A Retrospective Analysis of 122 Immune Thrombocytopenia Patients Treated with Dapsone: Efficacy, Safety and Factors Associated with Treatment Response
Authors: Colella Marina Pereira , Alves Elizio Chiacchio Ferraz , Delmoro Gabriela de França , Yamaguti-Hayakawa Gabriela G , Orsi Fernanda Andrade , De Paula Erich Vinicius , Annichino- Bizzacchi Joyce Maria 
Published: October 2019

Abstract
Dapsone has been used in the treatment of patients with immune thrombocytopenia (ITP) since the late 1980s. It is a drug that is inexpensive and well tolerated, but unfortunately, it is underused worldwide due to the lack of information regarding its mechanism of action, efficacy rates and safety profile. Our institution has an extensive experience with the drug, for it has been used as the standard 2nd line therapy in our ITP patients for the last 20 years.
In this study we aimed to assess the efficacy rate, frequency and gravity of side effects of dapsone therapy in ITP patients. As a secondary endpoint, we wanted to evaluate the possible clinical factors associated with a treatment response.
This was a single-center retrospective study, where medical charts of ITP patients in follow-up at our outpatient clinic in the period of 2011 to 2017 were reviewed for identification of patients treated with dapsone. Inclusion criteria were diagnosis of ITP and dapsone treatment for a period of at least 15 days. The recommendations from the international working group were used for the definitions of ITP diagnosis, classification and assessment of treatment responses (Rodeghiero F et al, 2009).
Medical charts from 272 ITP patients were reviewed, with the identification of 147 patients treated with dapsone during the follow-up period. Eight patients did not meet inclusion criteria due to short duration of dapsone treatment. Seventeen patients were excluded from the study, due to: concomitant use of other therapies for ITP (n=8), important missing data (n=7) and significant hypersplenism (n=2). The final total of evaluated patients was 122. Baseline characteristics of these patients are shown in Table 1. Dapsone treatment was normally initiated at the dose of 100mg/d. Only 22% of patients were screened for G6PD deficiency before dapsone initiation. Median treatment duration was 6 months, with a maximum treatment duration of 15 years. The median study follow-up period was of 3.4 years (1.3 months-17.6 years).
The overall response rate in this cohort was 66%, including 24% of complete responses. Clinical characteristics associated with a greater chance of treatment failure were previous splenectomy (p=0.003) and three or more previous therapies (p=0.02). Among all responders, in 24% a relapse occurred while on dapsone treatment. Therefore, a sustained response was observed in 51% of the study cohort. Patients with a complete response had a much lower relapse rate, of only 7%. Interestingly, 81% of the responders maintained the response after the interruption of treatment, for a median time of 26 months. As expected, splenectomy was performed later on in only 16% of the responders, a much lower rate than observed in non-responders (61%).
Side effects were reported in 16% of the patients in this cohort: symptomatic hemolytic anemia (n=5), symptomatic methemoglobinemia (n=5), gastrointestinal symptoms (n=4), and others (n=5). Treatment was interrupted due to side effects in 11% of patients, the main cause in these cases was hemolytic anemia (n=5), followed by methemoglobinemia (n=4). Elevations of methemoglobin levels were observed in 83% of the evaluated patients (n=45), but these elevations were usually mild, with a median methemoglobin level of 2,6%. Methemoglobinemia occurred more often in older patients. Reductions in hemoglobin (Hb) levels during the use of dapsone were seen in 94% of the patients. Median Hb fall was 1,7g/dL. Only 49% of the patients reached Hb levels consistent with a diagnosis of anemia. Responders presented significantly greater reductions in their Hb levels than non-responders: median Hb drop of 1.9g/dL vs 1.2g/dL (p=0.004) (Figure 1).
Our findings suggest that dapsone has adequate efficacy and is well tolerated in ITP patients. We observed a sustained response in 51% of the patients, that lasted for over 2 years after the suspension of the drug in most of the responders. When used as a 2nd line therapy, it has a role as a splenectomy-sparing agent. The main side effects observed were hemolysis and methemoglobinemia, but in general they were mild and well tolerated. Patients with previous splenectomy and greater number of treatments were less likely to respond to dapsone. Although the mechanism of action is still unclear, our observation that the degree in the drop of Hb is greater in responders suggests a possible role of the blockage of the reticuloendothelial system in the therapeutic effect of the drug.

Disclosures
De Paula: Hematology and Transfusion Medicine Center, University of Campinas: Employment.