Pixantrone May Have a Better Cardiac Profile Than Other Anthracyclines; Two Randomized Trials Are Underway

NEW YORK—Early studies of pixantrone, a chemotherapeutic agent in clinical development primarily in lymphoma, suggest that it is active and potentially less cardiotoxic than other anthracenedione agents. John P. Leonard, MD, clinical director of the Center for Lymphoma and Myeloma and associate professor of medicine at Weill Medical College of Cornell University/New York Presbyterian Hospital, outlined early findings about pixantrone at the Chemotherapy Foundation Symposium XXIV. The agent is being developed by Cell Therapeutics, Inc. (CTI) in Seattle.

In recent years, about 300 patients have been treated with pixantrone in phase I and II trials, Dr. Leonard said. All the studies included cardiac monitoring and strict screening for cardiac issues. Of 80 patients in three phase I single-agent trials, 26 had recurrent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia. Of these 26 patients, 6 responded (23%, 1 CR).

In a phase II single-agent trial of 33 patients with relapsed aggressive lymphomas, 9 responded (27%, 5 CRs). The median duration of response was 11+ months. The main toxicity was neutropenia. Dr. Leonard noted that these patients had received a median prior cumulative dose of doxorubicin of 300 mg/m². "Seven patients had an asymptomatic LVEF [left ventricular ejection fraction] decline; they had previously all received significant doses of anthracyclines. These were generally mild. Only one patient had a greater than 20% decline," he said.

In three phase I-II lymphoma trials, pixantrone was substituted for agents in standard chemotherapeutic regimens, replacing etoposide in ESHAP, mitoxantrone in FND-R, and doxorubicin in CHOP-based regimens. In a phase II trial presented by Camboni at ASCO in 2004, pixantrone was substituted for etoposide in the ESHAP regimen in patients with relapsed/aggressive NHL. Of 18 evaluable patients, 61% had a response (7 CRs). Half of the responding patients went on to stem cell transplant.

The principal toxicity was hematologic, with mild decreases in LVEF seen in eight patients. "So, acceptable toxicity, meaningful activity in these pretreated patients," Dr. Leonard said. Positive results were also seen in the other two combination studies.

Finally, he took note of a phase III study by Santoro et al that looked at the combination of pixantrone and rituximab (Rituxan) vs rituximab alone in relapsed indolent lymphoma patients with up to five prior regimens. Pixantrone was added to the standard four doses of rituximab. The study, which had to be closed because of slow accrual, was presented at ASCO this year. A total of 32 patients were enrolled. Even with that small number, the response rate more than doubled with the addition of pixantrone, from 33% to 75% (P = .02). Progression-free survival was also significantly better.

Throughout the trials, the main dose-limiting toxicities were neutropenia or other cytopenias, "not surprising in this class of agent," Dr. Leonard said. About 13% of patients had some element of ejection fraction decline, primarily grades 1 and 2. The incidence of clinically significant heart failure was relatively low (3%), he said.

Randomized Trials

Two randomized trials are now underway that "hopefully, will establish the potential role of this agent in patients with lymphoma," Dr. Leonard said. One phase III study (PIX 301), which pits pixantrone as a single agent against other standard therapies, involves patients with relapsed aggressive lymphoma. They must have had two or more prior regimens. One of them could be a transplant. The patients must also have been treated with rituximab.

"It's a kind of a dealer's choice trial design," Dr. Leonard said, in which, for control patients, the investigator can choose from one of a list of standard agents known to have activity.

A phase II study (PIX 203) is comparing the CHOP-R regimen with a similar pixantrone regimen (CPOP-R) as upfront therapy in patients with diffuse large B-cell lymphoma (DLBCL). The trial is designed to show whether pixantrone can be substituted for doxorubicin with equal or better efficacy and better cardiac safety, he said.

Dr. Leonard concluded that pixantrone "seems to have activity in a heterogeneous group of patients including aggressive lymphomas and seems to be able to be combined with some of the standard regimens. . . . There are hints that it can be used in patients who have had prior anthracyclines, and perhaps that is an indicator that it may have a favorable cardiac profile."

Take Home Point

The investigational anthracenedione pixantrone has shown activity and cardiac safety in a number of phase I-II trials in lymphoma patients who have received prior anthracyclines, indicating that it may have a favorable cardiac profile. A phase III trial is ongoing.

The Science Behind the Study

"Pixantrone is in the anthracenedione class of agents, a DNA intercalator and topoisomerase II inhibitor," Dr. John Leonard said at the Chemotherapy Foundation Symposium, "but there are some differences in the chemical structure of pixantrone, compared to doxorubicin and mitoxantrone." Pixantrone lacks the hydroxyl groups that are responsible for free-radical production. Free radicals are thought to lead to cardiotoxicity, he said. But it has a pyridine ring that appears to maintain antitumor activity and potentially reduce cardiotoxicity.