New Look at Discontinued Drug in Older Patients With Acute Myeloid Leukemia

Administering gemtuzumab ozogamicin (GO) on a new schedule achieved impressive progression-free survival (PFS) and overall survival (OS) compared with standard chemotherapy in older patients with acute myeloid leukemia (AML) with favorable cytogenetics, according to a phase 3 study presented at the Plenary Session of the 53rd Annual Meeting of the American Society of Hematology (ASH). GO was taken off the market in 2010 due to toxicity concerns and is no longer available in the US.

“Research has demonstrated that GO has very potent anti-cancer properties, and with this study, we have identified a dosing regimen that gives patients the therapeutic benefit of the drug without some of the toxicities reported at higher doses,” stated lead author Sylvie Castaigne, MD, professor, department of hematology at Hôpital de Versailles, Versailles, France. “The standard of care has been daunorubicin plus cytarabine for many years. There hasn’t been a new therapeutic option for several decades, and with this research we are encouraged that GO may be able to improve overall outcomes for these AML patients with limited alternatives.”

GO is an anti-CD33 antibody conjugated with a toxin; the antibody binds to the surface of CD33-positive leukemia cells and releases the toxin (ie, calicheamicin) into the leukemia cells. The antibody is specifically targeted to the leukemia cells and theoretically spares toxicity to other cells that do not express CD33.

The phase 3, prospective, open-label, randomized trial enrolled newly diagnosed de novo AML patients aged 50 to 70 years. The new 3,3,3 regimen (ie, 3 mg/m² GO IV on days 1, 4, 7) was designed to give lower but repeated doses that might enhance the efficacy of GO and minimize hepatic and hematologic toxicities reported earlier with this antibody. Patients (N = 280) were randomized to arm A (standard daunorubicin plus cytarabine) or arm B (the same chemotherapy plus the GO 3,3,3 regimen). Those who achieved remission on 2 cycles of treatment were further randomized to 2 courses of consolidation therapy with the same treatments.

The experimental arm extended event-free survival (EFS) by just under 8 months. At 2 years, median EFS was 11.9 months with standard therapy versus 19.6 months with the addition of GO, a result that was highly significant (P = .0018). The addition of GO also extended OS: median OS was 19.2 months with standard chemotherapy versus 34 months with chemotherapy plus GO (P = .046).

Improvement in EFS and OS was observed in patients with favorable cytogenetics, but not in those with unfavorable cytogenetics, Castaigne emphasized. Fatal events occurred in 6.7% in the standard therapy arm versus 8.7% in GO arm. Adverse events of note in the GO arm included prolonged grade 3 thrombocytopenia in 19 patients and sinusoidal obstructive syndrome in 3 patients (2 fatal). No differences were observed between the treatment arms in the rate of severe sepsis or intensive care admission during therapy.

This study, and 2 other positive studies of GO reported at ASH will put pressure on Pfizer to reconsider applying for approval for GO. A Pfizer spokesperson said that the company plans to review results of the positive studies presented at ASH.