Outcomes of Thalassemia Patients Undergoing ...

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Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 August 01. Published in final edited form as: Biol Blood Marrow Transplant. 2014 December ; 20(12): 2066–2071. doi:10.1016/j.bbmt.2014.07.016.

Outcomes of Thalassemia Patients Undergoing Hematopoietic Stem Cell Transplantation by Using a Standard Myeloablative versus a Novel Reduced-Toxicity Conditioning Regimen According to a New Risk Stratification

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Usanarat Anurathapan1, Samart Pakakasama1, Pimsiri Mekjaruskul1, Nongnuch Sirachainan1, Duantida Songdej1, Ampaiwan Chuansumrit1, Pimlak Charoenkwan2, Arunee Jetsrisuparb3, Kleebsabai Sanpakit4, Bunchoo Pongtanakul4, Piya Rujkijyanont5, Arunotai Meekaewkunchorn6, Rosarin Sruamsiri7, Artit Ungkanont8, Surapol Issaragrisil9, Borje S. Andersson10, and Suradej Hongeng1,* 1Department

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of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand of Pediatrics, Chiangmai University Hospital, Chiangmai, Thailand 3Department of Pediatrics, Khonkaen University, Khonkaen, Thailand 4Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand 5Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand 6Queen Sirikit National Institute of Child Health, Bangkok, Thailand 7Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Naresuan University, Phitsanulok, Thailand 8Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 9Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 10Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas 2Department

Abstract

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Improving outcomes among class 3 thalassemia patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) remains a challenge. Before HSCT, patients who were ≥ 7 years old and had a liver size ≥ 5 cm constitute what the Center for International Blood and Marrow Transplant Research defined as a very high–risk subset of a conventional high-risk class 3 group (here referred to as class 3 HR). We performed HSCT in 98 patients with related and unrelated donor stem cells. Seventy-six of the patients with age < 10 years received the more conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan, ± fludarabine); the remaining 22 patients with age ≥ 10 years and hepatomegaly (class 3 HR), and in several instances additional comorbidity problems, underwent HSCT with a novel reduced-toxicity conditioning (RTC) regimen (fludarabine and busulfan). We then compared the outcomes between these 2 groups (MAC versus RTC). Event-free survival (86% versus 90%) and overall survival (95% versus 90%) were not significantly different between the respective groups; however, there was a

Correspondence and reprint requests: Suradej Hongeng, MD, Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. [email protected] (S. Hongeng). Conflict of interest statement: There are no conflicts of interest to report.

Financial disclosure: The authors have nothing to disclose.

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higher incidence of serious treatment-related complications in the MAC group, and although we experienced 6 graft failures in the MAC group (8%), there were none in the RTC group. Based on these results, we suggest that (1) class 3 HR thalassemia patients can safely receive HSCT with our novel RTC regimen and achieve the same excellent outcome as low/standard-risk thalassemia patients who received the standard MAC regimen, and further, (2) that this novel RTC approach should be tested in the low/standard-risk patient population.

Keywords Thalassemia; Myeloablative; Reduced toxicity

Introduction Author Manuscript Author Manuscript

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for thalassemia patients [1]. A myeloablative conditioning regimen (MAC) of busulfan (Bu) followed by 4 days of cyclophosphamide (Cy) (BuCy4) has, for several years, been considered the standard of care for HSCT in severe thalassemias [2]. The outcome of HSCT is dependent on patients' pretransplantation risk factors, which are related to the degree of underlying organ damage, mostly commonly in the form of complications of chronic blood transfusions [3]. The currently used risk stratification for severe thalassemia patients undergoing MAC HSCT has significant limitations; it fails to recognize a very high–risk subgroup, consisting of patients who are ≥ 7 years old and who have hepatomegaly (liver size extending ≥ 5 cm below the costal margin). Such patients constitute what Mathews et al. and the Center for International Blood and Marrow Transplant Research have defined as a very high–risk subset of a conventional high–risk (HR) class 3 group [4,5]. This subset is characterized by a very high risk of graft rejection and regimen-related toxicity, including, but not limited to veno-occlusive disease (VOD)/sinusoidal obstruction syndrome, often leading to multiorgan failure and death [4,5]. This stimulated the design and evaluation of a number of different pretransplantation conditioning regimens for this group [3,6-11].

