Treating Chemotherapy-Induced Thrombocytopenia: Is It Time for Oncologists to Use Thrombopoietin Agonists?

Given the availability of new US Food and Drug Administration (FDA)-approved thrombopoietic agents, it is timely and of great interest to discuss how they might be used in the management of thrombocytopenia in cancer patients. Dr. Kuter’s review accurately summarizes the ontogeny of thrombocytes and the role of thrombopoietin in enhancing megakaryocyte development and differentiation.[1] While his article appropriately acknowledges that thrombocytopenia in cancer patients can have a variety of etiologies, such as immune thrombocytopenia and thrombocytopenias caused by infection or coagulopathy, thrombocytopenia in this setting is most commonly chemotherapy-induced. Thrombocytopenia is a major concern in cancer patients; not only does it result in an increased risk of bleeding, but, importantly, it can also lead to reductions in chemotherapy dose and frequency.

For cancer patients receiving chemotherapy with curative intent, dose reductions due to chemotherapy-induced thrombocytopenia may compromise their long-term disease-free survival. (platelet counts < 25,000/µL) is 3% to 4%, with less than 3% of chemotherapy-treated patients receiving platelet transfusions.[2] Nevertheless, while severe thrombocytopenia requiring platelet transfusions is relatively rare, dose reductions by the oncologists treating these patients are common; such dose reductions support the clinical need for effective thrombopoietic agents that could be used prophylactically to prevent chemotherapy-induced thrombocytopenia, and that would allow maintenance of chemotherapy dose density and intensity.

Since the time required for thrombopoietic agents to differentiate hematopoietic progenitors to megakaryocytes that produce platelets is 10 to 14 days,[3] these agents must be used prophylactically, before thrombocytopenia develops, if they are going to have practical clinical application in preventing chemotherapy-induced thrombocytopenia. Dr. Kuter presents his own anecdotal experience in using these agents prophylactically in cancer patients receiving chemotherapy, as well as results from small randomized phase II clinical trials. These clinical studies demonstrate a role for thrombopoietin agonists in improving compliance with cytotoxic regimens in cancer patients whose chemotherapy was delayed due to thrombocytopenia,[4] and they suggest that prophylactic use of eltrombopag or romiplostim might reduce the degree and duration of chemotherapy-induced thrombocytopenia. However, the long-term effect on survival in patients with cancer has not been established. Since guidelines pertaining to prevention and treatment of chemotherapy-induced thrombocytopenia are lacking, there is an urgent need for further studies of the benefit of thrombopoietin receptor agonists as compared with other therapies used in thrombocytopenic patients.

It is important to note that past experience with the use of other hematopoietic growth factors has not been without significant long-term safety concerns. The use of recombinant thrombopoietin proteins to prevent chemotherapy-induced thrombocytopenia was marred by patients’ development of autoantibodies to thrombopoietin that exacerbated their thrombocytopenia,[5] and, in the case of normal volunteer subjects, led to prolonged thrombocytopenia lasting weeks to months.[6,7] The clinical perspective on the role of hematopoietic growth factors in patients with cancer has been shaped most recently by negative clinical data related to the use of recombinant erythropoietic agents in patients with solid tumors.[8] In spite of very aggressive promotional efforts by the pharmaceutical companies that marketed these agents, enthusiasm for their integration into the management of chemotherapy-induced anemia waned dramatically when they were shown to be associated with an increased risk of deep-vein thrombosis and decreased survival due to tumor progression among erythropoietin-treated patients.[9] Current concerns about previously unanticipated clinical effects with the newer thrombopoietin receptor agonists, including the induction of marrow fibrosis,[10] and the theoretical concern that a cytokine that promotes hematopoietic stem cell self-renewal might promote growth or survival of malignant cells, have limited the widespread clinical adoption of these new thrombopoietin mimetics in the setting of cancer patients receiving chemotherapy.

An aspect of these drugs that is only briefly touched upon by Dr. Kuter is their potential use as radioprotective agents and their physiologic role in maintaining the hematopoietic stem cell compartment. While most endogenous thrombopoietin is made in the liver, local production of thrombopoietin by bone marrow stroma has been demonstrated[11] and may be critical to the ability of marrow stromal cells to maintain a self-renewing population of hematopoietic stem cells.[12]

Additional long-term risks that must be considered in the setting of chemotherapy-induced thrombocytopenia, given the increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) associated with the use of chemotherapy, are that chronic use of exogenous thrombopoietic agents could promote the development of these diseases; however, secondary development of MDS and AML has not been observed to date in clinical trials of these agents.[13]

The current success of thrombopoietic agents in treating immune thrombocytopenic purpura and aplastic anemia demonstrates the therapeutic abilities of these agents. Therefore, further investigation into their usefulness in other hematologic pathologies, such as chemotherapy-induced thrombocytopenia, is warranted. Dr. Kuter appropriately stresses the need for prospective, placebo-controlled, double-blinded clinical trials of the new thrombopoietin receptor agonists in the management of chemotherapy-induced thrombocytopenia, to address concerns about the safety and practical efficacy of these expensive new drugs before we accept them as standard therapies for prevention of thrombocytopenia associated with chemotherapy in our patients.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Kuter DJ. Managing thrombocytopenia associated with chemotherapy. Oncology (Williston Park). 2015;29:282-94.

2. Ten Berg MJ, van den Bemt PM, Shantakumar S, et al. Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study. Drug Saf. 2011;34:1151-60.

3. Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol. 2014;165:248-58.

4. Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer. 2014;22:1217-22.

5. Li J, Xia Y, Bertino A, et al. Characterization of an anti-thrombopoietin antibody that developed in a cancer patient following the injection of PED-rHuMGDF (abstract). Blood. 1999;94:51a.

6. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-8.

7. Basser RL, O’Flaherty E, Green M, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99:2599-602.

8. Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med. 2007;356:2445-8.

9. Hershman DL, Buono DL, Malin J, et al. Patterns of use and risks associated with erythropoiesis-stimulating agents among Medicare patients with cancer. J Natl Cancer Inst. 2009;101:133-41.

10. Ghanima W, Geyer JT, Lee CS, et al. Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up. Haematologica. 2014;99:937-944.

11. Guerriero A, Worford L, Holland HK, et al. Thrombopoietin is synthesized by bone marrow stromal cells. Blood. 1997;90:3444-55.

12. Sun H, Tsai Y, Nowak I, et al. Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis. Stem Cell Res. 2012;9:77-86.

13. Prica A, Sholzberg, M, Buckstein R. Thrombopoietin (TPO) receptor agonists in myelodysplastic syndromes (MDS): a systematic review and meta-analysis. Blood. 2013;122. Available from: http://www.bloodjournal.org/content/122/21/2806. Accessed February 13, 2015.