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Allogenic stem cell transplantation for nonmalignant disorders using matched unrelated donors
Biology of Blood and Marrow Transplantation 10:877-882 (2004) 䊚 2004 American Society for Blood and Marrow Transplantation 1083-8791/04/1012-0007$30.00/0 doi:10.1016/j.bbmt.2004.08.002
Allogenic Stem Cell Transplantation for Nonmalignant Disorders Using Matched Unrelated Donors Petter Svenberg,1,2 Mats Remberger,1,3 Johan Svennilson,1,2 Jonas Mattsson,1,3 Katarina Leblanc,1,3,4 Britt Gustafsson,2 Johan Aschan,3,4 Lisbeth Barkholt,1 Jacek Winiarski,2 Per Ljungman,4 Olle Ringdén1,3 1
Centre for Allogenic Stem Cell Transplantation; 2Department of Paediatrics; 3Department of Clinical Immunology; and 4Department of Haematology, Karolinska University Hospital, Huddinge, Stockholm, Sweden
Correspondence and reprint requests: Petter Svenberg, MD, Centre for Allogenic Stem Cell Transplantation, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden (e-mail: [email protected]). Received June 10, 2004; accepted August 18, 2004
ABSTRACT We here report 25 patients with nonmalignant disorders, ie, severe aplastic anemia (SAA, n ⴝ 12) or inborn errors of metabolism (IEM, n ⴝ 13), who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated high-resolution typed HLA-A, -B, and -DR1 identical donors. One patient had an HLA-B subtype-mismatched donor. Conditioning for SAA mainly consisted of cyclophosphamide and total body irradiation, and that for IEM consisted of busulfan and cyclophosphamide. All patients received antithymocyte globulin during conditioning. After HSCT, they were given cyclosporine combined with methotrexate for immunosuppression. Two patients rejected their grafts: 1 died of pneumonia, and the other was successfully regrafted. The cumulative incidence of acute graft-versus-host disease grades II to IV was 24%, whereas chronic graft-versus-host disease occurred in 21%. The 5-year survival rates were 83% in the SAA group and 85% in those with IEM. We conclude that HSCT with HLA-A, -B, and -DR1 genomically matched unrelated donors in combination with antithymocyte globulin in the conditioning regimen gives encouraging results in patients with SAA or IEM. © 2004 American Society for Blood and Marrow Transplantation
KEY WORDS Nonmalignant disorders lated donors
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Allogeneic hematopoietic stem cell transplantation
INTRODUCTION During the last 3 decades, hematopoietic stem cell transplantation (HSCT) has emerged as a curative therapeutic approach in an increasing number of lethal disorders affecting the hematopoietic system [1-5]. HSCT with HLA-identical sibling donors is also the treatment of choice for some rare congenital metabolic and nonmalignant lymphohematopoietic disorders [3-5]. However, because only one third of the patients have a genetically HLA-identical sibling, the use of HLA-matched unrelated donors (MUD) has increased over the last 10 years [6-11]. Patients with severe aplastic anemia (SAA) are treated with immunosuppressive therapy by using antithymocyte globulin (ATG) and cyclosporine (CsA) if an HLAidentical sibling donor is not available. However, if the patients do not respond to this treatment, then they may be given HSCT by using a MUD [5,9]. Patients
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Matched unre-
undergoing HSCT with MUD for SAA are therefore a selected high-risk group who have not been successfully treated. In patients with certain inborn errors of metabolism (IEM), HSCT is often the only possible cure [3,4]. Consequently, HSCT from an unrelated donor is also considered desirable in the absence of a well-matched related donor [12]. We report our experience with MUD-HSCT in 25 patients with lifethreatening nonmalignant disorders.
PATIENTS AND METHODS Patients
Between 1993 and 2003, 25 patients with nonmalignant disorders underwent HSCT with HLA-A–, HLA-B–, and HLA-DR– compatible MUDs, except 1, who had an HLA-B subtype-mismatched donor. All received ATG during conditioning. Eleven patients 877
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had SAA, and 1 had Fanconi anemia. Thirteen patients had IEM: mucopolysaccharidosis (MPS, n ⫽ 4), including 3 with Hurler disease (MPS type 1) and 1 with Sanfilippo syndrome (MPS type III); severe combined immune deficiency (SCID; n ⫽ 1) and hemophagocytic lymphohistiocytosis (HLH, n ⫽ 4); and leukodystrophy (n ⫽ 4), including 2 patients with metachromatic leukodystrophy and 2 with adrenoleukodystrophy (ALD). At the time of transplantation, their ages ranged from 0 to 39 years, with a median age of 6 years. Fourteen were male. The characteristics of the patients with SAA and of those with IEM are shown in Tables 1 and 2, respectively. Donors
