Compared with observation, treatment with intravenous immunoglobulin (IVIg) did not prevent the risk of developing chronic immune thrombocytopenia purpura (ITP) in children newly diagnosed with ITP, according to findings from a phase III trial published in Blood.
These findings suggest that “IVIg treatment should only be given based on individual patient characteristics, like in toddlers who fall often or teenage girls that have had their menarche, to stop or prevent bleeding,” explained coauthor Katja Heitink-Pollé, MD, PhD, from the University Medical Center Utrecht in the Netherlands. “But, we also have shown that observation is a good alternative to IVIg treatment – information that may be particularly useful for clinicians in low-income countries who cannot afford IVIg.”
The authors evaluated the two management strategies in a population of 206 pediatric patients (age range = 3 months to 16 years), in the multicenter, randomized, openlabel, parallel-group Treatment with or without IVIg for Kids with ITP (TIKI) trial. This is the largest study including an observation group of unselected pediatric patients with ITP, the authors noted.
Participants had platelet counts ≤20×109/L and had mild- to- moderate bleeding (grade 1-3 on the adapted Buchanan bleeding score, a system for grading hemorrhage specifically in children with ITP). Within seventy-two hours of an ITP diagnosis, 200 patients were randomized to receive single-dose IVIg 0.8 g/kg or to undergo observation with the addition of immunomodulatory treatment in cases of severe bleeding in the intention-to-treat analysis.
Median ages in the IVIg group and observation group were 3.6 years (range = 0.3-16.1 years) and 4.5 years (range = 0.5-16.6 years), respectively. Median platelet counts at the time of ITP diagnosis were 6×109/L (range = 1-60×109/L) and 3×109/L (range = 0-60×109/L), respectively.
The researchers determined that IVIg would need to produce a 15-percent difference in the development of chronic ITP (defined as a platelet count <100×109/L at 12 months after diagnosis) to be considered better than careful observation.
Chronic ITP developed in 10 IVIg-treated patients and 12 observation-only patients, which did not reach statistical significance (relative risk [RR] = 0.83; 95% CI 0.38-1.84; p=0.65).
Response rates with either management strategy also were similar at one week, one month, three months, six months, and 12 months post-ITP diagnosis (TABLE). While IVIg appeared to produce higher overall response rates than observation early after ITP diagnosis, the differences were not sustained at 12 months:
- 12-month overall response: 96% in the IVIg group vs. 96% in the observation-only group (RR=1.00; 95% CI 0.95- 1.06; p=1.00)
- 12-month complete response: 90% vs. 88% (RR=1.02; 95% CI 0.93-1.13; p=0.65)
In the observation-only group, 13 patients were admitted for a total of 18 bleeding events (10 grade 4-5 bleeding events), compared with two events in the IVIg-treated group. “All grade 4-5 bleeding events, mainly epistaxis and menorrhagia, were transient,” the authors wrote, “and patients recovered completely after medical intervention within a few days.”
Three patients randomized to observation required rescue medications due to bleeding during the first month following ITP diagnosis, while no patients in the IVIg group received rescue therapy. Hospital readmission or prolonged admission occurred in four patients receiving IVIg due to vomiting either with (n=2) or without (n=2) post-treatment headache. There were no deaths during the study period.
To determine which patients might not require IVIg treatment, the researchers looked at the baseline characteristics of patients at ITP diagnosis and found that patients who were were younger, had a shorter duration of symptoms before diagnosis, and a higher lymphocyte count at diagnosis were more likely to remain free of chronic ITP at 12 months of follow-up.
“If we can identify which clinical and/or laboratory parameters can predict response to IVIg, the treatment can be used in a more cost-effective manner,” Dr. Heitink-Pollé noted. “Also, if we are able to predict clinical course in individual patients, we can counsel parents and children more specifically and could make better choices in management. We believe that in the near future, we will have promising results [from clinical trials] evaluating both issues.”
In addition to providing reassurance to patients who may not be able to afford IVIg treatment, “our study increased our knowledge about ITP’s natural clinical course in children,” Dr. Heitink-Pollé said. “For example, the percentage of children who will develop chronic ITP is much lower than previously thought: 10 percent instead of the formerly reported 25 to 28 percent. This information is very useful to counsel parents and patients.”
Because patients with grade 4-5 bleeding events at diagnosis and those with platelet counts of >20×109/L at baseline were not included, the findings from this study may be limited in generalizability across specific patient subsets.
The authors report financial relationships with Sanquin Blood Supply.
Heitink-Pollé KMJ, Uiterwaal CSPM, Porcelijn L, et al. Intravenous immunoglobulin versus observation in childhood immune thrombocytopenia: a randomized controlled trial. Blood. 2018 June 26. [Epub ahead of print]