Abstract
After being pulled from the market 7 years ago, gemtuzumab ozogamicin has been reapproved by the FDA, this time for adults newly diagnosed with acute myeloid leukemia, as well as patients 2 years of age and older with relapsed/refractory disease. The CD33-targeting antibody–drug conjugate can be given as a single agent or in combination with chemotherapy.
Seven years after it was pulled from the market, gemtuzumab ozogamicin (Mylotarg; Pfizer) has been approved anew—this time for adults newly diagnosed with acute myeloid leukemia (AML), as well as patients 2 years of age and older with relapsed/refractory disease. The CD33-targeting antibody–drug conjugate (ADC) got the nod to be given as a single agent or in combination with chemotherapy.
“I'm convinced this is a good drug, and I'm very happy that it's back,” says Richard Stone, MD, director of the adult leukemia program at Dana-Farber Cancer Institute in Boston, MA.
Mark Litzow, MD, who heads the Mayo Clinic's acute leukemia group in Rochester, MN, is also pleased about gemtuzumab ozogamicin's (GO) renaissance. “I think its withdrawal at the time was unfortunate, although understandable,” he says.
In 2000, GO earned accelerated approval as monotherapy for patients with AML who were 60 years of age and older, had experienced an initial relapse, and weren't good candidates for standard intensive chemotherapy. The drug was “going on its merry way,” Stone says, “when the required confirmatory trial [SWOG-0106] came back negative.”
However, that trial assessed the drug in a different patient population, Stone points out: Newly diagnosed patients were randomly assigned to receive GO with chemotherapy, or chemotherapy alone. Nonetheless, he adds, “given the chemo-unfit population for whom GO was originally approved, conceiving of a randomized trial in that setting, with a good control arm, would have been difficult.”
Because SWOG-0106 failed to demonstrate superior efficacy of GO and yielded a higher rate of fatal toxicity, Pfizer voluntarily withdrew the drug in 2010. However, GO remained available through the company's compassionate use programs and continued to be evaluated in investigator-initiated studies, generating sufficiently encouraging data for a possible reapproval.
Three trials in particular helped sway the FDA. In ALFA-0701, among 271 patients with newly diagnosed AML, those randomly assigned to receive GO alongside chemotherapy had a longer median event-free survival than those given just chemotherapy: 17.3 months versus 9.5 months. AML-19 randomized 237 elderly patients who could not tolerate other therapies to receive single-agent GO or best supportive care; the median overall survival was 4.9 months and 3.6 months, respectively. In MyloFrance-1, 57 patients with initial disease relapse received single-agent GO; 15 achieved a complete remission that lasted 11.6 months on average.
Importantly, across these trials, patients were given GO on a fractionated schedule and at a lower dose than was originally approved. This was key in reducing the risk of hepatic veno-occlusive disease, the severe toxicity that prompted GO's market withdrawal.
With safety issues halting Seattle Genetics' development of vadastuximab talirine earlier this year, GO is the sole approved CD33-targeting ADC. “The challenge is this fine line between excess toxicity and therapeutic efficacy—exemplified by GO early on—because normal myeloid cells express CD33 too,” Litzow notes, adding that “there's interest, now, in directing CAR T cells at this antigen, but a lot of concern about doing so safely.”
Overall, this is a banner year for AML, Stone and Litzow agree, with GO being the fourth approved therapy. Midostaurin (Rydapt; Novartis) and enasidenib (Idhifa; Celgene/Agios) are targeted at more specific patient subsets. CPX-351 (Vyxeos; Jazz), however, is a fixed-dose liposomal formulation of daunorubicin and cytarabine—both commonly given with GO. “We still need to hash out which [GO plus conventional chemotherapy, versus CPX-351] to use and when,” Litzow says.
GO, ultimately, “is for almost everyone, seeing as more than 90% of patients have CD33-expressing blasts,” Stone observes. “I do think it will be used a good deal in AML, now that it's widely available again.” –Alissa Poh
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
RSS Feeds