Thrombocytopenia is a common problem in cancer patients. Aside from bleeding risk, thrombocytopenia limits chemotherapy dose and frequency. In evaluating thrombocytopenic cancer patients, it is important to assess for other causes of thrombocytopenia, including immune thrombocytopenia, coagulopathy, infection, drug reaction, post-transfusion purpura, and thrombotic microangiopathy. The incidence of chemotherapy-induced thrombocytopenia varies greatly depending on the treatment used; the highest rates of this condition are associated with gemcitabine- and platinum-based regimens. Each chemotherapy agent differs in how it causes thrombocytopenia: alkylating agents affect stem cells, cyclophosphamide affects later megakaryocyte progenitors, bortezomib prevents platelet release from megakaryocytes, and some treatments promote platelet apoptosis. Thrombopoietin is the main regulator of platelet production. In numerous studies, recombinant thrombopoietin raised the platelet count nadir, reduced the need for platelet transfusions, reduced the duration of thrombocytopenia, and allowed maintenance of chemotherapy dose intensity. Two thrombopoietin receptor agonists now available, romiplostim and eltrombopag, are potent stimulators of platelet production. Although few studies have been completed to demonstrate their ability to treat chemotherapy-induced thrombocytopenia, these agents may be useful in treating this condition in some situations. Chemotherapy dose reduction and platelet transfusions remain the major treatments for affected patients.
Pathophysiology of Chemotherapy-Induced Thrombocytopenia
Not all chemotherapy drugs cause thrombocytopenia in the same way. In reviewing the mechanism of thrombocytopenia, it is helpful to understand how platelets are made (Figure 2). Stem cells differentiate into cells committed to megakaryocyte differentiation (megakaryocyte colony-forming cells [Mk-CFCs]). At some stage, these cells stop their mitotic divisions and enter a process called “endomitosis,” in which DNA replication occurs without subsequent division of the nucleus or the cell. This gives rise to polyploid precursor cells with 2, 4, 8, 16, or 32 times the normal diploid DNA content. These polyploid megakaryocyte precursor cells then stop DNA synthesis and mature into large, morphologically identifiable megakaryocytes.
Mature megakaryocytes then produce platelets by a mechanism that is still poorly defined. In its simplest iteration, mature megakaryocytes extrude long cytoplasmic processes through endothelial cells, and large strands of platelet material (proplatelets) are released into the circulation, eventually becoming mature platelets, possibly through fragmentation in the lung. If not consumed in hemostasis, the mature platelet undergoes programmed cell death (apoptosis), determined by a “platelet clock.” This platelet clock depends on the presence of an anti-apoptotic protein called Bcl-x(L), a protein that restrains the pro-apoptotic proteins Bax and Bak.[28-31] When levels of Bcl-x(L) decline, Bax and Bak activity increase and trigger platelet apoptosis. The apoptotic platelets are cleared by the reticuloendothelial cell system; the spleen plays only a limited role in normal platelet homeostasis.
Different chemotherapy drugs affect the megakaryocyte and platelet production pathway at different steps (see Figure 2). Alkylating agents such as busulfan affect pluripotent stem cells.[33,34] Cyclophosphamide spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, but affects later megakaryocyte progenitors. Bortezomib has no effect on stem cells or megakaryocyte maturation but does inhibit nuclear factor kappa B, a critical regulator of platelet shedding. This probably explains the relatively short duration of thrombocytopenia following its administration.
Not all chemotherapy drugs reduce platelet production; some can actually increase the rate of platelet destruction. Indeed, platelet survival itself may be altered by some agents. The experimental chemotherapy agent ABT-737 reduces the activity of the platelet clock Bcl-x(L) and rapidly induces platelets to undergo apoptosis.[29,38] After a single dose of ABT-737, platelet levels dropped to 30% of baseline by 2 hours, dropped to 5% of baseline by 6 hours, started to recover to 10% of baseline by 24 hours, and returned to baseline after 72 hours. This was not due to platelet activation; rather, caspase-mediated apoptosis was induced, with a rapid appearance of phosphatidylserine on the platelet surface and clearance of these cells from the circulation by the reticuloendothelial system in the liver. Although this mechanism has not been evaluated for most standard chemotherapy drugs, etoposide also increases platelet apoptosis by reducing Bcl-x(L) activity.
Finally, chemotherapy may enhance platelet clearance by immune mechanisms. In the treatment of many lymphomas, administration of single-agent fludarabine has been noted to produce an immune thrombocytopenia in up to 4.5% of patients. This ITP typically responds to rituximab. Platelet destruction is also increased when chemotherapy drugs produce a drug-dependent secondary immune thrombocytopenia, but this effect is uncommon.
The Role of Thrombopoietin in Platelet Production
The hematopoietic growth factor thrombopoietin is the key regulator of platelet production. In animals or humans deficient in thrombopoietin or its receptor, the platelet count is 10% to 15% of normal values.[41,42] Megakaryocyte, erythroid, and myeloid precursor cells are all reduced in such knock-out animals, but the white blood cell (WBC) and RBC counts are normal.
Thrombopoietin is usually made in a constant (“constitutive”) rate in the liver, lacks a storage form, and is released into the circulation. At non-physiological levels in animals, large quantities of desialylated platelets may slightly increase hepatic thrombopoietin production. Once in the circulation, most thrombopoietin is cleared by avid thrombopoietin receptors on platelets and possibly on bone marrow megakaryocytes. These cells bind, internalize, and then degrade thrombopoietin. The small residual amount of thrombopoietin in the circulation accounts for the basal rate of platelet production. Thrombocytopenia does not increase the hepatic thrombopoietin production rate, and no other physiologic stimulus has been shown to alter the rate of thrombopoietin production. With severe thrombocytopenia caused by chemotherapy, hepatic thrombopoietin mRNA levels are unchanged despite a 10- to 20-fold increase in the concentration of thrombopoietin. Hepatic damage results in a proportional decrease in thrombopoietin production.
Circulating thrombopoietin levels are inversely related to the rate of platelet production. With the reduction in platelet production as a result of chemotherapy, thrombopoietin clearance is reduced and levels rise (see Figure 1). There is a log-linear relationship between the rise in thrombopoietin concentration and the fall in the platelet count after chemotherapy. In contrast, in most ITP patients, the platelet production rate is not reduced,[49,50] thrombopoietin clearance is normal, and levels do not rise. This primitive form of regulation of a hematopoietic growth factor is similar to that by which the basal levels of G-CSF and macrophage colony-stimulating factor are directly maintained by the circulating mass of neutrophils and monocytes, respectively. The only exception seems to be erythropoietin, levels of which are determined by a hypoxia-induced factor–mediated renal sensor of the hemoglobin concentration. There is no such sensor of the platelet count.
Thrombopoietin binds to its receptor on many hematopoietic cells and exerts its effect on most stages of megakaryocyte growth (see Figure 2). Thrombopoietin is necessary for the viability of hematopoietic stem cells; when the thrombopoietin receptor is absent, humans are born with thrombocytopenia and develop pancytopenia over subsequent years.[52-54] Thrombopoietin stimulates mitosis of Mk-CFCs. Its major effect (at exceedingly low concentrations) is to increase megakaryocyte endomitosis and increase megakaryocyte ploidy, greatly expanding the megakaryocyte pool. Thrombopoietin then stimulates megakaryocyte maturation. It is unclear whether thrombopoietin plays any role in platelet shedding. An underappreciated property of thrombopoietin is that it prevents apoptosis of early and late megakaryocytes, an effect that may play a major protective role in patients receiving radiation and chemotherapy (as discussed below).
Inflammatory cytokines such as interleukin (IL)-6 and IL-11 may also stimulate platelet production by mechanisms independent of thrombopoietin.[57,58]
Clinical Development of Thrombopoietin Molecules
The development of clinically relevant thrombopoietin molecules has occurred in two phases: creation of the early recombinant thrombopoietins and then development of the recent thrombopoietin receptor agonists.
With the discovery of thrombopoietin in 1994, two recombinant thrombopoietin molecules were developed (Figure 3). Recombinant human thrombopoietin (rhTPO) was a fully glycosylated thrombopoietin protein made in CHO (Chinese hamster ovary) cells. The other, pegylated recombinant human megakaryocyte growth and development factor (PEG-rhMGDF), was a non-glycosylated protein comprising the first 163 amino acids of thrombopoietin coupled to polyethylene glycol. Both molecules were potent stimulators of platelet production, with half-lives of about 40 hours. In healthy volunteers, both agents demonstrated the same time course of platelet response after a single dose: by day 3, megakaryocyte ploidy increased; by day 5, platelet counts started to rise; by days 10 through 14, a peak platelet count was obtained; and by day 28, platelet counts returned to their baseline values.
Between 1995 and 2000, both recombinant thrombopoietins underwent extensive clinical development in oncology settings. Development of both was stopped due to concerns over neutralizing antibody formation against PEG-rhMGDF. Despite differences between the structure of PEG-rhMGDF and that of rhTPO, antibody formation against PEG-rhMGDF might have been due to the route of administration. After early studies suggested that rhTPO might induce antibody formation when given by a subcutaneous route, rhTPO was thereafter given intravenously, with no subsequent antibody formation. In contrast, PEG-rhMGDF was given only subcutaneously, and in several studies patients developed neutralizing antibody to the recombinant protein.[60,61] In 525 healthy volunteers given up to three monthly doses of PEG-rhMGDF, 13 (2.5%) developed thrombocytopenia due to the formation of antibodies to PEG-rhMGDF that cross-reacted with endogenous thrombopoietin, creating thrombopoietin deficiency and thrombocytopenia. All subjects recovered, but some required immunosuppressive treatment.[60,61]
Despite the failure of one of these recombinant thrombopoietin molecules, interest turned to developing newer thrombopoietin molecules (now called thrombopoietin receptor agonists) with novel properties and less risk of antibody formation. In 1997, a 14-amino-acid peptide was identified that had no sequence homology to thrombopoietin but bound to the thrombopoietin receptor; when dimerized, it had the same activity as rhTPO. To overcome its short half-life in the circulation, this peptide was inserted into an IgG4 heavy chain to produce romiplostim, a “peptibody” with a half-life of 120 hours (see Figure 3). When injected into healthy volunteers, romiplostim produced a dose-dependent platelet count rise that began at day 5 and peaked by day 14. Single doses of 10 µg/kg produced peak platelet counts of 1,600,000/µL in healthy volunteers, an eightfold increase over baseline. There was no effect on the number of WBCs or RBCs.
A separate approach identified small molecules that bound and activated the thrombopoietin receptor. One of these, eltrombopag, bound the thrombopoietin receptor in the transmembrane region, an area different from where thrombopoietin or romiplostim bound, and activated the thrombopoietin receptor in a different fashion.[65-67] When given to healthy volunteers for 10 days, eltrombopag produced a 50% increase in the platelet count with no effect on the WBC or RBC count.
Both of these thrombopoietin receptor agonists have undergone extensive clinical development, and both increased the platelet count in over 85% of patients with ITP.[1,4,68-71] Both have been approved in many countries for the treatment of ITP; prolonged use of both has produced sustained increases in platelet counts for years, with minimal or no adverse events.[69,72] Additionally, eltrombopag is now approved for the treatment of thrombocytopenia in patients with hepatitis C infection requiring antiviral treatment and in patients with aplastic anemia in whom immunosuppressive therapy has failed.[74,75] In the latter disease, treatment was also associated with an increase in WBCs and RBCs.
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