Original Article

Bone Marrow Transplantation (2008) 42, 589–595; doi:10.1038/bmt.2008.227; published online 11 August 2008

Cord Blood Stem Cells

Unrelated cord blood transplantation in children with idiopathic severe aplastic anemia

K W Chan1, L McDonald1, D Lim1, M S Grimley1, G Grayson1 and D A Wall1

1Division of Pediatric Blood and Marrow Transplantation, Texas Transplant Institute and Methodist Children's Hospital, San Antonio, TX, USA

Correspondence: Dr KW Chan, Division of Pediatric Blood and Marrow Transplantation, Texas Transplant Institute, 7711 Louis Pasteur Drive, Suite 708, San Antonio, TX 78229, USA. E-mail: kawah.chan@mhshealth.com

Received 2 April 2008; Revised 4 June 2008; Accepted 6 June 2008; Published online 11 August 2008.



Early results of unrelated cord blood transplantation (UCBT) for severe aplastic anemia (SAA) were poor with a high rate of engraftment failure. This was attributed to the combination of lower graft cell dose and intact host immune system. We performed UCBT in nine children (median age 9 years) with refractory SAA using increasingly immunosuppressive preparative regimens. The time from diagnosis to UCBT was 3.4–20 months (median age 7.2 years), with all children having failed at least one course of immunosuppression. Donor/recipient HLA matching was six of six (n=1), five of six (n=2) and four of six (n=6). The median nucleated cell dose infused was 5.7 × 107 cells/kg (range 3.5–20 × 107 cells/kg). Six patients were engrafted after the first UCBT. Two of the three patients without hematopoietic reconstitution were engrafted after a second UCBT. All children receiving greater than or equal to120mg/kg of CY in the preparative regimen were engrafted. The median time to myeloid engraftment was 25 (17–59 days) days. Acute GVHD developed in two, and chronic GVHD in five patients. Five patients developed EBV viremia post transplant (lymphoproliferative disorder in three patients). At a median follow-up of 34 months, seven patients are alive and transfusion-independent. UCBT is a feasible treatment strategy for children with refractory SAA lacking a well-matched adult donor.


severe aplastic anemia, children, unrelated cord blood transplants, graft failure, EBV-lymphoproliferative disorder



For children with idiopathic severe aplastic anemia (SAA) without a matched related donor immunosuppressive therapy (IST) is the standard first-line treatment. The 6-month response rate is high, ranging from 55 to 77%.1, 2, 3 However, hematologic improvement is often not sustained and only 40% of patients remain disease-free at 10 years.4 The management of patients with refractory or recurrent SAA is challenging. Many receive additional IST with disappointing results. Scheinberg et al.5 reported an overall response rate of 30% with a second course of immunosuppression, but no complete remissions were seen. Similarly, a series of Japanese patients who lacked a high-resolution matched unrelated donor were retreated with IST and showed an 11% response rate at 6 months.6 In addition, with increased immunosuppression an increased risk of clonal transformation was also reported.6 According to data from the European Group for Blood and Marrow Transplantation (EBMT) 17–36% of SAA patients eventually required hematopoietic stem cell transplantation (HSCT) as salvage therapy.7

Results of alternate donor HSCT for refractory SAA have improved in recent series.7, 8 Favorable prognostic factors include younger age, early referral to transplant and donor–recipient matched by high-resolution HLA typing.9, 10, 11 Current guidelines recommend proceeding to HSCT for children after failing one course of IST, provided a fully matched donor at DNA levels for both classes I and II antigen is available.12 Unfortunately, many patients, especially those from ethnic minority groups or less homogeneous populations, do not have adult donors who fulfill the current matching criteria as recommended by the National Marrow Donor Program (NMDP).13 The results of transplantation using more HLA-disparate donors have remained unsatisfactory, with higher rates of engraftment failure and lower survival.7, 8, 9, 10, 11, 14 Therefore, the optimal therapeutic approach for children with SAA who lack a highly matched unrelated donor requires further evaluation.

