Thrombocytopenia Remains a Difficult Treatment Target

NEW ORLEANS—More 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 & Upjohn.

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 mimetics—molecules that bind to the thrombopoietin receptor but do not have any of the structure of the thrombopoietin molecule—have 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 regimen’s 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 chemotherapy.”

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 described below.

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.”