The donors were procured from various national donor registries. All patients were recently retrospectively retyped with polymerase chain reaction/ sequence-specific priming high-resolution typing for HLA class I and II antigens [13,14]. All donors were fully HLA-A, -B, and -DR1 matched, except 1 (the donor for patient 644), who had an HLA-B subtype mismatch. Twenty patients received bone marrow. Five patients were given peripheral blood progenitor cells from donors treated with granulocyte colonystimulating factor (G-CSF) [15]. The mean nucleated cell dose, corrected for donor peripheral blood leukocytes, was 3.6 ⫻ 108/kg (range, 0.6-59.3 ⫻ 108/kg). Fifteen of the donors were male, and 10 were female. Their ages ranged from 21 to 47 years, with a median age of 40 years. Conditioning
One patient with SAA was conditioned with cyclophosphamide (Cy) 50 mg/kg for 4 consecutive days, followed by 2 Gy of total lymph node irradiation (TLI) on 3 consecutive days. The subsequent patients with SAA received conditioning that consisted of Cy 60 mg/kg/d for 2 consecutive days in combination with fractionated total body irradiation (TBI)—3 Gy for 2 days (n ⫽ 6), a single dose of 10 Gy of TBI (9 Gy to lungs; n ⫽ 3), a single dose of 7.5 Gy of TBI (dose rate, 26 cGy/min); 2 Gy of TLI for 4 days (n ⫽ 1); and busulfan 4 mg/kg/d for 4 days (n ⫽ 1) [16]. Five of the patients given fractionated TBI were also given fludarabine 30 mg/m2/d for 3 days. The patient with Fanconi anemia was conditioned with fludarabine 30 mg/m2/d for 5 days followed by Cy 10 mg/kg/d for 2 days. Twelve patients with IEM were given busulfan 4 mg/kg/d for 4 days followed by 4 days of Cy 2 g/m2/d [17]. One patient was given Cy 60 mg/d for 2 days and fractionated TBI 3 Gy for 4 days. Four patients with HLH were also given etoposide 30 mg/kg. To prevent hemorrhagic cystitis caused by Cy, intravenous (IV) fluids 3 L/m2/d were given, together with mesna 6 878
times in 24 hours at 20% of the Cy dose (Tables 1 and 2). All patients received rabbit ATG (Thymoglobulin; IMTIX, Sangstat-Lyon, France); the total dose ranged between 2.9 and 12.8 mg/kg, with a median of 9.0 mg/kg [18]. Prophylaxis and Treatment of Graft-versus-Host Disease
Eighteen patients received 4 doses of methotrexate (MTX) combined with CsA [19]. MTX was given in a dose of 15 mg/m2 IV on day ⫹1 and 10 mg/m2 on days 3, 6, and 11, according to the Seattle protocol [19]. CsA was started on the day before transplantation with an IV dose of 2.5 to 5 mg/kg ⫻ 2, followed by 1.5 to 3.5 mg/kg ⫻ 2 from the day of transplantation. The higher dose was given to smaller children. On day ⫹1, or as soon as the patient could take CsA orally, 6.25 to 10 mg/kg ⫻ 2 was given. This regimen was maintained for 12 to 24 months after HSCT, and the dose was adjusted according to renal function and serum CsA concentrations. During the first month, we aimed at a CsA trough concentration in whole blood of 200 to 300 ng/mL. Four patients received CsA as described previously and received mycophenolate mofetil 15 mg/kg twice daily from day 0 to day ⫹28 after the stem cell transplantation instead of MTX [20]. Three patients (patients 954, 955, and 971) received tacrolimus 4 mg ⫻ 2 from day ⫺3 and sirolimus 6 mg ⫻ 2. On day ⫺2, the dose of sirolimus was decreased to 2 mg ⫻ 2. Thereafter, both the sirolimus and tacrolimus dosages were adjusted according to plasma levels. Tacrolimus was given for 18 months in the absence of graft-versus-host disease (GVHD), and the dose of sirolimus was tapered after 3 months. At the first sign of grade I acute GVHD, we gave prednisolone 2 mg/kg/d to adults and 2 to 3 mg/kg/d to children for 1 week [16]. Thereafter, the dose was reduced, depending on the response. Some patients with severe GVHD also received methylprednisolone IV or psoralen and UV light. Chronic GVHD was classified as limited or extensive [21] and was treated with prednisolone and CsA [22]. Supportive Care
All patients were kept in reverse isolation until the absolute neutrophil count (ANC) reached 0.2 ⫻ 109/L for 2 consecutive days [16]. Four patients with SAA and 8 with IEM were given G-CSF 0.3 mg/d IV from day ⫹10 after HSCT until ANC reached ⬎0.5 ⫻ 109/L for 2 consecutive days. Details regarding supportive care have been reported elsewhere [15-18]. Statistics
Analysis was performed as of May 3, 2004. The actuarial probabilities of survival, acute GVHD grades II to IV, and chronic GVHD were calculated by the
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Table 1. Severe Aplastic Anemia: Patient and Donor Characteristics
Patient No.
Diagnosis
CMV Serology
Recipient Age (y)/Sex
Donor Age (y)/Sex
Cell Dose (MNCⴛ108/kg)
Conditioning
Donor
Recipient
G-CSF 5g/kg/d
Acute GVHD Grade
Chronic GVHD Grade
Outcome
249 418 441
SAA SAA SAA
39/F 1/F 12/F
42/F 40/M 36/F
2.5 4.6 3.7
Bu ⴙ Cy 10 Gy TBI ⴙ Cy Cy ⴙ TLI
ⴙ ⴙ ⴚ
ⴙ ⴙ ⴙ
N N Y
I I II
0 0 0
485
SAA
19/F
44/M
1.3
ⴚ
ⴙ
Y
0
Mild
520 731 887 909 919 955 971 954
SAA SAA SAA SAA SAA SAA SAA FA
30/M 9/F 37/M 6/F 39/M 38/F 10/F 8/M
41/F 42/M 39/M 21/M 43/M 43/F 40/F 41/F
1.5 4.3 0.6 8.3 8.3 8 8 8.3
7.5 Gy TBI ⴙ Cy ⴙ TLI 10 Gy TB1 ⴙ Cy fTBI ⴙ Cy fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu Cy ⴙ Flu
A&W A&W Dead, Evans syndrome A&W
ⴚ ⴚ ⴚ ⴚ ⴙ ⴙ ⴙ ⴚ
ⴙ ⴚ ⴙ ⴙ ⴙ ⴙ ⴙ ⴙ
Y Y N N N N N N
I I 0 I 0 0 0 I
Mild 0 0 0 0 0 0 0
Dead, ARDS A&W A&W A&W A&W A&W A&W A&W
MNC indicates mononuclear cells; Bu, busulfan; fTBI, fractionated total body irradiation; Flu, fludarabine; FA, Fanconi anemia; A & W, alive and well.
