ii. CONGENITAL DISORDERS Page 2

12. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A et al. N Engl J Med 1989; 321:1174-1178.

This article is of historic interest since this was the first ever performance of an umbilical cord blood transplant. The patient was cured of Fanconi anemia.

13. Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease. Bhattacharya A, Slatter M, Curtis A, Chapman CE, Barge D, Jackson A et al. Bone Marrow Transplant 2003; 31:403-405.

The authors report the first patient with chronic granulomatous disease who underwent successful HLA identical sibling umbilical cord stem cell transplantation after myeloablative conditioning. The patient presented with colitis, confirmed as CGD at 2 years of age. Following BU16/CY200 conditioning, he had cord blood transplant from his unaffected HLA identical sister. A year post-transplant, his colitis had resolved clinically and on radioisotope scan growth has improved. Neutrophil oxidative burst was 92% normal with full donor lymphocyte reconstitution.

14. Brief report: correction of X-linked lymphoproliferative disease by transplantation of cord-blood stem cells. Vowels MR,Tang RL, Berdoukas V, Ford D, Thierry D, Purtilo D et al. N Engl J Med 1993; 329: 1623 -1625.

A boy with X-linked lymphoproliferative disease was transplanted with cord blood stem cells from an HLA-identical sibling. A conditioning regimen not involving radiation was used, consisting of cyclophosphamide, melphalan, and antithymocyte globulin. The transplant resulted in correction of the genetic defect and the patient’s hypogammaglobulinemia.

15. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, Allison-Thacker J, Wood S, Wenger DA, Rubinstein P, Hopwood JJ, Krivit W, Kurtzberg J. N Engl J Med. 2004;350:1960-9.

Hurler's syndrome (the most severe form of mucopolysaccharidosis type I) causes progressive deterioration of the central nervous system and death in childhood. Allogeneic bone marrow transplantation before the age of two years halts disease progression and prolongs life. The authors report on 20 children who were treated with cord-blood transplants from unrelated donors and a myeloablative preparative regimen that did not involve total-body irradiation. The cord-blood donors had normal alpha-L-iduronidase activity (mean number of cells, 10.53x10⁷ per kilogram of body weight) and were discordant for up to three of six HLA markers. Seventeen of the 20 children were alive a median of 905 days after transplantation, with complete donor chimerism and normal peripheral-blood alpha-L-iduronidase activity (event-free survival rate, 85 percent). Transplantation improved neurocognitive performance and decreased somatic features of Hurler's syndrome. The authors concluded that cord blood from unrelated donors appears to be an excellent source of stem cells for transplantation in patients with Hurler's syndrome and that cord-blood transplantation favorably altered the natural history of Hurler's syndrome.

16. Advances in the treatment of mucopolysaccharidosis type I. Muenzer J, Fisher A. N Engl J Med. 2004;350:1932-4.

In a perspective about the above cited article, the authors briefly review the mucopolysaccharidoses and point out that it is appropriate to diagnose mucolpolysaccharidosis type I in all patients with alpha-L-iduronidase deficiency, reserving the designation of Hurler's syndrome for the severe form of the disease. The disorders are ideal candidates for treatment because residual enzyme activity of 1 to 2 percent is all that is needed to prevent storage disorders. For optimal benefit, any intervention must occur before the progressive accumulation of glycosaminoglycans leads to irreversible tissue and organ damage.

More than 300 transplantations, initially of bone marrow and now of umbilical-cord blood, have been performed worldwide in patients with Hurler's syndrome. This therapy is effective for the somatic disease, except for bone and eye disease. Cord-blood transplantation appears to be as effective as bone marrow transplantation. Life expectancy is increased, hepatosplenomegaly resolves, cardiac disease is stabilized and there is improvement in the range of motion of joints, airway disease and hearing. However, there is minimal effect on the progression of the skeletal disease.

Hematopoietic stem-cell transplantation is now the treatment of choice for a child with Hurler's syndrome who is younger than two years of age and has minimal or no central nervous system disease. Transplantation is currently not recommended for the severe form of Hunter's syndrome or Sanfilippo's syndrome, since neurologic preservation has not bee observed in either disorder. Enzyme replacement therapy is recommended for patients with milder or attenuated forms of mucopolysaccharidosis type I and for patients with neurologic impairment.

17. 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.

IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) is a disorder of regulatory T-cell function, which can be associated with a fatal outcome early in life. Most IPEX patients develop symptoms related to autoimmunity during the first 3 months of their life. The most common presenting features are enteropathy, diabetes mellitus and failure to thrive and many patients also have eczema, hemolytic anemia, thrombocytopenia (from autoantibodies), autoimmune hypothyroidism, splenomegaly and lymphadenopathy. Allogeneic SCT can be curative for this disorder, but pre-transplant disease-related complications may preclude a full myeloablative conditioning regimen.