Unrelated donor cord blood transplant (UCBT) has increasingly been used in the treatment of childhood leukemia, and the outcome is comparable with that from unrelated donor grafts.15 The reported experience of UCBT in SAA is more limited and less favorable. Information on pediatric cases has mostly been included in registry data with few details available.16, 17 Other reports were published as case studies18 and many involved predominantly adult patients.19, 20, 21 We reviewed the record of nine consecutive children with idiopathic SAA who received UCBT as a salvage therapy after the failure of IST. The primary outcomes of interest were engraftment, transplant-related toxicity, overall and disease-free survival.


Patients and methods

Patient characteristics and donor selection

The medical records of nine consecutive children with acquired SAA who underwent UCBT between March 2001 and April 2007 at our program were reviewed. Severe aplastic anemia was defined by standard criteria.22 Patients with Fanconi anemia and other constitutional BM failure syndromes were excluded. No patient had clonal chromosomal abnormalities. All had failed at least one course of IST earlier (antithymocyte globulin (ATG), cyclosporine and steroid), and five did not respond to a second course of IST. All were transfusion-dependent at the time of transplant. Patients did not have a family member match (at least five of six HLA antigens), or an unrelated donor (6 HLA-A, B and DR loci).

Typing of HLA antigens was performed by DNA-based methodology: high-resolution technique was used for class II antigens, whereas low-resolution typing was used for HLA-A and -B loci. Cord blood (CB) units were located through various banks in the United States. Selection was primarily on the basis of prethaw nucleated cell dose (target of 5 × 107 total nucleated cells per kg, but a minimum of 2.5 × 107/kg). Following this, the choice was based on the best HLA compatibility, with at least four of six loci matching. HLA-DRB1 compatibility between the donor and the recipient was given preference.

Transplantation protocols and supportive care

Transplantation protocols were approved by the institutional review board of the Methodist Children's Hospital. Written informed consent for treatment was obtained from the patients or parents/guardians. The first two patients received chemotherapy only for conditioning (2 CY/ATG) and busulfan/fludarabine per ATG). The last seven patients received a regimen that consisted of fludarabine 35mg/m2/day i.v. for 5 days (days −6 to −2), CY, rabbit ATG (Thymoglobin, Genzyme, Cambridge, MA, USA) 3mg/kg/day for 3 days (days −3 to −1) and TBI 2Gy in a single fraction on day −1. Initially the dose of CY was 50mg/kg i.v. on day −6. After the first two cases failed to engraft, the dose was increased to 60mg/kg/day for 2 days (days −6 and −5) in two patients, and 50mg/kg for 3 days (days −6, −5 and −4) in three patients. Total body irradiation was omitted in the 4-month-old infant. The GVHD prophylaxis regimen included a calcineurin inhibitor (cyclosporine or tacrolimus), in combination with methylprednisolone, methotrexate or mycophenolate mofetil. Patients were hospitalized in rooms equipped with high-efficiency particulate air filtration systems and received antimicrobial prophylaxis according to institutional policies. All patients received hematopoietic growth factor from the day of CB infusion until the ANC exceeded 2 × 109/l. Cytomegalovirus infection was monitored weekly by DNA quantitation in the peripheral blood, using PCR analysis. Measurement of EBV genome in the blood and screening for other viruses was performed when compatible clinical symptoms were present.

Patients with no evidence of donor cell engraftment were evaluated for second UCBT if there was no active infection or organ dysfunction. Selection criteria for CB units were similar to those for the initial transplants. Units with the largest cell dose were of first priority. Although DRB1 molecular matching was still preferred, it was placed as a second priority to cell dose for the subsequent transplant. The design of the preparative regimen was to overcome alloimmunization. Two patients received a second UCBT. They were conditioned with CY (120mg/kg i.v. over 2 days) and TBI 6Gy (in three fractions). In addition, alemtuzumab was used in one patient and extracorporal photopheresis in another.