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Thalassemia patients often have a long history of frequent blood transfusions as part of their medical management history. Therefore, they also have an excessive risk for graft failure and regimen-related toxicity/mortality. We now hypothesized that patients with hemoglobinopathies, here exemplified by thalassemia, who have a normal, if not hyperactive immune system, need to be preconditioned in a more comprehensive way than is typically done for other patients. The far-reaching treatment program would encompass 3 distinct phases. The first part would be one of medical management, and consists of oral hydroxyurea to reduce erythroid marrow expansion, together with chelation therapy to reduce (hepatic) iron deposits, thereby decreasing the risk for hepatic toxicity of the conditioning regimen. The second phase would involve the added immunosuppressive benefit of 2 courses of timed, sequential pharmacological therapy that are added without imposing significant toxicity on the third phase, the conditioning program itself, which consists of a reduced-toxicity conditioning (RTC) regimen of fludarabine (Flu) with Bu and antithymocyte globulin (ATG), as previously spear-headed by Russell et al. and de Lima et al. for hematological malignancies, and which has proven itself to be both medically safe

Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 August 01.

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and fraught with an extremely low risk for graft failures in patients who receive both matched related and unrelated donor grafts [12,13]. Finally, when procuring the graft itself, we would routinely strive for securing as many cells as possible to minimize the risk for graft failure.

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We recently introduced this new comprehensive concept of pretransplantation pharmacological immunosuppression therapy followed by Flu and Bu as a composite conditioning platform forclass 3 HR thalassemia patients [14]. In the current investigation, we compared the outcomes of an expanded cohort of older (class 3 HR) patients undergoing HSCT with our novel approach (expanded from 13) with that of younger class 3 patients who received a standard MAC (BuCy4-based) regimen. To our knowledge, no one has hitherto comparatively analyzed the outcome of severe thalassemia patients who underwent transplantation with these risk-stratified conditioning approaches. Based on the very favorable outcome in this highest-risk subpopulation, we suggest that this modified RTC program should be considered for more widespread testing also in low/standard-risk patients. Patients and Methods

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One hundred and twenty consecutive thalassemia patients underwent HSCT at the Ramathibodi Hospital between 1989 and 2013. In the current comparison, we excluded 7 patients who received cord blood stem cells, 8 patients who received a different RTC regimen [15] and, more recently, 7 patients who have been treated on a haploidentical donor transplantation program. Therefore, 98 patients were included. Sixty-five of these 98 patients received related and 33 patients received unrelated donor grafts. The data concerning some of these 98 patients were previously reported [14,16,17]. Patients and donors or their parents/caregivers signed informed consent before treatment. We stratified patients to receive MAC or RTC regimens depending on age and hepatomegaly (≥ 5 cm below right costal margin). The patients who were older than 10 years and had hepatomegaly received the RTC regimen; all were classified as class 3 according to the criteria proposed by Lucareilli et al. [1]. This group of patients is also stratified as class 3 HR as described previously [4,5]. Among the 22 patients who received the RTC regimen, 2 had rejected a previous HSCT and 1 had rejected 2 previous HSCTs. In addition, several of these 22 patients also had serious comorbidities; 2 had diabetes mellitus type 1, 1 had extensive extramedullary hematopoiesis, 2 patients had a history of pulmonary hypertension, and 7 had previously undergone splenectomy [18].