The authors report a 7-year-old boy with an immune deficiency consistent with IPEX, who had successfully undergone a cord blood transplant at age 6 following a submyeloablative conditioning regimen consisting of fludarabine, busulfan and anti-thymocyte globulin. The patient received a HLA 5/6 matched, unrelated donor umbilical cord blood transplant providing 1.1x10⁸ TNC/kg and 3x10⁵ CD34+ cells/kg. Fourteen months post-transplant the patient has no evidence of GVHD, infection or airway issues but continues to have poor linear growth, and is receiving growth hormone injections.

The long-term prognosis for patients with IPEX syndrome is poor. A recent review of previously reported patients (n=52) indicated that only six of these patients have survived long term. Allogeneic SCT can be curative for this disorder, but mixed results have been seen. Considering the fact that some IPEX patients may have experienced significant organ toxicity before transplant that could complicate the use of high-dose chemotherapy, a reduced intensity preparative regimen may be preferable to minimize toxicity.

18. Unrelated cord blood transplantation in an infant with severe multisystem Langerhans cell histiocytosis: clinical outcome, engraftment and culture of monocyte-derived dendritic cells. Meyer-Wentrup F, Foell J, Wawer A, Burdach S. Bone Marrow Transplant. 2004;33:875-6.

Langerhans cell histiocytosis (LCH) is a rare disease of still unknown etiology characterized by the accumulation of abnormal Langerhans cells in locations where they are normally not found. The authors report umbilical cord blood transplantation from an unrelated donor with a single HLA-mismatch at the B locus in a 15-month-old infant with severe multisystem LCH. At 4 months after discontinuation of immunsuppressive therapy the patient shows no signs of LCH or GVHD and is in good clinical condition. The authors state that their data add evidence to the concept of treating refractory severe LCH with hematopoietic cell transplantation, and further state that umbilical cord blood transplants may represent a curative treatment option particularly since many affected patients are infants.

19. Umbilical cord blood stem cell transplantation from unrelated HLA-matched donor in an infant with severe congenital neutropenia. Mino E, Kobayashi R, Yoshida M, Suzuki Y, Yamada M, Kobayashi K. Bone Marrow Transplant. 2004;33:969-71.

Severe congenital neutropenia (Kostmann syndrome) is an inherited hematologic disorder with severe neutropenia from early infancy. Most patients die because of infection. Although more than 95% of patients respond to therapy with recombinant human granulocyte colony-stimulating factor, about 10% of such patients develop MDS/AML, and the mortality rate of such patients is 70%. The authors report a 6-month-old boy who received a cord blood transplant using an HLA-matched (as determined by DNA typing) unrelated donor. A total of 6.4 x 10⁷ nucleated cells/kg were infused after conditioning with busulfan/horse antihuman thymocyte serum/cyclophosphamide. Engraftment was prompt and no GVHD developed under treatment with cyclosporin A and methyl prednisolone. The patient maintains normal hematopoiesis at 32 months posttransplant and his mental and physical development are normal.

20. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Peters C, Charnas LR, Tan Y, et al. Blood. 2004;104:881-8.

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Twelve of the transplants were performed using umbilical cord blood. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P <.01). The authors concluded that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

21. Purine nucleoside phosphorylase deficiency (PNP-def) presenting with lymphopenia and developmental delay: successful correction with umbilical cord blood transplantation. Myers LA, Hershfield MS, Neale WT, Escolar M, Kurtzberg J. J Pediatr. 2004;145:710-2.

Purine nucleoside phosphorylase deficiency (PNP-def) is a rare immunodeficiency syndrome generally characterized by profound T-cell deficiency with variable B-cell function. Patients with PNP-def are susceptible to opportunistic infections similar to those associated with SCID, buts the onset may be delayed beyond infancy. However, these characteristics may vary among patients, and in the same patient, over time. Two thirds of patients with PNP-def have neurologic abnormalities and one third have autoimmune disease. A high frequency of neurologic disease distinguishes PNP-def from SCID and most other immunodeficiencies. Most patients die of infection and none have survived adolescence without undergoing bone marrow transplantation.

The male patient in this report presented atypically with few infections and normal T-cell function. Progressive lymphopenia, ataxia, and developmental delay led to diagnosis. Umbilical cord blood transplantation, performed at age 3½ years, corrected the immunodeficiency. He was transplanted with 7.6 x 10⁷ nucleated cells per kilogram body weight from a 5/6 antigen matching, unrelated, female umbilical cord blood donor. At over 1 year after transplantation, immunoglobulin concentrations are normal, the ataxia has resolved, and he has normal receptive language and cognitive abilities but mild expressive speech delay. He has gross motor delay and hyopotonia. In all areas of development, he is learning at the same rate as his peers.

