Biology of Blood and Marrow Transplantation
Volume 16, Issue 3 , Pages 344-349, March 2010

Successful Hematopoietic Stem Cell Transplantation in 2 Children with X-Linked Chronic Granulomatous Disease from Their Unaffected HLA-Identical Siblings Selected Using Preimplantation Genetic Diagnosis Combined with HLA Typing

  • Evgenios Goussetis

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • Corresponding Author InformationCorrespondence and reprint requests: Evgenios Goussetis, MD, SCT-Unit, Aghia Sofia Children's Hospital, Thivon and Mikras Asias, 11527 Athens, Greece.
    • ,
  • Christopher P. Konialis

      Affiliations

    • Department of Molecular Genetics and Preimplantation Genetic Diagnosis, Intergenetics Hellas, Diagnostic Genetic Center, Athens, Greece
    • ,
  • Ioulia Peristeri

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Vasiliki Kitra

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Maria Dimopoulou

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Theoni Petropoulou

      Affiliations

    • First Pediatric Clinic, Aghia Sofia Children's Hospital Medical School, University of Athens, Athens, Greece
    • ,
  • George Vessalas

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Andreas Papassavas

      Affiliations

    • Hellenic Cord Blood Bank, Foundation for Biomedical Research, Academy of Athens, Athens, Greece
    • ,
  • Marianna Tzanoudaki

      Affiliations

    • Immunology Department, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Georgia Kokkali

      Affiliations

    • Center for Human Reproduction, Genesis Athens Hospital, Athens, Greece
    • ,
  • Eftychia Petrakou

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Antonia Spiropoulos

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece
    • ,
  • Constantinos G. Pangalos

      Affiliations

    • Department of Molecular Genetics and Preimplantation Genetic Diagnosis, Intergenetics Hellas, Diagnostic Genetic Center, Athens, Greece
    • ,
  • Konstantinos Pantos

      Affiliations

    • Center for Human Reproduction, Genesis Athens Hospital, Athens, Greece
    • ,
  • Stelios Graphakos

      Affiliations

    • Stem Cell Transplant Unit, Aghia Sofia Children's Hospital, Athens, Greece

Received 3 September 2009; accepted 10 October 2009. published online 15 October 2009.

Article Outline

We report 2 children with X-linked chronic granulomatous disease (X-CGD) who underwent hematopoietic stem cell transplantation (HSCT) using grafts from their siblings selected before implantation to be both unaffected and HLA-matched donors. Preimplantation genetic diagnosis (PGD) along with HLA-typing were performed on preimplantation embryos by single-cell multiplex polymerase chain reaction using informative short tandem repeat markers in the HLA locus together with the gene region containing the mutations. Two singleton pregnancies resulted from the intrauterine transfer of selected embryos; these developed to term, producing 1 healthy female and 1 X-CGD carrier female, which are HLA-identical siblings to the 2 affected children. Combined grafts of umbilical cord blood (UCB) and bone marrow (BM) stem cells were administered to the recipients after myeloablative (MA) conditioning at the ages of 4.5 years and 4 years, respectively. Both patients are well, with complete donor hematopoietic and immunologic reconstitution, at 18 and 13 months posttransplantation, respectively. This report demonstrates that HSCT with HLA-matched sibling donors created by PGD/HLA typing of in vitro fertilized embryos is a realistic therapeutic option and should be presented as such to families with children who require a non-urgent HSCT but lack an HLA-genoidentical donor.

