NEW ORLEANS—The addition of the first humanized anti-CD33 monoclonal antibody, gemtuzumab ozogamin, combined with standard chemotherapy can significantly reduce the risk of relapse and increase rates of event-free survival (EFS) in pediatric patients with acute myeloid leukemia (AML), according to the results of a study reported here at the American Society of Hematology Annual Meeting (Abstract 355 ).
“Targeting CD33 can be an effective addition to therapy for AML, and gemtuzumab is clearly beneficial in refractory AML patients, with about one-third going into remission,” the lead author, Alan Gamis, MD, MPH, Chief of the Section of Oncology, Division of Hematology/Oncology, at Children's Mercy Hospital and Clinics, said in an interview. “Those patients are desperate for treatment since the retrieval rate for relapsed, refractory patients is low.”
For children diagnosed with AML, their post-treatment relapse rate is one of the major indicators of their potential for long-term survival. Escalation of treatment intensity for childhood AML has increased EFS, but at a cost of excessive toxicity and toxic mortality, compelling a search for more targeted, less toxic alternatives, he explained.
“Chemotherapy has limits, particularly in children, where increasing doses further can become too toxic and still not achieve the desired effect on the cancer. This study is significant because it shows for the first time that this targeted treatment can augment the effects of chemotherapy in children and effectively reduce their risk of relapse.” The therapy was most effective in the patients most at risk, he added.
Gemtuzumab received FDA accelerated approval in 2000 after successful Phase I trials in newly diagnosed AML. Then a Phase III presentation at the 2009 ASH Annual Meeting showed no benefit in complete remission, which was the primary endpoint, with gemtuzumab. Although that trial was criticized for design flaws, its manufacturer, Pfizer, voluntarily withdrew the agent from the market in 2010 because the potential risks outweighed the potential benefits (OT 8/10/10 and 10/10/10 issues).
“Subsequently, several trials have shown a benefit in disease-free survival or relapse risk in a subgroup of low-risk or intermediate-risk AML,” he noted. “AML is a heterogeneous disease. We don't expect that one agent would work for all patients. Gemtuzumab could be an important option for critical patients. It appears to have a real impact in increasing the likelihood of long-term survival in high-risk patients.”
Gamis presented the results of a Phase III trial of 1,022 children, average age of 10, with newly diagnosed de novo AML treated with gemtuzumab (511 patients) or a standard treatment regimen (511 patients), followed by additional chemotherapy for low-risk patients and stem cell transplants (SCT) for high-risk patients.
The patients were randomly assigned to receive standard therapy alone or two doses of gemtuzumab at 3 mg/m2 per dose on day 6 of induction and on day 7 of intensification in a five-cycle chemotherapy backbone.
Use of SCT was stratified by the patients' overall risk group assignment based on cytogenetics, FLT3-ITD high allelic ratio, and induction response, in which high-risk patients were allocated to best allogeneic donor SCT after intensification, low-risk patients received chemotherapy only, and those at intermedia tisk were assigned to transplant if there was a matched family donor. The patient demographics of both arms were similar.
Overall, compared with standard regimens, the addition of gemtuzumab was associated with better rates of disease-free survival (61% vs. 55%) and reduced relapse risk (33% vs. 41%), and three-year EFS (53% vs. 47%), although the drug did not significantly increase three-year overall survival (69% vs. 65%). There was no significant improvement of induction complete response (88% vs. 85%).
Low-risk patients showed a marked improvement in the risk of relapse, down to 20 percent from 30 percent, he noted. “Intermediate-risk patients who received SCT had a significant reduction in risk of relapse. Surprisingly, high-risk patients showed a strong trend in reduction in risk of relapse and improvement in disease-free and overall survival.”
All high-risk patients had a transplant with either a matched-related or unrelated donor.
“These results are encouraging, as combining gemtuzumab with chemotherapy appears to reduce the risk of disease relapse, which translates into improved EFS in children with AML,” he said. “Importantly, the therapy seemed to have a particularly lasting effect among those patients who achieved remission in the course of treatment. Although gemtuzumab was previously removed from the market due to lack of clinical value in earlier trials, this growing body of positive data in populations of critical need may be sufficient to bring it back as a commercial treatment option.”
The protocol therapy was well tolerated, he noted, with a treatment-related mortality of two percent in induction and five percent overall, with no difference by study arm. The cumulative five-year non-leukemic mortality was slightly higher in the gemtuzumab arm (8.6%) than the standard therapy arm (5.9%), mostly due to infections.
At a news conference at the meeting that highlighted promising novel strategies, Gamis added: “We do not use five courses of therapy as we did in the past. We hope this will reduce the risk of infections.”
At his presentation during an oral session at the meeting, Gamis said that although survival in pediatric AML has improved over the past several decades, alterations in therapy are still needed. “CD33 targeting reduces the relapse risk and merits further investigation. “Other agents had come before, with few successes. Gemtuzumab has the benefit of helping 80 to 85 percent of children who have CD33+ antigens. We might be able to add it to standard therapy at induction for low-risk patients and enhance the benefits of SCT for high-risk patients.”
In an interview after the news conference, the moderator, Joseph Mikhael, MD, Associate Professor in the Division of Hematology/Oncology at the Mayo Clinic in Scottsdale, Arizona, and Associate Dean of the Mayo School of Graduate Medical Education, said, “The data from this trial are encouraging. Patients reach improved EFS.
“We need to look in a more sequential manner at endpoints in pediatric AML. Some therapies may have a negative complete remission, but may be effective later on. We need to take a long-term perspective and look deeper when evaluating novel agents.”
Gamis noted that the Children's Oncology Group is currently testing several other novel agents. One such agent under investigation at Seattle Genetics is SGN33A-001. A single-arm, open-label, dose-escalation Phase I study is evaluating safety and tolerability in patients with CD33+ AML. “The hope is if this or similar agents are approved, we can revisit their addition to therapy and further refine those who might benefit the most,” Gamis said.
“I hope that Pfizer has enough ammunition to go back to the FDA to see about a path to approval of gemtuzumab. We clearly see benefit in AML patients who are low-risk or intermediate-risk alone. We hope gemtuzumab can go back to clinical testing.”