Gemtuzumab 'Promising' for AML in Older Patients

Zosia Chustecka

November 12, 2012

Another call for gemtuzumab ozogamicin to be returned to the market comes after a second clinical trial shows benefit in older patients with acute myeloid leukemia (AML). The results show that 1 dose of gemtuzumab ozogamicin added to chemotherapy significantly improves survival without increased toxicity.

Both clinical trials showing benefit were investigator-led and were first reported last year at the annual meeting of the American Society of Hematology. Since then, the trial headed by Sylvie Castaigne, MD, professor of hematology at the Hôpital de Versailles in France, was published in the Lancet (2012;379:1508-1516).

Now, thetrial headed by Alan Burnett, MD, FMedSci, professor of hematology at the Cardiff University School of Medicine in the United Kingdom, has been published in the November 10 issue of the Journal of Clinical Oncology.

In an accompanying editorial, Donna Neuberg, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, explains that these results "merit reconsideration of the availability of gemtuzumab ozogamicin as a component of therapy for older patients diagnosed with AML."

Voluntarily Withdrawal

Gemtuzumab ozogamicin, marketed as Myotarg by Pfizer, was used to treat patients with AML for about 10 years. It was voluntarily withdrawn from the market in the United States in 2010. The product consists of a humanized anti-CD33 antibody, which targets the CD33 protein found in about 90% of AML patients. The antibody is linked to the cytotoxic agent N-acetyl gamma calicheamicin, which is similar to an anthracycline. The US Food and Drug Administration granted accelerated approval in 2000 for its use in patients with AML who were 60 years or older and who had experienced a relapse of their disease; it was used to improve the effectiveness of chemotherapy.

Clinical trials to assess the effect gemtuzumab ozogamicin on overall survival continued after its approval. A planned interim analysis from one such trial, the Southwest Oncology Group (SWOG) S0106 trial, found "a lack of efficacy in the presence of enhanced toxicity," and resulted in the product's withdrawal.

In their study, Dr. Burnett and colleagues note that the dose approved, 9 mg/m² daily, was "too high when combined with chemotherapy, particularly with respect to liver toxicity."

They previously found that a lower dose — 3 mg/m² daily — could be safely combined with chemotherapy (Blood. 2006:108:551a-552a [abstr 1950]). That small trial also provided some preliminary evidence of a survival benefit without additional toxicity, in contrast to the results of the S0106 trial, they note.

Larger Trial Shows Improved Survival

Dr. Burnett and colleagues then conducted this larger trial, which also shows improved survival with little increased toxicity.

It involved 1015 older patients (median age, 67 years; range, 51 to 84 years) with untreated AML or high-risk myelodysplastic syndrome who received induction chemotherapy with either daunorubicin/cytosine arabinoside or daunorubicin/clofarabine. They were randomized to receive gemtuzumab ozogamicin on day 1 of the first course of chemotherapy or to receive nothing.

The 3-year survival results were significantly better with than without gemtuzumab ozogamicin (25% vs 20%; hazard ratio [HR], 0.87; P = .05). In addition, the 3-year cumulative incidence of relapse was significantly lower with gemtuzumab ozogamicin (68% vs 75%; HR, 0.78; P = .007). The benefit was apparent across all subgroups, the researchers note.

Dr. Burnett and colleagues conducted a meta-analysis of their 2 trials, which involved 2228 patients. From those results, they conclude that "it is clear that gemtuzumab ozogamicin at 3 mg/m² administered simultaneously with daunorubicin (50 mg/m²) as part of induction therapy is safe, significantly reduces relapse risk, and improves overall survival."

Progress in Older AML Patients

"Although there was some controversy around the use of gemtuzumab ozogamicin following its withdrawal in the United States 2 years ago, these results appear to be extremely promising and suggest no cause for concern if the appropriate dose is given," Dr. Burnett said in a statement.

Kate Law, PhD, director of clinical research at Cancer Research UK, which funded the trial, said that, "in general, the outlook for leukemia patients has improved dramatically in recent decades. When leukemia is diagnosed in older patients, it's much harder to treat. There is a real need for effective treatments that are suitable for this age group."

This trial shows that "gemtuzumab ozogamicin may have particular benefits for patients over 60, who may be unsuitable for other more intensive treatments," she said in a statement.

In her editorial, Dr. Neuberg agrees that gemtuzumab ozogamicin is a promising component of the treatment regimen for older patients with untreated AML.

However, she says that more data are needed. Dr. Burnett and colleagues report only the results of the randomization to gemtuzumab ozogamicin, but the trial was a complex one (2 different chemotherapy schedules were used initially), and another randomization to consolidation chemotherapy took place after the induction therapy. The results of the randomized chemotherapy intervention are not yet mature, and will be reported elsewhere, they explain.

Dr. Neuberg notes that further analysis is needed "to understand the data more fully so that we can assess just how a single dose of gemtuzumab ozogamicin has led improved rate of overall survival."

The trial was funded by Cancer Research UK. Dr. Burnett reports serving as a consultant or advisor to Pfizer. Dr. Neuberg has disclosed no relevant financial relationships.

J Clin Oncol. 2012;30:3905-3906, 3924-3931. Editorial, Abstract