In childhood immune thrombocytopenia (ITP), intravenous immunoglobulins (IVIG) treatment shortens the duration of thrombocytopenia and bleeding symptoms but does not prevent the development of chronic ITP (Heitink-Pollé et al. Blood 2018). This suggests that IVIG is efficacious in patients who would otherwise recover spontaneously. Thirty percent of children show no response to IVIG. We aim to target IVIG treatment to those who benefit most. We hypothesized that IVIG responders can be distinguished from non-responders by a specific immune profile.
To predict treatment responses to IVIG, a secondary analysis was performed in IVIG-treated children of the Treatment with or without IVIG for Kids with ITP(TIKI) randomized controlled trial. Children with newly diagnosed ITP, a platelet count <20x109/L, non-severe bleeding and an age below 7 years were included in this analysis (N=80). Patients were systematically profiled at diagnosis before treatment with IVIG, including clinical data, targeted genotyping, immunophenotyping of lymphocyte subsets and testing for antigen-specific platelet autoantibodies. A complete sustained platelet response was defined as a platelet count >100x109/L at week 1 and 4 after IVIG treatment. From an input of 46 variables, supervised statistical learning (Elastic net) was used to select predictors of absence of a sustained platelet response after IVIG administration.
In total 32/80 patients (40%) did not show a sustained platelet response to IVIG; 23 patients showed no one-week platelet response and 9 relapsed from an initial response. Non-response to IVIG was associated with a large deletion in the Fc-gamma receptor locus (copy number region 1, encompassing FCGR2Cand FCGR3B), Buchanan bleeding Score > 1, lower hemoglobin levels, insidious disease onset and absence of anti-platelet IgG autoantibodies. Together, these five variables achieved a reasonable discrimination between IVIG-responders and non-responders with a receiver-operator-characteristic AUC of 0.81. Non-responders were classified with a sensitivity of 0.98 and a low specificity of 0.54. All children that were predicted to have a complete sustained response had favorable disease outcomes. Misclassifications occurred mostly in patients who showed a partial response to IVIG.
When we used this set of predictors in children below 7 years of age that were included in the observation arm of the trial (N=67), children with persistent thrombocytopenia during follow-up were distinguished (6-month non-response, AUC 0.78; 12-month non-response, AUC 0.85), suggesting that children with persistent ITP showed similar disease characteristics as patients who did not respond to IVIG. Furthermore, this independently validated the association of the identified variables with prolonged ITP disease trajectories in patients who were not included during the statistical identification of the variables.
In children below 7 years of age with newly diagnosed ITP, patients with persistent thrombocytopenia and IVIG non-responders were distinguished with high sensitivity by a limited set of clinical and immune variables. Our data strongly support the hypothesis that IVIG is efficacious in patients who would otherwise recover spontaneously. While we will continue to investigate the underlying immune phenomena, these findings potentially allow the design of a model to predict responses to IVIG at diagnosis. Due to the low specificity, the current set of variables cannot yet be used to withhold IVIG therapy. However, based on the high sensitivity, we conclude that a group of children with self-limiting ITP and a complete sustained response to IVIG can be accurately identified.
Porcelijn:Sanquin Blood Supply Foundation: Employment. De Haas:Sanquin Blood Supply Foundation: Employment.
Asterisk with author names denotes non-ASH members.