Key Words: Preimplantation genetic diagnosis/HLA testing, Hematopoietic stem cell transplantation, X-linked chronic granulomatous disease

 

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Introduction 

X-linked chronic granulomatous disease (X-CGD) is an inherited defect in phagocyte nicotinamide adenine dinucleotide phosphate oxidase resulting from a deficiency of gp91phox component. At the molecular level, X-CGD is caused by mutations affecting the CYBB gene on chromosome Xp21.1 1, 2. As a result of impaired phagocytic ability, affected persons suffer from severe recurrent infections, both bacterial and fungal, resulting in the formation of infiltrating granulomatous lesions. Despite prophylactic therapy, long-term survival remains poor; only 50% of patients are alive at the age of 30 years 3, 4. Allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-matched sibling donor (MSD) has achieved long-term cure of X-CGD in 80% to 90% of cases 5, 6. A healthy MSD is not available in the vast majority of the cases, however. For such patients, a matched unrelated donor (MUD) is a suitable option, but at the cost of increased teatment-related morbidity and mortality (TRM) 5, 7. Preimplantation genetic diagnosis (PGD) for single-gene diseases was developed to help families desiring a new pregnancy to select unaffected embryos in vitro, thereby avoiding the need for pregnancy termination. Recently, this strategy has been combined with HLA typing with the aim of selecting suitable histocompatible embryos as potential stem cell donors for affected siblings 8, 9, 10. There is limited experience with this methodology and even less with its completed clinical application, however.

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Methods 

Patient Characteristics 

Patient 1 

In this 4.5-year-old boy with an established diagnosis of X-CGD since infancy, diagnosis was confirmed by respiratory burst screening tests and by DNA CYBB gene sequencing (R73X C → T mutation). Despite both antimicrobial and interferon-γ prophylaxis, the patient had recurrent infections from the age of 4 months onward, and granulomatous colitis was diagnosed at the age of 1.7 years.

Patient 2 

This 4-year-old boy was diagnosed with X-CGD at age 6 months by both functional and molecular tests (R157X C → T mutation). Before presenting for HSCT, he had experienced multiple cervical abscesses despite receiving antibiotic prophylaxis.

Donor Selection 

Neither patient had an HLA-genoidentical sibling donor. The patients' parents came to the Diagnostic Genetic Centre in Athens on their own initiative for genetic consultation. After detailed genetic counseling, the couples came to the Centre for Human Reproduction, Genesis Athens Hospital for complete counseling regarding in vitro fertilization (IVF) and embryo biopsy procedures. The clinical protocol was approved by the center's Institutional Research and Ethics Committee for the IVF treatment, embryo biopsy, and PGD procedures required for the transfer of unaffected and HLA-identical embryos to the mother's uterus. Written informed consent concerning the PGD/HLA typing procedure, as well as the cryopreservation of nontransferred embryos for future use, in accordance with the Helsinki Declaration, was obtained from both couples. A single cycle of IVF was initiated for each couple, and standard hormonal stimulation and culture techniques were used to generate embryos for PGD and HLA genotyping 11, 12. All fertilized embryos were cultured and biopsied by laser on day 3 in the first couple and on day 5 for the second couple [13]. Embryo genotyping was performed using a nested multiplex polymerase chain reaction (PCR) approach, involving first- and second-round amplification of the informative polymorphic short tandem repeat (STR) markers previously selected by extensive HLA genotyping and haplotype analysis of the family members. Detection of the disease mutation was performed by minisequencing [14]. Embryos identified to be HLA-identical to the patients and unaffected by X-CGD (homozygous wild-type allele or heterozygous mutation) were transferred 6 days after fertilization to the uterus of the respective mothers. The 2 singleton full-term pregnancies resulted in the birth of 1 healthy and 1 X-CGD carrier female siblings. Confirmatory genetic testing was performed using chorionic villus sampling in the first trimester for CGD mutations and HLA typing. To rule out the possibility of extreme inactivation of the X chromosome in the case of the heterozygotic sibling donor carrying the nonmutated CYBB, postnatal neutrophil superoxide production was measured.