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Histocompatibility—HLA was determined by conventional serologic typing or DNA typing with intermediate- or high-resolution sequence-specific oligonucleotide probes for class I and II loci. Conditioning Regimens MAC regimen: The MAC regimen [16,17] consisted of Bu 1 mg/kg taken orally or .95 to 1.2 mg/kg i.v. every 6 hours for 4 days (day -9 to day -6) and cyclophosphamide 50 mg/kg infused daily for 4 days (day -5 to day -2) in patients who received matched related donor stem cells (BuCy4). Because of the risk of graft failure, the patients who received unrelated


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and mismatched related donor stem cells had the BuCy4 regimen modified as follows: Flu 30 mg/m2/day i.v. was given once daily for 6 days (day -15 to day -10), Bu (the same dose as previously mentioned) for 4 days (day -15 to day -12), Cy 50 mg/kg for 4 days (day -9 to day -6), and antilymphocyte globulin (Fresenius, Graefelfing, Germany) 10 mg/kg/day was infused daily for 4 days (day -5 to day -2). RTC regimen, Group 3 HR patients: Pretransplantation management was utilized for all patients who received the RTC regimen [14]. Before starting the immunosuppressive phase, all patients received hydroxyurea 20 mg/kg/day daily ≥ 3 months to decrease erythroid marrow expansion[14,15]. The RTC regimen consisted of 2 phases.

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The first phase was sequential pharmacological pretransplantation immunosuppression (PTIS). The first 11 patients received 1 cycle; subsequently, we used 2 cycles of PTIS consisting of Flu 40 mg/m2/day i.v. for 5 days and dexamethasone (Dex) 25 mg/m2/day i.v. for 5 days. This treatment was administered on days -28 to -24 (1 cycle) and subsequently on days -56 to -52 and days -28 to -24 (2 cycles) before transplantation. PTIS is given to suppress recipient T cell and facilitate sustainable engraftment. Two patients in the first 11patient group, who received only 1 cycle of Flu-Dex, had unstable donor chimerism in the first 100 days after HSCT. Because there was no clinical toxicity from the Flu-Dex, we administered 2 cycles, 28 days apart, in the next 11 patients. The second phase was the conditioning regimen, which consisted of Flu 35 mg/m2/day i.v. for 6 days (day -10 to day -5) followed by Bu 130 mg/m2 i.v. once daily for 4 days (day -10 to day -7) and ATG (Thymoglobulin; Sanofi-Genzyme Canada, Ontario, Canada) 1.5 mg/kg/day for 3 days (day -4 to day -2).

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Stem Cell Grafts—The T cell replete bone marrow or peripheral blood stem cell graft was infused on day 0. For patients undergoing RTC, peripheral blood stem cells were collected to target 5-10 × 106 CD34+ cells/kg recipient weights. Graft-versus-host Disease Prophylaxis—For graft-versus-host disease (GVHD) prophylaxis, all patients started cyclosporin or tacrolimus 2 to 4 days before transplantation. In addition, all MAC patients received a short course of methotrexate, whereas the patients in the RTC group received mycophenolate mefotil for 60 days.

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VOD Prevention and Treatment—Because the patients in RTC group are at high risk of VOD, we therefore monitored weight, fluid balance, and liver function tests closely. For the treatment of VOD, we usually gave supportive care including analgesia, diuretics, and packed red cell transfusion to keep hematocrit > 30. We also tried to minimize nephrotoxins and hepatotoxins. Statistics—Survival probability was estimated by the Kaplan-Meier method.

Results The 5-year event-free and overall survival for all 98 patients were 87% (95% confidence interval [CI], 76.6% to 91.1%) and 94% (95% CI, 86.3% to 97.1%), respectively. The 5-year Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 August 01.

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event-free survival estimated for recipients in the related- donor group was 88% (95% CI, 76.4% to 93.5%) compared with 82% (95% CI, 63.2% to 91.2%) in the unrelated-donor group respectively (P = .46) (Figure 1A). The 5-year overall survival rate estimated for recipients in the related-donor group was 94% (95% CI, 84.1% to 97.6%) compared with 94% (95% CI, 76.4% to 98.3%) in the unrelated-donor group (P = .96) (Figure 1B). MAC versus RTC Groups

