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Avascular Necrosis of Bone Following Allogeneic Stem Cell Transplantation: MR Screening and Therapeutic Options

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Avascular Necrosis of Bone Following Allogeneic Stem Cell Transplantation: MR Screening and Therapeutic Options Bone Marrow Transplantation, (1998) 22, 565–569 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Avascular necrosis of bone following allogeneic stem cell transplantation: MR screening and therapeutic options A Wiesmann1, P Pereira2,PBo¨hm3, C Faul1, L Kanz1 and H Einsele1 1Department of Hematology and Oncology, 2Department of Diagnostic Radiology, 3Department of Orthopedics, University of Tu¨bingen, Germany Summary: chondral bone, whereas osteonecrosis of the metaphyseal or diaphyseal bone is commonly referred to as bone infarct.1 With improvement in long-term survival after allo- There are several causes of osteonecrosis such as trauma, geneic stem cell transplantation, late complications with benign and malignant hematologic diseases, radiation, significant morbidity are of increasing importance. We alcoholism, Gaucher’s disease, collagen disease and retrospectively analysed 272 recipients of an allogeneic decompression disease.2–9 Treatment with corticosteroids is stem cell transplant for the development of osteo- another risk factor in the pathogenesis of osteonecrosis as necrosis. The incidence among allograft recipients was first mentioned in 1950.10 Therefore, avascular necrosis is 6.3% (17/272) for the whole patient population, and a well-described complication after renal and cardiac trans- 11.8% (17/144) for long-term survivors. All patients plantation, especially in patients receiving high-dose ster- were treated with high-dose prednisolone, 16 for severe oids for graft rejection.10–17 In 1987, Atkinson et al18 first acute or extensive chronic graft-versus-host disease described a 10% incidence of osteonecrosis after allogeneic (GVHD) and one patient for graft rejection. The mean bone marrow transplantation from HLA-identical sibling age at time of diagnosis was 33 years (range 16–45) and donors. Since then, few studies have addressed this late the mean time from transplant to diagnosis of complication.19–23 osteonecrosis was 13 months. Osteonecrosis was diag- We retrospectively analyzed 17 out of 272 patients after nosed by magnetic resonance (MR) imaging, which allogeneic stem cell transplantation who developed an avas- allows early detection of osteonecrosis and assessment cular necrosis of the bone diagnosed by clinical symptoms of stage. At the time of diagnosis, eight patients had and confirmed by MR imaging. stage I, three patients stage II, three patients stage III and three patients stage IV osteonecrosis according to MR criteria. All but one patient had involvement of the Patients and methods femoral head. The median total dosage of prednisolone at the time of diagnosis was 189 mg/kg (single manifes- Patients tation 150 mg/kg; multiple manifestations 313 mg/kg) Seventeen (eight female, nine male) out of 272 patients with a total range of 13–555 mg/kg. Six patients were developed avascular necrosis after allogeneic stem cell treated by conservative means, 77 patients underwent transplantation (nine patients with CML, three AML, three surgery (three core decompression, eight joint ALL, two SAA). Eleven patients had undergone allogeneic replacement). MR screening of patients receiving high- transplantation from a matched sibling donor and six dose steroids might help to detect osteonecrosis at an patients from a matched unrelated donor between 1987 and early stage and thus prevent progression by early inter- 1996 (see Table 1). vention, for example, by core decompression. Keywords: avascular necrosis; allogeneic stem cell trans- plantation; magnetic resonance-steroids Conditioning regimens Eight patients received TBI (12 Gy) and cyclophosphamide 60 mg/kg once daily for 2 days (total dose 120 mg/kg), with two patients receiving an additional dose of VP-16 With improvement in long-term survival after allogeneic (40 mg/kg). Five patients received busulfan 4 mg/kg p.o. in bone marrow transplantation, late complications with sig- four divided doses daily for 4 days (total dose 16 mg/kg) nificant morbidity are of increasing importance. in addition to intravenous cyclophosphamide (120 mg/kg). Osteonecrosis is a general term applied to conditions One patient was treated with cyclophosphamide resulting in necrosis of bone and marrow elements. Avascu- (120 mg/kg) and ALG (Merieux, Leimen, Germany), and lar necrosis indicates involvement of the epiphysis or sub- one patient with cyclophosphamide (4 × 50 mg/kg). Supportive care Correspondence: Dr H Einsele, Department of Hematology and Oncology, University of Tu¨bingen, Otfried Mu¨ller Str. 10, 72076 Tu¨bingen, Germany Patients were admitted to the hematologic