therefore, we decided to treat him using an NST conditioning regimen. He was given 180 mg/m2 of fludarabine, 70 mg/m2 of melphalan and 2 Gy of TBI, followed by transplantation of 3 × 108/kg bone marrow cells from an unrelated donor. Short-term methotrexate and tacrolimus were administered as prophylaxis against GVHD. Hematopoietic recovery was prompt and a chimeric analysis on day 23 disclosed that his bone marrow cells consisted entirely of donor-derived cells. Throughout conditioning, a low dose of dopamine and carperitide was administered continuously, and transfusions of RBC were performed to keep his hemoglobin concentration around 7 g/dl. Cardiac, renal and liver functions were well preserved, despite febrile events and administration of antibiotics following allo-BMT. According to Bearman's RRT scoring, the patient developed grade 3 mucositis but other organ RRT was scored below grade 2. On day 32, grade II acute GVHD developed, but was confined to the skin; this responded to prednisolone. Hematopoiesis gradually improved 3 months after allo-BMT; his WBC was 2.5 × 109/l and hemoglobin concentration 7.0 g/dl. Surprisingly, at this time point, his cardiac function had improved drastically. His LVEF had increased to 50.1% (Figure 1), and the serum BNP concentration returned to a normal range (54.4 pg/ml). He no longer manifested symptoms of heart failure, and required treatment with only losartan. However, his serum ferritin concentration was still high (12 213 ng/ml, Figure 2) and computed tomography (CT) revealed that iron deposition was still present in the heart as well as liver. Thirty months after allo-BMT, the WBC was 4.5 × 109/l and hemoglobin 12.5 g/dl without need for blood transfusion. The serum concentration of ferritin and BNP had decreased to 5688 ng/ml and 8.1 pg/ml, respectively (Figure 2). UCG showed a further significant functional improvement (Figure 1). This patient has been receiving phlebotomy to treat the iron overload for further improvement (Figure 2).

Figure 1
figure1

Ultrasound cardiography performed before and after allo-BMT. LVDd, LV internal diameter in diastole; LVDs, LV internal diameter in systole; LVEF, left ventricular (LV) ejection fraction.

Figure 2
figure2

Clinical course of the patient after non-myeloablative BMT. BNP, serum level of brain natriuretic peptide (normal, <58.4 pg/ml).

In this patient, the prompt improvement in cardiac function 3 months after BMT might not have correlated with the hematologic changes, since his hemoglobin concentration had not yet increased at that time, which had still required RBC transfusions. In addition, iron deposition still remained in the heart as seen in the CT scan. Therefore, the decrease in iron stores or amelioration of hemochromatosis by the successful BMT cannot account for the prompt improvement of left ventricular systolic function. It was recently reported from postmortem examinations that a fraction of cardiomyocytes from female patients who had undergone sex-mismatched allo-BMT were positive for Y chromosome staining, suggesting that donor-derived bone marrow cells can contribute to cardiomyocyte formation.5 Animal experiments also have demonstrated that cardiac function improves several weeks after BMT, possibly through cell fusion or trans-differentiation, although the exact mechanisms remain to be determined.6, 7 Therefore, in this case, donor-derived bone marrow cells might partially contribute to the amelioration of cardiac dysfunction, rather than a decrease in iron deposition by the successful BMT resulted in an improvement in heart failure due to hemochromatosis. In this context, bone marrow cells as a stem cell source might be suitable for patients with organ damage, since bone marrow cells contain hematopoietic and mesenchymal stem cells, which can differentiate into other tissues such as cardiomyocytes to repair the injured organs.6, 8

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Kunisaki, Y., Takase, K., Miyamoto, T. et al. Marked improvement of cardiac function early after non-myeloablative BMT in a heavily transfused patient with severe aplastic anemia and heart failure. Bone Marrow Transplant 40, 593–595 (2007). https://doi.org/10.1038/sj.bmt.1705764

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