HSCT 

Umbilical cord blood (UCB) was collected, frozen, and stored in liquid nitrogen as described previously [15]. Given the limited experience with UCB transplantation (UCBT) in patients with X-CGD, we decided to combine UCB and bone marrow (BM) HSC from the same donors, to ensure stable long-term engraftment. Therefore, after parental written consent was provided, when the 2 sibling donors reached age 16 months, reduced-volume BM was harvested. Both patients were conditioned with busulfan (Bu; 16 mg/kg i.v) and cyclophosphamide (Cy; 200 mg/kg i.v.). Graft-versus-host disease (GVHD) prophylaxis comprised cyclosporine A and a short course of methotrexate (MTX). Time to white blood cell engraftment was defined as the first of 3 consecutive days with a neutrophil count > 0.5 × 109/L, and platelet engraftment was defined as the first of 3 consecutive days on which a platelet count > 20 × 109/L was maintained without transfusion. To assess engraftment and the degree of chimersm, patients were monitored at different time points, using a PCR assay to identify genetic polymorphism of STRs. Superoxide production by neutrophils was measured by the dihydrorhodamine (DHR) test. Expression of gp91phox on neutrophils was measured using the 7D5 monoclonal antibody (mAb) and flow cytometry.

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Results 

PGD/HLA Typing of Embryos 

Each family was subjected to a single clinical IVF cycle. A total of 48 embryos were tested for the 2 couples. Eight of these embryos were diagnosed as unaffected and HLA-matched, and 2 embryos from each cycle were transferred, resulting in 2 singleton pregnancies and 2 newborns, 1 healthy and 1 X-CGD carrier. All X-CGD–unaffected embryos not transferred were cryopreserved for eventual future use. Table 1 summarizes the PGD/HLA typing results.

Table 1. Summary of the PGD/HLA typing results
FamilyIVF CycleEmbryos FormedHLA-Matched, CGD-Unaffected EmbryosEmbryos TransferredPregnancies
11376∗21
21112†21

PGD indicates preimplantation genetic disease; CGD, chronic granulomatous disease. Biopsies were performed at the cleavage stage (day 3 after fertilization) for family 1 and at the blastocyst stage (day 5 after fertilization) for family 2.

∗Four embryos were homozygous for the wild-type allele.

†Both embryos were carriers for the CGD mutation.

Graft Characteristics 

The numbers of UCB-nucleated and CD34+ cells collected from the first donor (1.4 × 107/kg and 3.5 × 104/kg, respectively) were deemed insufficient to secure long-term engraftment. Therefore, we decided to increase the number of hematopoietic progenitors by harvesting a reduced BM volume from the same donor. In the case of second donor, and despite an adequate number of cells in the UCB unit, we decided to harvest a small volume (100 mL) of BM to further enrich the number of hematopoietic progenitors. Coinfusion of BM cells in the second case was chosen because of the extremely limited experience with matched related UCBT in X-CGD and the high risk of graft failure reported in small series of children undergoing unrelated UCBT [16]. In both cases, BM was harvested when the donors reached the age of 16 months. Details on the number of nucleated and progenitor cells of the grafts are given in Table 2.

Table 2. Characteristics of patients, donors, and grafts, and transplantation outcome
Patient 1Patient 2
Age, years4.54
SexMaleMale
Donor sexFemaleFemale
X-CGD carrier donorNoYes
UCB volume collected, mL112143
UCB nucleated cells/kg1.4 × 10710 × 107
UCB CD34+ cells/kg0.35 × 1052.8 × 105
BM volume collected, mL174100
BM nucelated cells/kg3.2 × 1083 × 108
BM CD34+ cells/kg13.6 × 1067.5 × 106
Neutrophil engraftmentDay +20Day +18
Platelet engraftmentDay +19Day +17
GVHDNoNo
ChimerismFull donorFull donor

CGD indicates chronic granulomatous disease; UCB, umbilical cord blood; BM, bone marrow; GVHD, graft-versus-host disease.

