Do Not Pass on GO in Childhood KMT2A-Rearranged AML (and Collect 20% Improvement in EFS)

Rearrangements in lysine methyltransferase 2A (KMT2A) occur in 10 percent of patients with acute leukemia, including 20 percent of children with acute myeloid leukemia (AML).^1,2  Overall survival (OS) of patients with KMT2A-rearranged AML remains less than 50 percent, highlighting need for more optimal treatment regimens.¹  Interestingly, more than 100 5′ fusion partners of KMT2A have been identified to date,³  and the identity of the specific fusion partner strongly influences prognosis and clinical outcomes in patients with AML or acute lymphoblastic leukemia (ALL).^4–6 

Gemtuzumab ozogamicin (GO) is a monoclonal antibody-drug conjugate that targets the transmembrane sieglec protein CD33, which is present on the cell surface of most AML cases.⁷  A meta-analysis of five independent studies showed reduced relapse rates and improved OS in adults with AML with the addition of GO to conventional chemotherapy.⁸ 

Higher CD33 cell surface expression has also been associated with inferior disease-free survival and OS in children with AML.^9,10  These data and the favorable outcomes of adult AML trials nominated GO as a promising drug for pediatric-specific investigation. The Children's Oncology Group (COG) AAML0531 phase III clinical trial (NCT00372593) randomly assigned 1,070 children and adolescents/young adults (AYAs) from the ages of one month to less than 30 years with de novo AML, to receive conventional multiagent chemotherapy (arm A) versus chemotherapy plus GO 3 mg/m² (arm B) administered in induction 1 (all patients) and intensification 2 (patients treated with chemotherapy only/without hematopoietic stem cell transplantation) cycles. Event-free survival (EFS) at three years with GO addition was improved (53% for arm B vs. 47% for arm A; p=0.04) primarily via reduction in relapse risk (RR; 32.8% vs. 41.3%; p=0.006), though no difference in OS was detected (69% for arm B vs. 65% for arm A; p = 0.39). Importantly, no increased risk of veno-occlusive disease/sinusoidal obstruction syndrome was seen with GO addition to chemotherapy in AAML0531.¹¹ 

In a recent subgroup analysis of AAML0531 data, Dr. Jessica Pollard, Dr. Erin Guest, and COG colleagues investigated the potential benefit of GO specifically in children and AYAs with KMT2A-rearranged AML, which has been shown to express particularly high CD33 protein levels.¹⁰  Amongst 1,022 evaluable study subjects, 215 (21%) harbored KMT2A rearrangements.

The investigators found that children and AYAs with KMT2A-rearranged AML also had improved five-year EFS (48% for arm B vs. 29% for arm A; p=0.003) and decreased RR (40% vs. 66%; p=0.001), though five-year OS was again not significantly better (63% for arm B vs. 53% for arm A; p=0.054). Strikingly, the greatest benefit of GO addition was detected in patients with KMT2A-rearranged AML and previously defined high-risk fusion partners, including MLLT6, ABI1, MLLT10, and MLLT1.¹²  In this patient subset, EFS improved from 6 percent with “no GO” on arm A to 27 percent with GO on arm B (p=0.013), and relapse rates were reduced from 90 percent without GO to 66 percent with GO (p=0.027). As expected, patients with KMT2A-rearranged AML had generally worse outcomes than those without KMT2A rearrangements, with five-year EFS of 38 percent versus 51 percent (p<0.001) and OS of 58 percent versus 66 percent (p=0.02), respectively. This difference was particularly pronounced in “no GO” patients with EFS of 29 percent if KMT2A-rearranged, and 50 percent if non–KMT2A-rearranged (p<0.001). Remarkably, pediatric patients with KMT2A-rearranged versus non–KMT2A-rearranged AML treated with GO had comparable EFS (48% vs. 53%; p=0.325) and OS (63% vs. 66%; p=0.643), suggesting that the increased clinical risk associated with KMT2A rearrangements may be abrogated by GO addition to chemotherapy.