Rituximab for the Treatment of Chronic Immune Thrombocytopenic Purpura

PICHON RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; REY-ARES, L.

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

Immune or idiopathic thrombocytopenic purpura (ITP) is an acquired hematologic disorder characterized by the presence of thrombocytopenia and bleeding. It is usually benign and of self-limited course. The annual incidence is 4-5.3/100,000 children and 5.8-6.6/100,000 adults, affecting mainly women. ITP is considered chronic if the platelet counts remain under 100 x 109/L twelve months after diagnosis, and it occurs in 20% of the cases. Between 20 and 50% of the patients will achieve complete remission after some years of evolution. Between 0.1 and 1% of the patients die due to severe bleeding of vital organs, usually of intracranial hemorrhage.Treatment inducing an increase in platelet count is indicated for patients with counts ≤20 x 109/L. First line treatment includes the administration of intravenous immunoglobulin G and/or glucocoticoids. The second line options for patients with chronic or persistent ITP include: splenectomy, rituximab, danazol, azatioprine, micofenolate, dapsone, ciclofosfamide and vincristine.TechnologyRituximab is a chimeric monoclonal antibody (murine/human), representing a glycosylated immunoglobulin. It binds specifically to antigen CD20, expressing both in normal B and tumor cells.Rituximab indication for ITP is not approved (off-label) by the National Administration of Drugs, Food and Medical Technology (ANMAT) and the U.S. and Europe regulatory agencies.PurposeTo assess the available evidence on the efficacy, safety and coverage related aspects regarding rituximab use for patients with ITP.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems. If RCTs were not found, other studies of less methodological strength were reviewed.ResultsA systematic review, three prospective uncontrolled studies, two retrospective uncontrolled studies and one congress presentation were found as well as five clinical practice guidelines and eight coverage policies.The systematic review estimated an average overall response (platelet count ≥50 x 109/L) of 62.5% (CI 95% 52.6-72.5) and a complete response (≥150 x 109/L) of 46.3% (29.5-57.7). The median response time to treatment was 5.5 weeks with an interquartile range (IR) between 3 and 6.6. The response duration was 10.5 months (IR 6.3-17.8). Severe life-threatening events were experienced by 3.7 patients and 2.9% died.The case series showed a 40-68% complete response rate and a 31-70% overall response rate. Regarding safety profiles, mild and transient adverse effects were observed in 25% of the patients, mostly related to the infusion, and serious between 13 and 17%; the most common being serum sickness. No deaths were recorded.The Argentina, United Kingdom and Germany ITP treatment and diagnosis guidelines as well as the international consensus include rituximab among the second line treatments.Both the state health insurances and the U.S. private health systems cover rituximab as second line for ITP treatment.Each 100 mg rituximab vial costs approximately 2,600 Argentine pesos ($AR) 2012 and $AR 13,500 each 500 mg vial.ConclusionsNo studies of good methodological quality were found on rituximab for patients with ITP. Nonetheless, several case series suggest it is effective for the treatment of patients with chronic ITP refractory to standard treatment with an acceptable toxicity profile. Since there is no comparator, part of the effect attributed to rituximab could caused by spontaneous remission, present in 20-50% of these patients during their disease evolution. Lastly, rituximab is considered one of the possible second line treatments in the clinical practice guidelines in different countries worldwide, among which is Argentina.