Table 2. Inborn Errors of Metabolism: Patient and Donor Characteristics
Patient No.
Diagnosis ALD MLD MPS III FHLH
644 707 750 784 793 848 855 897 931
FHLH ALD FHLH MPS I SCID MLD MPS I MPS I FHLH
Donor Age (y)/Sex
CMV Serology
Cell Dose (MNCⴛ108/kg)
Conditioning ⴙ ⴙ ⴙ ⴙ
Donor
Recipient
G-CSF 5g/kg/d
Acute GVHD Grade
Chronic GVHD Grade
6/M 1/M 4/M 1/F
43/F 35/M 37/F 25/F
2.9 7.7 2.1 18.1
Bu Bu Bu Bu
Cy Cy Cy Cy ⴙ VP-16
ⴙ ⴚ ⴙ ⴚ
ⴚ ⴚ ⴙ ⴚ
N N N Y
0 II II I
0 0 0 NE
1/M 39/M <1/M 1.5/M 0.5/M 18/F 1/M 1/F 0.5/M
42/M 28/M 47/M 28/F 41/M 31/M 30/M 32/M 23/M
5.7 1.6 59.3* 25.8 43 1.46 18.5 2.9 5.7
Bu ⴙ Cy ⴙ VP-16 fTBI ⴙ Cy Bu ⴙ Cy ⴙ VP-16 Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy ⴙ VP-16
ⴚ ⴚ ⴚ ⴚ ⴚ ⴚ ⴚ ⴙ ⴙ
ⴚ ⴚ ⴙ ⴚ ⴚ ⴚ ⴚ ⴚ ⴙ
Y Y Y Y Y Y Y N N
II I II II 0 0 0 I I
0 Mild 0 0 0 Mild 0 0 Mild
Outcome A&W A&W Dead, pneumonia Dead, VOD, CMV pneumonia A&W A&W A&W A&W A&W A&W A&W A&W A&W
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ALD indicates adrenoleukodystrophy; MLD, metachromatic leukodystrophy; MPS I, mucopolysaccharoidosis type 1 (Hurler disease), MPS III, Sanfilippo syndrome; FHLH, familial hemophagocytic lymphohistiocytosis, SCID, severe combined immune deficiency; Bu, busulfan; VP-16, etoposide; fTBI, fractionated total body irradiation; VOD, veno-occlusive disease; A & W, alive and well; NE, not evaluable. *Patients who received a PBSC graft.
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393 412 422 525
Recipient Age (y)/Sex
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Kaplan-Meier method, taking censored data into account, and were compared by using the log-rank test. The Mann-Whitney U test was used for comparing the day of engraftment. RESULTS Engraftment and Transfusions
Two patients (patients 422 and 707) rejected their grafts. Patient 422, a patient with Sanfilippo A disease, died of pneumonia on day 175 after the transplantation. Patient 707 underwent a second transplantation with the same donor after conditioning with fludarabine 30 mg/m2/d for 5 days and ATG at a total dose of 3.8 mg/kg. This patient is alive and a full donor chimera 2 years after the retransplantation. An ANC ⬎0.5 ⫻ 109/L was reached at a median of 19 days (range, 11-26 days) for the bone marrow patients. In those receiving peripheral blood stem cells (PBSC), the median was 11 days (range, 10-27 days; P ⫽ .18). Patients given bone marrow reached a platelet level of 30 ⫻ 109/L at a median of 24 days (range, 12-150 days), whereas those given PBSCs had platelet engraftment at a median of 12 days (range, 8-41 days; not significant; P ⫽ .3). Patients receiving G-CSF had a faster neutrophil engraftment: median, day 16 (range, 10-27 days) versus day 19 (range, 14-35 days; P ⫽ .07). The SAA patients received a median of 6 erythrocyte concentrates (range, 2-12) in the first 2 months and a median of 13 platelet transfusions (range, 3-21). In the patients with IEM, the corresponding figures were 4.5 (range, 0-17) and 7 (range, 0-29; not significant).
Figure 1. Cumulative probability of survival after HSCT in patients with nonmalignant disorders—IEM (inborn errors of metabolism) and SAA (severe aplastic anaemia)— by using matched unrelated donors.
GVHD grade II. Of the 4 patients who received mycophenolate mofetil plus CsA as prophylaxis, 1 developed grade I acute GVHD, and another developed a mild form of chronic GVHD. The cumulative incidence of acute grade II to IV GVHD was 24% in all patients. Six of 13 children (⬍18 years) developed grades II to IV acute GVHD, but none of the adults did (P ⫽ .05). Of those who developed acute grade II GVHD, 4 of the 6 had received G-CSF [23]. None of the children, but 4 of the 6 adults, developed chronic GVHD (P ⫽ .02). The cumulative incidence was 21%; 24 of 25 patients were valuable for chronic GVHD. None of the patients who were given a PBSC graft developed chronic GVHD. No patient died of GVHD (Tables 1 and 2).
