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Fractionated Dosing May Put Gemtuzumab Back in Play

Carlson, Robert H.

doi: 10.1097/01.COT.0000413006.24316.a2

SAN DIEGO—A drug once on the US market to treat acute myeloid leukemia (AML) but was then withdrawn (OT, 8/10/10 and 10/10/10) may have a new life, following a positive study from a French group presented here at the American Society of Hematology Annual Meeting (Abstract 6).

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The prospective open-label, randomized Phase III trial conducted by the Acute Leukemia French Association (ALFA 0701) found that fractionated doses of gemtuzumab ozogamicin (Mylotarg) combined with standard chemotherapy in newly diagnosed AML patients age 50 to 70 significantly increased event-free, overall, and relapse-free survival.

“Based on our results, this regimen may be considered a new standard of care for front-line therapy in de novo AML patients,” said lead author Sylvie Castaigne, MD, Professor in the Department of Hematology at Hôpital de Versailles.

The drug had been approved in the US for elderly AML patients, but was withdrawn by Pfizer from the US market after the randomized Phase III Southwest Oncology Group (SWOG) S0106 trial showed that toxicity and mortality rares were significantly higher with non-fractionated dosing of gemtuzumab ozogamicin versus standard chemotherapy.

Dr. Castaigne said she hopes this new trial, which was sponsored by her institution, “will change the mind of Pfizer so they will try to get a new market position.”

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Daunorubicin, Ara C, Gemtuzumab

Participants in ALFA 0701, age 50 to 70 with previously untreated de novo AML, were randomly assigned to an induction regimen of daunorubicin at 60 mg/m2 on days 1-3 with Ara C at 200 mg/m2 on days 1-7 (134 patients), or to that regimen plus gemtuzumab at 3 mg/m2 on days 1, 4, and 7 (137 patients).

The 50-70 age range was selected, Dr. Castaigne noted, because there is an ongoing trial comparing the same two regimens in the 15-50 age range.

In cases of complete remission (CR) or pathological complete remission (CRp), the control arm patients continued with first consolidation, comprising daunorubicin at 60 mg/m2 on day 1 and AraC at 1 gm/m2 given over 12 hours on days 1-4, while the gemtuzumab arm received that same regimen plus gemtuzumab at 3 mg/m2 on day 1.

Second consolidation regimens were the same other than for daunorubicin, which was given at 60 mg/m2 on days 1 and 2.

The primary study endpoint was event-free survival, and secondary endpoints included response rate, disease-free survival, overall survival, and safety over a three-year follow-up period.

At two years, 71% of 139 control patients and 71% of 139 gemtuzumab patients had a complete response, with pathologic complete remission reported in 4% and 10% of patients, respectively, for combined CR+CRp rates of 75% for controls and 81% of the gemtuzumab group, respectively.

Treatment failure occurred in 21% of 139 control and 12% of gemtuzumab patients; and early death, in 4% and 6.5% of patients, respectively.

“The benefit in event-free survival was observed in all age groups and translated into a longer median overall survival for gemtuzumab ozogamicin: 19.2 months for controls and 34 months for gemtuzumab ozogamicin,” Dr. Castaigne said.

And median relapse-free survival was 12.5 months for 104 control patients and 28.1 months for 113 of the gemtuzumab ozogamicin group.

Overall survival was particularly noted in the subgroup of patients with favorable or intermediate cytogenetics, she added.

(In OT's 10/10/10 article on the withdrawal of gemtuzumab ozogamicin, Hagop Kantarjian, MD, Professor and Chairman of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, said he thought it ironic that the drug was withdrawn, given the emphasis today on individualized anticancer therapy: “We talk about targeted treatments benefiting selected subsets of patients, and yet in leukemia, we withdraw a drug that is benefiting subsets of patients, because of the results in the average population.”)

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Toxicities: Some Veno-occulsive Disease

Sepsis was the most common nonhematologic adverse event in ALFA 0701, occurring in 16% of the control group and 20% of the gemtuzumab group. That was followed by liver problems in 8% of the controls and 13% of the gemtuzumab patients, the latter including three cases of veno-occlusive disease. Bleeding and cardiac events were essentially equal in both groups.

