expert roundtables

Biological and Clinical Predictive Factors of Response in Patients With Chronic Immune Thrombocytopenia

by Adam Cuker, MD, MS, Terry Gernsheimer, MD, Howard A. Liebman, MD

Overview

Therapy for patients with immune thrombocytopenia (ITP) should be chosen based on a variety of factors, including the presence of bleeding, platelet count, patient lifestyle choices, and potential side effects. Platelet count often is used as a marker to determine disease severity and the need for treatment, but predictive factors of response based on patient-related factors would aid in treatment decision making and outcomes. Research focused on predictive factors of treatment response in patients with ITP is ongoing. A recent study was conducted to examine the efficacy of a salvage treatment with rituximab in adults and to identify biological and clinical predictors of response. Researchers found that female patients and those younger than 40 years of age had a higher probability of achieving response with treatment, with younger women having the highest long-term response. Another study assessed whether peripheral blood CD4+ T cells, Th17-associated cytokines, and the mRNA expression level of Th17 transcription factor—RORγt—were associated with responsiveness to corticosteroid treatment in patients with newly diagnosed ITP. The study showed that Th17 cell levels in the peripheral blood were positively associated with treatment response, with patients with lower levels of Th17 cells being unresponsive to corticosteroid treatment. Yet another recent study of patients responsive to corticosteroid treatment evaluated bone marrow endothelial progenitor cells and demonstrated that reduced and dysfunctional bone marrow endothelial progenitor cells had a role in the pathogenesis of corticosteroid-resistant ITP. Our featured experts in the field discuss biological and predictive factors of treatment response in patients with ITP.


Q: Are there biological and clinical predictive factors for treatment response that can be used to determine individualized therapy in patients with chronic ITP?

Terry B. Gernsheimer, MD

Director of the University of Washington
Medical Transfusion Service
Professor of Medicine, Division of Hematology
University of Washington
Seattle, WA

“I am not impressed that we can really look at a patient’s immune profile yet to decide whether this therapy may be better than that therapy for this patient.”

Terry B. Gernsheimer, MD

Clinical factors for treatment response can include whether a patient has comorbidities, whether it is secondary or primary ITP, whether he or she is going to need surgery, whether he or she presents with bleeding, lifestyle itself, and whether he or she requires anticoagulation therapy or aspirin therapy. As for age as a clinical factor, older age groups are more likely to be chronic and are at a higher risk of bleeding over the age of 60 or 65 years. Also, certainly for patients who are at risk of or who have had liver disease, I tend to stay away from eltrombopag. I am not impressed that we can really look at a patient’s immune profile yet to decide whether this therapy may be better than that therapy for this patient. There are interesting concepts about that, but I am just not convinced yet that we can look at a patient’s biological markers and say, Íž”Oh I know what treatment we should be picking here.”

Howard A. Liebman, MD

Donald I Feinstein Chair in Medicine
Professor of Medicine and Pathology
Jane Anne Nohl Division of Hematology
USC Norris Cancer Hospital
Los Angeles, CA

“There are good clinical things that a physician should think about (eg, age,comorbidities, secondary versus primary ITP, diabetes, hypertension) that are really more important than trying to find out whether interleukin 17 or Th1 or Th2 phenotype is going to define therapy.”

Howard A. Liebman, MD

There are no biological markers, even though there are things that are suggested that may modify platelet clearance rates, such as antibodies directed against the 1b9 complex; the asialo receptors resulting clearance independent of Fc receptors, and so on. Animal models suggest it, but there is no real extensive trial that really has assessed it. It is also not easy to look at antibodies, and cytokine profiles are worthless in terms of biological markers. It is all retrospective looks at outcomes as opposed to a prospective study. I think a lot of this would fail in a prospective study. There are good clinical things that a physician should think about (eg, age, comorbidities, secondary versus primary ITP, diabetes, hypertension) that are really more important than trying to find out whether interleukin 17 or Th1 or Th2 phenotype is going to define therapy.

Adam Cuker, MD, MS

Assistant Professor of Medicine
Director, Penn Comprehensive Hemophilia and Thrombosis Program
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

“What we do not do yet routinely is use any sort of biomarker to inform treatment decisions beyond the platelet count, but I think that that is a goal for the future. There are a lot of other biomarkers that have been explored that could potentially inform treatment.”

Adam Cuker, MD, MS

We have some pretty crude tools that we use right now, such as the platelet count, bleeding history, age, gender, and duration of disease, to inform treatment decisions. What we do not do yet routinely is use any sort of biomarker to inform treatment decisions beyond the platelet count, but I think that that is a goal for the future. There are a lot of other biomarkers that have been explored that could potentially inform treatment. There is some decent evidence that the presence of antibodies against the GPIBIX-V complex predicts refractoriness to certain treatments. There is a nice paper that was just published in Blood that suggests that patients with ITP who have fewer endothelial progenitor cells and dysfunctional endothelial progenitor cells are more likely to be refractory to corticosteroids. All of those sorts of data are compelling, but they’ve never been validated in well-done, appropriately powered clinical trials, and I think that, as we’ll talk about in a question that’s coming up, that’s a new frontier in ITP that I expect to be explored over the next 10 years or so.

References

Kong Y, Cao XN, Zhang XH, et al. Atorvastatin enhances bone marrow endothelial cell function in corticosteroid-resistant immune thrombocytopenia patients. Blood. 2018;131(11):1219-1233.

Marangon M, Vianelli N, Palandri F, et al. Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long-term response. Eur J Haematol. 2017;98(4):371-377.

Neunert CE. Management of newly diagnosed immune thrombocytopenia: can we change outcomes? Blood Adv. 2017;1(24):2295-2301.

Zhang Y, Ma T, Zhou X, Chen J, Li J. Circulating level of Th17 cells is associated with sensitivity to glucocorticoids in patients with immune thrombocytopenia. Int J Hematol. 2018;107(4):442-450.

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