Infections
Fifteen patients had bacteremia: 9 caused by coagulase-negative staphylococci, 3 by ␣-streptococci, and 1 by Staphylococcus aureus. Another patient (patient 848) had bacteremia caused by Escherichia coli and 1 (patient 887) by Citrobacter species. Cytomegalovirus (CMV) DNA was detected by polymerase chain reaction in the blood of 8 patients (42%). One patient with HLH (patient 525) died of interstitial CMV pneumonia and veno-occlusive liver disease on day 36 after transplantation. Three patients, 2 with reactivated herpes simplex virus (patients 249 and 525) and 1 with varicella-zoster virus (patient 731), recuperated well after treatment. Patient 520, with SAA, developed acute respiratory distress syndrome (ARDS) and died of adenovirus type II positive pneumonia on day 241 after transplantation. Graft-versus-Host Disease
Nine patients had no signs of acute GVHD. Ten patients had acute GVHD grade I, and 6 had acute 880
Survival Rates
The overall 5-year survival rate was 84% (Figure 1). The median follow-up of the surviving patients was 3.6 years (range, 0.8-14.5 years). The probability of survival was 83% in the SAA group and 85% in the IEM group. Two of the SAA patients died, 1 of Evans syndrome (patient 441) and 1 of ARDS (patient 520; Table 1). Among the patients with IEM, there were 2 deaths: 1 patient with Sanfilippo syndrome (patient 422) who died of pneumonia and 1 patient with HLH (patient 525) who died of CMV pneumonia and venoocclusive disease. The remaining 21 patients are alive and well (Tables 1 and 2). DISCUSSION Our aim was to evaluate the outcome of HSCT in patients with nonmalignant disease who had received closely matched unrelated grafts at Huddinge University Hospital, of whom 12 had SAA and 13 had IEM.
MUD-HSCT for Nonmalignant Disorders
Two of the 25 patients rejected the transplant. It is noteworthy that no rejection occurred in the SAA patients, although this group is prone to rejection [2,10]. The patients in the SAA group were presumably a high-risk group, having experienced treatment failure with immunotherapy and having received numerous transfusions before transplantation [9]. To avoid rejection in these patients, no patient had been given the standard regimen with Cy alone. In 1 patient, Cy was combined with TLI, and in another patient, Cy was combined with busulfan. However, in all other patients, Cy was combined with TBI with or without fludarabine. Various regimens have thus been used, but we recommend fludarabine, Cy, and fractionated TBI because of its lower toxicity. The use of ATG during conditioning may also have prevented rejection in these patients [18]. The engraftment of neutrophils and platelets was faster in PBSC patients than in those receiving bone marrow, although the difference was not statistically significant. In larger studies, PBSC grafts are associated with faster engraftments of neutrophils and platelets, probably because of the larger number of CD34⫹ cells in these grafts [15]. The times to engraftment were similar to those reported in comparable patients with leukemia [16]. The incidence of infections in this study also resembled that in patients with malignant diseases— 58% with bacterial septicemia and 42% with reactivation of CMV [24]. The latter occurred mainly in the SAA patients, of whom 6 of 7 were seropositive before the transplantation. One death due to CMV occurred in a patient with HLH, and 2 other deaths were caused by infections: 1 from ARDS (adenovirus type II) and 1 from pneumonia. ATG was primarily given to reduce the risk of graft rejection, but this also probably played a role in the low incidence of acute GVHD. None of the patients developed GVHD grade III or IV. We have previously shown, using unrelated donors, that ATG reduces the risk of acute GVHD after HSCT [25]. More children than adults developed moderate acute GVHD (P ⫽ .05). Despite the correlation between acute and chronic GVHD [26,27], none of them developed chronic GVHD, whereas 4 of 6 adults did. This would suggest that age may be more important than acute GVHD as a risk factor for chronic GVHD in this small patient population. The prolonged immunosuppression— up to 2 years—may also be a reason for the low incidence of chronic GVHD. In this study, only 5 patients received PBSC grafts. None developed chronic GVHD. However, in larger studies, there is a strong association between PBSC grafts, compared with bone marrow grafts, and chronic GVHD [28]. Chronic GVHD is not desirable in patients with nonmalignant diseases, and, therefore, bone marrow grafts may be preferable.
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We found an encouraging 5-year survival of 84% among these 25 patients. This indicates that an HLA-A, -B and -DR1 MUD is an acceptable alternative for patients with nonmalignant disorders who lack a matched sibling donor. The circumstance that all cases but 1 were genomically matched for the major HLA antigens is probably of major importance for the outcome [7]. Although only 12 SAA patients were included, a 5-year survival of 83% is promising in comparison with other (albeit larger) studies [9,10,29]. Our data suggest that a well-matched unrelated donor could be considered earlier in the course of the disease in such patients, because prolonged immunosuppressive treatment increases the risk for immunization, subsequent rejection, and infections. In the patients with IEM, the 5-year survival was 85%, which is also encouraging, although it is lower than with HLAidentical sibling donors [17]. However, in these patients, there is no other curative treatment. Therefore, HSCT is considered as soon as the diagnosis is made and a suitable donor can be found [3,4,12]. It should be pointed out that although the 5-year survival is favorable, this study does not question previous recommendations concerning the optimal time of transplantation. In those with life-threatening nonmalignant disorders who do not have an HLA-identical sibling, an HSCT with a well-matched unrelated donor seems to be the treatment of choice. If such a donor is not available, then an alternative could be a cord blood transplant or a haploidentical related donor transplant [30-32]. However, with a cord blood transplant, engraftment is delayed, and the risk of rejection may be higher, especially if the cell dose is low. With haploidentical related donors, T-cell depletion is necessary to minimize the risk of GVHD. With this approach, rejection and immunoincompetence may be a problem, with a subsequent increased risk of posttransplantation infections. In conclusion, our study suggests that patients with nonmalignant disorders can successfully undergo transplantation with an unrelated graft if the donor is closely HLA-A, -B, and -DR1 matched with highresolution techniques and if ATG is included in the conditioning regimen. Under these circumstances, outcome is similar to that in HLA-identical sibling transplantations.
