Sickle Cell Disease

Bone Marrow Transplantation (2004) 34, 405–411. doi:10.1038/sj.bmt.1704606 Published online 12 July 2004

Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease

T V Adamkiewicz1, P S Mehta4, M W Boyer1,3, A Kedar4, T A Olson1,3, E Olson1, K Y Chiang1,3, D Maurer2, M J Mogul4, J R Wingard5 and A M Yeager1,3

  1. 1Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
  2. 2Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
  3. 3Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
  4. 4Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA
  5. 5Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA

Correspondence: Dr AM Yeager, University of Pittsburgh Cancer Institute, 5150 Centre Ave., Ste. 520, Pittsburgh, PA 15232, USA. E-mail: yeagera@upmc.edu

Received 22 March 2004; Accepted 27 April 2004; Published online 12 July 2004.

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Abstract

The lack of healthy HLA-identical sibs limits the use of allogeneic hematopoietic cell transplantation in children with high-risk sickle cell disease (SCD). We evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with SCD who had cerebrovascular accidents (CVAs) and did not have HLA-matched sib donors. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. Neutrophil levels above 0.5 times 109/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 times 109/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease (GVHD; two grade II, one grade III), and one developed extensive chronic GVHD. One patient had graft failure and autologous hematopoietic recovery. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD at 40 and 61 months, respectively, after UPBCT. These observations demonstrate the feasibility of UPBCT in children with SCD. Further studies of UPBCT for SCD are needed but, because of risks of procedure-related morbidity and graft rejection, should be restricted to pediatric patients with high-risk manifestations of SCD.

Keywords:

placental (cord blood) cells, allogeneic hematopoietic cell transplantation, sickle cell disease, allogeneic transplantation

Sickle cell disease (SCD; hemoglobin SS) causes substantial morbidity and mortality.1, 2 Ischemic cerebrovascular accidents (CVAs) occur in approximately 10% of children with SCD and can recur in 50–90%.3, 4, 5 Chronic red cell transfusions that maintain hemoglobin S levels below the heterozygous range must be continued indefinitely to prevent recurrent CVAs in children with SCD.6, 7 Chelation with deferoxamine decreases but does not always prevent the complications of iron overload in these patients,8, 9, 10 who may also develop alloimmunization against red cell antigens or HLA antigens.10, 11, 12

Transplantation of allogeneic hematopoietic cells (bone marrow or placental blood cells) from HLA-identical healthy sibs can establish normal erythropoiesis, abrogate symptoms and eliminate the need for chronic transfusions and chelation in children with high-risk SCD. More than 200 children and young adults have undergone bone marrow transplantation (BMT) from HLA-matched sibs13, 14, 15, 16, 17, 18, 19 for complications of SCD that included CVAs, recurrent acute chest syndrome20 or recurrent vaso-occlusive crises. These studies have shown overall survival and event-free survival of approximately 90 and 80%, respectively. Rejection of HLA-identical donor marrow occurred in 8–15% of these patients and was the major cause of treatment failure. Placental blood cell ('cord blood') transplantation from HLA-matched or one-antigen HLA class I-mismatched sibs in children with SCD has shown similar outcomes, with 90% event-free survival and 10% graft failure.21 The lack of HLA-matched healthy sibs, who are available for fewer than 15% of otherwise eligible patients, is the major obstacle to allogeneic hematopoietic cell transplantation for high-risk SCD.15, 22, 23

Transplantation of placental blood cells from unrelated donors has been therapeutic in pediatric patients and some adult patients with hematologic malignancies, metabolic diseases or hematopoietic disorders.24, 25, 26, 27, 28, 29, 30, 31 Unlike unrelated BMT, transplantation of unrelated placental blood cells that are mismatched with the recipient at one or two HLA antigens may result in complete and sustained engraftment of donor cells without significantly increased risks of severe graft-versus-host disease (GVHD).29, 32 The ability to perform unrelated placental blood cell transplantation (UPBCT) with less than completely HLA-matched units increases the potential pool of hematopoietic cell donors for children with high-risk SCD.33, 34 Another potential advantage of UPBCT for SCD is the ability to target collection of placental blood cell units to ethnic or racial groups that are under-represented in bone marrow registries. In this study, we report the results of UPBCT in three children who had SCD and CVAs but who did not have healthy HLA-matched sibs.

