SAN DIEGO--Since thrombopoie-tin (TPO), the ligand for the Mpl
receptor, was cloned by four separate laboratories in 1994,
researchers have been exploring, with animal models and in clinical
settings, how it can be used to benefit patients. Kenneth Kaushansky,
MD, a prominent researcher in the field, summarized some of the
results of the studies to date, at the Sixth International Symposium
on Recent Advances in Hematopoietic Stem Cell Transplantation,
sponsored by the University of California, San Diego.
Numerous studies have established that thrombopoietin, a
hematopoietic growth factor, is the chief regulator of platelet
production. While hematologists have sought this platelet regulator
for decades, the results so far have been heartening, but not totally
successful when used in patients, said Dr. Kaushansky, of the
Division of Hematology, University of Washington, Seattle.
Dr. Kaushansky noted that several studies have reported the presence
of Mpl on leukemic blast cells and from patients with
myeloproliferative syndromes of all histologic types. But determining
the effect, if any, that TPO has on leukemic cells, has been tricky.
Measuring thymidine uptake has been the primary way to determine the
effects of TPO on the proliferation of leukemic cells. Unfortunately,
the cells only need to synthesize DNA once for this assay to be
positive, which is an effect that might have no clinical
One published study has addressed whether TPO induces long-term
proliferation. The scientists found only 4 of 15 cases of acute
myeloblastic leukemia (AML) in which thymidine uptake assay was
positive and grew in long-term culture of 2 to 4 weeks.
Interestingly, two cases grew as blasts, and in two others, the
leukemic cells ultimately underwent maturation.
There have been two published studies of the administration of
megakaryocyte growth and development factor (MGDF) following
chemotherapy, Dr. Kaushansky said. MGDF is a truncated version of
In both studies, MGDF was not toxic, and platelet recovery to
baseline was accelerated significantly. In this pair of studies,
however, the platelet nadirs were not severe. Dr. Kaushansky said
that additional studies of MGDF utilizing more aggressive
chemotherapy protocols will need to be done to prove its therapeutic efficacy.
In the only clinical trial involving pegylated recombinant human MGDF
(PEGrHuMGDF) in AML, physicians observed no toxicity. But the news
was not all good. Platelet recovery did not speed up nor was there a
reduction in the number of platelet transfusions required during
induction chemotherapy. Dr. Kaushansky noted that further studies are
now being done using different doses and dosing levels.
Use in Transplantation
Clinical trials with TPO in the transplantation setting have been
mixed, he said. In one animal study using a transplant of 105 marrow
cells, TPO in the recipient failed to accelerate platelet recovery.
However, its administration to the donor greatly accelerated recovery
of platelets and reticulocytes in recipients, regardless of whether
the latter received TPO. When 106 marrow cells were used, TPO did
lead to accelerated platelet recovery in transplant recipients.
There have been numerous trials involving TPO in autologous marrow
and peripheral blood stem cell (PBSC) transplantation, Dr. Kaushansky
said. But the only positive trial used marrow; hematopoietic recovery
was not affected by TPO in PBSC transplants.
In a study in which rhTPO was used in patients in whom platelet
engraftment was significantly delayed following autologous
transplantation, only two of 37 patients experienced improved
platelet counts with use of rhTPO.
Dr. Kaushansky also theorized about a possible role for
thrombopoietin in thrombocytopenic patients with hepatic failure.
While there are many potential causes for the thrombocytopenia seen
in liver failure patients, such as splenic pooling, aplastic anemia
of hepatitis virus infection, and interferon therapy for chronic
hepatitis, it is possible that inadequate thrombopoietin in the liver
could also be contributing, since the liver is a major site of
This seems to be the case, since liver transplantation immediately
augments serum TPO levels, an effect that then leads to platelet
recovery. It remains to be determined, however, whether the
administration of TPO to such patients is beneficial or even feasible
(since the timing of transplantation precludes use of TPO in a timely