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Seventy-six patients were assigned to receive the MAC regimen and 22 patients were allocated to the RTC regimen. This is based on a new risk stratification described previously [4,5]. The patient characteristics of the 2 risk groups are described in Table . The event-free survival estimated for recipients in MAC and RTC groups was 86% (95% CI, 73.8% to 90.7%) and 90% (95% CI, 64.8% to 97.3%), respectively (P = .5) and the overall survival was 95% (95% CI, 86.4% to 98.0%) and 90% (95% CI, 64.7% to 97.3%), respectively (P = . 9) (Figure 2A,B). The thalassemia-free survival estimated for recipients in MAC and RTC was 88% (95% CI, 75.2% to 91.5%) and 93% (95% CI, 66.2% to 98.2%), respectively (P = . 50). In the MAC group, 6 of 76 patients (8%) had graft rejection. In contrast, none in the RTC patient group had graft rejection (P = .10). At the time of report, all patients in both groups who are free of thalassemia have full donor chimerism, except 1 patient in MAC group who has stable mixed chimerism (80% donor chimerism) 7 years after HSCT. Severe grade III and IV acute GVHD and extensive stage chronic GVHD occurred equally between the MAC and RTC groups (Table 1).

Discussion Author Manuscript Author Manuscript

Improving the clinical outcome of class 3 HR thalassemia after an allogeneic HSCT remains a challenge. Mathews et al. and the Center for International Blood and Marrow Transplant Research [4,5] previously reported on the poor outcome of patients in a newly defined class 3 HR subset after HSCT when using BuCy4. The major contributory factor for the poor outcome in these patients was the combination of a high risk for graft rejection and serious regimen-related toxicity/treatment-related mortality (TRM). Earlier attempts to reduce regimen-related toxicity in a similar cohort of patients were made by reducing the cumulative of doses of Bu and Cy. Experience from such an approach, as reported by the Pesaro group, suggested that although reduction of TRM was achieved, there was a significantly higher risk of graft rejection [8]. Although other investigators have reported an improvement in outcome of class 3 patients after HSCT, we would carefully argue that most, if not all, of such published data refer to class 3 patients in general, but they do not address the very high-risk subset of class 3 (class 3HR) that was defined by Mathews et al. and Sabloff et al. [4,5]. It is noteworthy that although 6 of 76 patients (8%) in our MAC group suffered graft failure, our second cohort of 22 class 3 HR patients undergoing our new approach with PTIS followed by a BuFlu-based RTC regimen demonstrated that all patients can achieve stable full donor chimerism [14 and current report]. We suggest that our new PTIS RTC approach is of particular benefit for these class 3 HR patients, who are now offered the chance to safely achieve full engraftment without thalassemia in exchange for a more limited risk of


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serious treatment-related toxicity. However, the risk of serious toxicity and (still) a relatively high graft failure point out that this methodology may be of additional benefit to other class 3 patients as well. Six patients in the MAC group had graft rejection. Three of these 6 patients received unrelated and the other 3 patients received related-donor stem cells. For the unrelated patients, 2 received 2 allele mismatched stem cells (6/8 HLA allele–matched donor) and 1 received bone marrow stem cells with the dose of CD34+ less than 2 × 106 cells/kg. For the related patients, 1 of them received 1 antigen-mismatched stem cells (5/6 HLA matched donor) and 2 received bone marrow stem cells with the dose of CD34+ less than 2 × 106 cells/kg. We suggest that disparity of HLA matching and low CD34+ dose may be the causes of rejection.

