The pathophysiology of immune thrombocytopenia (ITP) is complex and encompasses innate and adaptive immune responses, as well as megakaryocyte dysfunction. Rituximab is administered in relapsed cases and has the added benefit of inducing treatment-free remission in over 50% of patients. Nevertheless, the responses to this therapy are not long-lasting, and resistance development is frequent. B cells, T cells, and plasma cells play a role in developing resistance. To overcome this resistance, targeting these pathways through splenectomy and novel therapies that target FcγR pathway, FcRn, complement, B cells, plasma cells, and T cells can be useful. This review will summarize the pathogenetic mechanisms implicated in rituximab resistance and examine the potential therapeutic interventions to overcome it. This review will explore the efficacy of established therapies, as well as novel therapeutic approaches and agents currently in development. 

Rituximab resistance in ITP and beyond

Background Rituximab is a monoclonal anti-CD20 antibody used as a second-line treatment for immune thrombocytopenia (ITP). As additional treatments for ITP emerge, identifying the most appropriate patients and optimal timing for rituximab are important but challenging without established predictors of response to therapy. Objectives The purpose of this study was to describe demographic, clinical, and laboratory characteristics of pediatric and adult patients with ITP to identify differences in evaluation before rituximab administration and correlates of platelet response. Methods This is a retrospective cohort study describing the characteristics of patients with ITP treated with rituximab from 2010 to 2020 at two academic tertiary care centers. Results A total of 64 patients met criteria for inclusion. Complete rituximab response (56%) was not significantly different between children (58%, n = 24) and adults (55%, n = 40). Response rate was similar in those with primary versus secondary ITP (53% vs 62%). Among patients treated with rituximab, Evans Syndrome was more common in children than adults (42% vs 18%). Immunologic labs assessed before rituximab varied by age and were more commonly evaluated in children (lymphocyte subsets 88% vs 22%). Immunologic markers, including antinuclear antibody, direct antiglobulin testing, immunoglobulin levels, and lymphocyte subsets, did not predict response to rituximab in pediatric or adult patients with ITP. Conclusions Pre-rituximab immunologic evaluation varied significantly between adults and children, which could represent institution-specific practice patterns or a more general practice difference. If the latter, underlying immunodeficiency in adults with ITP may be underrecognized. Standardized guidance for pre-rituximab immunologic evaluation is needed.

Response to rituximab in children and adults with immune thrombocytopenia (ITP).

Antinuclear antibody (ANA) can be positive in children with primary immune thrombocytopenia (ITP), but the effect of ANA titre and its variation on outcomes of children with primary ITP remains unclear. Here, we conducted a single‐centre retrospective cohort study of children with primary ITP at the Peking Union Medical College Hospital in China. A total of 324 children with primary ITP included in this study were followed for a median time of 25 months. In this cohort, 39.2% had an ANA titre of 1:160 or higher. Results from a generalized estimating equation model revealed that patients with higher ANA titres had lower platelet counts at onset but a higher recovery rate of subsequent platelet counts. Results from Cox regression models adjusted for potential confounders revealed that patients with ANA titres of 1:160 or more were more likely to develop to autoimmune disease (AID) than those without, and the risk of AID development increased with the rise of ANA titres (p value for trend less than 0.001). These data highlight the predictive value of ANA titre for platelet counts and the risk of AID development in children with primary ITP.

The effect of antinuclear antibody titre and its variation on outcomes in children with primary immune thrombocytopenia

Immune thrombocytopenia is the most common autoimmune disorder involving blood types. In several studies, the role of T CD4+ cells in patients with immune thrombocytopenia has been associated with different results. Therefore, in this study, with the aim of applied research in the pathogenesis of immune thrombocytopenia, the relationship was investigated between the number of T CD4+ cells, serum levels of IL-11 and IL-17 cytokines, and platelet count. In this regard, 100 patients with immune thrombocytopenia and 100 healthy individuals were included in the study. The T CD4+ cell counts were examined by flow cytometry and in addition, serum levels of interleukins 11 and 17 were measured by ELISA. The results of this study showed that the number of T CD4+ cells and plasma level of IL-17 were not significantly different between the two groups, but plasma levels of IL-11 in the patient group were significantly higher than the control group (P = 0.286). Overall, in this study, the level of cytokine IL-11 was significantly increased in comparison with IL-17 and T CD4+ cells in patients with immune thrombocytopenia, so it is suggested that measurement of cytokine IL-11 level in these patients could be considered as a critical diagnostic marker and indicator in the stages of disease progression.

/pdf/the-relationship-between-different-interleukins-and-t-helper-31l2l11s.pdf

The relationship between different interleukins and T helper cells count in patients with immune thrombocytopenia.

Autoimmune cytopenias following pediatric hematopoietic cell transplant.

BACKGROUND Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplant (HSCT) is a rare but complex and serious complication Detailed descriptions of cases and management strategies are needed due to lack of prospective trials OBJECTIVES Describe the incidence, clinical characteristics, and management of AIHA after HSCT in a pediatric cohort METHODS This is a retrospective cohort study of 33 pediatric patients with AIHA after HSCT at an academic tertiary care center from 2003 to 2019 RESULTS The overall incidence of AIHA after allogeneic HSCT was 38% (33/868) AIHA was significantly more common after transplant for nonmalignant versus malignant diagnoses (70% [26/370] vs 14% [7/498], p < 0001) AIHA developed at a median of 47 months (range 10-297) after transplant Sixteen of 33 patients (485%) required new AIHA-directed pharmacologic therapy; 17 (515%) were managed on their current immunosuppression and supportive care Patients managed without additional therapy were significantly older, more likely to have a malignant diagnosis, and tended to develop AIHA at an earlier time point after transplant Patients received a median of two red blood cell transfusions within the first 2 weeks of diagnosis and a median of one AIHA-directed medication (range one to four), most commonly corticosteroids and rituximab CONCLUSIONS AIHA after HSCT is rare but occurs more commonly in patients transplanted for nonmalignant diagnoses While some pediatric patients who develop AIHA after transplant can be managed on current immunosuppression and supportive care, many require AIHA-directed therapy including second-line medications

Characteristics and outcomes of autoimmune hemolytic anemia after pediatric allogeneic stem cell transplant.

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Response to rituximab in children and adults with immune thrombocytopenia (ITP).

Characteristics and outcomes of autoimmune hemolytic anemia after pediatric allogeneic stem cell transplant.