Also see RELATED-DONOR CORD BLOOD TRANSPLANTS and REVIEWS

ii. CONGENITAL DISORDERS

Also see SICKLE CELL DISEASE AND THALASSEMIA

1. Trends in haematopoietic cell transplantation for inborn errors of metabolism. Boelens JJ. J Inherit Metab Dis. 2006;29:413-20.

Only for Hurler syndrome, X-ALD and infantile Krabbe disease, are detailed studies available suggesting that HCT is indicated for carefully selected cases. Improvement of transplantation techniques and alternative therapies may change the recommended (contra-)indications for transplants in these disorders. A recent example of emerging transplantation techniques is the fast availability of unrelated cord blood (UCB). UCB makes HCT feasible in patients with rapidly progressive neurological diseases.

The main rationale for HCT in inborn errors of metabolism (IEM) is still based on the provision of correcting enzymes by donor cells within and outside the blood compartment. However, the exact mechanisms for therapeutic benefit of HCT are not completely understood and may differ between the various diseases. For instance, in X-linked adrenoleukodystrophy (X-ALD) the mechanism may be related to halting the CNS inflammatory process associated with myelin injury.

In this mini-review, the authors discuss the outcome/effect of HCT on Hurler syndrome, X-ALD, and infantile Krabbe disease, since these are the diseases with the best detailed studies. In addition, the authors comment on new trends in HCT for IEMs: (1) unrelated cord blood as an emerging stem cell source, (2) enzyme replacement therapy in combination with HCT and (3) mesenchymal stem cell transplantation.

In regard to unrelated UCB as an emerging stem cell source, the authors emphasize that the availability of an unrelated donor is a limiting factor. Many children lack a matched family donor, and recruitment of an unrelated adult donor sometimes takes months, too long for the treatment of a (rapidly) progressive disorder. Within a month from diagnosis, HCT can be performed using UCB as a stem cell source. In addition, better engraftment rates are reported for UCB in comparison to other stem cell sources.

The authors summarize the advantages of banked umbilical cord blood as follows: (1) rapid availability, associated with (2) a lower incidence of GVHD (therefore less stringent criteria for HLA-matching), (3) reduced likelihood of transmitting infection (viral), (4) less graft failure reported for IEM, and finally (5) suggestions of capability for transdifferentiation (to osteoblasts and astrocytes, for instance) because of a more primitive stem cell population.

2. Results of unrelated cord blood transplant in Fanconi anemia patients: risk factor analysis for engraftment and survival. Gluckman E, Rocha V, Ionescu I, Bierings M, Harris RE, Wagner J, Kurtzberg J, Champagne MA, Bonfim C, Bittencourt M, Darbyshire P, Fernandez MN, Locatelli F, Pasquini R; Eurocord-Netcord and EBMT. Biol Blood Marrow Transplant. 2007;13:1073-82.

The authors retrospectively analyzed results of unrelated cord blood transplantation (UCBT) in 93 Fanconi anemia (FA) patients. Median age at transplantation was 8.6 years (1-45). The units transplanted were HLA-A, -B, or -DRB1 identical in 12 cases, 1 HLA mismatch in 35 cases, and 2 or 3 HLA differences in 45 cases. The median number of nucleated cells (NC) and CD34+ cells infused of recipient weight was 4.9x10(7)/kg and 1.9x10(5)/kg, respectively. Participating centers selected the preparative regimen of their choice, in 57 patients (61%), it included Fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted mostly of cyclosporine with prednisone.

The cumulative incidence (CI) of neutrophil recovery was 60+/-5% at day +60. In multivariate analysis, Fludarabine containing regimen and NC infused >or=4.9x10(7)/kg were associated with higher probability of recovery. CI of grade II-IV acute and of chronic GVHD (aGVHD, cGVHD) was 32%+/-5% and 16%+/-4%, respectively. Overall survival (OS) was 40%+/-5%. In multivariate analysis, factors associated with favorable outcome were use of Fludarabine in the conditioning regimen, number of NC infused>or=4.9x10(7)/kg, and negative cytomegalovirus (CMV) serology in the recipient.

The authors concluded that factors easily modifiable such as donor selection and a Fludarabine-containing regimen can considerably improve survival in FA patients given a UCBT.

