NEW ORLEANSMore than 300,000 US patients a year who receive
chemotherapy will experience significant thrombocytopenia, Howard
Ozer, MD, PhD, said at a symposium preceding the American Society of
Hematology 41st annual meeting. The symposium was sponsored by MCP
Hahnemann University, where Dr. Ozer is director of the Cancer
Center, and supported by an unrestricted educational grant from
Pharmacia & Upjohn.
Use of platelet transfusions has risen during the last 10 to 20 years
to a greater extent than that of any other blood component, said
Jeffrey McCullough, MD, of the University of Minnesota. Although
hematology/oncology and bone marrow transplant patients represent
only about 30% of platelet transfusion patients, they use more than
half of the total platelet production, he said.
The costs of platelet transfusions includes the cost of recruiting
donors and collecting the platelets, as well as costs incurred in
hospitals related to inventory, patient monitoring, crossmatching or
HLA typing, and increased nursing and physician time. So if
there were an alternative strategy to platelet transfusion that could
avoid these costs, it would be extremely valuable, and I think this
is one of the exciting potentials of throm-bopoietin therapy,
Dr. McCullough said.
C. Glenn Begley, MD, PhD, of the Royal Melbourne Hospital, Victoria,
Australia, addressed the difficulties researchers have encountered in
developing throm-bopoietic agents.
The clinical need does not really match the physiology of
thrombo-poietin, he said. The delayed action of thrombopoietin
reflects the complex intrinsic biology of megakaryocytes and platelet
production. Thus, he said, if you want an instant increase in
platelets, throm-bopoietin is not the molecule.
The two most important platelet-stimulating agents developed to date,
he said, are thrombopoietin and interleukin-11 (IL-11, Neumega). Both
agents act on megakaryocytes and precursors via specific receptors
present on the cell surface.
IL-11 is FDA approved, Dr. Begley said, but the increases in platelet
counts produced by this agent are really fairly modest,
approximately twofold, and it has some important adverse
effects, such as fluid retention.
Thrombopoietin has been shown to be the principal physiologic
regulator of platelet development. In 1994, several groups identified
and cloned thrombo-poietin, Dr. Begley said, and two forms of the
molecule have been developed for clinical assessment.
Scientists at Genentech produced a full-length glycosylated
recombinant molecule known as recombinant human thrombopoietin or
TPO. This agent, which is the most closely related to the natural
endogenous thrombopoietin, is being co-developed with Pharmacia &
Amgen developed a product known as pegylated recombinant
megakaryocyte growth and development factor (MGDF), which is a
truncated, pegylated variant of thrombopoietin. Initial trials of
MGDF were disappointing due to the development of neutralizing
antibodies, but this can be prevented, he said, if the MGDF is
administered intravenously rather than subcutaneously. MGDF is now
being clinically developed by scientists at a Japanese company,
Kirin, as an intravenously administered agent.
In addition, thrombopoietin peptide mimeticsmolecules that bind
to the thrombopoietin receptor but do not have any of the structure
of the thrombopoietin moleculehave been studied in animals and,
to date, have not been associated with formation of antibodies.
Saroj Vadhan-Raj, MD, of M.D. Anderson Cancer Center, described three
clinical trials of TPO used with nonmyelo-ablative chemotherapy at
her institution. These trials, she said, suggest that the timing of
the TPO dosing may be more important than the number of doses given.
The initial phase I trial of TPO involved 79 sarcoma patients
receiving doxorubicin and ifosfamide (Ifex). The first chemotherapy
cycle was used as a control. The second cycle was followed by a
single intravenous dose of TPO.
The single dose was surprisingly effective, she said. It
raised the circulating platelet counts by 60% at the lowest dose
level and by more than 200% at the highest dose level, and this rise
in platelet count was associated with dose-related increases in bone
marrow megakaryocytes. However, she said, there was no significant
impact on the platelet nadir, even when multiple doses were tried.
Although platelets rise rapidly with TPO, the peak biologic effect
does not occur until day 12; the platelet nadir with
doxorubicin/ifosfamide also occurs around day 12. The researchers
realized it would helpful to administer TPO earlier, but hesitated
because of the regimens 4-day length. Given earlier, she said,
during or before chemotherapy, we may cause more harm than
benefit by sensitizing the progenitor cells to the effects of
Further studies showed that 1 week after the single TPO dose, the
proportion of progenitor cells in S-phase is markedly increased, but
around day 4, there is no significant increase. This gave us
some level of comfort in terms of amending the schedule to give TPO
doses before chemotherapy, she commented.
This dosing concept is being further tested in the third trial of TPO
Use With Carboplatin
The second study included 29 ovarian cancer patients, most of whom
had received prior therapies. They were being treated with high-dose
carboplatin (Paraplatin), which causes a relatively late platelet
nadir. TPO was given subcutaneously every other day for four doses
after the second chemotherapy cycle.
In cycle 2 with TPO, mean platelet counts were higher than in cycle 1
without TPO, Dr. Vadhan-Raj reported. The duration of grade 3
thrombocytopenia was reduced from 6 days to 3 days, and platelet
transfusions were reduced from 75% to 25%.
Six patients received TPO as secondary prophylaxis. They were given
carbo-platin alone, and if they experienced significant
thrombocytopenia, then TPO was added to the next cycle.
All six patients had grade 4 thrombocytopenia, and five required
platelet transfusions in cycle 1. In cycle 2, use of TPO, four doses
every other day, delayed the platelet nadir, attenuated the nadir,
and enhanced platelet recovery. Three of the five patients who had
received transfusions in cycle 1 did not require them in cycle 2.
The Third Trial
The objective of the third trial, which is ongoing, is to optimize
the TPO schedule in sarcoma patients receiving doxorubicin/ifosfamide
and possibly translate this dosing schedule to use with other
regimens that produce a similar early platelet nadir.
Cycle 1 again was a control cycle. In cycle 2, patients received four
doses of TPO in five different schedules: two doses before
chemotherapy and two doses after; three doses before and one after;
one dose before and three after; all four doses before chemotherapy;
and all four doses after chemotherapy.
Preliminary results showed that 10 of the 12 patients receiving three
TPO doses before and one dose after chemotherapy had a higher
platelet nadir in cycle 2, compared with cycle 1, and a higher
platelet count. Giving all four doses after chemotherapy had no
significant impact on platelet nadir or recovery.
To summarize, Dr. Vadhan-Raj said that optimal scheduling of TPO may
depend on the length of the chemotherapy regimen and the timing of
the platelet nadir.
With a short chemotherapy regimen, especially when it is
causing delayed nadir, such as with carboplatin, postche-motherapy
TPO dosing may be sufficient to impact the nadir and the need for
platelet transfusion, she said. With long regimens,
especially if they are causing earlier nadir, we may have to use
predosing of TPO.