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Methods

Patients (Table 1)

The patients (two male, one female) were three, 6 and 12.5 years old, respectively, at the time of UPBCT. Clinically apparent ischemic CVAs occurred when the patients were 2, 5 and 5 years old, respectively, and all patients had residual hemipareses with evidence of brain infarction on magnetic resonance imaging (MRI) and cerebral arterial occlusions on magnetic resonance angiography (MRA). All patients were receiving chronic red cell transfusions. Patient 1 began chronic transfusions at age 5 years and had been receiving iron chelation therapy with subcutaneous or intravenous deferoxamine for 4 years before UPBCT. Before undergoing UPBCT, this patient had a serum ferritin level of 2169 ng/ml. A percutaneous liver biopsy showed no evidence of fibrosis and had an iron content of 7006 mug/g of dry tissue. Patients 2 and 3 began chronic transfusions approximately 1 year before UPBCT and were not receiving chelation therapy. Patients 1 and 3 had recurrent vaso-occlusive pain crises as well as CVAs, and patient 1 had recurrent priapism. Patient 2 underwent emergency splenectomy at age 9 months for sequestration crisis and had transient ischemic attacks despite chronic red cell transfusions. Patient 1 had a history of petit mal epilepsy and attention deficit disorder.


Protection of human subjects

The institutional review boards of Emory University and the University of Florida reviewed and approved the protocol for UPBCT. The parents of each patient provided informed consent, and patient 1 also provided assent for the procedure. An impartial witness attended the consent form review and signing process. Data and safety monitoring was provided to ensure compliance with the clinical research protocol.

HLA typing and selection of unrelated placental blood units

Serological typing of patient and donor HLA-A and HLA-B antigens was performed by the standard National Institutes of Health two-stage microlymphocytotoxicity assay. Typing of HLA-DRB1 alleles was first performed by low- to intermediate-resolution methods using commercially available sequence-specific oligonucleotide probe (SSOP) hybridization with genomic DNA amplified by the polymerase chain reaction (PCR). Confirmatory high-resolution typing of HLA-DRB1 antigens in donor and recipient pairs was then performed by DNA sequencing. The unrelated placental blood cell units were obtained from the Placental Blood Program of the New York Blood Center, New York, NY for patients 1 and 3 and from the St Louis Cord Blood Bank, St Louis, MO for patient 2. The units were mismatched at one HLA-B antigen and one HLA-DRB1 antigen in patient 1 and at one HLA-A and one HLA-B antigen in patients 2 and 3 (Table 1). Each cryopreserved placental blood cell unit was shipped to the transplantation center before initiation of pre-transplantation chemotherapy and was stored in the vapor phase of a liquid nitrogen freezer until the day of UPBCT.

Pre-transplantation conditioning regimen and placental blood cell infusion

Each patient received an immunosuppressive and myeloablative preparative regimen consisting of oral busulfan 40 mg/m2/dose given every 6 h for a total of 16 doses from the ninth day through the sixth day before UPBCT, intravenous cyclophosphamide 50 mg/kg/dose daily for a total of four doses on the fifth day through the second day before UPBCT and intravenous equine anti-human thymocyte globulin 30 mg/kg/dose daily for a total of three doses on the fourth day through the second day before UPBCT. This regimen was identical to that used in the international collaborative study of related allogeneic BMT in children with high-risk SCD.15 To decrease the risk of seizures associated with busulfan35 and reported after BMT from HLA-matched sibs in children with high-risk SCD,15, 19 each patient received prophylactic phenytoin from the 10th day before transplantation until 6 months after UPBCT. On the day of UPBCT, the placental blood cell unit was thawed, processed according to previously published methods36 and infused through a central venous catheter.

