Hematopoietic Stem Cell Transplantation for Patients with Mucopolysaccharidosis II

Abstract

There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiologic findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were collected from 27 new cases and 119 published cases and were compared with 51 ERT and 15 untreated cases. Glycosaminoglycan (GAG) levels were analyzed by liquid chromatography tandem mass spectrometry in blood samples from HSCT, ERT, and untreated patients as well as age-matched controls. Long-term magnetic resonance imaging (MRI) findings were investigated in 13 treated patients (6 ERT and 7 HSCT). Mean age at HSCT was 5.5 years (range, 2 to 21.4 years) in new patients and 5.5 years (range, 10 months to 19.8 years) in published cases. None of the 27 new patients died as a direct result of the HSCT procedure. Graft-versus-host disease occurred in 8 (9%) out of 85 published cases, and 9 (8%) patients died from transplantation-associated complications. Most HSCT patients showed greater improvement in somatic features, joint movements, and activity of daily living than the ERT patients. GAG levels in blood were significantly reduced by ERT and levels were even lower after HSCT. HSCT patients showed either improvement or no progression of abnormal findings in brain MRI while abnormal findings became more extensive after ERT. HSCT seems to be more effective than ERT for MPS II in a wide range of disease manifestations and could be considered as a treatment option for this condition.

Keywords: Enzyme replacement therapy; Hematopoietic stem cell transplantation; Hunter syndrome; Iduronate-2-sulfatase; Mucopolysaccharidosis II.

Figure 1. Levels of GAGs in patients with MPS II

Figure 1A: Dermatan sulfate (DS) levels Figure 1B: Heparan sulfate (HS-NS) levels Figure 1C: Heparan sulfate (HS-0S) levels Figure 1D: Mono-sulfated keratan sulfate (Mono-KS) levels Figure 1E: Di-sulfated keratan sulfate (Di-KS) levels GAGs were measured in untreated MPS II (n=15), ERT attenuated (n=20), ERT+HSCT attenuated (n=2), ERT severe (n=31), ERT+HSCT severe (n=20) and controls (n=115). Untreated patients were compared to treated patients by Student’s t-test. All treatments (enzyme replacement therapy-ERT and hematopoietic stem cell transplantation-HSCT) provided a reduction of GAG levels compared to untreated patients. For patients with a severe phenotype: in DS, HS-0S and mono sulfated-KS, ERT+HSCT provided significantly lower levels (p<0.0001, p<0.0005, p<0.005, respectively) when compared to ERT only. *p<0.05; **p<0.005; ***p < 0.0005; **** p < 0.0001.

Figure 2. MRI findings of Cases 1 & 7

A: Case 1- A 24-year-old patient with over 8 years of ERT (attenuated): His intellect is normal, but he has recurrent episodes of seizures, shivering, and dizziness with regurgitation of the heart valves. Brain atrophy, ventricular dilatation, white matter signal changes, cribriform changes, and cystic lesions are present at 12 years. At 24 years, multiple and larger cystic lesions are seen in basal ganglia, thalamus, the corpus callosum as well. Large cisterna magna and ventricular enlargement and brain atrophy are more prominent. Scores in categories I and IV are worsening (Table 1). Red arrows represent white matter signal changes; blue arrows represent cystic or cribriform regions; white arrows represent ventricular enlargement and brain atrophy. B: Case 7- A 24-year-old patient with HSCT at 6 years (attenuated): MRI before HSCT shows multiple cystic lesions in basal ganglia and white matter. These lesions are diminished when he was 8, 16 and 24 years old. The score in category I is improved. Red arrows represent white matter signal changes; blue arrows represent cystic or cribriform regions.

Figure 3. MRI findings of Cases 4 & 11

A: Case 4- A 10-year-old patient with over 7 years ERT (severe); MRI before ERT shows small cystic lesions and white matter signal changes, moderately enlarged ventricle. At 10 years old, severe atrophic brain and enlarged ventricle are observed. In categories III and IV, the scores are worsening (Table 1). Red arrows represent white matter signal changes; blue arrows represent cystic or cribriform regions; white arrows represent ventricular enlargement and brain atrophy. B: Case 11- A 15-year-old patient with HSCT at 4 years old (severe). MRI before and after HSCT did not show any abnormal finding without change.