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Previous studies have reported thalassemia-free survival rates of 50% to 80% after HSCT in patients with thalassemia with class 3 HR features, such as older age and hepatomegaly [4,5,7,9-11]. Mathews et al. has reported using treosulfan, Flu, and thiotepa for a conditioning regimen in 24 class 3 HR patients and the result showed that thalassemia-free and overall survival were 77.8% and 86.6%, respectively [10]. In this current study, the 22 class 3 HR patients who underwent PTIS RTC can achieve both event-free and overall survival in excess of 90%, whereas thalassemia-free survival is around 93% in this group. We want to emphasize that, by design, our study included patients with not only class 3 HR features but also those who had failed a previous HSCT, as well as patients who suffer comorbidities, such as diabetes mellitus, extramedullary/hepatic hematopoiesis, pulmonary hypertension, and those having undergone a splenectomy, all of which are recognized as risk factors for TRM; furthermore, 5 of the 22 patients received grafts from mismatched donors. With this adverse risk information in mind, we suggest that our approach should be considered promising for use in highrisk patients who are evaluated for possible HSCT. There is a trend for increasing overall and event-free survival rate in the unrelated transplantation group in this current study compared with the previous study (event-free and overall survival rates: 71% and 82%, respectively) [17]. This is due to better HLA matching by using high-resolution DNA typing including HLA A, B, C, and DRB1 in the current practice, instead of only HLA A, B, and DRB1.

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In conclusion, our novel comprehensive management program addresses all components that contribute to high risk for both treatment-related death and graft failure in patients with hemoglobinopathies. The sequential administration of hydroxyurea, followed by PTIS and subsequently an RTC regimen of Flu, Bu, and ATG, paired with a relatively high number of hematopoietic progenitor cells (on average > 5 × 106 CD34+ cells/kg of recipient weight), has been demonstrated to result in a high level of safety and durable engraftment in this group of patients with high-risk class 3 thalassemia. Based on the very favorable outcome in this highest-risk subpopulation, we suggest that this modified RTC program should be considered for more widespread testing in low and standard-risk patients to further decrease the risk of toxicity and graft failures among these patients as well. In addition, the rapid achievement of stable engraftment in the 5 patients who had partially mismatched donors


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suggests that this new program could be safely modified for use with alternative donors in patients who lack fully matched donors.

Acknowledgments This study was supported by funding from the Ram- athibodi Foundation, the National Research University Grant, the Mahidol University Research Grant, the Office of the Higher Education Commission and Mahidol University under the National Research University Initiative, Thailand Research Fund, and Research Chair Grant from the National Science and Technology Development Agency (NSTDA) and Mahidol University (support to S.H.), the UT MD Anderson CCSG Core CA16672 (support to B.S.A.), and the Thailand Research Fund (RTA 488-0007) (support to S.I.).

References

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1. Lucarelli, G., Clift, R. Marrow transplantation in thalassemia. 3rd. Malden, MA: Blackwell Scientific; 2004. p. 1412 2. Lucarelli G, Polchi P, Galimberti M, et al. Marrow transplantation for thalassaemia following busulphan and cyclophosphamide. Lancet. 1985; 1:1355–1357. [PubMed: 2861312] 3. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. New Engl J Med. 1990; 322:417–421. [PubMed: 2300104] 4. Mathews V, George B, Deotare U, et al. A new stratification strategy that identifies a subset of class III patients with an adverse prognosis among children with beta thalassemia major undergoing a matched related allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2007; 13:889– 894. [PubMed: 17640592] 5. Sabloff M, Chandy M, Wang Z, et al. HLA-matched sibling bone marrow transplantation for betathalassemia major. Blood. 2010; 117:1745–1750. [PubMed: 21119108] 6. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in adult thalassemia. Blood. 1992; 80:1603–1607. [PubMed: 1520885] 7. Sodani P, Gaziev D, Polchi P, et al. New approach for bone marrow transplantation in patients with class 3 thalassemia aged younger than 17 years. Blood. 2004; 104:1201–1203. [PubMed: 15039283] 8. Lucarelli G, Clift RA, Galimberti M, et al. Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood. 1996; 87:2082–2088. [PubMed: 8634461] 9. Bernado ME, Zecca M, Piras E, et al. Treosulfan-based conditioning regimen for haematopoietic stem cell transplantation in patients with thalassemia major. Br J Haematol. 2008; 143:548–551. [PubMed: 18986389] 10. Mathews V, George B, Viswabandya A, et al. Improved clinical outcome of high risk thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with treosulfanbased conditioning regimen and peripheral blood stem cell grafts. PLoS One. 2013; 8:e61637. [PubMed: 23637873] 11. Hussein AA, Al-Zaben A, Ghatasheh L, et al. Risk adopted allogeneic hematopoietic stem cell transplantation using a reduced intensity regimen for children with thalassemia major. Pediatr Blood Cancer. 2013; 60:1345–1349. [PubMed: 23424175] 12. Russell JA, Tran HT, Quinlan D, et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002; 8:468–476. [PubMed: 12374451] 13. de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004; 104:857–864. [PubMed: 15073038] 14. Anurathapan U, Pakakasama S, Rujkijyanont P, et al. Pretransplant immunosuppression followed by reduced-toxicity conditioning and stem cell transplantation in high-risk thalassemia: safe approach to disease control. Biol Blood Marrow Transplant. 2013; 19:1254–1262. [PubMed: 23769818]


