Focal splenic lesions in type I Gaucher disease are associated with poor platelet and splenic response to macrophage-targeted enzyme replacement therapy

Abstract

Focal splenic lesions (FSL) occur in Gaucher disease type I (GD1), but their clinical significance is not known. Previous studies estimated the prevalence of FSL at 4% (pediatric) to 33% (adult) of GD1 patients and reported an association with splenomegaly. We tested the hypothesis that the presence of FSL is associated with suboptimal response to macrophage-directed enzyme replacement therapy (ERT). Additionally we investigated whether FSL were associated with other phenotypic features of GD1. The splenic parenchyma was assessed by MRI performed for routine evaluation of GD1 in 239 consecutive GD1 patients with intact spleens. The prevalence of FSL was 18.4% (44/239). Following a mean of 3.5 years of ERT, platelet response was inferior among patients with FSL (80,700 ± 9,600 to 90,100 ± 7,200/mm(3) , P = 0.2) compared to patients without FSL in whom there was a robust platelet response: 108,600 ± 5,670 to 150,200 ± 6,710/mm(3), P < 0.001. Compared to patients without FSL, patients harboring FSL had worse thrombocytopenia (platelet count: 83,700 ± 8,800 vs. 112,100 ± 4,200/mm(3), P = 0.004), greater frequency of pre-ERT splenomegaly, and greater post-ERT splenomegaly (8.5 ± 0.77 vs. 4.8 ± 0.25× normal, P < 0.001). Additionally, the prevalence of osteonecrosis was higher among patients with FSL compared to patients without FSL (38 vs. 20.7%, P = 0.026). FSL appear to be a determinant of response to ERT, suggesting studies comparing relative efficacy of newly emerging therapies for GD1 should adjust for this factor. Moreover, occurrences of FSL coincide with more severe manifestations of GD1 such as avascular osteonecrosis.

Fig. 1

a, b MRI of two patients with splenic lesions. a Axial T1-weighted gradient-echo image through the liver and spleen demonstrates a heterogenous mass (white arrow) in the splenic hilum with focal areas of decreased signal within the lesion and within the splenic parenchyma. The black arrow represents streaky heterogeneity in isolation, which would not be regarded as an FSL. Patient presented as 46-year-old male with N370S/84GG genotype. Liver size was 2.7× normal and spleen size was 29.97× normal. Hemoglobin was 9.8 gm/dL, and platelet count was 44×10⁹/L. He had a Hermann score of 4 and severity score index (SSI) of 14. After 8 years of ERT, spleen size was 11.8× normal with a platelet count of 78×10⁹/L. b Axial T1-weighted spin-echo image through the liver and spleen demonstrates multiple low-signal masses diffusely through the splenic parenchyma. Patient presented as a 55-year-old male with N370S/84GG genotype. Liver size was 2.7× normal, and spleen size was 19× normal. Hemoglobin was 11.8 gm/dL and platelet count was 64×10⁹/L. He had a Hermann score of 5 and SSI of 19

Fig. 2

Frequency of FSL at different levels of splenomegaly. Patients were placed in four categories of spleen size based on normal spleen size (× N). The percentage of patients with FSL in each spleen size category was determined

Fig. 3

Platelet response to enzyme replacement therapy (ERT). Patients had platelet counts determined at their most recent visit prior to ERT in both groups. Patients had post-ERT platelet results at a mean of 3.5 years after initiation of therapy. Error bars are provided and represent SEM. P values represent paired t-test comparing each group before and after therapy