Post transplantation care and assessments

Prophylaxis of acute GVHD consisted of methylprednisolone 2 mg/kg daily from the fifth day through the 19th day after UPBCT30 and either cyclosporine (patient 1) or tacrolimus (patients 2 and 3). Each patient received intravenous granulocyte colony-stimulating factor (G-CSF) 10 mug/kg daily beginning on the fifth day after UPBCT until the absolute neutrophil count (ANC) exceeded 2 times 109 cells/l for two successive days. Patients received red cell transfusions to maintain hemoglobin levels above 10 g/dl and platelet transfusions to maintain platelet levels above 50 times 109/l. All blood products were irradiated to 25 Gy to decrease the risk of transfusion-associated GVHD and leukoreduced to decrease the risks of alloimmunization and transmission of cytomegalovirus (CMV). Hematologic recovery was defined as an absolute neutrophil count greater than 0.5 times 109/l for three consecutive days, a platelet level greater than 50 times 109/l without transfusions and a hemoglobin level greater than 10 g/dl without transfusions. Donor cell engraftment was determined by quantitative PCR analysis of informative polymorphic variable number of tandem repeat (VNTR) regions.37 Acute and chronic GVHD were assessed and graded according to published criteria.38, 39 Performance status of each patient was assessed by the Lansky play-performance scale.40

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Results (Table 2)

Engraftment

The doses of mononuclear placental blood cells at cryopreservation were 2.7, 7.1 and 10.3 times 107 cells/kg and after thawing and processing were 1.7, 5.7 and 9.3 times 107 cells/kg for patients 1, 2 and 3, respectively. The doses of CD34+ cells infused in patients 1 and 2 were 1.8 and 2.7 times 105 /kg, respectively; these data were not available for patient 3. Neutrophil recovery occurred at 23, 38 and 42 days after UPBCT, and platelet recovery occurred at 62, 81 and 121 days after UPBCT. Complete engraftment of donor cells by VNTR assays on peripheral blood DNA occurred at 26 days after UPBCT in patient 1 and at 51 days after UPBCT in patient 3 and remained at 100% thereafter. Patient 2 had graft failure and complete autologous hematopoietic recovery, with 100% host cells by VNTR at 4.5 months after UPBCT and with increasing levels of hemoglobin S (7 and 12% at 5 and 5.5 months, respectively, after transplantation). The patient resumed chronic red cell transfusions at 6 months after UPBCT and is now receiving chelation therapy with subcutaneous deferoxamine. Patients 1 and 3 have had no detectable hemoglobin S in blood samples since 3.5 months after UPBCT and have not required red cell transfusions since 7 and 4.5 months, respectively, after UPBCT. In association with donor cell engraftment in patients 1 and 3, the percentage of hemoglobin F progressively increased from undetectable levels before UPBCT to 18–21% by 3.5–5 months after UPBCT and then gradually declined to 1.5–7% by 15–25 months after UPBCT.

GVHD

All patients developed moderate or severe acute GVHD. Patient 1 developed cutaneous and gastrointestinal grade III acute GVHD at 18 days after UPBCT, and patients 2 and 3 developed grade II cutaneous acute GVHD at 9 and 46 days, respectively, after UPBCT. Skin biopsies from patients 1 and 3 and gastrointestinal tract biopsies from patient 1 showed histopathologic features of acute GVHD; no biopsies were obtained from patient 2. Manifestations of acute GVHD resolved in all patients after addition of or increased dosage of methylprednisolone. Approximately 10 months after UPBCT, patient 1 developed extensive chronic GVHD of the skin and liver, which resolved after treatment with methylprednisolone, tacrolimus and mofetil mycophenolate for approximately 28 months.

Other complications

No patients developed mucositis or hepatic veno-occlusive disease. At 20 days after UPBCT, patient 1 developed severe hypertension that required intravenous nitroprusside and was complicated by a generalized seizure. Brain imaging studies showed no evidence of hemorrhage or new infarcts. Owing to its potential contribution to hypertension and neurotoxicity, cyclosporine was discontinued and tacrolimus was initiated. Hypertension was subsequently well controlled with oral enalapril and amlodipine, and the patient had no further seizures or neurologic sequelae.

