Bone Marrow Transplantation (2007) 39, 311–313 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00
www.nature.com/bmt
LETTER TO THE EDITOR
Marrow transplantation for severe aplastic anemia with significant renal impairment Bone Marrow Transplantation (2007) 39, 311–313. doi:10.1038/sj.bmt.1705583; published online 22 January 2007 Bone marrow transplantation (BMT) from an HLAmatched sibling donor (MSD) is the treatment of choice in young patients with severe aplastic anemia (SAA) and matched unrelated donor transplant is an option for patients without a MSD after failing immunosuppressive therapy (IST). Anecdotal data in patients with multiple myeloma (MM) and renal insufficiency suggest the feasibility of allografting,1 the outcomes of BMT in patients with SAA with significant renal impairment are not known. Renal impairment resulting from drug toxicities may occur in patients with aplastic anemia (AA) treated with IST. The
Table 1
rarity of the disease, however, precludes the possibility of well-designed prospective studies in this patient population. We identified three cases of SAA with significant renal impairment from databases of 77 consecutive patients who underwent BMT for acquired AA between 1996 and 2005 at two tertiary care centers: St George’s Hospital, London, England (n ¼ 48) and Princess Margaret Hospital, Toronto, Canada (n ¼ 29). The characteristics and outcomes of these patients are summarized in Table 1. Two patients had endstage renal impairment secondary to immunoglobulin (Ig) A nephropathy before the diagnosis of AA (patients 1 and 3). The other patient (patient 2) developed cyclosporineinduced nephrotoxicity related to prior IST. Patient 1 was transplanted before the introduction of minimally intensive conditioning (MIC) protocols at our
Characteristics and outcomes of SAA patients with renal impairment undergoing BMT
Characteristics
Patient 1
Patient 2
Patient 3
R/D age (years) R/D gender Etiology of AA Type of donor Severity of AA Cause of renal impairment
33/37 M/M Idiopathic MSD Very severe IgA nephropathy
40/49 F/F Allopurinol-induced MSD Very severe IgA nephropathy
Duration of renal impairment before BMT (years) CrCl at BMT (ml/min) Dialysis-dependent Therapies for AA before BMT
5 11 Yes None
Performance status at BMT (Karnofsky) Time from diagnosis of AA to BMT (months) Conditioning regimen (dosages reflect total dose)
40 3 CY 87.5 mg/kga ATG
GVHD prophylaxis Source of stem cells Days to neutrophil engraftment Chimerism studies Regimen-related toxicity (Bearman Criteria, JCO, 1998)
Cyclosporine BM 17 Not done Cardiac Gr.II Pulmonary Gr.III Severe Rhabdomyolysis None None D (+216 day) —
53/20 M/M Idiopathic MUD Severe CSA toxicity resulting from IST before BMT 1 43 No 1. ATG+CSA 2. ATG 3. Oxymetholone 80 34 Alemtuzumab 75 mg Flu 30 mg/day 4 dayb CY 300 mg/m2 4 day MMF BM 33 100% None
AGVHD CGVHD Outcome Performance status at current follow-up (Karnofsky)
None None A (+686 day) 100
9 20 No None
80 1 Alemtuzumab 60 mg Flu 30 mg/day 4 dayb CY 10 mg/KBW 4 day MMF BM 15 97% None
None None A (+385 day) 90
Abbreviations: A ¼ alive; aGVHD ¼ acute GVHD; cGVHD ¼ chronic GVHD; ATG ¼ antithymocyte globulin; BM ¼ bone marrow; BMT ¼ bone marrow transplantation; CrCl ¼ creatinine clearance; CSA ¼ cyclosporine; CY ¼ cyclophosphamide; D ¼ donor; D ¼ deceased; d ¼ days; F ¼ female; Flu ¼ fludarabine; Gr ¼ grade; GVHD ¼ graft-versus-host disease; IST ¼ immunosuppressive therapy; KBW ¼ kilograms of body weight; M ¼ male; MMF ¼ mycophenolate mofetil; MSD ¼ matched sibling donor; MUD ¼ matched unrelated donor; R ¼ recipient; SAA ¼ severe aplastic anemia. a Usual dose 200 mg/kg, reduced for CrCl. b Dose reduced by 50% for CrCl.
