Allogeneic Hematopoietic SCT for Alpha-Mannosidosis: an Analysis of 17 Patients
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Bone Marrow Transplantation (2012) 47, 352–359 & 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12 www.nature.com/bmt ORIGINAL ARTICLE Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients M Mynarek1, J Tolar2, MH Albert3, ML Escolar4, JJ Boelens5, MJ Cowan6, N Finnegan7, A Glomstein8, DA Jacobsohn9,JSKu¨ hl10, H Yabe11, J Kurtzberg12, D Malm13, PJ Orchard2, C Klein1,TLu¨ cke14 and K-W Sykora1 1Hannover Medical School, Department of Pediatric Hematology and Oncology, Hannover, Germany; 2University of Minnesota, Department of Pediatrics, Division of Hematology, Oncology, Blood and Marrow Transplantation, Minneapolis, MN, USA; 3Ludwig Maximilians University, Department of Pediatric Hematology and Oncology, Munich, Germany; 4University of North Carolina at Chapel Hill, Program for Neurodevelopmental Function in Rare Disorders, Chapel Hill, NC, USA; 5University Medical Center Utrecht, Department of Pediatrics: Stem Cell Transplantation Unit, Utrecht, The Netherlands; 6University of California San Francisco, Children’s Hospital, Blood and Marrow Transplant Division, San Francisco, CA, USA; 7Great Ormond Street Hospital for Children NHS Trust, Metabolic Office, London, UK; 8University Hospital Oslo, Department of Pediatrics, Oslo, Norway; 9Children’s National Medical Center, Department for Pediatric Bone Marrow Transplantation, Washington, DC, USA; 10Charite´ University Medicine Berlin, Department of Pediatric Hematology, Oncology and BMT, Berlin, Germany; 11Tokai University School of Medicine, Department of Cell Transplantation and Regenerative Medicine, Shimokasuya, Isehara, Japan; 12Duke University Medical Center, The Pediatric Blood and Marrow Transplant Program, Durham, NC, USA; 13University Hospital of North Norway, Department of Gastroenterology, Tromsoe, Norway and 14Ruhr University Bochum, Department of Neuropediatrics, University Children’s Hospital, Bochum, Germany Alpha-mannosidosis is a rare lysosomal storage disease. Introduction Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. Alpha-mannosidosis (MIM 248500) is a rare lysosomal This retrospective multi institutional analysis describes 17 storage disorder with an autosomal recessive inheritance. It patients that were diagnosed at a median of 2.5 (1.1–23) is caused by mutations in the MAN2B1 gene (MIM 609458) years and underwent HSCT at a median of 3.6 (1.3–23.1) located on chromosome 19 (19p13.2-q12), coding for the years. In all, 15 patients are alive (88%) after a median intracellular enzyme alpha-mannosidase. Deficient alpha- follow-up of 5.5 (2.1–12.6) years. Two patients died within mannosidase activity leads to lysosomal accumulation of the first 5 months after HSCT. Of the survivors, two mannose-rich oligosaccharides.1,2 Though its incidence is developed severe acute GvHD (4 ¼ grade II) and six not precisely known, it is estimated that about one in developed chronic GvHD. Three patients required re- 500 000 live births suffer from alpha-mannosidosis.3 transplantation because of graft failure. All 15 showed Patients usually appear healthy at birth, but develop stable engraftment. The extent of the patients’ develop- progressive mental retardation, skeletal changes, hearing mental delay before HSCT varied over a wide range. loss, hydrocephalus, hepatomegaly and recurrent After HSCT, patients made developmental progress, infections.3 Traditionally, alpha-mannosidosis has been although normal development was not achieved. Hearing classified into two groups: severe (‘early onset’, ‘infantile’, ability improved in some, but not in all patients. We ‘type II’) and mild (‘late onset’, ‘type I’). conclude that HSCT is a feasible therapeutic option that Lately, three clinical subtypes have been suggested: may promote mental development in alpha-mannosidosis. Type 1: A mild form with slow progression of mental Bone Marrow Transplantation (2012) 47, 352–359; retardation and usually without skeletal abnormalities. It is doi:10.1038/bmt.2011.99; published online 9 May 2011 diagnosed at X10 years of age unless other factors—for Keywords: alpha-mannosidosis; hematopoietic SCT; example, an affected sibling—lead to an earlier diagnosis. lysosomal storage disease; inborn errors of metabolism; Type 2: A moderate form, clinically diagnosed before neurodevelopment; outcome 10 years of age. Type 2 patients show skeletal abnor- malities and a slow progression of mental retardation. These patients usually develop ataxia at the age of 20–30 years. Type 3: A severe form with skeletal abnormalities and a Correspondence: Dr K-W Sykora, Medizinische Hochschule Hannover, rapid and obvious progression that is diagnosed at an early Abteilung fu¨ rpa¨ diatrische Ha¨ matologie und Onkologie, Carl-Neuberg- age. This form usually leads to an early death.3 Strasse 1, Hannover 30625, Germany. The three clinical phenotypes of alpha-mannosidosis are E-mail: [email protected] Received 20 January 2011; revised 21 March 2011; accepted 22 March not clearly distinguishable; they form a continuum of 2011; published online 9 May 2011 varying severity. HSCT in alpha-mannosidosis M Mynarek et al 353 The prediction of the clinical course for an individual HSCT data: Lansky or Karnofsky index, known pre- patient is difficult. Lyons et al.4 reported three Hispanic transplant risk factors, conditioning, GvHD-prophylaxis, males with alpha-mannosidosis that, despite early clinical donor type, stem cell source, number of transfused signs, showed relatively benign long-term outcomes. nucleated cells, CD34 positive cells and CD3 positive cells, Normal development leading to an independent life seems engraftment (WBC41000/mL, thrombocytes 420.000/mL to be achieved only occasionally.5 Unfortunately, long- and 450.000/mL), time course of chimerism, acute term studies with higher patient numbers have not been regimen-related toxicity, grade of GvHD. published. Many mutations in MAN2B1 have been Post-HSCT data: infections, neurodevelopmental status, described,6 but due to the low number of cases, it was results of audiometry, psychiatric status, skeletal status, not possible to identify a correlation between genotype and alpha-mannosidase activity in WBC after HSCT, phenotype.3 evidence of late therapy-related complications. If there Therapeutic options have been rare up to now. Early was no systematic neurodevelopmental testing, physi- attempts to treat patients with alpha-mannosidosis with cians were asked to give a clinical impression of the zinc did not lead to clinical and developmental improve- current status of their patients. ments.7 Enzyme replacement therapy has only been studied 8,9 in animal models, and clinical studies in humans are Statistical analysis in preparation. More recently, enzyme replacement using Kaplan–Meier analysis was performed for OS and EFS. gene therapy has been studied in a cat model. Using Graft failure (with or without second transplantation) and direct intracerebral injection of an adenoviral vector, death were defined as events. expression of alpha-mannosidase was achieved in neurons leading to milder symptoms and longer survival in the 10 treated cats. Results Thus, hematopoietic SCT (HSCT) is currently the only clinically available approach to enzyme replacement. It has Recruitment 11 been shown to have effects both in a cat model and in A total of 17 patient questionnaires were returned by humans, but only a few cases in humans have been 11 transplant centers. Of those, 14 were sent by physicians 12–16 published. The largest experience with HSCT for with a special interest in HSCT for lysosomal storage lysosomal storage diseases exists in Hurler’s disease, diseases. Of those patients, six had been published before in which good long-term neurodevelopmental outcomes (Patient #1, #2, #5, #10;14 #7;12 #9).19 In three cases, the 17 can be demonstrated (reviewed by Aldenhofen et al. ). parents contacted us directly after having received the letter via the ISMRD. Objective Although HSCT is considered the standard therapeutic Pre-HSCT data option in alpha-mannosidosis,18 this recommendation is Patients were diagnosed at a median age of 2.5 years based on the very limited safety and efficacy data in (range 1.1–23 years). In all, 12 were male and five female. humans that are available to date. Before confirmation by enzymatic testing, mucopoly- To get a more complete view of the outcome, we saccharidosis was suspected due to skeletal malformation performed a retrospective multicenter analysis of patients (n ¼ 13) developmental delay (n ¼ 8), hearing loss (n ¼ 5), with alpha-mannosidosis who were treated with HSCT. recurrent otitis (n ¼ 5), recurrent infections (n ¼ 5), speech delay (n ¼ 2) and hepato(spleno)megaly (n ¼ 2; data avail- able in 16 of 17 patients). For all patients, data on Patients and methods mannosidase activity were available, confirming reduced or lacking activity in either peripheral blood leukocytes or Patients were identified via physicians who had treated serum. patients with inherited errors of metabolism by HSCT and Before HSCT, an assessment of major mannosidosis- via the International Advocate for Glycoprotein Storage related problems was performed in most patients. Hearing Diseases (ISMRD, Mr J Forman, Petone, New Zealand). was impaired to varying extents in all nine patients in Mr Forman and his co-workers were asked to forward a whom those data were available. A hearing aid was letter to those who may have undergone HSCT. In this necessary in six patients.