intensive care Received 9 March 1998; accepted 20 April 1998 unit and nursed in laminar air flow units until discharge. Avascular necrosis after allogeneic stem cell transplant A Wiesmann et al 566 Table 1 Characteristics of 17 patients developing avascular necrosis of bone after allogeneic stem cell transplantation. Patient Sex Age Diagnosis Conditioning Donor GVHD GVHD Max. pred. Total pred. No. regimen prophylaxis stage (mg/kg/day) (mg/kg) 1 F 20 ALL TBI/VP-16/Cy related CsA II 4.4 58 2 M 16 SAA Cy/ALG related CsA (rejection) 6 222 3 M 19 ALL TBI/Cy related CsA II 10 328 4 M 33 CML TBI/Cy unrelated CsA/MTX III 23 281 5 F 19 SAA Cy unrelated CsA IV 27 408 6 M 41 CML Bu/Cy related CsA/MTX II 5 146 7 F 45 CML Bu/Cy unrelated CsA/MTX II 20 181 8 F 45 AML TBI/Cy related CsA/MTX II 2 197 9 F 33 CML Bu/Cy related CsA II 2 13 10 M 35 CML TBI/Cy unrelated CsA/MTX II 15 555 11 F 32 AML TBI/VP-16/Cy related CsA II 10 404 12 M 40 CML TBI/Cy unrelated CsA/MTX II 7.5 518 13 F 27 CML TBI/Cy related CsA II 5.0 285 14 M 21 ALL TBI/Cy related CsA II 2.5 120 15 M 22 AML Bu/Cy related CsA II 2 45 16 F 26 CML TBI/Cy unrelated CsA/MTX I 5 155 17 M 26 CML Bu/Cy related CsA/MTX II 2 44 Max. pred. = maximal prednisolone dose. Table 2 Characteristics of avascular bone necrosis after allogeneic stem cell transplantation Patient Day of Stage of AVN Follow-up Localisation No. of Therapy Follow-up No. diagnosis (progression) time of involved (months after of AVN AVN joints diagnosis) (months) 1 +135 I(III) 36 hip 1 conservative alive 2 +284 I(IV) 24 hip 2 decompression (9) alive 3 +304 III/IV 84 hip 1 arthroplasty (36) alive 4 +340 III/IV 48 hip 1 arthroplasty (36) died, 4.5 years after Tx (pneumonia) 5 +436 III 84 hip, humerus 3 conservative alive 6 +402 II 12 hip 1 conservative alive 7 +95 II 15 hip 2 conservative alive 8 +345 III 12 hip 1 arthroplasty (5) alive 9 +289 III 9 hip 1 conservative alive 10 +865 I(II) 18 hip 2 decompression (3) alive 11 +419 I(III) 24 hip, humerus 3 decompression (6) alive 12 +813 II 36 hip 1 arthroplasty (2) died 5 years after Tx (sepsis) 13 +372 I(IV) 106 hip 1 arthroplasty (42) alive 14 +309 I(III) 66 hip, knee 3 conservative alive 15 +457 IV 12 hip 1 arthroplasty (12) alive 16 +783 I 10 hip 1 conservative died 3 years after Tx (sepsis) 17 +542 I(III) 24 hip 2 conservative alive AVN = avascular necrosis; Tx = transplantation. Supportive infusion therapy (parenteral feeding, vitamins) performed to 10 and finally 20 or more mg/kg/day. Taper- was administered through a tunneled Hickman catheter. ing of the steroid dosage was initiated when clinical signs Patients received prophylactic antibiotics, antifungal and and symptoms of acute GVHD improved. antiviral drugs as well as passive immunoglobulin prophy- laxis (0.25 mg/kg every 3 weeks). Diagnosis and staging of osteonecrosis GVHD prophylaxis and therapy All patients received cyclosporin from day −1 until at least Symptomatic patients (pain, stiffness etc) were diagnosed day +100 or longer, eight patients additionally received a by conventional radiography and MR imaging. Osteo- short course of methotrexate (15 mg/m2 day 1, 10 mg/m2 necrosis was classified according to MR criteria: stage I: days 3 and 6). Acute graft-versus-host disease grade II or non-homogenous loss in signal intensity in T1; II: wedge- more was treated with 2 mg/kg/day prednisolone. In non- shaped crescent sign; III: crescent sign sequestra/cortical responding patients, the dose of prednisolone was increased collapse; IV: degenerative changes with narrowed joint to 5 mg/kg/day. If necessary, a further dose escalation was space.24–27 Avascular necrosis after allogeneic stem cell transplant A Wiesmann et al 567 Results Seventeen out of 272 recipients of an allogeneic marrow transplant developed avascular necrosis as a long-term complication. The incidence was 6.3% among all patients and 11.8% (17/144) for long-term survivors. All 17 patients received prednisolone treatment post-transplant; 16 patients for treatment of acute severe GVHD (one patient grade I, 13 patients grade II, one patient grade III and one patient grade IV) and one patient for graft rejection. The average maximum prednisolone dose was 13 mg/kg/day with a range of 2–27 mg/kg/day. At the time of diagnosis of osteonecrosis the average age was 33 years (range 16–45 years) and the mean time from transplant to manifestation of osteonecrosis was 13 months (Table 2). On the appear- ance of clinical symptoms such as pain and stiffness, only 8/17 patients were diagnosed as having stage I osteonecrosis according to MR criteria (Figure 1), all other patients had already progressed to more advanced stages: three patients to stage II, three to stage III and three to stage III/IV. All but one patient developed osteonecrosis of the femoral head, 10 patients had unilateral and four patients bilateral manifestations.
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