The authors emphasize the need to thoroughly investigate lymphopenic infants. A close collaboration between this patient's pediatrician and subspecialists led to early diagnosis of PNP-def despite atypical features. Knowledge gained from subsequent evaluations has expanded knowledge of the natural history of this rare disorder.

22. Results of the cord blood transplantation study (COBLT): Clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with inborn errors of metabolism. Kurtzberg J, Carter SL, Sahdev I, et al. Biol Blood and Marrow Transplant 2005;11(2, Suppl.1):82.

Outcomes of unrelated umbilical cord blood transplantation were reported in 32 patients with inborn errors of metabolism. A common protocol was used for the preparative regimen (busulfan, cyclophosphamide, ATG) and GVHD prophylaxis (cyclosporine and steroids). Diagnoses were MPS I Hurler's syndrome (n=13), Hurler-Sheie syndrome (n=2), Sanfilippo's syndrome (n=2), I-cell disease (n=1), Krabbe's disease (n=7), Tay-Sachs disease (n=2), and adrenoleukodystrophy (ALD) (n=5). Median age was 1.83 years.

The cumulative incidence of neutrophil engraftment was 84% in a median of 26 days, and the incidence of grade III/IV aGVHD was 19%. Seven patients died, 1 before and 6 after transplantation. The surviving patients with MPS syndromes, Tay-Sachs disease and Krabbe's disease all stabilized and/or gained skills postransplantation. One of 5 patients with ALD experienced disease progression, whereas all others stabilized and continue to gain developmental skills.

The authors concluded that umbilical cord blood transplantation provides rapid access to donors and favorably alters the natural history of the disease and should be considered for patients with metabolic diseases who are eligible for transplantation therapy.

23. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W, Kurtzberg J. N Engl J Med. 2005;352:2069-81.

Krabbe's disease, or globoid-cell leukodystrophy, is an autosomal recessive disorder due to deficiency of the lysosomal enzyme galactocerebrosidase and characterized by failure of the process of myelination in the central and peripheral nervous systems, rapidly progressive neurologic deterioration, and death. In the infantile form, symptoms appear before six months of age and include irritability, dysphagia, progressive spasticity, mental deterioration, blindness, deafness, seizures, and death, usually before two years of age.

The authors assessed the safety and efficacy of transplantation of umbilical-cord blood from unrelated donors with partial HLA mismatches for the treatment of two groups of infants with Krabbe's disease. Krabbe's disease was diagnosed prenatally or at birth because of a family history of the disease in 11 patients, and they underwent transplantation as newborns; 14 children without a family history of the disease underwent transplantation in infancy after the onset of clinical symptoms.

The rates of donor-cell engraftment and survival were 100 percent and 100 percent, respectively, among the asymptomatic newborns (median follow-up, 3.0 years) and 100 percent and 43 percent, respectively, among the symptomatic infants (median follow-up, 3.4 years). Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement.

The authors concluded that transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement.

24. Successful unrelated umbilical cord blood transplantation in children with Shwachman-Diamond syndrome. Vibhakar R, Radhi M, Rumelhart S, Tatman D, Goldman F. Bone Marrow Transplant. 2005;36:855-61.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic insufficiency and variable degrees of neutropenia. SDS patients are at risk of developing myelodysplasia, aplastic anemia, and leukemic transformation. The role and timing of allogeneic hematopoietic stem cell transplantation (HSCT) in SDS remain controversial.

This is a report of three SDS patients with severe aplasia transplanted using unrelated umbilical cord blood (UCB). Patients received melphalan (180 mg/m²), etoposide (1200 mg/m²), anti-thymocyte globulin (90 mg/kg), and total lymphoid irradiation (500 cGy); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and prednisone.

Myeloid engraftment occurred promptly with absolute neutrophil count >500 cells/mm³ on day 15 +/- 5 and all patients displayed 100% donor chimerism by 2 months post transplant. The major complication of transplant was GVHD, with all patients developing grade II or III acute GVHD, one progressing to chronic extensive GVHD. Patients are alive 309, 623, and 2029 days post transplant. Factors important in HSCT outcome for SDS may include transplantation at a young age, avoidance of cyclophosphamide, and adequate GVHD prophylaxis.

Importantly, these cases also suggest that unrelated UCB, in the absence of a matched family member, is an excellent alternative stem cell source for SDS patients undergoing HSCT.

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