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15. Hongeng S, Pakakasama S, Chuamsumrit A, et al. Reduced intensity stem cell transplantation for treatment of class 3 Lucarelli severe thalassemia patients. Am J Hematol. 2007; 82:1095–1098. [PubMed: 17674372] 16. Hongeng S, Pakakasama S, Chaisiripoomkere W, et al. Outcome of transplantation with unrelated donor bone marrow in children with severe thalassemia. Bone Marrow Transplant. 2004; 33:377– 379. [PubMed: 14676781] 17. Hongeng S, Pakakasama S, Chuansumrit A, et al. Outcome of transplantation with related- and unrelated-donor stem cells in children with severe thalassemia. Biol Blood Marrow Transplant. 2006; 12:683–687. [PubMed: 16737942] 18. Mathews V, George B, Lakshmi KM, et al. Impact of pretransplant splenectomy on patients with beta-thalassemia major undergoing a matched related allogeneic stem cell transplantation. Pediatr Transplant. 2009; 13:171–176. [PubMed: 18482210]

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(A). Event free survival of 98 thalassemia patients undergoing related and unrelated donor HSCT (related: n = 65; unrelated: n = 33). (B) Overall survival of 98 thalassemia patients undergoing related and unrelated donor HSCT (related: n = 65; unrelated: n = 33).


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Author Manuscript Author Manuscript Author Manuscript Figure 2.

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(A) Event-free survival of 98 thalassemia patients undergoing HSCT with MAC versus RTC regimens (MAC: n = 76; RTC: n = 22). (B) Overall survival of 98 thalassemia patients undergoing HSCT with MAC versus RTC regimens (MAC: n = 76; RTC: n = 22).


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Table 1

Patient Characteristics

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Characteristic

MAC Regimen

RTC Regimen

No. of patients

76

22

Age at transplantation,

8(2-10)

17 (10-20)

44/32

9/13

Homozygous β thalassemia

17

7

β Thalassemia/hemoglobin E

59

15

64/12

1/21

median (range), y Male/female Type of thalassemia

Source of stem cells Bone marrow/peripheral blood HLA matching

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Related

50

15

6/6 HLA antigen match

44

13

5/6 HLA antigen match

6

2

26

7

6/6 Allele match

13

-

5/6 Allele match

6

-

4/6 Allele match

2

-

8/8 Allele match

2

4

7/8 Allele match

3

3

Acute, grade II-IV

18 (22%)

5 (23%)

Acute, grade III-IV

5(6%)

3 (13%)

Chronic

8(10%)

4 (18%)

Extensive

4 (5%)

1 (4%)

Hemorrhagic cystitis

6 (7%)

1 (4%)

Herpes zoster infection

3 (4%)

2 (8%)

Cytomegalovirus infection

2 (2%)

1 (4%)

Sepsis

4 (5%)

Autoimmune hemolytic anemia

1 (1%)

-

Seizure

3 (4%)

-

VOD

5 (6%)

2 (8%)

5 (7%)

2 (9%)

Unrelated

GVHD

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Procedure-related complications

Causes of death

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Graft failure

1

Bleeding

1

-

Viral infections

1

-

Fungal infection

1

1

Accident

1

1

114(11.5-262)

36 (5-88)

Follow-up, median (range), mo
