New Lease of Life for Gemtuzumab, Now It Shows Survival Advantage

Zosia Chustecka

December 11, 2011

December 11, 2011 — A drug that was voluntarily withdrawn from the market in the United States because it did not improve survival in patients with newly diagnosed acute myeloid leukemia (AML) has now shown a survival advantage in the same type of patients in 2 separate trials. The new data may breathe a new lease on life into the product, the monoclonal antibody gemtuzumab ozogamicin (Mylotarg, Pfizer).

Both trials are being presented here at the American Society of Hematology (ASH) 53rd Annual Meeting, and 1 of the trials, from the Acute Leukemia French Association (ALFA), was selected for the plenary session and highlighted in a press conference.

The ALFA trial was headed by Sylvie Castaigne, MD, professor of hematology at the Department of Hematology, Hôpital de Versailles, France, and showed that adding gemtuzumab to standard chemotherapy significantly improved overall survival, as well as event-free survival, when compared with chemotherapy alone.

"This is an important study," commented Martin Tallman, MD, chief of leukemia services at Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press conference. "We have had only 2 drugs for acute myeloid leukemia for a number of decades, and this may represent a major advance," he told journalists.

Pfizer told Medscape Medical News that it was reviewing the data from both of the new studies, which were investigator-initiated and not supported by the company.

New Targeted Approach

For decades, the standard treatment of AML has been based on a combination of 2 chemotherapy agents, daunorubicin and cytarabine, explained Dr. Castaigne.

Gentuzumab ozogamicin, which was first approved more than 10 years ago, offers a new targeted approach, she said. It combines a monoclonal antibody directed against CD33 antigen, which is expressed by the majority of leukemic cells in AML, and links it to a potent cytotoxic agent, chalicheamicin.

The product was approved by the US Food and Drug Administration in 2000 for use as an adjunct to chemotherapy in patients with relapsed AML, but it was an accelerated approval, and subsequent clinical trials were required. However, the later trials, as well as postmarketing experience, did not show evidence of clinical benefit in patients with AML, and toxicity was significant enough to warrant a black box warning.

One of the required postapproval studies (SWOG S0106) explored use of the product in patients with newly diagnosed AML aged 18 to 60 years, and found that adding gemtuzumab to chemotherapy did not improve survival compared with chemotherapy alone, but increased the fatal induction toxicity rate. As a result, in October 2010, Pfizer (which had acquired the drug from Wyeth) voluntarily withdrew it from the US market.

In Europe, the drug remains available, but only on a compassionate-use basis for patients with relapsed AML, Dr. Castaigne explained.

Reducing Toxicity

One of the problems with gemtuzumab was toxicity, she commented. Adverse effects included hematological toxicity, frequent liver toxicity, and cases of veno-occlusive disease, some of which were fatal, she said.

Dr. Castaigne and colleagues decided to try the drug at a lowered dose schedule to see whether this toxicity could be reduced. Whereas the old studies used a dose of 9 mg/m2 on days 1 and 14, and the SWOG S0106 study used a dose of 6 mg/m2 for induction, and then 5 mg/m2 (up to 3 doses given 28 days apart), Dr. Castaigne's team developed a new dosing schedule of 3 mg/m2 on days 1, 4, and 7.

Two preliminary phase 2 studies were performed to assess the safety of this new dosing regimen, both alone and in combination with chemotherapy in patients with advanced AML. On the basis of these results, Dr. Castaigne and colleagues then proceeded with the phase 3 trial presented at the meeting.

This study was conducted in 280 patients with newly diagnosed AML who were aged 50 to 70 years; this age range was chosen because another study in younger patients, with another new agent, was already being conducted in France, she noted.

All patients underwent induction, as well as first and second consolidation with daunorubicin plus cytarabine. Half of the patients were randomly assigned to also receive gemtuzumab, which was added to the chemotherapy at each stage of treatment.

The addition of gemtuzumab significantly improved both event-free and overall survival, Dr. Castaigne reported. The gemtuzumab group had 76 events vs 104 events (P = .00018), and a median overall survival of 34 months vs 19.2 months (P = .046).

Toxicity was acceptable, she commented. The main adverse event was prolonged thrombocytopenia with an increased need for platelet transfusion, but this was manageable. There were also a few rare episodes of veno-occlusive disease, she noted. This developed in 3 of the 139 patients who received gemtuzumab, and 2 of these 3 patients died. "We are pretty sure that these cases were due to the drug," she commented, but noted that the frequency of this adverse effect was lower than had been seen in earlier trials with higher doses of the drug.

"This study is really quite tantalizing," commented Charles Abrams, MD, associate chief of the Division of Hematology/Oncology at the University of Pennsylvania in Philadelphia. Speaking at a premeeting press briefing, he predicted that there will now be a resurgence of interest in gemtuzumab, adding that "this is a drug that wasn't studied fully enough."

Another Positive Study

The second positive study with gemtuzumab presented at the meeting, designated NCRI AML 16 (intensive), was conducted in the United Kingdom and Denmark, and was headed by Alan Burnett, MD, from Cardiff University School of Medicine in Wales.

This study involved 1115 patients (aged 51 - 84 years), of whom 806 had newly diagnosed AML. Another 194 patients had secondary AML, and 115 patients had high-risk myelodysplastic syndrome. Patients received 2 courses of daunorubicin with cytarabine or clofarabine, followed or not by a third course with or without azacytidine maintenance. Half of the patients were randomly assigned to also receive gemtuzumab, but at a dose of 3 mg/m2 on day 1 of the induction chemotherapy, which is a third of the dose that was used in the French trial.

The addition of gemtuzumab to induction chemotherapy did not lead to unacceptable increases in toxicity, and it both improved disease control and delivered a significant overall survival benefit for older patients overall, Dr. Burnett and colleagues reported. The 2-year overall survival was 35% with gemtuzumab vs 29% without gemtuzumab (P = .04).

There was a greater benefit from gemtuzumab in patients with newly diagnosed AML, and also with patients with AML who had intermediate risk cytogenetics, the researchers reported, adding that these findings are consistent with those from their previous AML 15 and AML 16 (nonintensive) trials. However, these previous trials did not show a significant improvement in overall survival, although there was an improvement in a subset of patients in the AML 15 trial ( J Clin Oncol . 2011;29:369-377).

Dr. Castaigne said that the new data from the AML16 (intensive) study were confirmation of the results from the ALFA study that she was presenting.

Manufacturer Considering Next Step

In an interview with Medscape Medical News, Mace Rothenberg, MD, senior vice president at Pfizer Oncology, said the company was now reviewing the data from both of these new positive trials with gemtuzumab. "We have to consider whether the data is robust enough, and does it show a favorable risk/benefit ratio for the drug?"

It will take some time to go over the details of both new studies, and to see how the new results fit in with the SWOG trial that led to the drug's withdrawal, he said. The dose of gemtuzumab was different in each of these studies, and the age range of the patients varied. "We will have to see if there is plausible argument that the drug has benefit at an acceptable rate of toxicity," Dr. Rothenberg concluded.

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 6 (Castaigne) and Abstract 582 (Burnett). Presented December 11 and 12, 2011.

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