NEW ORLEANS ― Adding gemtuzumab ozogamicin to the treatment regimen can improve event-free survival in children, adolescents, and young adults with acute myeloid leukemia (AML). The addition of this drug appears to lower the risk for relapse among those who have achieved remission, according to new data presented here at the American Society of Hematology (ASH) 55th Annual Meeting.
Gemtuzumab ozogamicin is not currently available; it was marketed as Mylotarg (Pfizer) but was voluntarily withdrawn in 2010. However, it is still being investigated in clinical trials, and positive results from several trials during the last few years have led to calls for the drug to be returned to the market.
In the AML trial now presented, researchers found that from the time of study enrollment, gemtuzumab was significantly associated with better overall event-free survival (hazard ratio [HzR], 0.83; P = .04) as well as relapse-free survival (HzR, 0.74 [0.6-0.93; P = .01]). However, no significant improvement was observed for overall survival (HzR, 0.91 [0.74-1.13]).
At 3 years, event-free survival was 53% for those who had received gemtuzumab, compared with 47% for patients who did not (P = .05). Overall survival at 3 years was similar between the 2 groups: 69% vs 65% (P = .18).
Event-free survival significantly improved with gemtuzumab, commented lead author Alan S. Gamis, MD, MPH, of Children's Mercy Hospital and Clinics in Kansas City, Missouri. "But there was no improvement of induction complete response."
Although relapse rates were consistently reduced in all risk groups, he said during a press briefing, "In intermediate-risk and high-risk patients, the benefit was limited to those who underwent stem cell transplant."
The lower relapse rate was also offset in low-risk patients by toxicity-related mortality. "And overall survival improved but did not achieve statistical thresholds for significance," said Dr. Gamis.
Neverheless, this study shows that CD33 targeting (by gemtuzumab) reduces relapse risk, and this merits further investigation, he said.
Survival in AML is gradually improving, owing to chemotherapy intensification and stem cell transplantation, Dr. Gamis commented. In addition, supportive care is also improving.
However, there are limits to treatment escalation, Dr. Gamis noted. Toxic mortality runs at about 10% to 19%, and more than 8% of patient may have late cardiac sequelae. In addition, there have been limits on success. Event-free survival is achieved in 46% to 59% of patients, and overall survival is about 56% to 74%. Thus, better and less toxic treatments are needed.
Return to Market?
Gemtuzumab is a recombinant, humanized anti-CD33 monoclonal antibody attached to the cytotoxic antitumor antibiotic calicheamicin. The antibody binds to and is internalized by tumor cells expressing CD33 antigen, and it delivers the attached calicheamicin to CD33-expressing tumor cells. It was originally approved by the US Food and Drug Administration (FDA) in 2000 to treat relapsed AML and for treatment of older patients who were not eligible for other treatments. That was an accelerated approval based on phase 1 trials that showed overall remission rates in both children and adults, explained Dr. Gamis.
However, a phase 3 trial in adults showed no benefit in remissions, and because of that, gemtuzumab was voluntarily removed from the market in 2010.
Major Undertaking
This study in AML was a major undertaking from the Children's Oncology Group, and the results show that some patients benefit from it, commented Jeffrey E. Rubnitz, MD, PhD, division chief of leukemia at St. Jude Children's Research Hospital in Memphis, Tennessee.
"In this AML study, as a group, patients who received it had better outcomes, although it did not really improve overall survival," said Dr. Rubnitz, who was approached by Medscape Medical News for independent commentary. "Other studies have shown that it is active in other patient populations."
Although gemtuzumab is not currently available commercially, these results demonstrate that CD33 is a viable target, and this strategy is currently being studied, Dr. Rubnitz said. "There is actually a great deal of interest in CD33."
He added that there also has been some discussion of bringing gemtuzumab back on the market.
"I don't know where that conversation is going, or if there are negotiations going on," he said. "Even though it was beneficial in this study, it didn't have a dramatic effect or increase overall survival as people has hoped it would."
Study Details
The rate of post-treatment relapse is one of the major indicators of the potential for long-term survival. In this study, Dr. Gamis and colleagues sought to determine whether adding the monoclonal antibody gemtuzumab to standard chemotherapy might improve event-free survival in pediatric AML patients, without causing excessive toxicity and mortality.
The phase 3 trial included 1070 children with a median age of 9.5-9.9 years, and of this cohort, 1022 of were eligible for analysis. The median follow-up was 3.6 years for those that were alive.
Patients were randomly assigned to receive standard therapy alone or 2 doses of gemtuzumab 3 mg/m2/dose on day 6 of Induction I and on day 7 of Intensification II, as part of a 5- cycle chemotherapy regimen. The use of stem cell transplant was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio [HAR], and response to the first induction), and high-risk patients were allocated to best allogeneic donor transplant after induction. Those determined to be at low risk received chemotherapy only, and intermediate-risk patients were assigned to stem cell transplant if there was a matched family donor.
The protocol therapy was well tolerated, with a toxic mortality rate of 2% during induction and 5% overall, and there were no differences between the 2 study arms. Gemtuzumab added to standard chemotherapy was associated with a reduced risk for relapse (41% vs 33%). In multivariate analyses, the author found that the addition of gemtuzumab was significantly associated with improved event-free survival, as compared with standard therapy, even after adjusting for significant adverse risk factors that included age of less than 2 years, initial WBC > 100,000 x 109/L, and black race.
However, gemtuzumab plus chemotherapy was not associated with significantly better induction complete remission, as compared with standard therapy (88% vs 85%; P = NS).
American Society of Hematology (ASH) 55th Annual Meeting: Abstract 355, presented December 8, 2013.
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