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Spring 1997Volume 4, Number 1 |
Although the existence of hematopoietic growth factors has been postulated for more than 25 years, only over the past decade have human cytokines been identified, cloned, and studied in clinical trials. Numerous new molecules have been produced and tested, but only erythropoietin, sargramostim, filgrastim, and aldesleukin have achieved a place in clinical practice. The major limitation of these cytokines has been the limited range of progenitors targeted by each. Recently, several presentations at the annual meeting of the American Society of Hematology clarified the potential role of thrombopoietin in a broad range of clinical applications in human bone marrow and stem cell transplantation.
Thrombopoietin, also known as TPO or MGDF (megakaryocyte growth and differentiating factor), was first cloned and identified in 1994 as the factor responsible for homeostatic platelet production. Culture of bone marrow in TPO results in a marked increase in megakaryocyte number, size, and ploidy. These effects were paralleled in vivo in mice treated with TPO. Of greater interest, however, was the observation that platelet counts rose rapidly in mice that had received myelosuppressive chemotherapy followed by treatment with TPO.
Bertolini and colleagues tested the ability of megakaryocyte progenitors expanded in vitro to obviate the need for platelet transfusion after autologous blood stem cell transplantation. CD34-enriched blood stem cells were cultured in TPO for seven days. Platelet progenitors increased by more than 50-fold as assessed by flow cytometry. When given in addition to the standard autologous transplant after high-dose chemotherapy, the use of platelet transfusions was reduced. Two patients required no platelet transfusions, with platelet nadirs of only 17,000 and 27,000, respectively. Infusion of the cultured cells was well tolerated.
| . . . when rhTPO was given to patients who were not receiving chemotherapy, not only did platelet counts increase above baseline, but a significant rise in multilineage progenitors in the peripheral blood was also noted. This finding suggests that rhTPO will play a role in mobilization for blood stem cell harvest. |
In a Phase I study reported by Vadhan-Raj and colleagues, 18 patients with sarcoma under treatment with adriamycin and ifosfamide were given one or two doses of rhTPO in increasing amounts. rhTPO proved to be a potent stimulator of platelet production under these conditions. With multiple dosing, nadir platelet counts were higher and patients spent fewer days with moderate-to-severe thrombocytopenia.
Moreover, when rhTPO was given to patients who were not receiving chemotherapy, not only did platelet counts increase above baseline, but a significant rise in multilineage progenitors in the peripheral blood was also noted. This finding suggests that rhTPO will play a role in mobilization for blood stem cell harvest.
The multilineage potential of TPO was underscored in the study by Piabello and colleagues, who used TPO in addition to FLT3 ligand for expansion of cord blood cells in stroma-free cultures. Primitive stem cells as well as committed progenitors from all lineages were produced for as long as six months of culture, far longer than in current systems.
Finally, Ulich and colleagues introduced PEG-rhMGDF, a truncated form of TPO conjugated with polyethylene glycol to prolong its half-life. A single-dose of PEG-rhMGDF prevented thrombocytopenia in mice following a myelosuppressive dose of carboplatin. Harker and coworkers have used this cytokine in combination with filgrastim to completely abrogate neutropenia and thrombocytopenia in rhesus monkeys treated with hepsulfam.
Use of rhTPO for mobilization will likely improve the quality of blood stem cell harvests and result in more rapid hematopoietic recovery posttransplant. Administration of rhTPO or TPO-expanded progenitors posttransplant will also be evaluated to reduce transfusion requirements. If the pegylated form performs as well in clinical trials as it has in preclinical studies, the ease of its single-dosing schedule will represent a marked improvement over the cytokines currently in use.
Donna Przepiorka, MD, PhD
Section of Blood and Marrow Transplantation
The University of Texas
MD Anderson Cancer Center
Houston, Texas
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