Indications for HSCT: overview

Table 1 identifies the IMD for which allogeneic HSCT is currently indicated or under investigation. HSCT is currently not indicated for selected IMD, including adrenomyeloneuropathy (AMN), Alexander syndrome, Morquio syndrome (MPS IV), vanishing white matter disease, Zellweger syndrome, cerebrotendinous xanthomatosis, Fabry syndrome, Canavan syndrome, and cystinosis. Therefore, these disorders are not included in Table 1 or the discussion.

Hurler syndrome (MPS IH)

Hurler syndrome (MPS IH), the most severe phenotype of α- l -iduronidase deficiency, is an autosomal recessive disorder characterized by progressive accumulation of stored glycosaminoglycans (GAGs). Hurler and other phenotypes of MPS I (Scheie [MPS IS, attenuated] and Hurler-Scheie [MPS IH/S, intermediate]) are a broad, continuous clinical spectrum. Accumulation of GAGs results in progressive, multisystem dysfunction that includes psychomotor retardation, severe skeletal malformations, life-threatening cardiopulmonary complications, and early death. Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Group for Blood and Marrow Transplant (EBMT) indicate that more than 500 allogeneic HSCTs have been performed worldwide for children with MPS IH since 1980, making it the most commonly transplanted IMD.

HSCT for children with MPS IH is effective, resulting in increased life expectancy and improvement of clinical parameters. To derive maximum long-term benefits in children with MPS IH, allogeneic HSCT must be performed early in the disease course before the onset of irreversible damage. Donor-cell engraftment after HSCT has usually resulted in rapid reduction of obstructive airway symptoms and hepatosplenomegaly. Cardiovascular function benefits from HSCT as certain pathologic conditions before transplant clearly improve. Hearing, vision, and linear growth also improve in many transplanted patients. In addition, hydrocephalus is either prevented or stabilized. Although cerebral damage already present before HSCT seems to be irreversible, successful HSCT is able to prevent progressive psychomotor deterioration and improve cognitive function.

Recent HSCT experience shows significantly improved graft outcomes when compared with earlier results. It seems that early engrafted survival rates of 25% to 70% can be attributed to a clinical learning curve, restricted donor availability, graft failure, mixed chimerism, and transplant-related morbidity and mortality. A recent risk analysis showed that graft failures increased with the use of T-cell depleted grafts and reduced intensity conditioning and decreased with the use of dose-adjusted busulfan (BU).

An enzymatically matched normal sibling is the preferred HSCT donor for children with MPS IH. However, in the past decade, unrelated CB has been used with increasing frequency as a graft source for children without a matched sibling donor. CB offers several potential advantages compared with BM or PB for HSCT, including better availability, greater tolerance for HLA mismatch, lower incidence and severity of graft-versus-host disease (GVHD), and reduced likelihood of transmitting viral infections. Laboratory studies suggest that CB stem cells may be capable of transdifferentiation into osteoblasts, chrondoblasts, and neurons. Use of CBT for children with MPS IH has been associated with high rates of chimerism, engraftment, and overall survival. Similar results are noted for CBT in other selected IMD.

Because of these data, the EBMT developed transplantation guidelines for patients with MPS IH in 2005. The guidelines are widely used today and include a standardized BU/cyclophosphamide (CY) conditioning regimen, an enzymatically normal matched sibling BM donor if available, and if not, CB as the preferred graft source ( http://www.ebmt.org ).

Fig. 1 provides a comparison of European survival outcomes for MPS IH patients receiving traditional HSCT (BMT or PBT; 1994–2004) with that of patients who were treated according to the EBMT guidelines (2005–2008). Mixed chimerism, observed in 29% of patients transplanted between 1994 and 2004, declined to 5% of patients transplanted between 2005 and 2008.

Event-free survival (defined as alive and engrafted) of MPS IH patients after HSCT, according to the period of transplantation. HSCTs for 1994 to 2004 (n = 146) used various protocols standard for the period. HSCTs for 2005 to 2008 (n = 44) used EBMT protocol of standardized BU/CY conditioning and donor hierarchy of unrelated CB (second only to matched noncarrier sibling). ( Data from Refs. )

A recent EUROCORD-Duke University MPS IH collaborative study showed that early transplant (ie, within 4.6 months from diagnosis) with CB and BU/CY conditioning was associated with improved engraftment and overall survival. Furthermore, 94% of engrafted survivors achieved full donor chimerism.