Patients 1 and 2 had episodes of bacteremia with coagulase-negative Staphylococcus species, which were treated with vancomycin. Patient 1 developed several other infections, including disseminated herpes zoster, enteritis associated with Clostridium difficile, enteritis caused by adenovirus, esophagitis caused by Candida species, and recurrent sinusitis and bacteremias caused by Klebsiella pneumoniae or group B beta-hemolytic Streptococcus species. These infections resolved after treatment with antiviral, antifungal or antibacterial agents. Patient 2 developed asymptomatic antigenemia with CMV at 39 days after UPBCT and received a 21-day course of intravenous ganciclovir. Patient 3 had no documented or suspected infectious episodes after UPBCT.

Approximately 42 months after transplantation, patient 1 developed exocrine pancreatic insufficiency that was manifested by fat malabsorption and for which he receives oral pancreatic enzyme replacement therapy. This patient had no documented episodes of acute or chronic pancreatitis before or after transplantation. He also developed hypothyroidism, the etiology of which is unknown, for which he receives oral levothyroxine.

Patients 1 and 2 had follow-up MRI and MRA evaluation of the central nervous system (CNS) at 60 and 36 months, respectively, after UPBCT, which showed no changes from the pre-transplant studies. Patient 3 had a brain MRA study at 30 months after UPBCT that showed progression of left internal carotid stenosis to complete occlusion and evidence of collateral revascularization when compared to a study obtained approximately 6 weeks before UPBCT. Brain MRI in this patient showed no new ischemic lesions.

Long-term followup (Table 2)

All patients are alive and off all immunosuppressive agents at 40, 44 and 61 months, respectively, after UPBCT. Patients 1 and 3 have play-performance scores of 100%. Patient 2 has persistent pain episodes despite chronic transfusion therapy and has a play-performance score of 70%. Patients 2 and 3 have maintained their age- and gender-appropriate percentiles for height and weight, but patient 1, who had both severe acute and extensive chronic GVHD, is now below the fifth percentile for both. Patient 1 is in age-appropriate grade in school, but patients 2 and 3 receive special education because of their initial cerebral ischemic events.


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Discussion

This report provides the proof of principle that unrelated placental blood cells are an alternative source of hematopoietic cells for transplantation in children with high-risk SCD. Even with a greater degree of HLA antigen disparity between donor and recipient, fewer patients develop acute and chronic GVHD after UPBCT than after unrelated, non-T-cell depleted BMT.28 The exact influence of HLA disparities on outcome of UPBCT is not fully established. However, without the requirement for complete (ie, HLA-A, HLA-B and HLA-DRB1) matching between donor and recipient, at least 90% of children with high-risk SCD who lack HLA-matched healthy sibs may have potential unrelated placental blood cell units matched for four or more HLA antigens.33, 34, 41 Using high-resolution HLA typing, most of the unrelated placental blood units thus identified are compatible with potential recipients at either four of six HLA antigens (approximately 90%) or five of six HLA antigens (approximately 50%), and only about 5% are matched for all six HLA antigens;33 [and current unpublished information].

Although reports of related hematopoietic cell transplantation for SCD have included patients with CVAs, recurrent acute chest syndrome, recurrent painful vaso-occlusive crises or other complications, we limited our study to children with SCD-associated CVAs. This group is at risk for subsequent CVAs and requires chronic transfusions and chelation, procedures with both acute and long-term risks. Furthermore, children with SCD-associated CVAs may have progressive CNS ischemia despite chronic transfusion regimens42 or treatment with hydroxyurea.43 In contrast, vascular disease in the CNS stabilizes or improves44 and rarely progresses19 after related allogeneic BMT for SCD. One of the two patients with sustained engraftment in this study had no new CNS ischemic lesions 60 months after UPBCT. The other patient had evidence of progressive CNS vasculopathy on MRA at 30 months after UPBCT, but because of the long interval between pre-transplant and follow-up MRA studies it is not known whether those changes occurred before or after UPCBT. Progression of stenosis in large cerebral arteries has occurred in some children with SCD who received BMTs from HLA-matched sibs;45, 46 [and F Bernaudin, personal communication], but its etiology remains unclear.