Letter to the Editor
312
institutes. The combination of cyclophosphamide (CY) and antithymocyte globulin (ATG) is a standard preparative regimen for AA.2 High-dose CY has been used successfully for autologous stem cell transplantation in MM with renal insufficiency, and in general, no dosage adjustment is suggested in the presence of renal failure.3 It has been shown that clearance of CY is decreased in patients with renal impairment, resulting in increased systemic drug exposure,4 and there have been case reports of fatal complications such as myopericarditis and prolonged myelosuppression.5 Therefore, we modified the CY dose for creatinine clearance. Despite these modifications, this patient experienced significant regimen related toxicity (RRT) and died of multiorgan failure 7 months post-transplant, including severe rhabdomyolysis of uncertain cause. We have previously reported the feasibility of successful donor engraftment in heavily pretreated patients with AA using a MIC regimen consisting of fludarabine, low-dose CY and alemtuzumab.6 On the basis of these observations, we chose a MIC regimen and used alemtuzumab in the conditioning protocol for patients 2 and 3. Fludarabine dose was adjusted to 50% according to the creatinine clearance. No dose modifications are necessary for alemtuzumab in the presence of renal impairment; therefore, we used the dose according to the institutional protocols. To avoid further damage to compromised renal function, we used mycophenolate mofetil alone for graft-versus-host disease (GVHD) prophylaxis. Calcineurin inhibitors are well known to cause direct acute and chronic nephrotoxicity. A recent retrospective study demonstrated that longterm use of calcineurin inhibitor is independently associated with the development of chronic kidney disease following non-myeloablative hematopoietic cell transplantation.7 Patients 2 and 3 did not develop any acute or chronic GVHD and were off all immunosuppressants by 12 and 9 months post-transplant, respectively. Patient 3 was also considered for renal transplantation from the same donor to take advantage of transplant tolerance. Unfortunately, her BMT donor was not deemed suitable for kidney donation owing to underlying hypertension. The patient has now started requiring regular dialysis support, 11 months post-transplant and 2 months after stopping all immunosuppressants. The therapeutic goal of marrow transplantation in AA is sustained donor engraftment with minimal risk of RRT and GVHD. These cases demonstrate that with appropriate modifications of the conditioning regimen such as use of a MIC regimen and a calcineurin-free GVHD prophylaxis, BMT is feasible in patients with SAA with significant renal impairment. We recognize that the intensity of the conditioning regimen may not be the only factor relating to the poor outcome of patient 1. He clearly had a more significant degree of renal impairment compared with patients 2 and 3, and was dialysis-dependent before transplantation. Such carefully selected patients may be candidates for combined kidney and marrow transplant approach as previously demonstrated by the Boston group.1 Hamaki et al.8 demonstrated a successful allogeneic stem cell transplant for AA in a patient with renal insufficiency secondary to Bone Marrow Transplantation
IgA nephropathy. The conditioning regimen consisted of ATG, melphalan 60 mg/m2 and total lymph node irradiation 4 Gy, and GVHD prophylaxis comprised cyclosporine and prednisolone. They demonstrated that the pharmacokinetic properties of melphalan were not altered on dialysis and concluded that this conditioning regimen may be another alternative to conventional CY and ATG in patients with renal impairment. Interestingly, two out of our three cases, as well as the only other case of BMT for SAA with renal impairment published in the literature, involve renal impairment secondary to IgA nephropathy. Is this a chance association or is there an underlying autoimmune phenomenon linking AA and IgA nephropathy? There has been some suggestion that IgA nephropathy may represent a stem-cell disorder, and BMT has been shown to reverse the pathology of the disease in murine models.9 On the basis of these observations, it was proposed that therapeutic effect of BMT may not only be related to donor cells replacing the recipient’s immune cells, but also replenishing the damaged glomerular cells.10 No improvement in renal function, however, was noted in our two patients with IgA nephropathy. Our cases suggest that BMT in SAA patients with significant renal impairment may be feasible with acceptable toxicity using a MIC regimen. A potent GVHD preventative effect of alemtuzumab enabled us to use a calcineurin-free GVHD prophylaxis regimen and prevent further damage to the compromised renal function. These patients should not be denied the option of BMT, if clinically indicated. A Gerrie1, J Marsh2, JH Lipton1, H Messner1 and V Gupta1 1 Blood and Marrow Transplant Program, Princess Margaret Hospital, Toronto, Ontario, Canada; 2 Division of Hematology, Department of Cellular and Molecular Sciences, St George’s Hospital and Medical School, London, UK E-mail:
[email protected]
References 1 Buhler LH, Spitzer TR, Sykes M, Sachs DH, Delmonico FL, Tolkoff- Rubin N et al. Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 2002; 74: 1405–1409. 2 Storb R, Blume KG, O’Donnell MR, Chauncey T, Forman SJ, Deeg HJ et al. Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. Biol Blood Marrow Transplant 2001; 7: 39–44. 3 Ballester OF, Tummala R, Janssen WE, Fields KK, Hiemenz JW, Goldstein SC et al. High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency. Bone Marrow Transplant 1997; 20: 653–656. 4 Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int 2002; 61: 1495–1501.
Letter to the Editor
313 5 Yamamoto R, Kanda Y, Matsuyama T, Oshima K, Nannya Y, Suguro M et al. Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure. Bone Marrow Transplant 2000; 26: 685–688. 6 Gupta V, Ball SE, Sage D, Ortin M, Freires M, Gordon-Smith EC et al. Marrow transplants from matched unrelated donors for aplastic anaemia using alemtuzumab, fludarabine and cyclophosphamide based conditioning. Bone Marrow Transplant 2005; 35: 467–471. 7 Weiss AS, Sandmaier BM, Storer B, Storb R, McSweeney PA, Parikh CR. Chronic kidney disease following non-myeloabla-
tive hematopoietic cell transplantation. Am J Transplant 2006; 6: 89–94. 8 Hamaki T, Katori H, Kami M, Yamato T, Yamakado H, Itoh T et al. Successful allogeneic blood stem cell transplantation for aplastic anemia in a patient with renal insufficiency requiring dialysis. Bone Marrow Transplant 2002; 30: 195–198. 9 Imasawa T, Nagasawa R, Utsunomiya Y, Kawamura T, Zhong Y, Makita N et al. Bone marrow transplantation attenuates murine IgA nephropathy: role of a stem cell disorder. Kidney Int 1999; 56: 1809–1817. 10 Imasawa T. Roles of bone marrow cells in glomerular diseases. Clin Exp Nephrol 2003; 7: 179–185.
Bone Marrow Transplantation