ERT became available for patients with MPS I in 2003. Although ERT is not the primary treatment of MPS IH, it is hypothesized that ERT before HSCT can improve the pretransplant medical condition of the child and decrease the prevalence of HSCT- and MPS IH-related complications. Intravenously administered enzyme does not cross the blood-brain barrier (BBB), so ERT is not able to prevent CNS deterioration. ERT trials in patients with attenuated forms of MPS I (Scheie, Hurler-Scheie) have shown reduced organomegaly, decreased sleep apnea/hypopnea, improved pulmonary function, and increased physical ability.

The combination of ERT and HSCT for MPS IH children has been evaluated in single and multicenter studies. Investigators found that although ERT was well tolerated, the combination of ERT and HSCT did not significantly affect rates of survival, engrafted survival or HSCT-associated morbidity when compared with HSCT alone. However, in the EUROCORD-Duke University study, children receiving HSCT within 4.6 months of diagnosis showed a trend toward significantly higher survival when ERT was used before CBT (n = 23, 83% survival) than when ERT was not used before CBT (n = 70, 63% survival, P = .19). An ongoing CIBMTR comparison study of more than 250 children, including 20% who received ERT with HSCT, may address questions of efficacy and outcome. Currently, many transplant centers administer ERT to MPS IH patients before HSCT and continue this treatment until the patients either start conditioning or achieve donor-derived engraftment.

Despite these areas of success, some disease manifestations persist or can even progress after HSCT. For example, musculoskeletal disorders secondary to the IMD do not resolve following HSCT and often require orthopedic surgical interventions. In addition, neurocognitive dysfunction and corneal clouding that developed before HSCT may be irreversible.

The long-term clinical outcome for MPS IH children receiving HSCT seems to be promising, yet variable from child to child. This variability is presumably caused by factors such as genotype, age, and clinical status before HSCT, donor enzyme activity level, donor chimerism (mixed or full), stem-cell source (CB, BM, or PB), and resultant enzyme activity level in the recipient. Neurocognitive outcomes may be enhanced by higher chimerism/enzyme activity levels ; however, the impact of these levels on outcomes needs continued evaluation. An international long-term follow-up study involving European and North American centers is under way to evaluate the influence of various patient, donor, and transplant characteristics on HSCT outcomes.

Overall, progress has been made. HSCT for children with MPS IH has become a safer procedure, with recent survival rates exceeding 90%. Quality of life for children with MPS IH following HSCT is also improving. Greater attention is being paid to timely diagnosis, prompt HSCT, and use of better procedures. In the absence of an enzymatically normal matched sibling donor, CBT is now routinely used to foster higher rates of full-donor chimerism and normal enzyme levels. Although HSCT is the procedure of choice for MPS IH, ERT is increasingly used as an adjuvant treatment before HSCT.

Hurler syndrome (MPS IH)

Hurler syndrome (MPS IH), the most severe phenotype of α- l -iduronidase deficiency, is an autosomal recessive disorder characterized by progressive accumulation of stored glycosaminoglycans (GAGs). Hurler and other phenotypes of MPS I (Scheie [MPS IS, attenuated] and Hurler-Scheie [MPS IH/S, intermediate]) are a broad, continuous clinical spectrum. Accumulation of GAGs results in progressive, multisystem dysfunction that includes psychomotor retardation, severe skeletal malformations, life-threatening cardiopulmonary complications, and early death. Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Group for Blood and Marrow Transplant (EBMT) indicate that more than 500 allogeneic HSCTs have been performed worldwide for children with MPS IH since 1980, making it the most commonly transplanted IMD.

HSCT for children with MPS IH is effective, resulting in increased life expectancy and improvement of clinical parameters. To derive maximum long-term benefits in children with MPS IH, allogeneic HSCT must be performed early in the disease course before the onset of irreversible damage. Donor-cell engraftment after HSCT has usually resulted in rapid reduction of obstructive airway symptoms and hepatosplenomegaly. Cardiovascular function benefits from HSCT as certain pathologic conditions before transplant clearly improve. Hearing, vision, and linear growth also improve in many transplanted patients. In addition, hydrocephalus is either prevented or stabilized. Although cerebral damage already present before HSCT seems to be irreversible, successful HSCT is able to prevent progressive psychomotor deterioration and improve cognitive function.

Recent HSCT experience shows significantly improved graft outcomes when compared with earlier results. It seems that early engrafted survival rates of 25% to 70% can be attributed to a clinical learning curve, restricted donor availability, graft failure, mixed chimerism, and transplant-related morbidity and mortality. A recent risk analysis showed that graft failures increased with the use of T-cell depleted grafts and reduced intensity conditioning and decreased with the use of dose-adjusted busulfan (BU).