ACKNOWLEDGMENTS This study was supported by grants from the Swedish Cancer Society (007-B02-16XAC), The Children’s Cancer Foundation (2002/074), The Swedish Research Council (K2003-32X-05971-23A), The Cancer Society in Stockholm (02:181), The Tobias Foundation, and The Karolinska Institute. 881
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Allogenic Stem Cell Transplantation for Nonmalignant Disorders Using Matched Unrelated Donors Petter Svenberg,1,2 Mats Remberger,1,3 Johan Svennilson,1,2 Jonas Mattsson,1,3 Katarina Leblanc,1,3,4 Britt Gustafsson,2 Johan Aschan,3,4 Lisbeth Barkholt,1 Jacek Winiarski,2 Per Ljungman,4 Olle Ringdén1,3 1
Centre for Allogenic Stem Cell Transplantation; 2Department of Paediatrics; 3Department of Clinical Immunology; and 4Department of Haematology, Karolinska University Hospital, Huddinge, Stockholm, Sweden
Correspondence and reprint requests: Petter Svenberg, MD, Centre for Allogenic Stem Cell Transplantation, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden (e-mail: [email protected]). Received June 10, 2004; accepted August 18, 2004
ABSTRACT We here report 25 patients with nonmalignant disorders, ie, severe aplastic anemia (SAA, n ⴝ 12) or inborn errors of metabolism (IEM, n ⴝ 13), who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated high-resolution typed HLA-A, -B, and -DR1 identical donors. One patient had an HLA-B subtype-mismatched donor. Conditioning for SAA mainly consisted of cyclophosphamide and total body irradiation, and that for IEM consisted of busulfan and cyclophosphamide. All patients received antithymocyte globulin during conditioning. After HSCT, they were given cyclosporine combined with methotrexate for immunosuppression. Two patients rejected their grafts: 1 died of pneumonia, and the other was successfully regrafted. The cumulative incidence of acute graft-versus-host disease grades II to IV was 24%, whereas chronic graft-versus-host disease occurred in 21%. The 5-year survival rates were 83% in the SAA group and 85% in those with IEM. We conclude that HSCT with HLA-A, -B, and -DR1 genomically matched unrelated donors in combination with antithymocyte globulin in the conditioning regimen gives encouraging results in patients with SAA or IEM. © 2004 American Society for Blood and Marrow Transplantation
KEY WORDS Nonmalignant disorders lated donors
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Allogeneic hematopoietic stem cell transplantation
INTRODUCTION During the last 3 decades, hematopoietic stem cell transplantation (HSCT) has emerged as a curative therapeutic approach in an increasing number of lethal disorders affecting the hematopoietic system [1-5]. HSCT with HLA-identical sibling donors is also the treatment of choice for some rare congenital metabolic and nonmalignant lymphohematopoietic disorders [3-5]. However, because only one third of the patients have a genetically HLA-identical sibling, the use of HLA-matched unrelated donors (MUD) has increased over the last 10 years [6-11]. Patients with severe aplastic anemia (SAA) are treated with immunosuppressive therapy by using antithymocyte globulin (ATG) and cyclosporine (CsA) if an HLAidentical sibling donor is not available. However, if the patients do not respond to this treatment, then they may be given HSCT by using a MUD [5,9]. Patients
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Matched unre-
undergoing HSCT with MUD for SAA are therefore a selected high-risk group who have not been successfully treated. In patients with certain inborn errors of metabolism (IEM), HSCT is often the only possible cure [3,4]. Consequently, HSCT from an unrelated donor is also considered desirable in the absence of a well-matched related donor [12]. We report our experience with MUD-HSCT in 25 patients with lifethreatening nonmalignant disorders.
PATIENTS AND METHODS Patients
Between 1993 and 2003, 25 patients with nonmalignant disorders underwent HSCT with HLA-A–, HLA-B–, and HLA-DR– compatible MUDs, except 1, who had an HLA-B subtype-mismatched donor. All received ATG during conditioning. Eleven patients 877
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had SAA, and 1 had Fanconi anemia. Thirteen patients had IEM: mucopolysaccharidosis (MPS, n ⫽ 4), including 3 with Hurler disease (MPS type 1) and 1 with Sanfilippo syndrome (MPS type III); severe combined immune deficiency (SCID; n ⫽ 1) and hemophagocytic lymphohistiocytosis (HLH, n ⫽ 4); and leukodystrophy (n ⫽ 4), including 2 patients with metachromatic leukodystrophy and 2 with adrenoleukodystrophy (ALD). At the time of transplantation, their ages ranged from 0 to 39 years, with a median age of 6 years. Fourteen were male. The characteristics of the patients with SAA and of those with IEM are shown in Tables 1 and 2, respectively. Donors
