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Gemtuzumab ozogamicin response linked to CD33 expression level in pediatric AML
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Treatment with gemtuzumab ozogamicin appeared to significantly reduce relapse risk and extend EFS in pediatric patients with acute myeloid leukemia and high CD33 expression, according to the results of a randomized trial.
However, the clinical benefit of gemtuzumab ozogamicin (Mylotarg, Pfizer) did not extend to patients with low CD33 expression, results showed.
Gemtuzumab ozogamicin targets CD33, which is expressed on AML blasts, according to study background. Although pediatric and adult trials have demonstrated the benefit of gemtuzumab ozogamicin, little study has focused on how response correlates with CD33 expression.
Thus, Jessica A. Pollard, MD, attending physician at Maine Children’s Cancer Center in Scarborough, Maine, and colleagues sought to study how CD33 expression influenced gemtuzumab ozogamicin response among children with AML.
The researchers prospectively quantified CD33 expression levels in 825 pediatric patients enrolled in the randomized, phase 3 AAML0531 trial conducted by the Children’s Oncology Group. Patients received a backbone of standard chemotherapy alone or in combination with gemtuzumab ozogamicin on day 6 of induction and day 7 of intensification.
Researchers used flow cytometry to determine CD33 mean fluorescent intensity (MFI) of myeloid progenitor cells and then divided the study cohort into four quartiles on the basis of CD33 expression. CD33 levels ranged from a median MFI of 34.62 (range, 2.68-67) in the first quartile (n = 208) to 435.9 (range, 29.6-1,351) in the fourth quartile (n = 206).
Complete response rates did not improve with the addition of gemtuzumab ozogamicin among patients with the lowest CD33 expression (75% vs. 73%). However, end-induction I complete remission rates appeared significantly higher among patients with the highest CD33 expression who received gemtuzumab ozogamicin (77% vs. 68%; P = .012).
The lowest expression cohort also did not demonstrate a benefit with gemtuzumab ozogamicin regarding rate of 5-year relapse risk (RR) from end of induction (36% vs. 34%) or 5-year EFS from study entry (53% vs. 58%).
However, patients in quartiles 2, 3 and 4 (n = 617) assigned to gemtuzumab ozogamicin had a significantly reduced rate of 5-year RR (32% vs. 49%; P < .001) and improved rate of 5-year EFS (53% vs. 41%; P = .005).
This differential effect persisted across all risk groups — specifically, all patients with low CD33 expression had similar outcomes regardless of exposure to gemtuzumab ozogamicin, whereas the addition of gemtuzumab ozogamicin to chemotherapy reduced 5-year RR and increased 5-year DFS in low-risk (RR = 13% vs. 35%, P = .001; DFS = 79% vs. 59%, P = .007), intermediate-risk (RR = 44% vs. 57%, P = .044; DFS = 51% vs. 40%) and high-risk (RR = 40% vs. 73%; P = .016; DFS = 47% vs. 28%) patients.
The researchers acknowledged their inability to determine a specific CD33 expression threshold for response as a study limitation.
“The current study is significant as the first to our knowledge to demonstrate, within the context of a large randomized pediatric AML trial, that gemtuzumab ozogamicin therapy is unlikely to have clinical benefit in patients with low CD33 expression,” Pollard and colleagues wrote. “Conversely, in patients with high CD33 expression, gemtuzumab ozogamicin seems to significantly improve disease-free response in all risk groups. Given limited commercial access to gemtuzumab ozogamicin, additional studies of novel CD33-targeted agents are needed in pediatric AML.” – by Cameron Kelsall
Disclosure: Pollard reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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