An enzymatically matched normal sibling is the preferred HSCT donor for children with MPS IH. However, in the past decade, unrelated CB has been used with increasing frequency as a graft source for children without a matched sibling donor. CB offers several potential advantages compared with BM or PB for HSCT, including better availability, greater tolerance for HLA mismatch, lower incidence and severity of graft-versus-host disease (GVHD), and reduced likelihood of transmitting viral infections. Laboratory studies suggest that CB stem cells may be capable of transdifferentiation into osteoblasts, chrondoblasts, and neurons. Use of CBT for children with MPS IH has been associated with high rates of chimerism, engraftment, and overall survival. Similar results are noted for CBT in other selected IMD.

Because of these data, the EBMT developed transplantation guidelines for patients with MPS IH in 2005. The guidelines are widely used today and include a standardized BU/cyclophosphamide (CY) conditioning regimen, an enzymatically normal matched sibling BM donor if available, and if not, CB as the preferred graft source ( http://www.ebmt.org ).

Fig. 1 provides a comparison of European survival outcomes for MPS IH patients receiving traditional HSCT (BMT or PBT; 1994–2004) with that of patients who were treated according to the EBMT guidelines (2005–2008). Mixed chimerism, observed in 29% of patients transplanted between 1994 and 2004, declined to 5% of patients transplanted between 2005 and 2008.

Event-free survival (defined as alive and engrafted) of MPS IH patients after HSCT, according to the period of transplantation. HSCTs for 1994 to 2004 (n = 146) used various protocols standard for the period. HSCTs for 2005 to 2008 (n = 44) used EBMT protocol of standardized BU/CY conditioning and donor hierarchy of unrelated CB (second only to matched noncarrier sibling). ( Data from Refs. )

A recent EUROCORD-Duke University MPS IH collaborative study showed that early transplant (ie, within 4.6 months from diagnosis) with CB and BU/CY conditioning was associated with improved engraftment and overall survival. Furthermore, 94% of engrafted survivors achieved full donor chimerism.

ERT became available for patients with MPS I in 2003. Although ERT is not the primary treatment of MPS IH, it is hypothesized that ERT before HSCT can improve the pretransplant medical condition of the child and decrease the prevalence of HSCT- and MPS IH-related complications. Intravenously administered enzyme does not cross the blood-brain barrier (BBB), so ERT is not able to prevent CNS deterioration. ERT trials in patients with attenuated forms of MPS I (Scheie, Hurler-Scheie) have shown reduced organomegaly, decreased sleep apnea/hypopnea, improved pulmonary function, and increased physical ability.

The combination of ERT and HSCT for MPS IH children has been evaluated in single and multicenter studies. Investigators found that although ERT was well tolerated, the combination of ERT and HSCT did not significantly affect rates of survival, engrafted survival or HSCT-associated morbidity when compared with HSCT alone. However, in the EUROCORD-Duke University study, children receiving HSCT within 4.6 months of diagnosis showed a trend toward significantly higher survival when ERT was used before CBT (n = 23, 83% survival) than when ERT was not used before CBT (n = 70, 63% survival, P = .19). An ongoing CIBMTR comparison study of more than 250 children, including 20% who received ERT with HSCT, may address questions of efficacy and outcome. Currently, many transplant centers administer ERT to MPS IH patients before HSCT and continue this treatment until the patients either start conditioning or achieve donor-derived engraftment.

Despite these areas of success, some disease manifestations persist or can even progress after HSCT. For example, musculoskeletal disorders secondary to the IMD do not resolve following HSCT and often require orthopedic surgical interventions. In addition, neurocognitive dysfunction and corneal clouding that developed before HSCT may be irreversible.

The long-term clinical outcome for MPS IH children receiving HSCT seems to be promising, yet variable from child to child. This variability is presumably caused by factors such as genotype, age, and clinical status before HSCT, donor enzyme activity level, donor chimerism (mixed or full), stem-cell source (CB, BM, or PB), and resultant enzyme activity level in the recipient. Neurocognitive outcomes may be enhanced by higher chimerism/enzyme activity levels ; however, the impact of these levels on outcomes needs continued evaluation. An international long-term follow-up study involving European and North American centers is under way to evaluate the influence of various patient, donor, and transplant characteristics on HSCT outcomes.