3. Two reports of single patients transplanted with cord bloods for correction of congenital disorders:

Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen. Tono C, Takahashi Y, Terui K, Sasaki S, Kamio T, Tandai S, Sato T, Kudo K, Toki T, Tachibana N, Yoshioka T, Nakahata T, Morio T, Nishikomori R, Ito E. Bone Marrow Transplant. 2007;39:801-804.

Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome. Lucas KG, Ungar D, Comito M, Bayerl M, Groh B. Bone Marrow Transplant. 2007;39:55-6.

4. Outcome in patients with Wiskott-Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan. Kobayashi R, Ariga T, Nonoyama S, Kanegane H, Tsuchiya S, Morio T, Yabe H, Nagatoshi Y, Kawa K, Tabuchi K, Tsuchida M, Miyawaki T, Kato S. Br J Haematol. 2006; 135:362-6.

A total of 57 patients with Wiskott-Aldrich Syndrome (WAS) were studied after undergoing stem cell transplantation (SCT) in Japan between January 1985 and December 2004. Eleven patients received transplants from human leucocyte antigen (HLA)-matched related donors, 10 from HLA-mismatched related donors, 21 from unrelated bone marrow donors, and 15 from unrelated cord blood donors. Nine of the 57 patients rejected the initial graft. The overall 5-year survival rate was 73.7% and the 5-year failure-free survival rate was 65.7% (failure was defined as rejection or death). The overall 5-year survival rates for patients receiving bone marrow and cord blood from unrelated donors were both 80.0%.

Based on univariate analysis, the factors associated with poor survival were: transplantation from an HLA-mismatched related donor, patient age of more than 5 years at the time of transplantation, and a conditioning regimen other than busulfan and cyclophosphamide (BU-CY) or busulfan, cyclophosphamide and antithymocyte globulin (BU-CY-ATG). In a multivariate analysis, a conditioning regimen other than BU-CY and BU-CY-ATG was the only independent factor associated with transplantation failure.

Given the improved outcome for WAS patients following transplantation from an unrelated donor, the authors concluded that patients with WAS should receive SCT as soon as possible after diagnosis.

5. Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Martin PL, Carter SL, Kernan NA, Sahdev I, Wall D, Pietryga D, Wagner JE, Kurtzberg J. Biol Blood Marrow Transplant. 2006;12:184-94.

Inherited metabolic storage diseases are a heterogenerous group of rare disorders due to mutations that cause deficiencies in various enzymes, thus resulting in an accumulation of toxic metabolites in various tissues. A subset of these conditions, lysosomal and peroxisomal storage diseases (LSDs), is characterized by severe neurologic deterioration and eventual death in the first or second decade of life. LSDs can be divided into the mucopolysacharidose, which are characterized by an accumulation of glycosaminoglycans causing damage to the brain, heart, cornea, cartilage, liver, and other organs; and sphingolipidoses, or leukodystrophies, which are characterized by defects in lysosomal acid hydrolases involved in sphingolipid catabolism resulting in demyelination in the central and peripheral nervous systems.

Allogeneic stem cell transplantation can prevent the progression of LSD symptoms by providing a continuous source of normal enzymes from engrafted donor cells, provided that the enzyme is produced by normal leukocytes. Over the past 2 decades, allogeneic BMT from matched related carrier and noncarrier donors has been shown to be beneficial in >200 patients with Hurler syndrome, and others with adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe disease (globoid leukodystrophy).

However, many children with LSDs who could benefit from allogeneic transplantation therapy lack an appropriately matched donor. Partially HLA-matched, banked, unrelated donor umbilical cord blood can provide donor stem cells for transplantation of children who lack suitable bone marrow donors.

