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CASE REPORT
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Successful Allogeneic Bone Marrow Transplantation for Diamond-Blackfan Anemia Complicated by Severe Cardiac Dysfunction due to Transfusion-Induced Hemochromatosis Sumie Tabata 1, Minako Mori 1, Yuya Nagai 1, Hisako Hashimoto 2, Hiroshi Arima 1, Seiji Nagano 1, Yoko Takiuchi 1, Daichi Inoue 1, Takaharu Kimura 1, Sonoko Shimoji 1, Soshi Yanagita 1, Kiminari Ito 2, Akiko Matsushita 1, Kenichi Nagai 2 and Takayuki Takahashi 1
Abstract A 21-year-old man who was diagnosed with Diamond-Blackfan anemia at 2 years of age came to our hospital with the hope of undergoing bone marrow transplantation (BMT). He had been red cell transfusiondependent for about 8 years; at presentation he had transfusion-induced hemochromatosis, a subsequent low left ventricular ejection fraction (LVEF) of 43%, and diabetes mellitus requiring insulin therapy. He received unrelated BMT with reduced intensity conditioning and sufficient GVHD prophylaxis. Regardless of the cardiac dysfunction, he had an uneventful course during pre- and post-grafting periods, and is currently doing well with an improved LVEF (55%), although he is still insulin dependent. Key words: allogeneic bone marrow transplantation, diamond-blackfan anemia, cardiac dysfunction, hemochromatosis (Inter Med 49: 453-456, 2010) (DOI: 10.2169/internalmedicine.49.2991)
Introduction Diamond-Blackfan anemia (DBA) is a rare type of pure red cell aplasia that predominantly affects infants and children. DBA was first reported by Josephs in 1936 (1), and was established as a distinct clinical entity by Diamond and Blackfan in 1938 (2). DBA is believed to be caused by an intrinsic defect in erythroid progenitor cells, and 25% of DBA patients carry a mutated allele of a gene encording ribosomal protein S19 (RPS19) (3). Forty percent of DBA patients present with various somatic malformations that mostly involve the cephalic area, limbs, hands, urogenital tract, and heart. The mainstay of treatment for DBA is corticosteroids, to which approximately 80% of patients initially respond. The remaining 20% of patients, who do not respond to corticosteroids, need chronic red cell transfusion or they are
treated with immunosuppressive agents (4). Although hematopoietic stem cell transplantation (HSCT) is a promising treatment for refractory cases (4, 5), this procedure may be highly risky for patients who have a history of heavy red cell transfusion. In these patients, especially in those whom the serum ferritin concentration exceeds 1,000 ng/mL, a high incidence of therapy-related mortality (TRM) such as graft rejection, veno-occlusive disease (VOD), and lifethreatening infection has been reported (6-8). Iron overloading itself causes organ damage. For example, it has been reported that iron accumulates in the myocardium when the serum ferritin level exceeds 1,800 ng/mL, and the incidence of cardiogenic mortality increases with a ferritin level over 2,500 ng/mL (9). Regarding the liver function, serum ALT/ AST concentrations are elevated with a ferritin level beyond 1,000 ng/mL (10).
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Department of Hematology and Clinical Immunology, Kobe City Medical Center General Hospital, Kobe and ２Department of Hematology, Institute of Biomedical Research and Innovation, Kobe Received for publication October 8, 2009; Accepted for publication November 1, 2009 Correspondence to Dr. Takayuki Takahashi,
[email protected]
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DOI: 10.2169/internalmedicine.49.2991
Ta bl e1 . La bo r a t o r yDa t ao nAdmi s s i o n Hematology
Chemistry
109
WBC RBC HB Ht Plt Reti
2.3 /L 155 104 / L g/dL 5.0 % 14.9 99 109 /L ‰ 5
Blast Pro Myelo Meta Band Seg Eos Bas Lym Mon
0 0 0 0 0 59 3 1 35 2
% % % % % % % % % %
TP Alb Che GOT GPT LDH CPK T-bil ALP γ-GTP BUN Cre UA Na K Cl Ca Glu CRP
7.4 4.1 271 47 66 160 108 0.3 269 117 15 0.4 3.7 140 4.2 106 9.3 258 0.1
Coagulation g/dL g/dL IU/L IU/L IU/L IU/L IU/L mg/dL IU/L IU/L mg/dL mg/dL mg/dL mEq/L mEq/L mEq/L mg/dL Mg/dL mg/dL
APTT PT Fig D-dimer
33.6 sec 79.8 % 288 mg/dL 0.4 µg/mL
Fe UIBC Ferritin
201 µg/dL 10 µg/dL 3676ng/mL
HbA1c
7.2 %
Bone Marrow NCC Megk M/E ratio Ery Blast Pro Myel Meta Band Seg Eos Bas Mon Lym Plasma Mφ
87,000 132 12 6.4 1.0 5.6 34.4 6.8 15.2 3.6 3.6 0.4 1.2 9.6 2.0 0.8
/µL /µL % % % % % % % % % % % % %
Karyotype 46,XY in all 20 divided cells
Case Report A 21-year-old man was diagnosed with DBA at the age of 2 years in 1985. He had been treated with prednisolone, anabolic steroid, and cyclosporine A. Despite these intensive treatments, the anemia did not improve, and he became transfusion-dependent from 1998. As a result of the heavy transfusion, he developed hemachromatosis and subsequent cardiac dysfunction and diabetes mellitus that required insulin therapy in 2003. He wanted to receive hematopoietic stem cell transplantation (HSCT) as a curative therapy for DBA; however, HSCT was judged to be contraindicated because of a low left vectricular ejection fraction (LVEF) due to hemachromatosis in another hospital. He consequently came to our hospital with the hope of undergoing HSCT in May 2006. To determine the indication of SCT, he was admitted and a total body examination was performed. Physically, his skin was bronze-colored, and palpebral conjunctivae were anemic. Hepatosplenomegaly, superficial lymph node swelling, and pretibial edema were not noted. During this period, 2 units of packed red cells were required once a week to maintain the hemoglobin level above 5 g/dL, and he was treated intravenously with the iron chelator, deferoxamine mesilate, at a dose of 2,000 mg/week. Concentrations of serum ferritin, blood sugar, and HbA1c were markedly elevated to 5,710 ng/mL (normally 20-250), 304 mg/dL (normally 70-110), and 7.1% (normally 3.8-5.4), respectively (Table 1). Because the serum ferritin level was above 5,000 ng/mL, transfusion-associated iron overload was evaluated as stage 4 (11). The renal and liver functions were not impaired. The heart, liver, and pancreas showed high-density imaging on CT scanning due to hemochromatosis (Fig. 1).
