Efficacy of Second Line Agents Dapsone & Azathioprine in Children & Adults with Immune Thrombocytopenia: Single Centre Experience from India
Authors: Ekbote Venkatesh Shreeganesh , George Biju , Mathews Vikram , Lakshmi Kavitha , Ganapule Abhijeet , Abubacker Fausia N , Korula Anu , Srivastava Alok 
Published: October 2019

Abstract
There are approximately 10 therapeutic agents listed as second line therapy for steroid refractory or relapsed ITP but there are no clear guidelines for timing & order of their use or that of splenectomy. At our center, we have used dapsone or azathioprine as second line therapy prior to splenectomy in such patients who do not have critical bleeding. This study describes the outcome of that approach.
Three hundred patients fulfilling ITP International Working Group definition of steroid non-response & relapse ITP (Rodeghiero et al Blood 2009) were included. Response to treatment was assessed using American Society of Hematology 2011 guidelines (Neunert et al Blood 2011). This analysis was approved by the institutional ethics committee. Patients received either dapsone (n = 170) at 1-2 mg/kg/day or azathioprine (n = 130) at 1-3 mg/kg/day in escalating doses based on physician preferences. Additional intermittent corticosteroids were given in 36 patients. Data was retrieved from individual medical records and electronic database. Statistical analysis was performed using SPSS version 16.0
Results: Baseline characteristics of the patients & outcome are described in Table 1. After 3 months of therapy, overall response was 58.6% while it was 58.8% for the dapsone group and 58.5% for azathioprine group. The number of patients achieving complete & partial response was 46% & 12.7% for overall group, 45.9% & 13% for dapsone group & 46.2% & 12.3% for azathioprine group. The median duration of response was 35 months (2-74 months) and was significantly longer with azathioprine - 60 months (2-60 months) compared to 27 months (5-74 months) with dapsone (p=0.015). Therapy was well tolerated with 4 patients discontinuing dapsone (methemoglobinemia, dapsone syndrome) and 2 discontinuing azathioprine (cytopenia). There were no deaths.
At a median follow up of 33 months (24-42 months), 67 (38%) of the 176 responders have relapsed. These included 49 patients that relapsed while on therapy and 18 that relapsed after cessation of therapy. Relapses were significantly more common with dapsone (40.3%) than azathioprine (20.4%) (p=0.002). The median time to relapse while on therapy was 14 months for both agents. Any response to second line therapy less than complete response (p=0.030) & steroid nonresponsive ITP (p=0.042) were significantly associated with increased risk of relapse on therapy. Overall, 59.6% patients responding to dapsone and & 79.5% of patients responding to azathioprine continue to remain in remission both on & off therapy. Patients who switched to dapsone at the time of relapse showed significantly better response rate - 54% than azathioprine - 22.2% (p<0.001). Forty one patients who failed second line therapy eventually underwent splenectomy, with a response rate of 70.7%.
In conclusion, the use of dapsone & azathioprine appears to be a safe approach, with need for splenectomy only in a few patients. The optimal dose & duration of therapy for these agents needs further evaluation in prospective studies.
Table 1. Patient Characteristics Characteristics Total (%) N = 300 Dapsone (%) n = 170 Azathioprine (%) n = 130 P value Children 104 (34.7) 64(37.7) 40(30.7) ns Adults 196 (65.3) 106(62.3) 90(69.3) ns Male:Female Ratio 0.56:1 0.68:1 0.42:1 0.069 Median ITP Duration (months) 5 (1-262) 4 (1-262) 6 (1-146) ns Steroid Non-responsive 144 90 (52.9) 54 (41.5) 0.062 Relapsed ITP 156 80 (47.1) 76 (58.5) 0.062 Overall Response 176 (58.6) 100 (58.8) 76 (58.5) ns Complete Response 138 (46) 78 (45.9) 60 (46.2) ns Relapse rates 67/176 (38) 40.3% 20.4% 0.002 ns = not significant

Disclosures
No relevant conflicts of interest to declare.