Engraftment, GVHD and event-free survival after UPBCT in children with SCD may substantially differ from those reported in children with other diagnoses. Graft failure occurred in one of the three patients despite an intensive preparative regimen and infusion of adequate doses of both mononuclear and CD34+ cells. This patient had reactivation of CMV and treatment with ganciclovir, factors that are strongly associated with rejection of unrelated placental blood cell grafts.26 The diagnosis of nonmalignant disease has also been identified as a risk factor for rejection after UPBCT.26, 31 Alloimmunization against HLA antigens may occur in patients with SCD,11, 12 and the presence of antidonor lymphocytotoxic antibodies correlates with increased risks of rejection after BMT.47 However, determination of antibodies against donor placental blood cells is not technically feasible and was not performed in any of the patients in this series.

One patient in this series developed severe acute and extensive chronic GVHD, as well as multiple infectious episodes that occurred in the clinical context of immunosuppression and immunodeficiency associated with GVHD. Although its incidence is lower after UPBCT than after unrelated BMT,29 acute GVHD nevertheless occurs in more than 50% of UPBCT recipients25, 26, 29, 30, 31 and is severe (grades III and IV) in 10–20%.25, 26, 29, 30, 31 In contrast, the incidence of acute GVHD in children with high-risk SCD who received BMTs from HLA-identical sibs ranges from 18–38% but is mostly mild to moderate (grades I and II).14, 15, 18, 19 The incidence of extensive chronic GVHD in children undergoing UPBCT (9%)31 is similar to that reported after BMT from HLA-identical sibs for high-risk SCD (3–8%).13, 14, 15, 18, 19 The degree of HLA disparity (greater than one antigen difference between donor and recipient vs zero to one antigen difference) has been suggested as a risk factor for development of GVHD,26 but other studies have not confirmed this observation.28, 29, 31 Aggressive approaches to treat or prevent acute GVHD may be needed in UPBCT for high-risk SCD.

Although all three patients in our study survived, the treatment-related mortality after UPBCT in children is 30% and almost 40% at 1 year and 2 years, respectively, after transplantation, without significant differences between patients who had underlying neoplastic diseases and those who had non-neoplastic diseases.29, 31 Overall survival in children and young adults with high-risk SCD who underwent allogeneic BMT13, 14, 15, 16, 18 or placental blood cell transplantation21 from HLA-matched healthy sibs is between 90 and 100%.

Our limited experience suggests that UPBCT may be curative in children with high-risk SCD who lack HLA-compatible sib donors, but is associated with substantial risks of morbidity and potentially mortality. Although hematopoietic cell transplantation is the only proven curative therapy for SCD, other treatments such as oral hydroxyurea,48, 49 novel transfusion strategies50 or oral chelators51 pose fewer short-term risks and could be considered in some children with SCD. Additional studies of UPBCT for SCD are warranted but should be undertaken with caution as we learn more about the factors that predict outcomes of UPBCT and as nontransplant therapies for SCD evolve and mature. These clinical trials should be approved by institutional review boards and offered initially to high-risk SCD patients, rather than using the more inclusive eligibility criteria used in the international collaborative study.15

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Acknowledgements

This study was supported by grants from the National Institutes of Health, Bethesda, MD (K23 HL04251) (TVA), (R01 CA40282 and U10 CA20549) (AMY), and by grants from the Emory Medical Care Foundation (TVA), the Phil Niekro Egleston Celebrity Classic/Jill Andrews Leukemia Research Fund (AMY), the Andrew McLeroy Memorial Research Fund (AMY), the Armstead-Barnhill Foundation for Sickle Cell Anemia Research (AMY) and the Stott Research Fund in Honor of Alex Jensen (AMY).