The donors were procured from various national donor registries. All patients were recently retrospectively retyped with polymerase chain reaction/ sequence-specific priming high-resolution typing for HLA class I and II antigens [13,14]. All donors were fully HLA-A, -B, and -DR1 matched, except 1 (the donor for patient 644), who had an HLA-B subtype mismatch. Twenty patients received bone marrow. Five patients were given peripheral blood progenitor cells from donors treated with granulocyte colonystimulating factor (G-CSF) [15]. The mean nucleated cell dose, corrected for donor peripheral blood leukocytes, was 3.6 ⫻ 108/kg (range, 0.6-59.3 ⫻ 108/kg). Fifteen of the donors were male, and 10 were female. Their ages ranged from 21 to 47 years, with a median age of 40 years. Conditioning
One patient with SAA was conditioned with cyclophosphamide (Cy) 50 mg/kg for 4 consecutive days, followed by 2 Gy of total lymph node irradiation (TLI) on 3 consecutive days. The subsequent patients with SAA received conditioning that consisted of Cy 60 mg/kg/d for 2 consecutive days in combination with fractionated total body irradiation (TBI)—3 Gy for 2 days (n ⫽ 6), a single dose of 10 Gy of TBI (9 Gy to lungs; n ⫽ 3), a single dose of 7.5 Gy of TBI (dose rate, 26 cGy/min); 2 Gy of TLI for 4 days (n ⫽ 1); and busulfan 4 mg/kg/d for 4 days (n ⫽ 1) [16]. Five of the patients given fractionated TBI were also given fludarabine 30 mg/m2/d for 3 days. The patient with Fanconi anemia was conditioned with fludarabine 30 mg/m2/d for 5 days followed by Cy 10 mg/kg/d for 2 days. Twelve patients with IEM were given busulfan 4 mg/kg/d for 4 days followed by 4 days of Cy 2 g/m2/d [17]. One patient was given Cy 60 mg/d for 2 days and fractionated TBI 3 Gy for 4 days. Four patients with HLH were also given etoposide 30 mg/kg. To prevent hemorrhagic cystitis caused by Cy, intravenous (IV) fluids 3 L/m2/d were given, together with mesna 6 878
times in 24 hours at 20% of the Cy dose (Tables 1 and 2). All patients received rabbit ATG (Thymoglobulin; IMTIX, Sangstat-Lyon, France); the total dose ranged between 2.9 and 12.8 mg/kg, with a median of 9.0 mg/kg [18]. Prophylaxis and Treatment of Graft-versus-Host Disease
Eighteen patients received 4 doses of methotrexate (MTX) combined with CsA [19]. MTX was given in a dose of 15 mg/m2 IV on day ⫹1 and 10 mg/m2 on days 3, 6, and 11, according to the Seattle protocol [19]. CsA was started on the day before transplantation with an IV dose of 2.5 to 5 mg/kg ⫻ 2, followed by 1.5 to 3.5 mg/kg ⫻ 2 from the day of transplantation. The higher dose was given to smaller children. On day ⫹1, or as soon as the patient could take CsA orally, 6.25 to 10 mg/kg ⫻ 2 was given. This regimen was maintained for 12 to 24 months after HSCT, and the dose was adjusted according to renal function and serum CsA concentrations. During the first month, we aimed at a CsA trough concentration in whole blood of 200 to 300 ng/mL. Four patients received CsA as described previously and received mycophenolate mofetil 15 mg/kg twice daily from day 0 to day ⫹28 after the stem cell transplantation instead of MTX [20]. Three patients (patients 954, 955, and 971) received tacrolimus 4 mg ⫻ 2 from day ⫺3 and sirolimus 6 mg ⫻ 2. On day ⫺2, the dose of sirolimus was decreased to 2 mg ⫻ 2. Thereafter, both the sirolimus and tacrolimus dosages were adjusted according to plasma levels. Tacrolimus was given for 18 months in the absence of graft-versus-host disease (GVHD), and the dose of sirolimus was tapered after 3 months. At the first sign of grade I acute GVHD, we gave prednisolone 2 mg/kg/d to adults and 2 to 3 mg/kg/d to children for 1 week [16]. Thereafter, the dose was reduced, depending on the response. Some patients with severe GVHD also received methylprednisolone IV or psoralen and UV light. Chronic GVHD was classified as limited or extensive [21] and was treated with prednisolone and CsA [22]. Supportive Care
All patients were kept in reverse isolation until the absolute neutrophil count (ANC) reached 0.2 ⫻ 109/L for 2 consecutive days [16]. Four patients with SAA and 8 with IEM were given G-CSF 0.3 mg/d IV from day ⫹10 after HSCT until ANC reached ⬎0.5 ⫻ 109/L for 2 consecutive days. Details regarding supportive care have been reported elsewhere [15-18]. Statistics
Analysis was performed as of May 3, 2004. The actuarial probabilities of survival, acute GVHD grades II to IV, and chronic GVHD were calculated by the
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Table 1. Severe Aplastic Anemia: Patient and Donor Characteristics
Patient No.
Diagnosis
CMV Serology
Recipient Age (y)/Sex
Donor Age (y)/Sex
Cell Dose (MNCⴛ108/kg)
Conditioning
Donor
Recipient
G-CSF 5g/kg/d
Acute GVHD Grade
Chronic GVHD Grade
Outcome
249 418 441
SAA SAA SAA
39/F 1/F 12/F
42/F 40/M 36/F
2.5 4.6 3.7
Bu ⴙ Cy 10 Gy TBI ⴙ Cy Cy ⴙ TLI
ⴙ ⴙ ⴚ
ⴙ ⴙ ⴙ
N N Y
I I II
0 0 0
485
SAA
19/F
44/M
1.3
ⴚ
ⴙ
Y
0
Mild
520 731 887 909 919 955 971 954
SAA SAA SAA SAA SAA SAA SAA FA
30/M 9/F 37/M 6/F 39/M 38/F 10/F 8/M
41/F 42/M 39/M 21/M 43/M 43/F 40/F 41/F
1.5 4.3 0.6 8.3 8.3 8 8 8.3
7.5 Gy TBI ⴙ Cy ⴙ TLI 10 Gy TB1 ⴙ Cy fTBI ⴙ Cy fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu fTBI ⴙ Cy ⴙ Flu Cy ⴙ Flu
A&W A&W Dead, Evans syndrome A&W
ⴚ ⴚ ⴚ ⴚ ⴙ ⴙ ⴙ ⴚ
ⴙ ⴚ ⴙ ⴙ ⴙ ⴙ ⴙ ⴙ
Y Y N N N N N N
I I 0 I 0 0 0 I
Mild 0 0 0 0 0 0 0
Dead, ARDS A&W A&W A&W A&W A&W A&W A&W
MNC indicates mononuclear cells; Bu, busulfan; fTBI, fractionated total body irradiation; Flu, fludarabine; FA, Fanconi anemia; A & W, alive and well.
