Dapsone salvage therapy for adult patients with immune thrombocytopenia relapsed or refractory to steroid and rituximab
Authors: Francesco Zaja, Luciana Marin, Marianna Chiozzotto, Simona Puglisi, Stefano Volpetti, Renato Fanin
Journal: American Journal of Hematology (2011)

Dapsone is an antibacterial sulfonamide with anti-inflammatory property, which showed therapeutic activity in patients with immune thrombocytopenia (ITP) [1-6]; the activity in patients who showed refractoriness to rituximab is unknown. We evaluated the effect of dapsone in 20 consecutive adult patients, median age 51 years, with primary ITP previously treated at least with steroids and rituximab. Median baseline platelet count was 19 × 109/L, and the median interval between diagnosis of ITP and dapsone therapy was 46 months. Response (platelet count ≥ 30 × 109/L) and complete response (CR; platelet count ≥ 100 × 109/L) were 55 and 20%, respectively; median time to response (TTR) was 1 month. All responders were able to interrupt any other specific anti-ITP treatment. The median duration of dapsone therapy in responders and the median response duration were 31 and 42 months, respectively. None of responders lost response during treatment. One patient in CR interrupted dapsone after 9 months and still maintained the response after 48 months. None of the patients interrupted the treatment for toxicity. All the patients were screened for normal glucose-6-phosphate-dehydrogenase (G6PD); two patients showed mild increase of methemoglobin (MHb). These results highlight the therapeutic activity and good safety profile of dapsone in patients with ITP who previously failed rituximab treatment. ITP is an acquired autoimmune disease characterized by increased platelet destruction, impaired megakaryocyte maturation with reduced platelet production, and possible hemorrhagic complications. Treatment is generally indicated for symptomatic patients, that is, those with active bleeding or very low platelet count (usually < 20–30 × 109/L). Glucocorticoids, potentially associated with intravenous high-dose immunoglobulin in those cases with high risk of major bleeding, represent the standard first line of treatment [7]. However, despite the high initial therapeutic efficacy, in most cases, steroids tapering or withdrawal is followed by a drop in platelet count and the need for additional treatment. Treatment of patients with relapsed or refractory symptomatic ITP, particularly of those who are not eligible for, refused or failed splenectomy, still lacks a gold standard therapy. Dapsone is an antibacterial sulfonamide synthesized in 1908 with antimicrobial effect against leprosy, pneumocystic Jiroveci pneumonia in AIDS, toxoplamosis, and malaria. Since 1950s, dapsone also was recognized to have activity in a number of noninfectious inflammatory diseases of the skin as dermatitis herpetiformis and blistering disorders. The anti-inflammatory effect of dapsone is not fully understood, but it appears at least targeted against neutrophils, with interference of myeloperoxidase, inhibition of lysosomal enzymes, chemotaxis, and integrin-mediated adherence function. This agent is contraindicated in patients with G6PD deficiency and has a good safety profile. Hemolytic anemia and an increase of methemoglobin (MHb) are the main reported side effects [8, 9]. Previous studies highlighted the therapeutic activity of dapsone as salvage therapy in primary ITP with 40–60% overall response rate and 15–50% CR rate [1-6]. The response to dapsone was unaffected by pretreatment characteristics such as sex, age, platelet count, or duration of ITP and was generally treatment dependent, even if the persistence of response after dapsone discontinuation has been registered in some patients. However, in none of previous studies the activity of dapsone was tested in patients who previously failed rituximab therapy. Here, we report the results of a single centre experience with the use of dapsone salvage therapy in the setting of adult patients with chronic ITP, previously unresponsive to or relapsing after rituximab treatment. Twenty Caucasian patients with primary ITP, median age 51 years (range 27–74 years), were included in the study. Patients' characteristics are summarized in Table I. All patients previously received treatment with steroids and rituximab and six underwent splenectomy. Median baseline platelet count was 19 × 109/L; the median interval between diagnosis of IT and dapsone therapy was 46 months (range 2–274 months). Response (R) and CR at month 6 were achieved in 11 (55%) and four (20%) patients, respectively; median TTR was 1 month (range 0.5–2 months). The median platelet count in responding patients at month 6 was 103 × 109/L (range 47–252 × 109/L). Univariate logistic regression showed no relationship between R and age, gender, patients' weight, and only a trend in favour of patients with shorter interval between diagnosis and dapsone therapy (P = 0.092). Ten patients suspended dapsone therapy, one because of persistent CR (still present 48 months after the interruption of therapy) and nine because of no response; 10 patients are still assuming dapsone, three at the dosage of 50 mg/daily and seven at 100 mg/daily. The median duration of dapsone therapy in all patients is 8.5 months (range 4–56); the median duration of response is 42 months (range 8–56) and the median duration of treatment in responders is 31 months (range 8–56; Table II). None of the responders lost response during treatment. The median time of observation, in all patients, is 43 months (range 4–53 months). Therapy was overall well tolerated and none of the patients interrupted the treatment because of toxicity. Two patients showed mild asymptomatic increase in MHb level to 7 and 8%, which spontaneously decreased, despite treatment prosecution, to 4 and 5%. None of the patients showed significant development of hemolysis. No other infectious, hematologic or extrahematologic complications and cases of hypersensitivity syndrome were documented. The results of this study confirm the activity of dapsone also in patients who previously failed rituximab therapy. The baseline clinical characteristics of our population and the therapeutic outcome appears very similar to those reported by Godeau et al. [3] in another European study with dapsone in ITP (Table III), showing an overall response and CR rates of nearly 50 and 20%, respectively (responses were evaluated using criteria similar to those adopted by us). Interestingly, in both experiences, the relapse rate during therapy was very low (0% in this study and 5% in the article of Godeau) indicating that, in responders, there is little probability to develop