Page 194 - 2020_11-Haematologica-web

Letters to the Editor
Long-term outcomes after splenectomy in children with immune thrombocytopenia: an update on the registry data from the Intercontinental Cooperative ITP Study Group
Immune thrombocytopenic purpura (ITP) is an acquired immune-mediated disease characterized by a decrease in platelet count due to antiplatelet autoanti- body-mediated increased platelet destruction and, in some cases, associated impaired platelet production.1
There has been a decline in the number of splenec- tomies performed as a second-line treatment after the introduction of new therapies, such as thrombopoietin- receptor agonists. However, the current availability of long-term data on these new second-line therapeutic options seems to suggest that splenectomy remains the more effective second-line intervention in ITP.2 Therefore, data on long-term outcomes of splenectomy in children are relevant.
The Splenectomy Registry of the Intercontinental Cooperative ITP Study (ICIS) Group collects information regarding children who underwent splenectomy to treat ITP, including perioperative management and follow-up data. A report of the first 134 patients was published in 2007.3 The present study aims to update the findings of the ICIS Splenectomy Registry by analyzing over a decade of new data, with a focus on long-term outcomes of children with primary ITP.
Details of the data collection forms of the Splenectomy Registry have been previously described.3 Investigators included patients with ITP in whom splenectomy was planned. For the analysis, we excluded records in which splenectomy was not reported or no platelet counts were available at follow-up. Investigators sought local ethics approval prior to patient entry, according to the regulato- ry requirements of each institution. Response to splenec- tomy was classified as a complete response (CR: ≥60% of platelet counts performed ≥1 month post-splenectomy ≥100x109/L), response (R: ≥60% of platelet counts ≥1 month post-splenectomy ≥30x109/L), or no response (NR: <60% of platelet counts ≥1 month post-splenecto- my ≥30x109/L).4 At least two counts after the first month post-splenectomy were required for outcome assess- ment. Refractoriness was defined as either the failure to achieve at least R or loss of R after splenectomy + clini- cally relevant bleeding.5
Bleeding events were classified as major and clinically relevant non-major (CRNM) according to current defini- tions of the International Society on Thrombosis and Haemostasis for patients on anticoagulants.6,7
The trajectory of platelet counts over time was investi- gated using generalized estimating equations (GEE) mod- els with basic splines to accommodate for the non-linear shape of the regression line. Predictors of response to splenectomy were explored using logistic regression analysis. Predictors associated with the outcome at P≤0.20 in univariable analysis were considered for multi- variable modeling. For model performance, simple boot- strap with 200 replications was used to estimate the opti- mism corrected (internally validated) area under the Receiver Operating Characteristic (ROC) curve. Significance was set at an alpha of 0.05. Analysis was performed in R.
A total of 267 patients were entered in the Registry between June 1997 and September 2017 by 82 investiga- tors from 63 institutions and 26 countries. Seventeen records were excluded due to incompleteness and 11 due to secondary ITP diagnosis. Hence, 239 patients were
included in the analysis. Eighty of those patients (80 of 239, 33%) came from a single institution (The Hospital for Sick Children [SickKids], Toronto, Canada). Patients at SickKids were identified using the ICD-9-CM and ICD-10-CA codes, which explains the large number of participants identified in this institution.
The median duration of follow-up was 25 months (25th-75th percentile: 7.8-53.4 months). One hundred and thirty-five patients (135 of 250, 54%) were females. Median age at the time of ITP diagnosis was 9.2 years (25th-75th percentile: 4.8-13.0 years).
Splenectomy was performed at a median age of 11.7 years (25th-75th percentile: 7.9-15.3 years). Sixty-two of the 239 patients (26%) had their splenectomy performed <1 year after diagnosis (i.e., before reaching chronic ITP status) and ten of those 62 patients (16%) had their splenectomy performed <3 months after ITP diagnosis (i.e., before reaching persistent ITP status).
There was one intra-abdominal bleeding event docu- mented during surgery. Eleven patients (11 of 239, 5%), including the patient with intra-abdominal bleeding, received peri-procedural red blood cell transfusions. Twenty-four patients (24 of 239, 10%) had fever at a median of 41 hours post-procedure (range: 6-99 hours). No deaths or episodes of sepsis in the immediate post- operatory period were recorded.
One-hundred and eighty-six patients were followed up for >6 months. No major bleeding events were reported on those patients. Sixteen patients (16 of 184, 8.7%) had a documented CRNM bleed; all cases were classified as CRNM bleed because of the need for hospitalization. Twenty patients (20 of 186, 11%) had at least one admis- sion due to fever or infection and five patients (5 of 186, 2.7%) were reported to have had sepsis (one viral, one due to Streptococcus B) on long-term follow-up. A system- atic review of studies conducted between 1966 and 1996 reported an incidence of invasive infection of 2.1% among 484 patients with ITP, including adults and chil- dren.8 In comparison, a more recent report including nearly 10,000 adults with ITP estimated the cumulative incidence of sepsis at 11.1% in splenectomized versus 10.1% in non-splenectomized patients.9 Age and the number of co-morbidities and longer follow-up of these patients (median of 25 months of total observation in our study vs. 35 months median time from surgery to sepsis in the adult study) were also associated with higher risk of sepsis and might explain the lower frequency seen in our study.
Trend of platelet count post-surgery in the first 30 days and up to 4 years post-surgery is shown in Figure 1. The peak platelet count after surgery was 549x109/L (range: 5- 1,944x109/L) at a median of 7 days (range: 1-35 days). The median platelet count between 30-60 days post- surgery was 337x109/L (25th-75th percentile: 128- 493x109/L). Generalized estimating equations showed a non-statistically significant decline in platelet count over time of 0.56x109/L per month, 95%CI: 1.15-0.04, P=0.08, after the first month post-splenectomy.
Frequency of CR/R/NR is shown in Figure 2. Overall, 93% of patients showed CR/R; this frequency is slightly higher than that reported among adult patients10 and might be explained by the high frequency of splenectomy performed before reaching chronic ITP status (26%) and by a relatively low number of patients who received sec- ond-line therapy (51 of 239, 21%). In addition, we observed a significant difference on the median time to surgery from ITP diagnosis before and after 2009 (median time: 1.7 years, 25th-75th percentile: 0.9-3.1 years, before and including 2009, and 3.2 years, 25th-75th percentile:
2682
haematologica | 2020; 105(11)