Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome
ABSTRACT Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome.
Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol.
The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are surviving with a median follow-up of 3 months (range, 1 to 7 months).
In children with Hurler syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to determine the effect of concomitant ERT on transplant outcomes.
Full-textDOI: · Available from: Maged I Gharib, Jul 25, 2014
- SourceAvailable from: Frits A Wijburg
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- "The proportion of unrelated versus related donors for HSCT has remained relatively stable as unrelated bone marrow donors have been replaced by unrelated cord blood donors. Use of laronidase in the peri-transplant period has been reported to be safe and well tolerated without interfering with engraftment or increasing the risk of graft-versus-host disease [6, 12, 16, 17, 31, 34]. Laronidase treatment may be particularly beneficial in patients in poor clinical condition prior to HSCT, to help improve their eligibility for transplant and tolerance of the full-intensity transplant conditioning [12, 16, 17, 24, 31]. "
ABSTRACT: Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler-Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since laronidase became available in 2003 (gap during 2006-2009: Hurler--0.2 year, Hurler-Scheie--0.5 year, Scheie--1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler-Scheie and Scheie patients (gap during 2006-2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with laronidase (42 out of 45 patients by 2009). CONCLUSIONS: Despite the availability of laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler-Scheie and Scheie phenotypes, which can lead to a sub-optimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients.European Journal of Pediatrics 01/2012; 171(6):911-9. DOI:10.1007/s00431-011-1644-x · 1.89 Impact Factor
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- "Since ERT has shown to result in a significant and relatively rapid improvement of respiratory and cardiovascular function [7-11], ERT may ameliorate the pre-transplant condition of a patient. It was shown that ERT prior to HSCT is well tolerated and may significantly improve the pre-transplant condition in selected patients [33-36]. In addition, there is evidence that ERT does not negatively influence engraftment [33-36]. "
ABSTRACT: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies. A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus. Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT. This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.Orphanet Journal of Rare Diseases 08/2011; 6(1):55. DOI:10.1186/1750-1172-6-55 · 3.36 Impact Factor
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- "Eight patients had complete donor engraftment and 11 of 12 survived at a median time of follow-up of 3 months (1 child died of pulmonary hemorrhage). Based on these case studies, it was concluded that the ERT and HCT combination therapy is safe and feasible, but prospective studies were needed to further evaluate the outcomes of co-modality therapy (Grewal et al 2005). The European study lead by Cox-Brinkman et al (2006) also observed that ERT with HCT has been well tolerated. "
ABSTRACT: More than 500 patients with mucopolysaccharidosis type IH (MPS IH; Hurler syndrome) have been treated with hematopoietic cell transplantation (HCT) throughout the world since the introduction of transplantation as therapy almost 30 years ago. More recently, the availability of recombinant alpha-L-iduronidase (IDUA) has resulted in the widespread treatment of less severe forms of MPS I with enzyme replacement therapy (ERT). In addition, over 50 MPS IH patients have been treated with a combination of ERT and HCT. The rationale for both ERT and HCT stems from the pivotal experiments performed 4 decades ago that showed alpha-L-iduronidase supplied in the environment can correct the accumulation of substrate in MPS I cells. Our purpose is to address the multiple applications associated with the therapeutic delivery of IDUA: intermittent delivery of recombinant protein (ERT), continuous administration through cellular therapy (HCT), the use of other stem cells or, potentially, correction of the enzyme defect itself through gene therapy approaches. Even though gene therapy and non-hematopoietic stem cell approaches, have yet to be tested in a clinical setting, it is possible that all these approaches will in the near future be a part of a paradigm shift from unimodal to multimodal therapy for MPS I.Targets & therapy 01/2009; 2(4):743-51.