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Professor of Molecular Medicine
Department of Hematology and Oncology
Taussig Cancer Institute
Cleveland, Ohio, USA
Keith R. McCrae, MD, has disclosed that he has received consulting fees from Dova, Novartis, Rigel, and Sanofi Genzyme.
Immune thrombocytopenia (ITP) is a common cause of thrombocytopenia in the absence of other identifiable causes and can occur at any age. It is a blood disorder characterized by a decrease in the number of platelets that can lead to easy or excessive bruising and bleeding. The field of ITP has advanced dramatically in the past 10-15 years. Fifteen years ago, we saw many patients in our clinic with so-called refractory ITP, and today, although we still see such patients, they are uncommon. Better understanding of ITP has led to new therapeutic advances that have improved the quality of life for many patients with ITP.
In parallel with improvements in medical therapy for ITP, we have seen the frequency with which splenectomy is performed (at one point, a first-line or second-line therapy for ITP) dramatically diminish. Of importance, improvements in ITP management were enabled by fundamental research. For example, we once thought and taught that ITP was a disorder of accelerated platelet destruction. However, clearance studies with autologous—rather than allogeneic—platelets demonstrated that overall platelet turnover was actually not significantly altered in many patients with ITP. Later, studies also demonstrated that antiplatelet antibodies not only bound to platelets but also to megakaryocytes in vitro and, in many cases, impaired megakaryocyte development and platelet production. Why some but not all of these antibodies have this effect remains an unanswered question.
These studies, of course, were enabled by prior scientific advances that characterized blood cell production and allowed the study of hematopoietic stem cells in vivo and in vitro. Ultimately, in parallel with the discovery and characterization of thrombopoietin, these studies enabled the power of industry to be brought to bear on ITP, with powerful strategies such as structural biology, high throughput screening of small molecules and others leading to the development of thrombopoietin-directed agents such as the thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and others that we use today, therapies that have revolutionized the management of patients with ITP. TPO-RAs are a class of platelet growth factors that mimic the action of TPO on megakaryocytes and megakaryocyte precursors, promoting their growth and differentiation and increasing platelet production.
Open Questions in the Clinical Care of Our Patients
Despite these advances, we do not have all the answers. Although we can provide effective therapy for most patients with ITP, we are a long way from personalized medicine for this disorder, and there are many clinical observations that we do not understand. We do not know, for example, in individual patients whether their ITP is primarily a result of decreased platelet production or enhanced platelet destruction—or perhaps an equal contribution of both. Answering questions such as these is essential, particularly given the emergence of even more novel agents such as FcRn inhibitors or newer inhibitors of signaling pathways thought to be involved in the pathogenesis of ITP that may attack many more aspects of ITP pathophysiology. Despite some TPO RAs binding to different regions of the TPO receptor, we really don’t know why patients who fail one of these agents may respond to another, particularly when agents such as eltrombopag and avatrombopag demonstrate significant structural homology. Also, despite very interesting preliminary clinical data, the role of complement in ITP remains relatively unexplored.
In addition to these questions, we have no idea why some patients with ITP will develop a long-term remission, ultimately sustaining a safe platelet count off their medication while others will experience a more chronic, severe, and relapsing course. We still largely lack prospective, randomized studies sufficiently powered to determine whether more aggressive therapy for newly diagnosed ITP leads to more prolonged remission or perhaps even cure of the disease. Still, support for this concept comes from several areas, including retrospective and controversial studies with rituximab, studies with TPO RAs, and a more recent prospective study of first-line mycophenolate mofetil in combination with corticosteroids.
Future Opportunities to Personalize ITP Therapy
The cost and logistics of comparing ITP drugs with one another, particularly given that ITP is a relatively rare disease, are prohibitive. However, I’d like to finish with a plea for more translational science in ITP. I believe that the ITP field and, indeed, many areas in nonmalignant hematology lag far behind our oncology colleagues in searches for disease mechanisms and biomarkers of ITP. This again is a challenging area since ITP is an uncommon disease.
The array of clinical responses in patients with ITP to a specific intervention suggests that all ITP is not created equal and that significant heterogeneity exists among patients. However, given the remarkable technologic advances and high throughput technologies, particularly DNA and RNA sequencing, as well as characterization of vast arrays of proteins in plasma or in cells, I believe that it is time to set the stage for the next generation of clinical trials in ITP. I think it is quite likely that biomarkers of ITP chronicity, responses to specific drugs for instance, can and will be identified if such broad approaches are adopted. A variety of potential biomarkers could then be tested more specifically in all clinical trials of ITP perhaps in the not-too-distant future. However, to do this, a concerted effort to collect and catalog samples from patients participating in clinical trials is critical.
My personal experience with patients with ITP and other hematologic disorders is that they are only too glad to donate a few tubes of blood to encourage research into their disease. There is indeed extra expense and effort in collecting such samples, but I would argue that we should not continue to plunge ahead pursuing only clinical endpoints and that samples for translational research should be a component of every new ITP trial beginning immediately.
As I noted at the beginning of this commentary, we have seen major advances in ITP. However, I believe that we are still only at the beginning of the journey toward understanding its biology, and I have not even mentioned deciphering its causes. Might studies such as those I have suggested make ITP a curable disease? This has been debated for a long time and I do not know the answer, but to approach this goal, we need a better understanding.
What are your most pressing questions about ITP management today?