Transplantation Outcome 

Both patients engrafted quickly after receiving a combined graft of UCB and BM cells. Neutrophil engraftment was achieved on day +20 in patient 1 and on day +18 in patient 2, and platelet engraftment occurred on days +19 and +17, respectively. Complete donor-derived hematopoietic chimerism was repeatedly detected after day +60 posttransplantation by studying STRs. Neither patient developed acute or chronic graft-versus-host disease (aGVHD, cGVHD). Cyclosporine (CsA) and replacement i.v. immunoglobulin were stopped at 6 months posttransplantation. Patient 1 had normal stools since day +30 posttransplantation, indicating resolution of colitis. In patient 1, both DHR and gp91phox expression were restored to normal on 100% of the neutrophils posttransplantation, whereas in patient 2, only 50% of neutrophils exhibited normal DHR and gp91phox expression posttransplantation. Repeated testing revealed similar results at various time intervals posttransplantation (Figure 1). At their last follow-up visit, both patients were in excellent clinical condition, demonstrating normal hematopoietic and immunologic reconstitution at 18 and 13 months posttransplantation, respectively.

  • View full-size image.
  • Figure 1 

    Oxidative burst activity of neutrophils, expression of gp91phox, and hematopoietic chimerism. Both H2O2-producing granulocytes after phorbol myristate acetate stimulation by fluorescent activated cell sorting analysis (DHR test) and expression of gp91phox posttransplantation were corrected after transplantation. DHR before transplantation (A and B) showed neutrophils with no oxidative burst activity, whereas both DHR (C and D) and gp91phox expression (E and F) at 18 and 13 months posttransplantation, respectively, for patients 1 and 2 showed 100% corrected neutrophils for patient 1 and a 50% mosaicism for patient 2. Hematopoietic chimerism analysis by STR-PCR at 18 and 13 months posttransplantation, respectively, for patients 1 and 2 revealed 100% donor genotype (G and H). Lane 1, donor; lane 2, recipient; lane 3, recipient posttransplantaton.

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Discussion 

The practice of conceiving an additional child with the intention of using it as an HSC donor for an affected sibling has been done for many years [17]. In the early years, parents planned to have another child by natural conception and hoped for an HLA-matching sibling. More recently, Verlinsky et al. [18] reported HLA typing combined with PGD in a case of Fanconi anemia. Although only 3/16 embryos for X-linked recessive inheritance will be both disease-free and HLA-identical, the likelihood of conceiving a matched donor using PGD/HLA typing is much greater than that with a spontaneous conception. Only a limited number of PGD centers offering HLA typing on human preimplantation embryos exist worldwide, limiting experience with the combination of IVF and PGD to achieve pregnancy and birth of a healthy HLA-compatible sibling. Published data from different series worldwide have reported 64 children born after PGD/HLA testing; the pregnancy rate per embryo transfer was 34% on average, varying depending on the IVF center and age of the mother 10, 19, 20. All 64 children were healthy and HLA-identical to their affected siblings. In these series, only 12 transplantations leading to the cure of affected siblings have been reported 19, 21, 22. Although no mistakes on HLA typing have been reported so far, the possibility of misdiagnosis of either HLA typing or PGD resulting from technical and human errors cannot be excluded 19, 23. Therefore, it must be made clear to the family that prenatal diagnosis is an absolute requirement to rule out an affected pregnancy. In addition, the use of this method raises a number of practical and ethical issues, such as the creation of human beings solely for instrumental use, most of which can be addressed by careful genetic and psychological counseling of the parents 24, 25, 26. Other significant open issues remain, including the fate of unused healthy HLA-nonidentical embryos that greatly exceed the number created to address infertility. The law on medically assisted reproduction should provide regulations regarding the use of PGD/HLA typing and determine the fate of unused healthy embryos. In some countries, regulations permit the transfer of selected embryos based on HLA typing in combination with PGD, whereas in others this is not allowed. Clearly, further research is required to elucidate the clinical, social, psychological, and economic issues that might be relevant to the application of this technology.

