IVIg and FcγRIIb in kids with ITP: individualizing therapy

In this issue of Blood, Heitink-Pollé et al present the long-awaited results of a very important recent study, the TIKI (treatment with or without IV immunoglobulin [IVIg] for kids with immune thrombocytopenia [ITP]) trial: a randomized, controlled trial comparing IVIg to observation in children with ITP at diagnosis, with the primary end point of evaluating the rate of chronic ITP in treated and untreated children.¹ 

Heitink-Pollé and colleagues performed this pivotal study over 6 years throughout The Netherlands, comparing treatment with a single dose of IVIg and observation, the latter being the standard recommendation for a child without major bleeding.²  The last pediatric trial comparing observation to treatment (steroids and IVIg) in children with ITP came from the Canadian Pediatric Group in 1993³  and did not evaluate eventual development of chronic disease. In 1985, Imbach et al⁴  reported earlier attainment of complete response in the IVIg arm compared with the prednisone arm but found no difference in disease persistence at 6 months. Thus, there exist no clear data, only meta-analyses⁵  and single-arm studies, suggesting a potential curative effect of IVIg. Given the side effect profile of IVIg and the emphasis on not overtreating children at diagnosis, the Dutch study is very important because the primary end point was development of chronic ITP based on initial management, a “hot topic” because of the potential for early intervention to modify the course of ITP disease. The definition of chronic ITP was changed during the study from 6 to 12 months duration of disease,⁶  but neither was statistically different between the 2 groups (see Figure 2 in Heitink-Pollé et al); however, many interesting effects were noted.

Not surprisingly, the children treated with a single 800 mg/kg dose of IVIg had a significantly higher rate of complete response from 1 week posttreatment through 1 month from diagnosis. This significant difference in favor of IVIg persisted between the 2 groups through 3 months (see Figure 2 in Heitink-Pollé et al), with more (81% vs 71%) children experiencing resolution of ITP at 6 months and no difference at 12 months. One possible reason for the lack of difference between the 2 groups was the relatively low rate, ∼10% instead of the expected 20% to 30%,⁷  of evolution to chronic disease. The incidence of severe bleeding was lower in the children treated with IVIg, but only 1/6 children on the observation arm starting the trial with grade 3 bleeding progressed to grade 4 bleeding, 7/8 within the first month. Although there was 1 case of intracranial hemorrhage in the observation arm, there was no mortality in either arm. There were 18 admissions because of bleeding in 13 patients in the observation arm and 5 admissions in the IVIg arm, 1 from allergy and 4 because of IVIg reactions such as headache, nausea, and/or vomiting. The authors estimated that 100 patients would need to be treated with IVIg to avoid 8 cases of grade 4 to 5 bleeding in the first month from diagnosis (likely with hospital admission) and, in doing so, severe adverse events attributable to IVIg would cause 5 hospital admissions or admission prolongations. Finally, the health-related quality of life (HRQoL) analysis of 107 of the 200 TIKI trial patients (published separately)⁸  showed a significant improvement in HRQoL in patients achieving a complete platelet response as was stated in the complete report.¹ 

Importantly, these were all prospective observations from a trial with an apparent very high rate of compliance: all patients were included in the analysis. One important caveat was that no premedication was given with the IVIg infusions. The common practice of giving acetaminophen, diphenhydramine, and/or corticosteroids with IVIg could possibly have reduced the IVIg side effects. Of note, it is possible that higher doses of IVIg divided over 2 or more days and/or combination treatments might induce an even better effect, although they also could have proved to be more toxic without improved benefit. Finally, the findings of this study are limited to children with ITP without major bleeding at presentation (grades 1-3).

Perhaps the most significant finding in the TIKI trial was confirmation that a polymorphism in FCGR2B had a major impact on outcome of both treated and untreated patients. Based on preliminary data suggesting FCGR2B variants affect both course of disease⁹  and response to IVIg in Kawasaki disease,¹⁰  the investigators performed multiplex ligation-dependent probe amplification to identify variants across FCGR genes. The FCGR2B polymorphism discussed in the study not only impacted the response to IVIg, but also, more importantly, it showed more rapid achievement of complete response even in children without treatment, confirming their earlier study. The FCGRB polymorphism did not predict chronicity, but patients with both heterozygous and homozygous variants improved sooner.

Taken together, these clinical and genomic findings could have a significant impact on individualizing the approach to newly diagnosed patients with ITP. While IVIg administered at diagnosis at a single infusion of 800 mg/kg will not impact development of chronic ITP, the authors report that patients who will eventually enter remission may likely achieve remission sooner if treated with IVIg. The genotype data provide the first opportunity to use genomics to personalize approach to treatment of childhood ITP. Utilizing these findings, IVIg treatment could be offered to patients who are most likely to benefit, and those who are not likely to recover as quickly, thus avoiding side effects in those least likely to benefit. If the turnaround time is rapid enough (as is planned in The Netherlands), identifying the variant allele could help to predict the expected disease course of a given patient, an important step toward a more targeted approach to the management of pediatric ITP.

In summary, the TIKI trial is a remarkable large, randomized, prospective study that demonstrates that although IVIg induces earlier remission, it does not appear to influence development of chronic ITP. As or potentially more important, TIKI confirms an earlier study showing that an FCGR2B polymorphism significantly influences the outcome of pediatric ITP in untreated patients as well as response to IVIg therapy. Both of these findings are major first steps in individualizing the treatment of children with ITP at diagnosis.