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Written in Blood

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 × 10 9 / L and had mildto-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 × 10 9 / L ( range = 1-60 × 10 9 / L ) and 3 × 10 9 / L ( range = 0-60 × 10 9 / 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 × 10 9 / 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 .”

TABLE . Response Rates at Different Time Points

Intravenous Immunoglobulin ( n = 100 )

Observation ( n = 100 )

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 .”

— KATJA HEITINK-POLLÉ , MD , PhD

Because patients with grade 4-5 bleeding events at diagnosis and those with platelet counts of > 20 × 10 9 / 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 .

REFERENCE

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 ]

Relative Risk ( 95 % CI ) p Value

26 ASH Clinical News August 2018