Assessment of outcome and statistical analysis

The day of engraftment was defined as the first of three days when the ANC exceeded 0.5 × 109/l. Patients who did not achieve this criteria at any time after UCBT were considered as primary graft failure (GF), whereas those with initial engraftment followed by a subsequent decline in ANC to <0.5 × 109/l were considered as secondary GF. Chimerism analysis using unfractionated peripheral blood was performed by DNA amplification of informative polymorphic short tandem repeats. Analysis usually began around the third week after transplant, and was repeated as indicated, according to the patients’ condition. Patients with sustained engraftment who survived more than 14 days, and more than 3 months were evaluated for acute and chronic GVHD, respectively. Survival and outcome data were collected and analyzed as of 1 April 2008, with a minimum follow-up of 12 months for all survivors. Actuarial survival was estimated using the Kaplan–Meier method. All surviving patients were censored at the time of evaluation and these observations were used for the generation of the survival curve.



Engraftment, chimerism and GF

Nine consecutive children with refractory SAA were treated. The median age was 9 years (range 0.3–15 years), and the median weight was 25kg (range 4.8–47.8kg). All had failed at least one course of immunosuppression. The median time from diagnosis of SAA to UCBT was 7.2 months (range 3.4–20 months). Donor/recipient characteristics and transplant details are summarized in Table 1. After the initial transplant, three patients had primary GF (five of six match unit n=1, four of six match unit n=2). Their total nucleated cells and CD34+ cell dose were similar to those of patients who were engrafted. One patient with progressive aspergillus sinusitis was too sick for further intervention; he died 59 days after transplant. Two underwent a second UCBT (both with four of six match units) and were engrafted. Therefore, a total of 11 UCBT (all single CB unit transplants) were performed. The median time to ANC recovery of the eight successful UCBT was 25 days (range 17–59 days), and the platelet count exceeding 20 × 109/l occurred in 43 days (range 28–93 days). Seven patients had more than 95% (complete) donor chimerism on all analyses. One patient showed mixed chimerism (75% donor cells) on the initial analysis and converted to 100% chimera on the second analysis. No secondary GF was encountered.

GVHD, infections and other complications (Table 2)

Of the eight successful UCBT, 2 patients developed grade II acute GVHD of the skin. Five patients developed chronic GVHD and four were extensive. Both children with acute GVHD progressed to chronic phase. Two other children also had features that might predispose them to this complication: one was a recipient of a second transplant and another had rapid immunosuppressant tapering for management of EBV-associated lymphoproliferative disorder (EBV-LPD). At the time of report three patients remain on systemic therapy.

Infections were common in this patient population. Eight of the eleven UCBT procedures were associated with bacterial sepsis during the neutropenic period. This included Gram-negative bacteremia and/or soft tissue infection in seven cases. In addition, two patients had systemic fungal infections: one developed candidemia and another suffered from aspergillus sinusitis that progressed despite antifungal therapy and granulocyte transfusion. After myeloid recovery, viral infection/reactivation was common, mostly associated with chronic GVHD and its treatment. Cytomegalovirus viremia was documented in three patients, none had visceral involvement; one patient had BK virus in the blood for 9 months and several episodes of multidrug-resistant herpesvirus type 1 infections of the oral cavity and the perianal area; one patient had recurrent episodes of localized varicella zoster; one patient developed candidal meningitis.

A high incidence of EBV reactivation was encountered. Five patients demonstrated elevated EBV viral load in the blood at a median of 82 days (range 33–164 days) after UCBT. Two patients had no specific symptoms but three presented with fever and multiple lymphadenopathy compatible with EBV-LPD. The latter patients were managed with reduction/discontinuation of immunosuppressive agents and rituximab. One patient had a complete response. Two patients had progressive lymphadenopathy. In one patient CY was added to the regimen and the LPD resolved. The other died of progressive lymphoma despite multiagent chemotherapy.