Deaths during induction occurred in 4% of the controls and 6.5% of the patients receiving gemtuzumab, while treatment-related deaths occurred in 8% of the controls (including five toxic deaths during autologous bone marrow transplantation) and 2% of the gemtuzumab group. The rates of transfer into the intensive care unit were 12% and 14%, respectively.

Prolonged thrombocytopenia was the most common hematological adverse event, Dr. Castaigne said.

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ASH President: ‘Results Remarkable’

After Dr. Castaigne's presentation, session moderator Armand Keating, MD, the newly installed president of ASH, called the ALFA study results remarkable.

And in an interview after the session, Dr. Keating said he thought that the idea of gemtuzumab ozogamicin as a new standard of care sounded interesting.

“There is a need for one, said Dr. Keating, Professor of Medicine, Professor of Biomaterials and Biomedical Engineering, and Director of the Division of Hematology and the Epstein Chair in Cell Therapy and Transplantation at the University of Toronto. “With peripheral blood transplants there is increased chronic GvHD—we don't have really good treatment for it—and the proportion of patients with really severe GvHD is increasing.”

He said that if the drug becomes available again, repeating the study would be a reasonable thing to do: “I would welcome further studies in this, and my prediction is that some centers will take it on, but the question is availability.”

He suggested that other centers do the studies in the context of a clinical trial so they gain experience with the drug “to be sure that their experience is such that there isn't an unexpectedly higher incidence of veno-occlusive disease, which worries me.”

The drug is not available in the US, which Dr. Keating said he believes is not because of regulatory issues but because there wasn't a good business case for further testing here.

A news conference held earlier in the meeting to highlight key “next-generation” leukemia studies included Dr. Castaigne's, and in the audience was the Chair of the ASH Committee on Communications, Peter Emanuel, MD, Director and Chair of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences.

In an interview afterwards, Dr. Emanuel was asked whether he thought that gemtuzumab might have a chance for re-approval based on this study.

He said that the impressive results from the trial would certainly renew interest in the drug. “But you know, only part of that is what the patients need,” he added. “Unfortunately, for the pharmaceutical part of it, it's an economical issue and we can't address that—only the industry sponsor can.”

He said he believed that the drug was withdrawn from the market because of a relative perceived poor efficacy and therefore poor utilization. “So maybe if it's used in a different setting with chemotherapy and [other agents], there'll be better efficacy like this trial is showing.”

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Pfizer: Economics Not a Factor in Withdrawal

An executive from Pfizer told OT, though, that economics was not a factor in the withdrawal of gemtuzumab.

“That was not the case,” said Mark Shapiro, MD, PhD, Senior Director and Global Medical Affairs Leader for Hematology Programs in Pfizer's Oncology Business Unit.

“We had extensive discussions with the FDA, and after reviewing the information, primarily the results from the SWOG study, it was decided that the best path forward was voluntarily withdrawing the drug.”

He said Pfizer fulfilled its post-approval commitment in that the Phase III study was completed, even though the study was not able to confirm clinical benefit. He said gemtuzumab had shown efficacy, but in surrogate endpoints, namely response rates, and not in endpoints such as overall or relapse-free survival.

And some toxicities were noted during the study as well, he said.

He noted that the drug is still commercially available in Japan. In Europe it is available on a compassionate-use basis, after Pfizer's marketing application was not accepted by the European regulators.

Dr. Shapiro said that there were many ongoing investigator-sponsored trials at the time the company withdrew the New Drug Application in 2010, and that these have continued.

Pfizer has continued to contribute funds to some of these cooperative groups and investigator-sponsored trials in the form of the study drug, he said, in some instances paying distribution costs of the drug to cooperative groups, and in some instances paying additional funds so that the study can be conducted if a group could not afford to conduct the study. He said this was not considered sponsorship because the company did not initiate the study.

Dr. Shapiro said it was premature to comment on what it might take to obtain approval for gemtuzumab ozogamicin, but he said Pfizer is reviewing data and other details of these studies in hopes that perhaps some path forward can be found for it.

© 2012 Lippincott Williams & Wilkins, Inc.
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