PDSA E-News: July 26, 2022

Treatment of Pediatric Immune Thrombocytopenia (ITP): A Systematic Review and Meta-Analysis of Prospective Clinical Trials

pediatrician child momIn this study, the use of thrombopoietin receptor agonists (TPO-RA) was compared to the use of rituximab (RTX) in treating children with ITP. The researchers combined findings from many individual studies and combined them into one analysis.

The results indicated that a similar number of children with ITP treated with TPO-RA vs RTX achieved a platelet count above 50,000 platelets per microlitre (µL) of blood without the need for concomitant rescue treatment. However, there was a higher probability of achieving a partial response (achieving a platelet count above 50,000 at least once during the course of the study) using a TPO-RA compared to using RTX. It also took a somewhat longer time to achieve a platelet response with RTX (6.75 weeks) than it did with a TPO agent (4.75 weeks).

There was a higher proportion of participants who did not respond to treatment and required rescue therapy in the RTX group. However, the number of side effects (called adverse events) reported was higher among the TPO-RA group. There was, however, a lot of variation in what was considered an ‘adverse event’ is among the different studies.

The likelihood of achieving a complete response (defined as a platelet count above 150,000) was similar between the RTX and TPO-RA groups. However, there were more participants who maintained their platelet count response using a TPO-RA than those treated with RTX, 74% vs 39% (romiplostim) and 38% (eltrombopag).



Comments from PDSA’s Medical Advisors:

This is a difficult study to fully digest because each of the individual studies are so different and because the two types of treatment work very differently. In order to provide generalizations, the authors combine results from several small individual studies that differ in how they define outcomes of importance. This makes it unclear if agents such as TPO-RAs were used in the same way in each individual study. This might contribute to the difference in outcomes with eltrombopag vs romiplostim, which is not typical of studies in adults with ITP. Management of treatment failures (such as, do patients who fail RTx respond to TPO-RAs?) is not discussed.

It is best to make only a few take home messages and not to act like a direct comparison between the two treatments has been acheived. First, both RTX and TPO-RAs can be used to treat pediatric ITP, often with good results. Second, continuous treatment with TPO-RAs induces more durable responses than one course of RTX, which is consistent with many studies in adults. If a child is being considered for either of these 2 treatments (and potentially for other treatments as well) a comprehensive individualized discussion needs to happen with the pediatric hematologist to review all the pros and cons of the different approaches.


Frequency and Utility of Bone Marrow Examination in Relapsed/Refractory Immune Thrombocytopenia (ITP)

medical researcherBone marrow examinations (BME) are used to exclude the diagnosis of blood disorders other than ITP that might be causing a drop in platelet count. In this study, the frequency and clinical benefit of BME in managing relapsed/refractory adult ITP was examined. Participants between 2012-2019 who had received at least one second-line ITP therapy (such as Rituxan®, Promacta/Revolade®, Nplate®, or splenectomy) were recruited into the study. The frequency of BME, characteristics that predicted a recommendation for a BME, predictors of an abnormal finding on BME, and impacts on ITP management were all investigated.

Of the 324 participants included in their study, 181 underwent a BME. Patients who underwent a BME were on average older (above 60 years), more likely to be male, had a previous splenectomy, and had already received a TPO-RA. Anemia (low red blood cell count), splenomegaly (enlarged spleen), and a lack of response to splenectomy were significant factors that increased the likelihood of the patient undergoing a BME. Living in a rural community did not influence the likelihood of getting a BME.

Abnormal BME findings were observed in 8/131, with uncertain findings present in 23/131 participants. An abnormal BME was defined as “identification of a hematologic neoplasm or disorder”. Uncertain findings referred to a reduced number of bone marrow cells or abnormal looking cells that did not meet the criteria for a specific diagnosis.

Abnormal BME findings seen more likely in participants with macrocytosis (enlarged red blood cells), pancytopenia (low levels of all three blood cell types: red blood cells, white blood cells, platelets) or bicytopenia (low levels of two types of blood cells). Some abnormal results came from suspected ITP cases prior to being considered for splenectomy or those who did not have a response to first line therapies, such as steroids and IVIG. Surprisingly, a lack of response to second-line therapies was not associated with abnormal BME findings. The study did not comment on predictors for an equivocal BME finding.

The frequency of BME in patients over 60 years old decreased over the last nine years. In patients under 60 years of age, the frequency of BMEs have remained stable over the same time period.

Overall, the study suggests that although BME are used to assist in the management of relapsed/refractory ITP patients, the value of doing them is low. A larger study could help address whether there is a particular group of relapsed or refractory ITP patients who would benefit the most from having a BME.



Comments from PDSA’s Medical Advisors:

ITP remains a “diagnosis of exclusion” meaning that other disorders have to be evaluated and excluded. As the authors discuss, this used to mean performig a BME in all patients before the diagnosis of ITP could be made. This approach infrequently elicited a new diagnosis unless patients had other clues by history (e.g. non-bleeding symptoms, enlarged lymph nodes or spleen), or other abnormalities (such as concurrent anemia or abnormal cells on blood film). Even then, BMEs continued to be performed routinely in individuals over the age of 60 years to exclude myelodysplasia (a disorder of abnormal platelet production) as a cause of thrombocytopenia; this is also no longer standard of care.

Rather, in the absence of such clues, we can often establish the diagnosis of “primary” or “secondary”, ITP especially when we see a robust response of corticosteroids or IVIG, which has little to no effect in almost all other conditions. The question has now become, what is the benefit of a BME if a robust reponse is not seen and/or if there are other abnormalties not usually found in ITP? This response-based diagnostic approach to ITP is complicated when an individual does not respond to corticosteroids or IVIG, but does respond to a TPO-RA, because these TPO-RAs can stimulate platelet production in other types of thrombocytopenia, such as non-ITP conditions.

Studies have shown that even TPO-RAs fail to durably increase platelet counts in 20-40% of patients in whom the diagnosis of ITP seems true. This new study suggests that BME leads to a new diagnosis in a relatively small percentage of individuals treated for a presumptive diagnosis of ITP who presumably failed to repond to first line agent and is certainly not required in all patients based on age alone. This study does support the utility of BME in those individuals who have symptoms or abnormalities of physical or laboratory examination that are not readily explained by a diagnosis of ITP.



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