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Editorials
Splenectomy for immune thrombocytopenia: the evolution and preservation of treatment
Allison Remiker1 and Cindy Neunert2
1Division of Pediatric Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL and 2Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA
E-mail: CINDY NEUNERT- cn2401@cumc.columbia.edu doi:10.3324/haematol.2020.261099
The management of immune thrombocytopenia (ITP) has evolved over the course of the past twen- ty-five years as new treatments have emerged (Figure 1). Despite such advances, splenectomy remains a viable choice. In this edition of Haematologica, Avila et al. provide long-term outcomes of pediatric patients with ITP who underwent splenectomy. Using data derived from the Splenectomy Registry of the Intercontinental Cooperative ITP Study (ICIS) group, an update of out- comes of patients with primary ITP who underwent splenectomy treatment between 1997 and 2017 was ana- lyzed.1 Findings from this study provide important and relevant information regarding splenectomy as an effec- tive treatment option for ITP, which in certain contexts may have improved outcomes.
Immune thrombocytopenia was first described even prior to the identification of platelets as a component of blood. Various conditions associated with purpura were described from the 11th to the 17th century.2,3 However, it was only in 1735 that Paul Gottleib Werlhof reported the first classical case of ITP4 in a teenage girl with cutaneous and overt mucosal bleeding symptoms following an infectious disease. This led to the eponym of “Werlhof’s Disease”, which was previously used to describe ITP.3 Over time, as microscopy technology progressed, platelets were discovered. Shortly after Bizzozero’s dis- covery of the association between presence and function of platelets in 1881, our understanding of the pathophys- iology of thrombocytopenia grew during the late 1880s.5
Hypotheses began to emerge regarding the pathophys- iology of ITP, with respect to a state of either poor platelet production versus a process of peripheral platelet destruction. In the early 1900s, Marino inoculated guinea pigs with rabbit platelets producing antiplatelet antibod- ies, this simulated ITP in humans suggesting an immune- mediated destructive cause.6 Years later, in 1916, Paul Kaznelson extrapolated the pathophysiology of immune- mediated hemolytic anemia to ITP and suggested that platelet destruction occurred in the spleen. This led to the first successful splenectomy in a 36-year-old woman with presumed chronic ITP, improving her platelet count from 2x109/L to 500x109/L.7,8 Finally, in 1950 Dr. Harrington injected himself with blood from a woman with ITP; his platelet count immediately dropped, recovering five days later. This experiment was the first to support the con- cept of an anti-platelet factor in the blood.9 Over the course of the following hundred years, knowledge of the pathophysiology of ITP has continued to expand to embrace a comprehensive recognition of the complex interactions in the immune system, in turn leading to a variety of novel treatment modalities.2,3 Despite these advances, splenectomy has continued to stand the test of
time since it was first performed in 1916, remaining a beneficial option for this condition.
Treatment guidelines for ITP were first established through the British Paediatric Haematology Group in 1992, soon followed by American Society of Hematology (ASH) guidelines in 1996. These initial guidelines out- lined expert consensus-based practice standards for the evaluation and treatment of children and adults with ITP.10,11 Subsequently, revisions of the ASH guidelines were published in 2011, and most recently in late 2019 applying more rigorous evidence-based methodology.12,13 Recommendations for secondary treatment for primary ITP in the original guidelines were limited to splenecto- my. There were minimal data on the use of splenectomy in children, with one study demonstrating a 72% rate of complete remission.14 Evidence of adverse effects was also insufficient, and non-specific to ITP. Both early guidelines encouraged delaying splenectomy until chil- dren had had ITP for at least 12 months and also reserved splenectomy for children with bleeding symptoms. The ASH 1996 guidelines further suggested that patients have a platelet count <10x109/L (ages 3-12 years), or 10- 30x109/L with bleeding symptoms (ages 8-12 years).10
The next significant breakthrough in the treatment for ITP occurred with rituximab. Rituximab, a monoclonal CD20 antibody, was first used for the treatment of B-cell lymphomas in the 1980s. The first report of its use for autoimmune disease was published in 1998, and, in 2001, Stasi et al. reported on the first prospective trial of ritux- imab in adult patients with chronic ITP (n=25).15,16 It was not until 2006, however, that the first trial was conducted in children.17 With this new advent of successful non-sur- gical treatment, the 2011 ASH guidelines suggested the use of rituximab or high-dose dexamethasone as initial treatments for persistent, chronic or refractory children while it was suggested that splenectomy be used after other measures had failed, and again be delayed to at least 12 months of disease with persistence with bleeding symptoms or need for improved quality of life (HRQoL).12 The most recent advancement in the treat- ment of ITP has been the development of the throm- bopoietin receptor agonists (TPO-RA) following recogni- tion of impaired thrombopoiesis and megakaryocyte apoptosis in ITP patients.18,19 Both eltrombopag and romi- plostim are now approved for children with persistent or chronic ITP who have insufficient response to corticos- teroids, immunoglobulins, or splenectomy. The most recent ASH guidelines recommended both the use of TPO-RA and rituximab prior to splenectomy, based only on single arm prospective studies. The pooled evidence demonstrated a 91% response rate to splenectomy after one month, and a 77% durable response, which was
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