Survival and causes of death

As of 1 April 2008, seven of nine patients are alive at a median follow-up of 34 months (range 12–82 months). The cumulative survival is 77% (95% CI 50–100%) (Figure 1). All patients are transfusion-independent, with a median Lansky performance score of 90 (range 70–100). Three patients remain on treatment for chronic GVHD. Two patients died on days 59 and 116 after transplant, respectively. The cause of death was fungal infection after initial GF and EBV-LPD after a second UCBT.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Survival post unrelated donor cord blood transplant.

Full figure and legend (38K)



In these reports the outcome of unrelated donor HSCT for SAA patients has improved. Patients of young age (<15–20 years) with an HLA-identical donor (based on oligonucleotide typing or better), and who were transplanted within one year of diagnosis have an overall survival between 70 and 80%.7, 8, 9, 10, 11 However, recipients of HLA-disparate grafts in those series had an inferior outcome with a survival rate of only 34–40%.8, 9, 10, 11 Currently, the chance of identifying high-resolution HLA-A, C, B and DRB1 loci matched unrelated adult donors for patients of the African, Hispanic and Asian origin is only between 53 and 64%.23 Other approaches to expanding the donor pool have included haplo-identical related or mismatched unrelated donors. In several small series, the results were encouraging, but T-cell depletion techniques have been difficult to move forward into practice because of labor-intensive techniques and the inconsistent supply of anti-T-cell antibodies.24, 25, 26 A more intensive preparation was used in some to reduce graft rejection.25, 26

Not much has been published on the use of UCBT in the treatment of SAA. A recent report from the Japan Cord Blood Bank Network included 31 patients with a median age of 28 years. All but four donor–recipient pairs were mismatched for 1–2 HLA loci. The 2-year overall survival for the entire group was 40%.17 Similarly, double UCBTs were used in 13 patients with inherited or acquired SAA, of whom five had previously rejected a transplant. At a median follow-up of 13 months, the overall survival was 55% (and 50% for those transplanted for the second time).27 The 3-year actuarial survival rate of 78% in our series compares favorably with that of transplants from both unrelated adult and CB donor sources. This result was achieved despite the high degree of donor–patient HLA mismatches. All of our patients were of Hispanic origin and none had a potential unrelated adult donor matched at the six antigen level. However, we were able to identify at least a four of six matched unit of appropriate cell dose for these children. This approach should be included as an alternative donor search in a less genetically homogeneous population or when the ethnic representation in the adult donor pool is relatively small.

Historically, preparative regimens of unrelated adult donor HSCT for aplastic anemia have utilized CY (200mg/kg), ATG and TBI at various dosages.28, 29 A 90% engraftment rate was reported in most series using a TBI dose of 3–5Gy but the success in HLA-mismatched cases was less consistent.29 In a dose de-escalation study Deeg et al.8 showed that when combined with CY and equine ATG, a single fraction of 2Gy TBI was equally efficacious and less toxic than when 4 or 6Gy was used. Overall GF rate was 5%, but this complication was more frequent among HLA-mismatched pairs. In addition, 10% of the patients did not tolerate equine ATG and received 12Gy of TBI instead. Therefore, the optimal TBI dose has not been established in all SAA patients. On account of the acute and long-term toxicity associated with irradiation, some groups have investigated the substitution of fludarabine for TBI in the conditioning regimen. This approach has resulted in fairly regular engraftment in related donor HSCT.30 However, an overall GF rate of 18% was reported in unrelated donor transplants, especially in patients over 15 years of age.31 In our experience the inclusion of fludarabine, and using a CY dose of at least 120mg/kg together with TBI of 200cGy and ATG, resulted in reliable and durable engraftment of UCBT. The TBI dose was the same as the optimal dose identified in a recent prospective dose-finding study.8