Table 2. Inborn Errors of Metabolism: Patient and Donor Characteristics
Patient No.
Diagnosis ALD MLD MPS III FHLH
644 707 750 784 793 848 855 897 931
FHLH ALD FHLH MPS I SCID MLD MPS I MPS I FHLH
Donor Age (y)/Sex
CMV Serology
Cell Dose (MNCⴛ108/kg)
Conditioning ⴙ ⴙ ⴙ ⴙ
Donor
Recipient
G-CSF 5g/kg/d
Acute GVHD Grade
Chronic GVHD Grade
6/M 1/M 4/M 1/F
43/F 35/M 37/F 25/F
2.9 7.7 2.1 18.1
Bu Bu Bu Bu
Cy Cy Cy Cy ⴙ VP-16
ⴙ ⴚ ⴙ ⴚ
ⴚ ⴚ ⴙ ⴚ
N N N Y
0 II II I
0 0 0 NE
1/M 39/M <1/M 1.5/M 0.5/M 18/F 1/M 1/F 0.5/M
42/M 28/M 47/M 28/F 41/M 31/M 30/M 32/M 23/M
5.7 1.6 59.3* 25.8 43 1.46 18.5 2.9 5.7
Bu ⴙ Cy ⴙ VP-16 fTBI ⴙ Cy Bu ⴙ Cy ⴙ VP-16 Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy Bu ⴙ Cy ⴙ VP-16
ⴚ ⴚ ⴚ ⴚ ⴚ ⴚ ⴚ ⴙ ⴙ
ⴚ ⴚ ⴙ ⴚ ⴚ ⴚ ⴚ ⴚ ⴙ
Y Y Y Y Y Y Y N N
II I II II 0 0 0 I I
0 Mild 0 0 0 Mild 0 0 Mild
Outcome A&W A&W Dead, pneumonia Dead, VOD, CMV pneumonia A&W A&W A&W A&W A&W A&W A&W A&W A&W
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ALD indicates adrenoleukodystrophy; MLD, metachromatic leukodystrophy; MPS I, mucopolysaccharoidosis type 1 (Hurler disease), MPS III, Sanfilippo syndrome; FHLH, familial hemophagocytic lymphohistiocytosis, SCID, severe combined immune deficiency; Bu, busulfan; VP-16, etoposide; fTBI, fractionated total body irradiation; VOD, veno-occlusive disease; A & W, alive and well; NE, not evaluable. *Patients who received a PBSC graft.
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393 412 422 525
Recipient Age (y)/Sex
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Kaplan-Meier method, taking censored data into account, and were compared by using the log-rank test. The Mann-Whitney U test was used for comparing the day of engraftment. RESULTS Engraftment and Transfusions
Two patients (patients 422 and 707) rejected their grafts. Patient 422, a patient with Sanfilippo A disease, died of pneumonia on day 175 after the transplantation. Patient 707 underwent a second transplantation with the same donor after conditioning with fludarabine 30 mg/m2/d for 5 days and ATG at a total dose of 3.8 mg/kg. This patient is alive and a full donor chimera 2 years after the retransplantation. An ANC ⬎0.5 ⫻ 109/L was reached at a median of 19 days (range, 11-26 days) for the bone marrow patients. In those receiving peripheral blood stem cells (PBSC), the median was 11 days (range, 10-27 days; P ⫽ .18). Patients given bone marrow reached a platelet level of 30 ⫻ 109/L at a median of 24 days (range, 12-150 days), whereas those given PBSCs had platelet engraftment at a median of 12 days (range, 8-41 days; not significant; P ⫽ .3). Patients receiving G-CSF had a faster neutrophil engraftment: median, day 16 (range, 10-27 days) versus day 19 (range, 14-35 days; P ⫽ .07). The SAA patients received a median of 6 erythrocyte concentrates (range, 2-12) in the first 2 months and a median of 13 platelet transfusions (range, 3-21). In the patients with IEM, the corresponding figures were 4.5 (range, 0-17) and 7 (range, 0-29; not significant).
Figure 1. Cumulative probability of survival after HSCT in patients with nonmalignant disorders—IEM (inborn errors of metabolism) and SAA (severe aplastic anaemia)— by using matched unrelated donors.
GVHD grade II. Of the 4 patients who received mycophenolate mofetil plus CsA as prophylaxis, 1 developed grade I acute GVHD, and another developed a mild form of chronic GVHD. The cumulative incidence of acute grade II to IV GVHD was 24% in all patients. Six of 13 children (⬍18 years) developed grades II to IV acute GVHD, but none of the adults did (P ⫽ .05). Of those who developed acute grade II GVHD, 4 of the 6 had received G-CSF [23]. None of the children, but 4 of the 6 adults, developed chronic GVHD (P ⫽ .02). The cumulative incidence was 21%; 24 of 25 patients were valuable for chronic GVHD. None of the patients who were given a PBSC graft developed chronic GVHD. No patient died of GVHD (Tables 1 and 2).