Overall, progress has been made. HSCT for children with MPS IH has become a safer procedure, with recent survival rates exceeding 90%. Quality of life for children with MPS IH following HSCT is also improving. Greater attention is being paid to timely diagnosis, prompt HSCT, and use of better procedures. In the absence of an enzymatically normal matched sibling donor, CBT is now routinely used to foster higher rates of full-donor chimerism and normal enzyme levels. Although HSCT is the procedure of choice for MPS IH, ERT is increasingly used as an adjuvant treatment before HSCT.

Other mucopolysaccharidosis syndromes

Compared with MPS IH, experience with HSCT for treatment of other MPS disorders is limited. Small numbers and lack of detailed functional outcome data hamper the development of specific therapy guidelines. Conceptually, the basis for the effectiveness of HSCT in these children is the same as those with MPS IH. However, the kinetics of cellular migration, differentiation, distribution, and effective enzyme delivery may differ. Also, there is wide clinical variability within and across specific MPS diseases. As with HSCT for other IMD, important factors in the outcome may be timing of transplant, graft source, and the underlying severity of the phenotype in a given child. To date, most of the published experience is in recipients of BMT. Recently, survival has been reported in small cohorts undergoing CBT, but their functional outcomes are not yet published.

A recent French report on 8 boys with Hunter syndrome (MPS II) treated with BMT (6 matched sibling, 2 unrelated donor) at 3 to 16 years of age and followed for 7 to 17 years showed an excellent survival rate (1 died of unrelated causes), stabilization of cardiovascular problems, resolution of hepatosplenomegaly, improvement in joint stiffness, arrested progression of perceptual hearing defect, and improvement in transmission hearing defects. Neuropsychological outcomes were variable and appeared to be related to the underlying phenotype and severity of symptoms at transplant. Two children with attenuated phenotype achieved adulthood with normal scholastic achievement, social integration, and language, whereas all children with severe phenotype lost ambulation and speech or developed seizures. Lack of neurologic improvement was also described in 3 BMT recipients in a 1999 report. In a recent report of 159 children with IMD treated with unrelated CBT, 6 MPS II boys were included. Their survival was consistent with that of the overall study group, but the study did not examine neurocognitive outcomes.

Despite benefits in the somatic features of the disease, the role of HSCT in MPS II remains controversial because of lack of convincing evidence of neurocognitive benefit. There are no published data on HSCT in very young, early stage, or asymptomatic children with “severe” MPS II phenotype. Limited genotype/phenotype correlation often leads to delays in identifying appropriate candidates for HSCT. However, in families with a known case, prenatal diagnosis and identification of an asymptomatic brother should be possible. ERT is available and likely to benefit some individuals; however, its high cost, lifelong duration, and inability to cross the BBB limit its overall usefulness.

The status of HSCT for Sanfilippo syndrome (MPS III) is similar to that of MPS II with inadequate data and inability to make specific recommendations about timing of transplant, graft source, and potential neurologic benefit. ERT is not currently available to treat children with MPS III. Eleven long-term survivors of BMT have been reported, but all showed decline in neurocognitive function. In a study performed by investigators at Duke University, 19 children with MPS III were treated with CBT. After transplant, 12 of 19 survived in the long term. Only the 2 children who were transplanted at less than 2 years of age showed modest gains in cognitive skills, but continue to have overall global developmental delay 3 to 5 years after CBT. Transplanted children seem to have fewer behavioral problems and better sleeping patterns when compared with nontransplanted children. Further evaluation and publication of the neurocognitive and developmental outcomes of patients with MPS III who have undergone CBT is critically important.

Maroteaux-Lamy syndrome (MPS VI) has multiple clinical phenotypes, but generally patients live into the second to fourth decade. In 1984, Krivit and colleagues reported a 13-year-old girl with the severe phenotype who had a matched sibling BMT, leading to normalization of arylsulfatase B activity in peripheral lymphocytes and granulocytes, increased liver enzyme activity, decreased urinary excretion of GAG, decreased hepatosplenomegaly, normalization of cardiopulmonary function, improved visual acuity, and improved joint mobility. In a separate report, BMT in 4 patients (3 with cardiomyopathy, 1 with severe obstructive sleep apnea) led to improvement in cardiopulmonary function, facial features, and quality of life. However, skeletal changes persisted or progressed. Lee and colleagues treated a 5-year-old boy with a severe phenotype with matched sibling CBT, leading to improvement in hepatosplenomegaly, facial features, skin, and joint mobility. In light of these benefits, HSCT can be considered a therapeutic option in patients intolerant to or failing ERT.