Graft rejection is a major concern in UCBT given the relatively low cell dose available in the donor graft, the relative immunocompetence of the host. In addition, many of the recipients have been heavily transfused by the time they come to transplant. Indeed, the reported incidence of primary GF after UCBT has been high. Rubinstein et al.16 reported only 8 of 19 patients were engrafted successfully. The Japanese Network series reported seven GF among the 24 evaluable patients after UCBT.17 On the basis of these discouraging results, the Japan Childhood Aplastic Anemia Study Group currently recommends against using UCBT as second-line therapy for non-responders.6 In our series, three of nine initial UCBT were associated with primary GF. We did not have any late graft loss. Of note, the graft characteristics (HLA match, total nucleated cells per kg, CD34/kg) of the non-engrafting patients were similar to those who were engrafted, but they received the lowest dose of CY (50mg/kg) in the conditioning regimen of their first UCBT. The five other patients on a similar preparative regimen, but containing a higher CY dose (120–150mg/kg) were engrafted. Two of the patients with primary GF had successful hematologic reconstitution after second UCBT. On account of the rapid availability of CB units, prompt re-transplantation may be lifesaving for these patients.

Mixed chimerism after UCBT is not infrequently observed in nonmalignant conditions.32 A high incidence of mixed chimerism was also reported in adult SAA patients after reduced-intensity conditioning.19 In contrast, complete donor chimerism was encountered in most other case reports.18, 20, 21 In our serial monitoring of chimerism, the outcome of engraftment was evident early post transplant. Only one patient demonstrated mixed chimerism and it was not persistent. It seems that earlier therapy and intensive immunosuppressive preparation for UCBT may facilitate prompt and complete donor engraftment.

The clinical course of our patients was complicated. A high frequency of Gram-negative sepsis was encountered early post transplant. This is not unexpected, considering the prolonged neutropenia these patients endured before and after transplant. This issue is magnified by the slower hematologic recovery after UCBT. We endorse the recommendation of early referral for transplantation33 and will pursue UCBT if a highly matched unrelated adult donor is not immediately identified and available. This is particularly pertinent in ethnic minorities when continual search is unlikely to identify a more suitable adult marrow donor at a later date.34

Viral reactivation was also common in this series. It was striking that five of our patients had elevated EBV genome in their blood post transplant and three developed EBV-LPD. Two did not responded to rituximab and one fatality occurred. The risk of EBV reactivation and lymphoproliferative disorder is increased in UCBT recipients who received ATG in their preparative regimen.35 Importantly, most children with SAA coming to transplant will have failed one or two courses of ATG/ALG in the months before transplant. This prolonged lymphopenia, irrespective of graft source, increases the likelihood of EBV and other virus reactivation. As most of the patients in our series had been exposed to equine ATG during their initial IST, we used rabbit ATG in the conditioning regimen. This latter product is more immunosuppressive and has been associated with a higher incidence of EBV-LPD in SAA patients after IST36 or alternative donor HSCT.28, 31 On account of the risk of this complication, we support the recommendation to screen for EBV viral load in the blood after transplant weekly, and to treat preemptively with rituximab for patients with persistently elevated or increasing viral loads.35, 37

One of the advantages of UCBT is the relative low incidence of severe acute GVHD, despite donor–recipient HLA mismatch. Kojima et al.17 reported a 33% incidence of severe GVHD in unrelated donor marrow transplantation in children with SAA. In our series, only two patients developed acute GVHD limited to the skin. This may be related to the ATG administration in close proximity to the CB infusion. Given the low rate of acute GVHD, we feel that the use of four of six HLA-antigen-matched donors can be justified. However, five of the eight surviving patients had chronic GVHD, probably as the result of high degree of donor/recipient mismatch, and probably suboptimal prophylaxis. This complication seems to be less frequent in unrelated donor transplants when alemtuzumab is used in conditioning.38, 39 Inclusion of this agent in the preparative regimen may be worth studying in the future.

In conclusion, UCBT is a feasible salvage therapy for SAA in children. The major complications are GF, infections (bacterial and viral) and EBV-LPD. Despite the encouraging results we are mindful that the data come from a retrospective analysis of a small number of patients. However, these children were managed by the same team with consistent donor selection criteria and supportive care measures. Given the low retrieval rate with a second course of IST for refractory SAA, our results support further evaluation of UCBT as an alternative treatment option for children who lack a molecularly matched unrelated donor and who have failed frontline immunosuppression.



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