Infections
Fifteen patients had bacteremia: 9 caused by coagulase-negative staphylococci, 3 by ␣-streptococci, and 1 by Staphylococcus aureus. Another patient (patient 848) had bacteremia caused by Escherichia coli and 1 (patient 887) by Citrobacter species. Cytomegalovirus (CMV) DNA was detected by polymerase chain reaction in the blood of 8 patients (42%). One patient with HLH (patient 525) died of interstitial CMV pneumonia and veno-occlusive liver disease on day 36 after transplantation. Three patients, 2 with reactivated herpes simplex virus (patients 249 and 525) and 1 with varicella-zoster virus (patient 731), recuperated well after treatment. Patient 520, with SAA, developed acute respiratory distress syndrome (ARDS) and died of adenovirus type II positive pneumonia on day 241 after transplantation. Graft-versus-Host Disease
Nine patients had no signs of acute GVHD. Ten patients had acute GVHD grade I, and 6 had acute 880
Survival Rates
The overall 5-year survival rate was 84% (Figure 1). The median follow-up of the surviving patients was 3.6 years (range, 0.8-14.5 years). The probability of survival was 83% in the SAA group and 85% in the IEM group. Two of the SAA patients died, 1 of Evans syndrome (patient 441) and 1 of ARDS (patient 520; Table 1). Among the patients with IEM, there were 2 deaths: 1 patient with Sanfilippo syndrome (patient 422) who died of pneumonia and 1 patient with HLH (patient 525) who died of CMV pneumonia and venoocclusive disease. The remaining 21 patients are alive and well (Tables 1 and 2). DISCUSSION Our aim was to evaluate the outcome of HSCT in patients with nonmalignant disease who had received closely matched unrelated grafts at Huddinge University Hospital, of whom 12 had SAA and 13 had IEM.
MUD-HSCT for Nonmalignant Disorders
Two of the 25 patients rejected the transplant. It is noteworthy that no rejection occurred in the SAA patients, although this group is prone to rejection [2,10]. The patients in the SAA group were presumably a high-risk group, having experienced treatment failure with immunotherapy and having received numerous transfusions before transplantation [9]. To avoid rejection in these patients, no patient had been given the standard regimen with Cy alone. In 1 patient, Cy was combined with TLI, and in another patient, Cy was combined with busulfan. However, in all other patients, Cy was combined with TBI with or without fludarabine. Various regimens have thus been used, but we recommend fludarabine, Cy, and fractionated TBI because of its lower toxicity. The use of ATG during conditioning may also have prevented rejection in these patients [18]. The engraftment of neutrophils and platelets was faster in PBSC patients than in those receiving bone marrow, although the difference was not statistically significant. In larger studies, PBSC grafts are associated with faster engraftments of neutrophils and platelets, probably because of the larger number of CD34⫹ cells in these grafts [15]. The times to engraftment were similar to those reported in comparable patients with leukemia [16]. The incidence of infections in this study also resembled that in patients with malignant diseases— 58% with bacterial septicemia and 42% with reactivation of CMV [24]. The latter occurred mainly in the SAA patients, of whom 6 of 7 were seropositive before the transplantation. One death due to CMV occurred in a patient with HLH, and 2 other deaths were caused by infections: 1 from ARDS (adenovirus type II) and 1 from pneumonia. ATG was primarily given to reduce the risk of graft rejection, but this also probably played a role in the low incidence of acute GVHD. None of the patients developed GVHD grade III or IV. We have previously shown, using unrelated donors, that ATG reduces the risk of acute GVHD after HSCT [25]. More children than adults developed moderate acute GVHD (P ⫽ .05). Despite the correlation between acute and chronic GVHD [26,27], none of them developed chronic GVHD, whereas 4 of 6 adults did. This would suggest that age may be more important than acute GVHD as a risk factor for chronic GVHD in this small patient population. The prolonged immunosuppression— up to 2 years—may also be a reason for the low incidence of chronic GVHD. In this study, only 5 patients received PBSC grafts. None developed chronic GVHD. However, in larger studies, there is a strong association between PBSC grafts, compared with bone marrow grafts, and chronic GVHD [28]. Chronic GVHD is not desirable in patients with nonmalignant diseases, and, therefore, bone marrow grafts may be preferable.
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We found an encouraging 5-year survival of 84% among these 25 patients. This indicates that an HLA-A, -B and -DR1 MUD is an acceptable alternative for patients with nonmalignant disorders who lack a matched sibling donor. The circumstance that all cases but 1 were genomically matched for the major HLA antigens is probably of major importance for the outcome [7]. Although only 12 SAA patients were included, a 5-year survival of 83% is promising in comparison with other (albeit larger) studies [9,10,29]. Our data suggest that a well-matched unrelated donor could be considered earlier in the course of the disease in such patients, because prolonged immunosuppressive treatment increases the risk for immunization, subsequent rejection, and infections. In the patients with IEM, the 5-year survival was 85%, which is also encouraging, although it is lower than with HLAidentical sibling donors [17]. However, in these patients, there is no other curative treatment. Therefore, HSCT is considered as soon as the diagnosis is made and a suitable donor can be found [3,4,12]. It should be pointed out that although the 5-year survival is favorable, this study does not question previous recommendations concerning the optimal time of transplantation. In those with life-threatening nonmalignant disorders who do not have an HLA-identical sibling, an HSCT with a well-matched unrelated donor seems to be the treatment of choice. If such a donor is not available, then an alternative could be a cord blood transplant or a haploidentical related donor transplant [30-32]. However, with a cord blood transplant, engraftment is delayed, and the risk of rejection may be higher, especially if the cell dose is low. With haploidentical related donors, T-cell depletion is necessary to minimize the risk of GVHD. With this approach, rejection and immunoincompetence may be a problem, with a subsequent increased risk of posttransplantation infections. In conclusion, our study suggests that patients with nonmalignant disorders can successfully undergo transplantation with an unrelated graft if the donor is closely HLA-A, -B, and -DR1 matched with highresolution techniques and if ATG is included in the conditioning regimen. Under these circumstances, outcome is similar to that in HLA-identical sibling transplantations.
ACKNOWLEDGMENTS This study was supported by grants from the Swedish Cancer Society (007-B02-16XAC), The Children’s Cancer Foundation (2002/074), The Swedish Research Council (K2003-32X-05971-23A), The Cancer Society in Stockholm (02:181), The Tobias Foundation, and The Karolinska Institute. 881
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