Dapsone in Relapsed/Refractory Adult and Pediatric ITP- a Longitudinal Panel Data Analysis Demonstrates Efficacy, Safety, and Dose Dependent Response Rate Mediated through Drop in Hemoglobin
Authors: Shah Shaan D. , Rathod Dinesh A. , Rathod Nita D. , Modi Gaurang B. , Vibhakar Aarti H. 
Published: December 2024

Background: Immune thrombocytopenic purpura (ITP) is an acquired autoimmune disease featuring an increased platelet destruction and impaired production. Dapsone, a sulfone drug, has therapeutic efficacy in ITP and is notably cheaper, but it is not included in the ‘Evidence-to-decision’ framework due to lack of robust data. The mechanism of action, response predictors, and dose response relationship is not well understood. To address this knowledge gap, we analyzed 58 ITP patients treated with dapsone.

Methods: This retrospective cohort study from two hematology centers included patients with primary ITP who were treated between 2006 to 2021. Data on demographics, ITP type, past treatments, transfusions, lab investigations, dapsone dose, response to treatment, and adverse events was analyzed after ethical committee approval. Bleeding episodes were graded according to WHO grading. American society of hematology 2019 guidelines were used to define ITP types, response, and remission. StataNow 18.5 was used to analyze data of 433 patient encounters for the survival analysis, interval-censored Cox regression, and logistic two-level mixed model regression.

Results: Fifty-eight patients (newly diagnosed=14, persistent=23, chronic=21) received dapsone after 1-4 prior treatments, a majority (n=56) being steroids. The cohort had an equal sex ratio and more adult patients (n=39). Details of transfusions before dapsone therapy-31% patients received 82 red cells and 8.6% required 17 platelets. No patients required transfusion after dapsone therapy. Response rate to prior treatments was 31%. Average dose of dapsone was 1.23mg/kg/day, non-responders received a higher dose (1.48 mg/kg/day, p&lt;0.001). Overall response rate to dapsone was 58.6%. Medians for time to response, duration of response, and follow-up period were 40, 151, and 142 days, respectively. Response within 6 months was noted in 94.1% patients and 44.8% patients maintained response at the last follow-up. Some non-responders (37.5%) had a short treatment duration of 16-62 days.

Kaplan-Meier curves showed a similar response and remission across ITP types, age, and sex. A subset of responders (52.6%) with a follow-up ≥1 year, achieved remission with median time to remission of 435 days. Platelet count increment paralleled with the dapsone dose. Dapsone could be discontinued in 6 patients who had a dapsone-free median response duration of 104 days. Cox regression showed association of response with the dapsone dose; there was no association with sex, age, previous treatment numbers, response to prior treatment, ITP types, baseline platelet counts, and concurrent treatments. One mg/kg/day increase in the dapsone dose was associated with the hazard of 2.39 of achieving response/remission (p=0.001, 95% CI: 1.4 - 4.1). The association was not seen when change in hemoglobin (Hb) from the baseline was added in the model suggesting that dapsone acts on platelets by reducing Hb (p=0.5). This was confirmed by the logistic two-level mixed model-the odds of a fall in Hb were 2.55 times higher with an increase in the dapsone dose by 1 mg/kg/day (p&lt;0.001, 95%CI: 1.6-4). The odds of a response/remission were 5.38 times higher in patients with a fall in Hb compared to those who had no Hb fall (p=0.008, 95% CI (1.55-18.6) after adjusting for the dapsone dose. A subset of patients (n=18) documented 21 adverse events- skin rashes (n=8), altered liver function (n=11), conjunctivitis (n=1), and methemoglobinemia (n=1). Two patients required dapsone discontinuation due to skin rashes (n=1) and conjunctivitis (n=1). One patient with symptomatic methemoglobinemia improved upon dose reduction. The CTCAE v5.0 severity grading was Grade 1 (n=20) and Grade 2 (n=1). No adverse event required hospitalization.

Conclusions: Dapsone responses were dose dependent and were mediated via drop in Hb. Dapsone should be considered in relapsed/refractory ITP not requiring rapid rise in platelets due to (1) its effectiveness irrespective of age, sex, number and response to prior treatments, ITP types, concomitant treatments, and baseline platelets, (2) low cost, (3) acceptable safety profile, and (4) comparable response rates to other treatment options except thrombopoietin receptor agonists and splenectomy. Dapsone should be given for 6 months before stopping or adding another drug. Stable platelet counts while tapering dapsone indicate sustained response.