Commentary (Glaspy)—Thrombopoietin: Biology and Potential Clinical Applications
Commentary (Glaspy)—Thrombopoietin: Biology and Potential Clinical Applications
Given the clinical utility of myeloid growth factors and erythropoietin (Epogen, Procrit) in the management of many cancer patients, it is understandable that the cloning and introduction into clinical trials of thrombopoietin was greeted with great expectations for the future utilization of this molecule in oncology. Drs. Prow and Vadhan-Raj have written a well-referenced review that summarizes the preclinical biology of thrombopoietin and the evidence that it is the physiologic regulator of thrombopoiesis in animals and humans. The authors also synopsize some of the data from early clinical trials. My own interpretation of the clinical data obtained to date with both the full-length clone (recombinant human thrombopoietin [rhTPO]) and the pegylated, truncated molecule (pegylated recombinant human megakaryocyte growth and development factor [PEG-rHuMGDF]) differs somewhat from both our initial expectations and the perspective provided by the authors.
Clinical Potential of Thrombopoietin in Oncology
For cancer patients, the clinical benefit of thrombopoietin will derive from the prevention of either platelet transfusions or bleeding episodes associated with thrombocytopenia. Although surrogate end points, such as the duration of severe thrombocytopenia, may be more feasible for clinical trials, ultimately, data that convince the clinician that thrombopoietin will affect transfusions or bleeding will be required to justify its use in treating patients with cancer.
Although the number of platelet transfusions in the United States is rising, the majority of these transfusions are given to patients undergoing surgery, especially cardiac surgery and solid organ transplantation, and to patients receiving either treatment for leukemia or high-dose chemotherapy procedures supported by autologous or allogeneic progenitor cells. One of the challenges to the effective use of either rhTPO or PEG-rHuMGDF in these settings is the relatively long interval, 12 days, between the initial dose of either molecule and the peak response in terms of platelet counts.[1-3]
Standard-Dose Myelosuppressive Chemotherapy—Most patients with solid tumors complete their treatment without receiving platelet transfusions. For this reason, some clinical trials of thrombopoietic cytokines have focused on the selected minority of chemotherapy patients who have already developed thrombocytopenia related to prior chemotherapy and who require further treatment.
As Drs. Prow and Vadhan-Raj point out, it may be possible to develop more aggressive multicycle chemotherapy regimens that result in better cancer outcomes and that increase the requirement for thrombopoietic cytokine therapy. Despite the availability of platelet transfusions, such aggressive multicycle chemotherapy regimens that conclusively alter the survival of common cancers have not yet been developed.
Moreover, the clinical trials carried out and published to date have not demonstrated that either rhTPO or PEG-rHuMGDF can alter the duration of severe thrombocytopenia (platelet count < 10,000 to 20,000/mm³) or the number of platelet transfusions administered to unselected patients receiving multicycle chemotherapy. This is an important issue, as the majority of patients treated with myeloid growth factors and erythropoietin fall into this category. Similarly, trials to date have not demonstrated the efficacy of either thrombopoietin in adult patients undergoing leukemia induction therapy, a setting in which myeloid growth factors have provided some benefit.
High-Dose Chemotherapy With Progenitor-Cell Support—In both allogeneic and autologous transplant settings, peripheral blood progenitor cells (PBPCs) are replacing bone marrow as a source of hematopoietic support. The use of PBPCs has been associated with a reduction in the duration of thrombocytopenia and the number of platelet transfusions following these procedures and, therefore, has reduced the potential for benefit from thrombopoietic cytokine therapy.
In clinical trials conducted to date, PEG-rHuMGDF has not decreased the duration of severe thrombocytopenia when administered either after PBPC infusion or before high-dose chemotherapy to increase pretransplant platelet counts. There is some evidence that rhTPO and PEG-rHuMGDF may have some potential value in PBPC mobilization regimens.
Pegylated recombinant human megakaryocyte growth and development factor has been shown to decrease the duration of severe thrombocytopenia following autologous bone marrow transplantation. This finding suggests that thrombopoietin therapy may benefit patients undergoing high-dose chemotherapy, provided that the expected duration of severe thrombocytopenia is longer than 17 days. Thrombopoietin has not been shown to ameliorate the thrombocytopenia associated with graft failure, a setting in which a substantial proportion of the platelet transfusions utilized by high-dose chemotherapy patients are given.
Taken in aggregate, the current data suggest that therapy with thrombopoietin will not eliminate the majority of platelet transfusions in patients receiving high-dose chemotherapy regimens.
Other Potential Clinical Applications of Thrombopoietin
There is evidence that thrombopoietin therapy may increase the yields obtained from normal platelet donors. Although the initial expectation was that thrombopoietin would decrease the need for platelet transfusions, the most important application of this molecule may prove to be to facilitate more effective platelet therapy. In this approach, the relatively long delay between thrombopoietin administration and peak effect is not an obstacle, and the beneficial effects of the drug will be realized in all arenas, including surgery, in which platelet transfusions are currently applied.
Obviously, safety is a key issue when a drug is administered to normal donors. One drawback to the safety database that has been developed with thrombopoietin therapy to date is the preponderance of clinical trials in patients with cancer receiving chemotherapy, a setting in which the incidence of thrombosis is already elevated. This makes it difficult to interpret the few thrombotic events that have occurred in these trials. It will be important to develop safety data outside of the cancer setting to support the future use of thrombopoietin in normal donors.
As Drs. Prow and Vadhan-Raj point out, there is a theoretical basis for studying thrombopoietin therapy in patients, such as those with immune thrombocytopenia, in whom thrombocytopenia is not associated with an appropriate increase in circulating endogenous thrombopoietin levels.
Therapy with thrombopoietin has been relatively safe, although its effect, if any, on the risk of thrombotic events is still under study. Unique aspects of the biology of thrombopoietin and thrombopoiesis, as well as the epidemiology of severe thrombocytopenia, suggest that the clinical utility of rhTPO and PEG-rHuMGDF will differ from that of erythropoietin and the myeloid growth factors.
Although much remains to be learned, it seems likely that thrombopoietin will be used in only a small minority of patients receiving myelosuppressive chemotherapy or undergoing high-dose chemotherapy with PBPC support. Thrombopoietin therapy will probably be found to benefit patients who, for whatever reason, are receiving hematopoietic support with bone marrow. Rather than preventing platelet transfusions, a major application of thrombopoietin may prove to be the acquisition of blood cells, including platelets, from normal donors and PBPCs from patients or allogeneic donors.
1. Basser R, Rasko J, Clarke K, et al: Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet 348:1279-1281, 1996.
2. Fanucchi M, Glaspy J, Crawford J, et al: Effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet counts before and after chemotherapy for carcinoma of the lung: A randomized, double-blind, placebo-controlled, dose escalation study. N Engl J Med 336:404-409, 1997.
3. Vadhan-Raj S, Murray L, Bueso-Rumos C, et al: Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med 126:673-681, 1997.
4. Bolwell B, Vredenburgh J, Overmoyer B, et al: Safety and biologic effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in breast cancer following autologous peripheral blood progenitor cell transplantation (PBPC) (abstract). Blood 90(10):171a, 1997.
5. Glaspy J, Vredenburgh J, Demetri GD, et al: Effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) before high-dose chemotherapy (HDC) with peripheral blood progenitor cell support (abstract). Blood 90(10):580a, 1997.