Pediatr Blood Cancer 2009;52:155–156 HIGHLIGHT by Clifford M. Takemoto, MD* Rituximab for ITP: A Long-Term Fix? (Commentary on Mueller et al., page 259) While the majority of children with ITP resolve their illness within several months without long-term sequelae, 20–30% will be chronically thrombocytopenic [1]. Effective therapies, such as steroids, IVIG and anti-D are available to increase the platelet count when needed for bleeding symptoms or risk of bleeding; however, the effect of these treatments are transient and are thought not to change the natural history of the disease. For children who follow a chronic course, splenectomy can offer a cure, resulting in normal or improved platelet counts in the majority, at the expense of increased infectious risks with encapsulated bacteria. In this issue of Pediatric Blood & Cancer, Mueller et al. describe durable responses in a subset of children with chronic ITP who were treated with Rituximab. This follows their initial report of a phase 1/2 trial in which 31% of children with chronic ITP (11 of 36) achieved sustained platelet counts of >50,000 per cu mm with 3 or 4 weekly doses of Rituximab [2]. These patients were followed for over a year. The authors found that 8 of the initial 11 responders maintained platelet counts over 150,000 per cu mm; the overall percentage of patients with platelets >50,000 per cu mm at a year was 31% (11 of 36) due to 3 patients classified initially as non- responders who subsequently improved. The rate of durable responses in children with ITP after treatment with Rituximab is similar to those reported by Wang et al. (37.5%) [3] and Taube et al. (36.4%) [4]. Furthermore, similar rates of long-term responses have been published for adults with ITP [5]. Although the numbers of patients in these studies are small and the follow up is relatively short, this experience suggests that Rituximab may provide an alternative to splenectomy in a subset of patients, if the goal is a long-lived platelet response. It is interesting to note that for many practicing pediatric hematologist/oncologists, this therapeutic option has already become a preferred first choice prior to splenectomy for the treatment of chronic ITP. In a survey of 297 ASPHO members presented with a vignette of a 5-year-old girl with chronic ITP and bleeding symptoms, Rituximab (44%) was the top choice over splenectomy (33%) and all other therapies [6]. Why its popularity? The long-term response rate with Rituximab (30 – 40%) [2 – 4] is lower than splenectomy (70–80%) [7], and Rituximab does not appear to have significantly better response rates than other agents that have been used for chronic ITP, including vincristine, mycophenolic acid, immuran, and thrombopoietic agents to name a few. Perhaps its popularity is due to its perceived tolerability and lack of toxicity, as well as the growing experience with its use in children. While the safety profile of Rituximab in adults has been established with large numbers of patients, the experience in children is, in comparison, quite limited. The cumulative experience thus far, however, suggests that Rituximab is well tolerated in pediatric patients. The most common side effects are infusion- related (chills, fever, angioedema, hypotension); serum sickness has also been reported [2]. A major concern of Rituximab has been its infectious risks due to the expected and prolonged depletion of B-lymphocytes. IgM levels have been demonstrated to be depressed after treatment, but IgG does not appear to change significantly. There have been infrequent and scattered case reports of opportunistic infections in children after Rituximab [8]. In adults treated with Rituximab and chemotherapy for malignancies, reactivation of viral infections such as Hepatitis B [9], CMV [10], and varicella-zoster [11] have been described. More recently, the FDA issued an alert reporting two adult patients with SLE on immunosuppressive medications who developed progressive multifocal leukoencephalopathy (PML) secondary to JC virus reactivation [12]. However, studies of immunocompetent children (without malignancy and/or concomitant immunosuppressive therapy) treated with Rituximab have not demonstrated an increased incidence of infections. Certainly, while these serious toxicities after Rituximab are rare, they underscore the fact that judicious use is appropriate. The durable responses also raise intriguing questions about the mechanism action of Rituximab. Rituximab is a chimeric mono- clonal antibody that targets CD-20, an antigen expressed selectively on mature B-lymphocytes. It has efficacy in treating a number of immune-mediated disorders in children other than chronic ITP, including autoimmune hemolytic anemia (AIHA), FVIII and FIX inhibitors, and SLE. Rituximab treatment rapidly reduces circulat- ing B-cells and IgM, but levels return to pretreatment ranges in 6– 12 months. This observation suggests that the mechanism of durable responses might not be due simply to a general reduction in antibody production. Recently, patients with ITP have been found to be deficient in a subset of relatively rare T lymphocytes called T regulatory lymphocytes (T-regs) [13]. These cells, marked by their expression of CD4, CD25 and Foxp3, appear to play a critical role in maintaining peripheral tolerance. Intriguingly, in patients with chronic ITP who respond to Rituximab, T-reg populations return to normal [14]. Thus, while the major target of Rituximab appears to be the B-cell compartment, its associated affect on the T-cell compartment, in particular the T-regs, may be essential to its ß 2008 Wiley-Liss, Inc. DOI 10.1002/pbc.21803 Published online 4 November 2008 in Wiley InterScience (www.interscience.wiley.com) —————— Pediatric Hematology, The Johns Hopkins University, Baltimore, Maryland *Correspondence to: Clifford M. Takemoto, Pediatric Hematology, The Johns Hopkins University, 720 Rutland Avenue/Ross 1125, Baltimore, MD 21205. E-mail: ctakemot@jhmi.edu Received 9 September 2008; Accepted 9 September 2008