The Cord Blood Transplantation Study (COBLT), sponsored by the National Heart, Lung, and Blood Institute, is a phase II multicenter study designed to evaluate the use of cord blood in allogeneic transplantation. In this report, the outcomes of cord blood transplantation in 69 patients with lysosomal and peroxisomal storage diseases are reported. Patients with mucopolysaccharidoses I to III, mucolipidoses (ML) II (n = 36), adrenoleukodystrophy (n = 8), metachromatic leukodystrophy (n = 6), Krabbe disease (n = 16), and Tay-Sachs disease (n = 3) were enrolled between August 1999 and June 2004. All patients received the same preparative regimen, graft-versus-host disease (GVHD) prophylaxis, and supportive care. End points included survival, engraftment, GVHD, and toxicity. Sixty-nine patients (64% male; 81% white) with a median age of 1.8 years underwent transplantation with a median cell dose of 8.7 x 10(7)/kg. One-year survival was 72% (95% confidence interval, 61%-83%). The cumulative incidence of neutrophil engraftment by day 42 was 78% (95% confidence interval, 67%-87%) at a median of 25 days. Grade II to IV acute GVHD occurred in 36% of patients. Similar to what has been observed after unrelated BMT, children with congenital disorders in this study had a low incidence of severe acute and chronic GVHD as compared with young children with leukemia.

Cord blood donors are readily available for rapid transplantation. Cord blood transplantation should be considered as frontline therapy for young patients with lysosomal and peroxisomal storage diseases.

6. Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency. Bhattacharya A, Slatter MA, Chapman CE, Barge D, Jackson A, Flood TJ, Abinun M, Cant AJ, Gennery AR. Bone Marrow Transplant. 2005 Aug;36:295-9.

Primary immunodeficiencies (PID) are a rare but important cause of mortality and morbidity in childhood. Untreated, the most severe disorders, known collectively as severe combined immunodeficiency (SCID), are invariably fatal within the first year of life. International registry data have demonstrated that other less immediately life-threatening PID have a poor long-term outlook. HSCT using an HLA-matched sibling donor or from an HLA-matched volunteer gives good results, with over 80% cure for patients with SCID and over 70% cure for patients with other PID.

Umbilical cord stem cell transplantation (UCSCT) has several advantages including ready availability of the donor unit, no risk to donor, low rate of viral contamination, low risk of graft-versus-host disease (GVHD), tolerance of 1-2 HLA mismatch and ease of arranging a date for transplantation. Furthermore, transplants often need to be arranged urgently, particularly for SCID, and GVHD is an unwanted complication (unlike in haematological malignancy where a graft-versus-leukaemia effect is encouraged).

There is little information regarding outcome of UCSCT for PID. A number of individual case reports have been published but only one small case series describing the outcome of UCSCT for primary immunodeficiency in eight patients. The authors report the results of UCSCT in eight patients with severe combined immunodeficiency (SCID), and six with other combined immunodeficiencies. Of the patients, 12 received unrelated cords, and two had sibling transplants.

The median time between identifying a cord from the registry and requesting the cord to be transferred to the centre for use was 8 days, a time period considerably shorter than the 4-6 weeks that it takes to receive marrow from a matched unrelated donor. Median age at transplant was 3.5 months, median nucleated cell dose was 0.8 10⁸/kg. All engrafted. Median time to neutrophil engraftment was 22 days, median time to platelet engraftment was 51 days. One developed significant grade III GVHD post transplantation. In six patients who have immuno-reconstituted sufficiently to evaluate, all have antibody responses to protein antigens. Donor chimerism has remained stable over time in all the patients, with no loss of graft.

Two patients in this series died. One was admitted on full mechanical ventilatory support for severe parainfluenza type 3 pneumonitis, and one had severe materno-fetal engraftment with GVHD and pneumonitis at presentation. These patients would fall into the high-risk group of patients with SCID in whom mortality has been historically very high. In contradistinction, two patients who were high risk for poor outcome, with Omenn syndrome and reticular dysgenesis, respectively, were successfully transplanted and have 100% donor chimerism.

In the authors' historical published series of SCID patients receiving marrow stem cells, depleted of T cells using CAMPATH-1 M and complement, 49% of 37 transplant episodes achieved engraftment, with 63% survival overall, compared to 86% survival and cure in this report. The current results also compare favorably with published pooled European data on the outcome of HLA-mismatched transplants for SCID between 1996 and 1999, with a survival of 77%. Results of HSCT for PID have been improving progressively - results for a matched unrelated donor transplant for SCID are 63%, and for other combined immunodeficiencies 42%. Although this series using UCSC is small, the data are at least comparable.

7. Unrelated umbilical cord stem cell transplantation for X-linked immunodeficiencies. Ziegner UH, Ochs HD, Schanen C, Feig SA, Seyama K, Futatani T et al. J Pediatr 2001; 138:570-573.

This report describes successful cord blood transplantation of 2 brothers aged 8 months and 4 years with X-linked lymphoproliferative syndrome, and an 11-year-old boy with X-linked hyperimmunoglobulin-M syndrome. Banked unrelated umbilical cord blood matched at 5 of 6 human leukocyte antigen loci was used to reconstitute the immune system. Pretransplant cytoreduction and posttransplant graft-versus-host prophylaxis were given. Hematopoietic engraftment and correction of the genetic defects were documented by molecular techniques. Two years after transplantation, all 3 patients have normal immune systems. The authors concluded that their data support the wider use of banked partially matched cord blood for transplantation in primary immunodeficiencies.

8. Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience. Knutsen AP, Wall DA. J Clin Immunol 2000; 20:466-476.

Eight children received unrelated cord blood hematopoietic cell transplantation for the treatment of combined immunodeficiency diseases. The patients ranged in age from 2 weeks to 8 years. The cord blood units were 3/6 HLA antigen matches in two children, 4/6 in four children, and 5/6 in two children, with molecular HLA-DR mismatch in three of the children. The average time for neutrophil engraftment (ANC >500/mm³) was 12 days (range 10-15 days) and the average time for platelet engraftment (platelet count >20,000/mm³) was 36 days (range 24-50 days). A patient with reticular dysgenesis failed to engraft following her first transplant, but fully engrafted after a second unrelated donor cord blood transplantation. Five of six patients exhibited grade I GVHD, while one child had grade IV skin and gut GVHD. Immunologic reconstitution demonstrated that cord blood stem cell transplantation resulted in consistent and stable T-, B- and natural killer (NK) cell development. The authors concluded that unrelated umbilical donor cord blood should be considered as an alternative source of stem cells for transplantation in children with severe combined immunodeficiency syndromes when an HLA-matched sibling is not available.
The authors indicated that another alternative is to use a T-cell-depleted HLA-haploidentical bone marrow, but there is typically a prolonged period for T-cell engraftment to occur, up to 3 to 6 months, and then weak T-cell function and B-cell antibody function frequently remains abnormal. Graft failure and the prolonged time to engraftment is a particular problem if the infant is already infected prior to the time of transplant. Benefits of a cord blood transplant include rapid and reliable recovery of immune function, low risk of GVHD, and low viral transmission rate.

9. Unrelated cord blood transplantation in a Fanconi anemia patient using fludarabine-based conditioning. de Medeiros CR, Silva LM, Pasquini R. Bone Marrow Transplant 2001; 28:110-112.

The authors point out that patients with Fanconi anemia are natural candidates for non-myeloablative transplantation, because of their cellular hypersensitivity to DNA cross-linking agents, such as cyclophosphamide and radiotherapy. They transplanted a 5-year-old girl with Fanconi anemia with a cord blood from an HLA-A, B and CRB1 identical unrelated donor. They used fludarabine and sublethal irradiation associated with cyclosporin and mycophenolate mofetil posttrransplant. The patient had minimal complications and no acute or chronic GVHD.

10. Fludarabine-based protocol for human umbilical cord blood transplantation in children with Fanconi anemia. Aker M, Varadi G, Slavin S, Nagler A. J Pediatr Hematol Oncol 1999; 21:237-239.

A 12-year-old girl with Fanconi anemia received a human umbilical cord blood transplant from a fully matched sibling donor following a conditioning regimen of fludabarine, ATG, and cyclophosphamide with no irradiation. The regimen was well tolerated with very mild toxicity and no major transplant-related complications or >grade II graft-versus-host disease. Engraftment was normal and sustained and chimerism was 100% donor origin as determined by restriction fragment length polymorphism.

11. Prompt and durable hematopoietic reconstitution by unrelated cord blood transplantation in a child with Fanconi anemia. Yoshimasu T, Tanaka R, Suenobu S, Yagasaki H, Yoshino H, Ueda T et al. Bone Marrow Transplant 2001; 27:767-769.

The authors describe an 8-year-old girl with Fanconi anemia whose hematopoiesis was successfully restored by unrelated umbilical cord blood transplantation. The patient had become resistant to androgen therapy, and developed intracranial hemorrhage and dyserythropoiesis. Her hematopoietic recovery after the transplantation was excellent and a complete chimerism has been durably maintained.

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