Immune thrombocytopenia (ITP) of childhood affects at least 3,000 children under 16 years of age each year. Although the condition often resolves itself over time, there are some cases that are refractory and challenging to manage. Cindy E. Neunert, MD, MSCS, a pediatric hematologist at NewYork-Presbyterian and Columbia, recently served as one of 28 pediatric hematologists who participated in a Pediatric ITP Consortium of North America (ICON) working group to develop a more precise vocabulary to describe difficult cases of ITP and better guide treatment decisions.
Below, Dr. Neunert, who is a past chair of ICON, discusses the process to come to consensus on definitions for the term "refractory" ITP that will enable clinicians to more practically and accurately manage challenging cases.
What is pediatric ITP?
Pediatric ITP is a heterogenous disease associated with acquired autoimmune destruction and impaired platelet production. ITP is one of the more common conditions seen by pediatric hematologists, however it is considered an orphan disease and a rare condition in general. Approximately 80% of children with pediatric ITP are expected to have a spontaneous recovery, while the remaining 20% will experience a range of chronic symptoms and have varied responses to and tolerance of therapies.
Having consensus on terminology enables providers to better characterize those patients who would benefit from escalation of therapy. Additionally, these are patients that may have an underlying condition, such as an immune disorder or have been mislabeled as ITP, and have an alternative cause to their thrombocytopenia and therefore merit further evaluation. Lastly, it is imperative that these patients be considered for inclusion in clinical trials and ITP research.
— Dr. Cindy Neunert
What prompted the development of the consensus guidelines for defining and classifying refractory ITP?
Providers have historically labeled challenging ITP cases as refractory. However, the field did not have a unified definition for this term that we felt helped patients. Our working group agreed that what was fundamentally needed was a common language for describing refractory ITP. Having clearly defined terminology would enable providers to better characterize those patients who would benefit from escalation of therapy, additional evaluation, and inclusion in clinical trials and ITP research.
What was your goal in establishing a consensus?
With most diseases and conditions, we label clinical issues based on their biology. But how do you understand the biology of a disease that's so rare and in which all the patients present so differently? We decided to start with what we could control, such as how we would group and classify these patients when studying their biology and entering their information into a database. In this way, we would not be starting with a huge group of heterogeneic patients, but rather could narrow our focus, for example, to all patients who failed B-cell therapy. What do they have in common? If we can get more specific in how we classify patients, then perhaps we can start to see the signals that differentiate them and ultimately help the patient.
What was the process involved in developing the consensus?
Our process began by identifying the major concepts and terms that we believed mattered most. We conducted a systematic review of more than 250 manuscripts in the published literature of the term refractory in pediatric ITP. Of these, 11 studies proposed a definition but without consensus. Additionally, we conducted a survey of ICON members that also revealed a lack of consensus on the definition of refractory.
During a three-day meeting, we engaged in an intense consensus-building process to establish definitions for the term "refractory" ITP. Our goal was to move away from labeling patients as refractory and instead focus on understanding the how treatments are linked to the underlying biology of the disease in order to enable more targeted research on subgroups of ITP patients and improve access to appropriate therapies. Specifically, in small and large groups, we discussed coming to consensus on:
- Timeline of the disease
- Trialed medications and mechanisms
- Platelet count and symptoms
- Emergent therapies
- Disease-modifying therapies
Terminology regarding patients who do not respond to disease-modifying therapies was particularly challenging to define. We had lengthy discussions on how many medications and for how many different classes of drug mechanisms of action are needed for a patient to be identified as refractory to disease-modifying therapies.
What are the key recommendations of the consensus?
We came to 100% agreement in defining challenging pediatric ITP as “no platelet response after treatment with all eligible emergent pharmacotherapies.” We also had complete agreement that pediatric patients with ITP who “continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease-modifying therapies represent a challenging subset of ITP.” In these situations, patients may be considered for clinical trials or novel therapies.
How will you expand on this work in the future?
We are now homing in on the smaller proportion of cases that reflect the definitions we developed for the guidelines. Three research studies are planned to test the utility and functionality of the new consensus guidelines:
- A retrospective study evaluating the correlation of this terminology to disease burden and risk of disease persistence or progression
- Compiling patient feedback on the terminology and definitions in discussion with ITP advocacy groups
- Developing a multicenter database to assess the clinical utility, biology, and patient outcomes of children categorized by these treatment response-based definitions.
