Determinants of Persisting Thrombocytopenia In Patients with Type 1 Gaucher Disease Treated with Alglucerase/Imiglucerase for 4–5 Years

Thrombocytopenia in type 1 Gaucher disease (GD) may result in surgical, obstetrical and spontaneous bleeding. Treatment with alglucerase/imiglucerase generally results in rapid improvement in platelet count but, in rare cases, the platelet response to therapy is slow or lacking. The factors underlying persisting thrombocytopenia despite treatment are poorly understood.

To identify patient characteristics associated with (and potentially predictive of) persisting thrombocytopenia despite therapy by retrospective analysis of ICGG Gaucher Registry data.

1,016 type 1 GD patients with an intact spleen, date of diagnosis and therapy initiation, no treatment breaks 4–5 years after therapy initiation, and known platelet counts, were classified into four groups by last platelet count 4–5 years after therapy initiation: >120 × 10⁹/l (n = 772); >100 to <120 × 10⁹/l (n = 94); >80 to <100 × 10⁹/l (n = 80); and <80 × 10⁹/l (n = 70, of which 20 had <60 × 10⁹/platelets/l). Patients were characterized by demographics, BMI; platelet count; anemia; biomarkers; hepatomegaly; splenomegaly; and skeletal assessments at baseline (therapy initiation) and after 4–5 years of therapy. Initial enzyme dose and cumulative average dose were noted. Possible associations with persisting thrombocytopenia were tested using a multivariate analysis calculating odds ratios adjusted for age at diagnosis and therapy initiation, genotype, sex, year of diagnosis, and year of therapy initiation.

Of the 1,016 patients in this study, 20 (2%) had platelet counts <60 × 10⁹/platelets/l after 4–5 years of therapy. These patients all had severe splenomegaly at baseline. Associations between persisting thrombocytopenia were found between baseline low platelet count (<80 × 10⁹/l), splenomegaly and anemia (p <0.0001). After 4–5 years, persisting thrombocytopenia was associated with anemia (p <0.0001), reduced WBC (p = 0.049), splenomegaly (p <0.0001), hepatomegaly (p = 0.006), bone pain (p = 0.035) and cumulative enzyme dose (dose range 18.6–55.5 U/kg/2weeks; doses <25^th percentile: p = 0.043). Too few data prevented reliable analysis of other bone parameters and biomarkers.

Persisting thrombocytopenia despite therapy is rare (2% of patients with platelets <60 × 10⁹/l). The strong association between splenomegaly, anemia and thrombocytopenia at therapy initiation and persisting thrombocytopenia after 4–5 years of treatment suggests that in a minority of cases extensive spleen involvement, possibly with fibrosis, may be predictive of thrombocytopenia that is refractory to treatment. Findings underline the importance of initiating treatment before irreversible complications have developed.

Cole:Genzyme Corp: Employment.