Although infusion of autologous HSC genetically modified to express gp91phox has been associated with some transitory benefits in a few patients, the safety and efficacy of gene therapy in X-CGD remain of major concern 27, 28. Currently, allogeneic HSCT from an HLA-matched donor is the only therapeutic modality with curative potential for patients with X-CGD. Allogeneic HSCT is best performed at an early age in children with recurrent serious infections despite antimicrobial prophylaxis 6, 29. A recent study of the efficacy of allogeneic HSCT in 20 patients with X-CGD found that the type of donor (MSD or MUD) had no effect on transplantation outcome [30]. It is obvious, however, that the efficacy and safety of MUD-HSCT should be examined in larger cohorts of patients. Moreover, a MUD is available for only 60% to 70% of the patients in need of a donor, possibly even lower in patients of ethnic minorities [31]. Experience with either related or unrelated UCB as the source of HSC for patients with X-CGD is very limited, and only a few cases have been reported so far [32].

Following the recently published first case report of successful HSCT of an X-linked-CGD patient using preimplantation female sex typing and HLA-typing [33], we describe 2 additional patients who underwent successful transplantation from a matched healthy sibling preselected by combined PGD and HLA typing. We chose to use PGD rather than female gender selection to detect the disease-specific mutation, to preclude the rejection of unaffected male embryos that cannot be differentiated from those affected when using fluorescein in situ hybridization (FISH) for female sex typing.

PGD/HLA typing technology should be considered and discussed with parents in cases where no suitable MSD is available and transplantation using an unrelated donor either carries significantly higher risks than the use of a sibling donor or is not possible because of the unavailability of a suitable MUD. The foregoing methodology can be applied in patients requiring nonurgent HSCT, such as patients with a genetic disease or children who may require transplantation in the future because of progression of an underlying disease, such as acute lymphoblastic leukemia ALL) in first complete remission (CR1) (20). In addition, the parents of the affected child still must be in reproductive age. Before making any decision, parents should be informed about the efficacy and safety of all alternative options, such as allogeneic HSCT using an MUD or an unrelated UCB unit. Parents also should be informed about the possibility of using BM or reduced-volume BM plus UCB, as in our patients reported here, especially when insufficient UCB cells are available. A high cell dose (> 3.7 × 107/kg) is considered crucial to sustain engraftment in patients with nonmalignant diseases undergoing MRD-UCBT [34]. Although in patient 2, the UCB nucleated cells would have been sufficient to secure engraftment without the addition of BM cells, we chose to combine UCB and BM to increase the cell dose because of the limited and not encouraging experience with UCBT in patients with X-CGD patients [32]. However, BM harvest, especially from a pediatric donor, is an invasive procedure and should be chosen only after UCB collection or transplantation fails. In such cases, we recommend delaying transplantation until the donor is between the ages of 12-24 months. Within this age range, depending on the recipient's weight, a reduced BM volume not exceeding 15 mL/kg donor weight should suffice. Alternative strategies pursued to obtain a high rate of engraftment in the presence of insufficient UCB include coinfusion of third-party mesenchymal stem cells [35] or mobilized CD34+ cells [36]. However, the available data are insufficient to offer such a strategy as an alternative to BM cells obtained from the same donor to increase the engraftment potential of the UCB graft.

In conclusion, transplant physicians should be aware of the feasibility and efficacy of the PGD/HLA typing method as well as the indications of its use. Regardless of the final decision, an immediate search for a suitable unrelated donor at the time of establishing the indication for HSCT should never be omitted.

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Acknowledgments 

Financial disclosure: The authors thank Dr F. Fiorentino (GENOMA, Rome, Italy) for his valuable assistance with the PGD/HLA testing of our first patient. They also thank Professor B. H. Belohradsky and Dr E. Renner (Abteilung für Antimikrobielle Therapie und Infektionsimmunologie, Kinderklinik und Poliklinik der Universität München) for assessing gp91phox expression.

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 Financial disclosure: See Acknowledgments on page 348.

PII: S1083-8791(09)00466-2

doi:10.1016/j.bbmt.2009.10.010

Biology of Blood and Marrow Transplantation
Volume 16, Issue 3 , Pages 344-349, March 2010

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