Fi g ur e1 . Hi g hr e s o l ut i o nCT s c a no ft hec he s ta nda bdo me n( Oc t o be r2 0 0 6 ) .Thehe a r t( A) ,l i v e r ,a ndpa nc r e a s( B) s ho w ahi g hi nt e ns i t yo ni ma g i ng ,i ndi c a t i ngt hea c c umul a t i o no fi r o ni nt he s eo r g a ns .
Echocardiography showed an impaired LV wall motion, LV dilatation, and a markedly low LVEF (43%). Although we considered that HSCT was risky, we finally decided to perform bone marrow transplantation (BMT) on
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DOI: 10.2169/internalmedicine.49.2991
Ta bl e2 . Ca r di a cFunc t i o na sEv a l ua t e d by Ec ho c a r di o g r a phy be f o r e a nda f t e rBMT
BMT
LVDs(mm) LVEF(%)
Remarks
Date
LVDd(mm)
2006.03.13
65
49
44
LA,LV dilatation(+)
2006.05.01
65
50
43
mid~apex:hypo, LA,LV dilatation(+)
2006.10.20
60
44
47
mid~apex:hypo, LA,LV dilatation(+)
2007.02.06
62
46
46
LA,LV dilatation(+)
20070.2.19
57
48
50
LA,LV dilatation(+)
2007.05.01
56
41
49
LA,LV dilatation(+)
2007.12.26
56
44
53
LA,LV dilatation(+)
2009.06.12
55
37
55
LA,LV dilatation(+)
BMT: bone marrow transplantation; LVDd: left ventricular end-diastolic dimension; LVDs: left ventricular end-systolic dimension; LVEF: left ventricular ejection fraction; LA: left atrium; LV: left ventricle; mid-apex hypo: hypokinesis in middle to apex portion.
receiving sufficient informed consent, because the HSCT comorbidity index (12) was 2 points (cardiac failure and diabetes) and his performance status was 0. He did not have an HLA-matched sibling donor, so he registered with the Japan Marrow Donor Program (JMPD). Despite intensive treatment with deferoxamine mesilate, the serum ferritin concentration was elevated to 7,470 ng/mL before BMT. He underwent unrelated BMT with an HLA fully matched donor in February 2007. A total of 3.8×108/kg donor marrow cells (of these, CD34+ cells comprised 4.78×106/kg) were infused. Reduced intensity conditioning (RIC) that consisted of 40 mg of fludarabine for 5 consecutive days, 95 mg of melphalan for 2 consecutive days, and 4 Gy of total body irradiation was employed. Graft-versus-host disease (GVHD) prophylaxis consisted of the conventional administration of tacrolimus and short-term methotrexate. From day 5 after BMT, 300 μg of filgrastim was given daily. Neutrophils were engrafted on day 17 after BMT. He became free of red blood cell and platelet transfusions on days 16 and 36, respectively. A platelet count of more than 50×109/L was achieved on day 210. The complete donor chimerism of marrow cells was confirmed by PCR on day 28. Regardless of the cardiac dysfunction, he showed an uneventful course during the pre- and post-grafting periods, including severe acute GVHD and VOD. Chronic GVHD was very mild. In May 2009, two years after BMT, echocardiography showed considerable improvement of LVEF (55%) (Table 2), although he was still insulin dependent. Serum ferritin levels were around 5,100 ng/mL; therefore, the iron-chelating agent was switched from deferoxamine mesilate to deferasirox (1,000 mg/day, orally).
Discussion One of the factors leading to the present successful BMT appears to be the RIC conditioning regimen employed to minimize cardiotoxicity. RIC may also have contributed to the avoidance of infectious events in this BMT, which frequently causes heart failure. Sufficient GVHD prophylaxis may have been another factor to avoid cardiac events. Therefore, the RIC conditioning regimen and sufficient GVHD prophylaxis may be important to perform HSCT when a patient has cardiac problems. There have been several reports regarding BMT for patients with transfusion-induced iron overload. Iron overload was generally improved after BMT (13-16). Improvement of the cardiac function after BMT was documented in 2 patients with severe aplastic anemia. One woman patient with severe cardiomyopathy survived for more than 5 years after allogeneic HSCT, and her cardiac function markedly improved during this period (17). Another woman patient with severe aplastic anemia complicated by severe transfusioncaused cardiomyopathy and diabetes mellitus survived for more than 500 days after BMT. Her LVEF recovered from 40 to 69% (18). From these reports and the present experience, patients with transfusion-induced cardiac dysfunction showing an LVEF value around 45% might be safely allotransplanted if other conditions are favorable. Regarding DBA patients who have received allogeneic HSCT, to our best knowledge, there has been no report of transplantation for patients with transfusion-induced cardiomyopathy (19-23).
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