mechanisms of resistance. Similar results as to activity and toxicity have been reported in several other reports both in pediatric and adult patients [1-6] (Table III). Apart from few anecdotic cases as the one reported in this study, where the response is maintained also on dapsone withdrawal, the hematological improvement is generally dependent on the chronic administration of therapy suggesting a palliative effect of this treatment. What does dapsone add to the therapeutic armamentarium now available for patients with ITP? At present, splenectomy remains the standard salvage therapy for patients with steroid dependent chronic ITP. However, nearly 30–40% of patients either show primary resistance or relapsed within 5 years after splenectomy. Furthermore, some patients have contraindications or refuse surgical intervention, and there is still some concern regarding the possible long-term increased risk of infectious complications. Several other immune suppressive agents as azathioprine [10, 11], cyclosporin-A [12], micophenolate mofetil [13, 14], some cytotoxic drugs as cyclophosphamide [15, 16] or vincristine [17] and some hormonal agent as danazol [18, 19] may be active in 30–50% of patients with ITP, but their administration is frequently associated with side effects. If compared with these multiple agents, dapsone appears characterized by similar, if not higher, therapeutic activity and a much more favorable safety profile. In this last decade, several studies indicated the therapeutic activity of rituximab 375 mg/mq given weekly for 4 weeks, with 60 and 40% short-term R and CR rates, respectively [20-23]. Factors in favor of rituximab are the curative purpose, the relative short-term period of therapy, the good compliance of the patients. However, rituximab is expensive, may worsen immune suppression and, although rarely, can cause infectious complications. Furthermore, nearly 20–40% of adult patients experience subsequent relapse in the first 2 years and those who achieve and maintain a long-term effect at 5 years is reported to be around 20 and 40% [23, 24]. Romiplostim and eltrombopag are two thrombopoietin mimetics now available for clinical use that stimulate megacaryocites prolipheration and overcome the inadequately increased platelet production occurring in most patients with ITP. These agents showed very good activity in nearly 80% of patients with ITP [26, 27] but have a palliative activity and necessitate continuous indefinite administration. At present, there are still some concern and perplexities regarding the possible long-term effect secondary to the chronic prolipherative pressure of megacaryocites and stem cells. In addition, complete safety in terms of increased bone marrow reticulin formation and of an increased risk of thromboembolism await for the results of currently ongoing long-term studies. If compared with these agents, dapsone is satisfactory as to toxicity. In this study, the incidence of hemolysis or methemoglobinemia was not significant and none of the patients experienced important side effects or interrupted therapy because of treatment intolerance. Other authors showed the development of reversible side effects requiring cessation of therapy in 2–10% of patients [4, 6]. In conclusion, dapsone appears to be a cheap medical alternative for patients with ITP and is active also in patients who failed previous rituximab therapy. The response is achieved in most cases after nearly 1 month of therapy, and it is generally maintained during therapy. Even if dapsone has a good safety profile, it is necessary to monitor the level of MHb and hemolysis particularly during the first weeks of therapy and to be aware of factors that may precipitate dapsone-induced methemoglobinemia as anemia, pneumonia, or lung diseases and to know how to manage this complication. A better comprehension of ITP pathophysiology and of dapsone mechanism of action will allow in the future a better and rational integration of this agent into the treatment algorithm of primary ITP. This study analyzes all consecutive adult patients with relapsed or refractory primary ITP according to the standardized criteria recently reported [28], who started therapy with dapsone from May 2005 to February 2011. Patients included in the study had a diagnosis of symptomatic or steroid-dependent ITP, relapsed or refractory at least to two lines of therapy including steroids and rituximab, with normal G6PD. All patients signed a written informed consent. Dapsone was given p.o. at the fixed dose of 50 mg/daily the first week and then at 100 mg/daily for 2 months. Nonresponders at this point interrupted therapy, while responders continued dapsone until disease progression, intolerability, withdrawal of consent. For patients achieving CR, dapsone tapering and eventually withdrawal was planned. No other cytotoxic or immunosuppressive drugs were given in association with dapsone. Patients with steroids dependency because of low platelet number (<20 × 109/L) or active bleeding were allowed to continue steroids at the individual minimal effective dosage sufficient to maintain a safe number of platelets. Nevertheless, only patients who achieved steroid discontinuation during or soon after dapsone were considered responsive. The primary objective of the study was to evaluate response rates at month 6 from the start of therapy according to standardized criteria [11], that is, R requiring a platelet count ≥ 30 × 109/L but <100 × 109/L, at least twofold increase of baseline count, and no bleeding; CR requiring a platelet count ≥ 100 × 109/L and no bleeding. Patients who were not able to suspend steroids after dapsone therapy were considered non responders. The evaluation of the response was made by monitoring the platelet count every week during the first month of treatment, then every 2 weeks up to the sixth month and then monthly. The secondary objectives of the study were the following: TTR, that is, the time necessary to achieve a platelet count of 30 × 109/L or more; the response duration; the relapse rate; the safety profile. R or CR duration was censored at the date of the last platelet count fulfilling the respective response criteria. The evaluation of adverse event incidence during therapy was performed according to NCI-CTC version 4.0). The logistic regression was used to assess whether response to dapsone was associated with age, gender, patients' weight, duration of the interval between diagnosis, and dapsone therapy. Francesco Zaja*, Luciana Marin*, Marianna Chiozzotto*, Simona Puglisi*, Stefano Volpetti*, Renato Fanin*, * Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi" DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy.