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.
Effect of rhTPO and PEG-rhMGDF in Cancer Patients Receiving Chemotherapy
Before considering the use of thrombopoietin agents in patients with cancer, it is important to note that solid tumors appear not to possess functional thrombopoietin receptors.[76,77] In one study using reverse-transcription polymerase chain reaction (RT-PCR) on 39 human cell lines and 20 primary normal and malignant human tissues, thrombopoietin receptor (c-mpl) transcripts were found in all megakaryocytic cell lines tested (DAMI, CMK, CMK-2B, CMK-2D, SO), in the CD34-positive leukemia cell line KMT-2, and in the hepatocellular carcinoma cell line Hep3B. While fetal liver and brain cells had detectable levels of c-mpl mRNA, none was found in primary tumors. In a more extensive study, microarray testing detected thrombopoietin receptor mRNA in 0 of 118 breast tumors and at very low levels in 14 of 29 lung tumors. Low but detectable thrombopoietin receptor mRNA was found by quantitative real-time PCR (QT-PCR) in some normal (14%–43%) and malignant (3%–17%) breast, lung, and ovarian tissues, but none of these tissues showed detectable thrombopoietin receptor protein by immunohistochemistry. Culture of breast, lung, and ovarian carcinoma cell lines with thrombopoietin receptor agonists showed no stimulation of growth. Finally, in none of the human clinical studies described next was there any stimulation of tumor growth by the administration of the recombinant thrombopoietins.
The recombinant thrombopoietins were studied in a wide variety of non-myeloablative settings. Unfortunately, the results of many of these studies have never been reported other than in abstract form. In general, thrombopoietin produced an earlier but higher nadir platelet count, shortened the duration of thrombocytopenia, reduced platelet transfusions, and enabled chemotherapy to be given on schedule.
When PEG-rhMGDF was administered to lung cancer patients for up to 16 days after treatment with carboplatin and paclitaxel, the median platelet count nadir was 188,000/µL (range, 68,000–373,000/µL) vs 111,000/µL (range, 21,000–307,000/µL; P = .013) in the placebo group (Figure 4). The nadir platelet count occurred earlier in the patients treated with PEG-rhMGDF; median time to nadir was 7 days vs 15 days (P < .001). The platelet count recovered to baseline in a median of 14 days in the PEG-rhMGDF patients as compared with > 21 days in those receiving placebo (P < .001). There was no effect on platelet transfusions or bleeding; only one patient in the placebo group required a platelet transfusion. The incidence of thrombosis was not increased.
In another study, rhTPO was administered on days 2, 4, 6, and 8 after a second cycle of carboplatin chemotherapy for patients with gynecologic malignancy (Figure 5). Compared with the first cycle, during which no rhTPO was administered, the mean platelet count nadir was higher (44,000/µL vs 20,000/µL; P = .002); the number of days with platelet count < 20,000/µL was lower (1 vs 4 days; P = .002); and the number of days with a platelet count < 50,000/µL was lower (4 vs 7 days; P = .006). The need for platelet transfusion in the group receiving rhTPO was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = .013). Administration of rhTPO improved recovery to a platelet count ≥ 100,000/µL (20 days for rhTPO in cycle 2 vs 23 days without rhTPO in cycle 1; P < .001).
In the third major study, patients with advanced malignancy were treated with carboplatin at 600 mg/m2 and cyclophosphamide at 1,200 mg/m2 in their first cycle. In subsequent cycles they also received PEG-rhMGDF for 1, 3, or 7 days after chemotherapy. Compared with cycle 1, those receiving the same chemotherapy dose on a subsequent cycle had a significantly higher platelet nadir (47,500/µL vs 35,500/µL; P = .003), and the duration of grade III or IV thrombocytopenia was significantly shorter (0 vs 3 days; P = .004). However, there was no difference in the time to platelet recovery. Administration of PEG-rhMGDF prior to chemotherapy did not show any benefit.
One study has suggested a possible survival benefit from treatment with PEG-rhMGDF. In the treatment of patients with relapsed NHL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy, maintenance of dose intensity and dose density correlates with improved survival. In a study of 38 NHL patients randomized to placebo (n = 16) or PEG-rhMGDF (n = 22), ICE was given on schedule to 42% of those on placebo and to 75% of those on PEG-rhMGDF (P = .008) with overall survivals of 31% and 59% (P = .06), respectively, after a median follow-up of 8.5 years. Patients on placebo were 4.4 times more likely to have a dose delay; in 83% of cases, the dose delay was due to thrombocytopenia. Grade IV thrombocytopenia was seen in 35% of the placebo group vs 15% of PEG-rhMGDF patients (P = .02), with platelet count nadirs of 20,000/µL and 49,000/µL (P = .008), respectively. Platelet transfusions were administered in 23% of placebo cycles and in 8% of PEG-rhMGDF cycles (P = .04).
There were no human radiotherapy studies with PEG-rhMGDF or rhTPO, but one important series of primate studies suggested that thrombopoietin might have a radioprotective effect.[82-86] When rhesus monkeys were sublethally irradiated, all blood lines were reduced 10 days later. Administration of rhTPO in a critical time period anywhere from 2 hours before until 4 hours after the irradiation markedly ameliorated the pancytopenia; in the study, platelet counts were 1,123,000/µL ± 89,000/µL without radiation therapy or thrombopoietin, 144,000/µL ± 62,000/µL with radiation therapy but without thrombopoietin, and 739,000/µL ± 165,000/µL with both radiation therapy and thrombopoietin. Assays for precursor cells of all lineages showed marked increases in viability when rhTPO was administered.
Effects of Thrombopoietin Receptor Agonists in Cancer Patients Receiving Chemotherapy
Although 6 years have elapsed since the approval of thrombopoietin receptor agonists for treatment of ITP, surprisingly few studies of these agents have been conducted in cancer patients undergoing chemotherapy. Only a small number of case reports and small series of patients with cancer have been published in this area.[88-91]
In one retrospective study, cancer patients were selected who had a platelet count < 100,000/µL and who had > 4-week delay in their chemotherapy or had dose reductions/modification in > 2 prior cycles. These patients were treated with romiplostim at 2 µg/kg weekly. Platelet counts improved in all of them, and 19 of 20 had platelet counts ≥ 100,000/µL. A total of 15 patients resumed chemotherapy, and all but one continued for 2 or more cycles without dose modifications. Three of 20 patients developed deep vein thrombosis (DVT).
In another blinded, placebo-controlled study, patients with solid tumors and a platelet count ≤ 300,000/µL receiving either gemcitabine alone (14 patients) or gemcitabine plus either cisplatin or carboplatin (12 patients) were randomized to receive eltrombopag or placebo on days −5 to −1 and days 2 through 6, starting from cycle 2; no study drug was administered for cycle 1. For patients receiving gemcitabine alone, the nadir platelet count for cycles 2 through 6 was 143,000/µL for eltrombopag vs 103,000/µL for placebo; for those receiving gemcitabine plus cisplatin or carboplatin, the nadir was 115,000/µL vs 53,000/µL for placebo. A total of 14% of all eltrombopag patients and 50% of placebo patients required dose reductions or delays in cycles 3 through 6. No DVTs were reported, but 16 of 19 patients treated with eltrombopag developed platelet counts > 400,000/µL.
Although this author anticipates that the thrombopoietin receptor agonists will have the same beneficial effects in chemotherapy treatment as did the recombinant thrombopoietins, studies are challenging in this area for many reasons, namely:
• Most standard chemotherapy regimens do not produce very high rates of thrombocytopenia, and when thrombocytopenia occurs, it is often short-lived.
• Platelet transfusions often resolve the thrombocytopenia and are usually needed for only 3 to 4 days.
• Chemotherapy regimens commonly associated with increased rates of thrombocytopenia are usually experimental; it remains unclear whether platelet production support with a thrombopoietin receptor agonist during chemotherapy is beneficial for the overall cancer outcome, which may be more limited by the chemotherapy than by the supportive care.
• Study design in this setting is also a concern. Although it is unlikely that concurrent administration of a thrombopoietic agent during chemotherapy would have any adverse effect, the doses and schedules for these agents have certainly not been established. It is unclear whether treatment with a thrombopoietin receptor agonist before or after chemotherapy is superior or whether administration of thrombopoietin at both times is required.
• Animal chemotherapy models would be of help to assess the dose and schedule of treatment with thrombopoietin receptor agonists. Unfortunately, eltrombopag is only active in chimpanzees and humans; romiplostim is active in most species, but there are no animal studies to inform human treatment.
Good clinical studies that address the dose and schedule for the thrombopoietin receptor agonists are essential. These should probably be conducted in patients who have developed significant thrombocytopenia during prior chemotherapy cycles. Pharmacokinetic/pharmacodynamic modeling suggests that the ideal schedule for eltrombopag might be 5 days before and 5 days after chemotherapy. The relevant endpoints for such studies would be:
• Avoid nadir platelet counts < 50,000/µL.
• Avoid platelet transfusions.
• Avoid bleeding events.
• Avoid chemotherapy dose reductions.
• Avoid chemotherapy delays.
1. Kuter DJ. General aspects of thrombocytopenia, platelet transfusions, and thrombopoietic growth factors. In: Kitchens C, Kessler C, Konkle B, editors. Consultative Hemostasis and Thrombosis. Philadelphia: Elsevier Saunders; 2013. p. 103-16.
2. Kuter DJ. Milestones in understanding platelet production: a historical overview. Br J Haematol. 2014;165:248-58.
3. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100:3457-69.
4. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98:10-23.
5. Kuter DJ. What is the potential for thrombopoietic agents in acute leukemia? Best Pract Res Clin Haematol. 2011;24:553-8.
6. Dimou M, Angelopoulou MK, Pangalis GA, et al. Autoimmune hemolytic anemia and autoimmune thrombocytopenia at diagnosis and during follow-up of Hodgkin lymphoma. Leuk Lymphoma. 2012;53:1481-7.
7. Hauswirth AW, Skrabs C, Schutzinger C, et al. Autoimmune thrombocytopenia in non-Hodgkin’s lymphomas. Haematologica. 2008;93:447-50.
8. Zent CS, Ding W, Reinalda MS, et al. Autoimmune cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma: changes in clinical presentation and prognosis. Leuk Lymphoma. 2009;50:1261-8.
9. Kyasa MJ, Parrish RS, Schichman SA, Zent CS. Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003;74:1-8.
10. Hodgson K, Ferrer G, Pereira A, et al. Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol. 2011;154:14-22.
11. Grewal PK, Aziz PV, Uchiyama S, et al. Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor. Proc Natl Acad Sci USA. 2013;110:20218-23.
12. Grewal PK, Uchiyama S, Ditto D, et al. The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med. 2008;14:648-55.
13. Von Drygalski A, Curtis BR, Bougie DW, et al. Vancomycin-induced immune thrombocytopenia. N Engl J Med. 2007;356:904-10.
14. Kuter DJ, Tillotson GS. Hematologic effects of antimicrobials: focus on the oxazolidinone, linezolid. Pharmacotherapy. 2001;21:1010-3.
15. Wang Y, Smith KP. Safety of alternative antiviral agents for neonatal herpes simplex virus encephalitis and disseminated infection. J Pediatr Pharmacol Ther. 2014;19:72-82.
16. Danziger-Isakov L, Mark Baillie G. Hematologic complications of anti-CMV therapy in solid organ transplant recipients. Clin Transplant. 2009;23:295-304.
17. Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood. 2010;116:2127-33.
18. Levi M. Cancer and DIC. Haemostasis. 2001;31(suppl 1):47-8.
19. Saba HI, Morelli GA, Saba RI. Disseminated intravascular coagulation (DIC) in cancer. Cancer Treat Res. 2009;148:137-56.
20. Kuter DJ, Rosenberg RD. Disorders of hemostasis. In: Beck WS. Hematology. Cambridge, MA: MIT Press; 1991. p. 577-98.
21. Humphreys BD, Sharman JP, Henderson JM, et al. Gemcitabine-associated thrombotic microangiopathy. Cancer. 2004;100:2664-70.
22. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. 2013;28:145-284.
23. Jodele S, Fukuda T, Vinks A, et al. Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2014;20:518-25.
24. Shimazaki C, Inaba T, Uchiyama H, et al. Serum thrombopoietin levels in patients undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1997;19:771-5.
25. 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.
26. Wu Y, Aravind S, Ranganathan G, et al. Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large outpatient oncology practice database, 2000-2007. Clin Ther. 2009;31(Pt 2):2416-32.
27. Machlus KR, Thon JN, Italiano JE, Jr. Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation. Br J Haematol. 2014;165:227-36.
28. Dowling MR, Josefsson EC, Henley KJ, et al. Platelet senescence is regulated by an internal timer, not damage inflicted by hits. Blood. 2010;116:1776-8.
29. Josefsson EC, James C, Henley KJ, et al. Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. J Exp Med. 2011;208:2017-31.
30. Josefsson EC, White MJ, Dowling MR, Kile BT. Platelet life span and apoptosis. Methods Mol Biol. 2012;788:59-71.
31. White MJ, Schoenwaelder SM, Josefsson EC, et al. Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. Blood. 2012;119:4283-90.
32. Berger G, Hartwell DW, Wagner DD. P-Selectin and platelet clearance. Blood. 1998;92:4446-52.
33. Fitchen JH, Deregnaucourt J, Cline MJ. An in vitro model of hematopoietic injury in chronic hypoplastic anemia. Cell Tissue Kinet. 1981;14:8590.
34. McManus PM, Weiss L. Busulfan-induced chronic bone marrow failure: changes in cortical bone, marrow stromal cells, and adherent cell colonies. Blood. 1984;64:1036-41.
35. DeZern AE, Petri M, Drachman DB, et al. High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases. Medicine (Baltimore). 2011;90:89-98.
36. Fitzgerald M, Fraser C, Webb I, et al. Normal hematopoietic stem cell function in mice following treatment with bortezomib. Biol Blood Marrow Transplant. 2003;3:193.
37. Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106:3777-84.
38. Zhang H, Nimmer PM, Tahir SK, et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 2007;14:943-51.
39. Leach M, Parsons RM, Reilly JT, Winfield DA. Autoimmune thrombocytopenia: a complication of fludarabine therapy in lymphoproliferative disorders. Clin Lab Haematol. 2000;22:175-8.
40. Hegde UP, Wilson WH, White T, Cheson BD. Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia. Blood. 2002;100:2260-2.
41. de Sauvage FJ, Carver-Moore K, Luoh SM, et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med. 1996;183:651-6.
42. de Sauvage FJ, Villeval JL, Shivdasani RA. Regulation of megakaryocytopoiesis and platelet production: lessons from animal models. J Lab Clin Med. 1998;131:496-501.
43. Carver-Moore K, Broxmeyer HE, Luoh SM, et al. Low levels of erythroid and myeloid progenitors in thrombopoietin- and c-mpl-deficient mice. Blood. 1996;88:803-8.
44. Grozovsky R, Begonja AJ, Liu K, et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med. 2015;21:47-54.
45. Yang C, Li J, Kuter DJ. The physiological response of thrombopoietin (c-Mpl ligand) to thrombocytopenia in the rat. Br J Haematol. 1999;105:478-85.
46. Peck-Radosavljevic M, Wichlas M, Zacherl J, et al. Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production. Blood. 2000;95:795-801.
47. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87:4068-71.
48. Kuter DJ. The physiology of platelet production. Stem Cells. 1996;14:88-101.
49. Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med. 1992;327:1779-84.
50. Gernsheimer T, Stratton J, Ballem PJ, Slichter SJ. Mechanisms of response to treatment in autoimmune thrombocytopenic purpura. N Engl J Med. 1989;320:974-80.
51. Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood. 2013;122:1122-8.
52. Muraoka K, Ishii E, Tsuji K, et al. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Br J Haematol. 1997;96:287-92.
53. Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA. 1999;96:3132-6.
54. Ballmaier M, Germeshausen M, Schulze H, et al. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001;97:139-46.
55. Choi ES, Hokom MM, Chen JL, et al. The role of megakaryocyte growth and development factor in terminal stages of thrombopoiesis. Br J Haematol. 1996;95:227-33.
56. Zauli G, Vitale M, Falcieri E, et al. In vitro senescence and apoptotic cell death of human megakaryocytes. Blood. 1997;90:2234-43.
57. Orazi A, Cooper RJ, Tong J, et al. Effects of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow. Exp Hematol. 1996;24:1289-97.
58. Bruno E, Hoffman R. Effect of interleukin 6 on in vitro human megakaryocytopoiesis: its interaction with other cytokines. Exp Hematol. 1989;17:1038-43.
59. Li J, Xia Y, Bertino A, et al. Characterization of an anti-thrombopoietin antibody that developed in a cancer patient following the injection of PEG-rHuMGDF (abstract). Blood. 1999;94:51a.
60. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-8.
61. 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.
62. Cwirla SE, Balasubramanian P, Duffin DJ, et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science. 1997;276:1696-9.
63. Molineux G. The development of romiplostim for patients with immune thrombocytopenia. Ann NY Acad Sci. 2011;1222:55-63.
64. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76:628-38.
65. Erickson-Miller C, Delorme E, Iskander M, et al. Species specificity and receptor domain interaction of a small molecule TPO receptor agonist (abstract). Blood. 2004;104:795a.
66. Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27:424-30.
67. Erickson-Miller CL, DeLorme E, Tian SS, et al. Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp Hematol. 2005;33:85-93.
68. Kuter DJ. Biology and chemistry of thrombopoietic agents. Semin Hematol. 2010;47:243-8.
69. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161:411-23.
70. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010;363:1889-99.
71. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28-36.
72. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121:537-45.
73. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357:2227-36.
74. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818-25.
75. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11-9.
76. Erickson-Miller CL, Pillarisetti K, Kirchner J, et al. Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors. BMC Cancer. 2012;12:405.
77. Columbyova L, Loda M, Scadden DT. Thrombopoietin receptor expression in human cancer cell lines and primary tissues. Cancer Res. 1995;55:3509-12.
78. Fanucchi M, Glaspy J, Crawford J, et al. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med. 1997;336:404-9.
79. Vadhan-Raj S, Verschraegen CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med. 2000;132:364-8.
80. Basser RL, Underhill C, Davis I, et al. Enhancement of platelet recovery after myelosuppressive chemotherapy by recombinant human megakaryocyte growth and development factor in patients with advanced cancer. J Clin Oncol. 2000;18:2852-61.
81. Moskowitz CH, Hamlin PA, Gabrilove J, et al. Maintaining the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin lymphoma. Ann Oncol. 2007;18:1842-50.
82. Neelis KJ, Dubbelman YD, Qingliang L, et al. Simultaneous administration of TPO and G-CSF after cytoreductive treatment of rhesus monkeys prevents thrombocytopenia, accelerates platelet and red cell reconstitution, alleviates neutropenia, and promotes the recovery of immature bone marrow cells. Exp Hematol. 1997;25:1084-93.
83. Neelis KJ, Hartong SC, Egeland T, et al. The efficacy of single-dose administration of thrombopoietin with coadministration of either granulocyte/macrophage or granulocyte colony- stimulating factor in myelosuppressed rhesus monkeys. Blood. 1997;90:2565-73.
84. Neelis KJ, Dubbelman YD, Wognum AW, et al. Lack of efficacy of thrombopoietin and granulocyte colony-stimulating factor after high dose total-body irradiation and autologous stem cell or bone marrow transplantation in rhesus monkeys. Exp Hematol. 1997;25:1094-103.
85. Neelis KJ, Qingliang L, Thomas GR, et al. Prevention of thrombocytopenia by thrombopoietin in myelosuppressed rhesus monkeys accompanied by prominent erythropoietic stimulation and iron depletion. Blood. 1997;90:58-63.
86. Neelis KJ, Visser TP, Dimjati W, et al. A single dose of thrombopoietin shortly after myelosuppressive total body irradiation prevents pancytopenia in mice by promoting short-term multilineage spleen-repopulating cells at the transient expense of bone marrow-repopulating cells. Blood. 1998;92:1586-97.
87. Demeter J, Istenes I, Fodor A, et al. Efficacy of romiplostim in the treatment of chemotherapy induced thrombocytopenia (CIT) in a patient with mantle cell lymphoma. Pathol Oncol Res. 2011;17:141-3.
88. Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer. 2014;22:1217-22.
89. Winer ES, Safran H, Karaszewska B, et al. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study. Cancer Med. 2015;4:16-26.
90. Chawla SP, Staddon A, Hendifar A, et al. Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide. BMC Cancer. 2013;13:121.
91. Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, et al. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26:2339-46.
92. Hayes S, Mudd PN, Jr, Ouellet D, et al. Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia. Cancer Chemother Pharmacol. 2013;71:1507-20.
93. Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010;362:600-13.
94. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. N Engl J Med. 1997;337:1870-5.
95. Antun AG, Gleason S, Arellano M, et al. Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies. Cancer. 2013;119:3784-7.
96. Kalmadi S, Tiu R, Lowe C, et al. Epsilon aminocaproic acid reduces transfusion requirements in patients with thrombocytopenic hemorrhage. Cancer. 2006;107:136-40.
97. Wardrop D, Estcourt LJ, Brunskill SJ, et al. Antifibrinolytics (lysine analogues) for the prevention of bleeding in patients with haematological disorders. Cochrane Database Syst Rev. 2013;7:CD009733.
98. Tepler I, Elias L, Smith JW 2nd, et al. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood. 1996;87:3607-14.
99. Wiseman GA, Gordon LI, Multani PS, et al. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood. 2002;99:4336-42.
100. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-17.
101. Budd GT, Ganapathi R, Adelstein DJ, et al. Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors. Cancer. 1997;80:1134-40.
102. Gross-Goupil M, Fourcade A, Blot E, et al. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer. 2012;48:721-7.
103. Ozaka M, Matsumura Y, Ishii H, et al. Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). Cancer Chemother Pharmacol. 2012;69:1197-204.
104. Choi JH, Oh SY, Kwon HC, et al. Gemcitabine versus gemcitabine combined with cisplatin treatment locally advanced or metastatic pancreatic cancer: a retrospective analysis. Cancer Res Treat. 2008;40:22-6.
105. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27:3778-85.
106. Stemmler HJ, Harbeck N, Groll de Rivera I, et al. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology. 2010;79:197-203.
107. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-96.
108. Inal A, Kaplan MA, Kucukoner M, et al. Cisplatin-based therapy for the treatment of elderly patients with non-small-cell lung cancer: a retrospective analysis of a single institution. Asian Pac J Cancer Prev. 2012;13:1837-40.
109. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-51.
110. Gronberg BH, Bremnes RM, Flotten O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:3217-24.
111. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;381:1817-26.
112. Ogura K, Goto T, Imanishi J, et al. Neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide, and dacarbazine (MAID) regimen for adult high-grade non-small round cell soft tissue sarcomas. Int J Clin Oncol. 2013;18:170-6.
113. Fayette J, Penel N, Chevreau C, et al. Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma. Invest New Drugs. 2009;27:482-9.
114. Jones SE, Schottstaedt MW, Duncan LA, et al. Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer. J Clin Oncol. 1996;14:2976-83.
115. Allegra CJ, Yothers G, O’Connell MJ, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009;27:3385-90.