Measurable Residual Disease Monitoring during Treatment for Pediatric Acute Myeloid Leukemia in First Relapse Predicts Outcome

Despite overall survival (OS) rates of approximately 80% in recent collaborative trials, relapse remains the predominant cause of death in childhood acute myeloid leukemia (AML). We present disease characteristics, prognostic factors, and outcome in children with first relapse of AML after primary therapy according to the NOPHO-DBH AML 2012 protocol.

Since 2013, patients with AML from the Nordic and Baltic countries, Hong Kong, the Netherlands, Belgium, Spain, and Israel have been included in the 2012 protocol. Patients experiencing first relapse before January 1^st, 2023, were included.

Disease characteristics, treatment details from both primary therapy and relapse, response assessments, and outcome were retrieved from the NOPHO-AML database and case report forms. Relapses after NOPHO-AML 2004 therapy were used as a comparison cohort (n=137). OS and 95% confidence intervals (CI) were assessed using the Kaplan-Meier method. Cox proportional models, including core binding factor (CBF) aberrations, time to relapse, and stem cell transplantation (SCT) in first complete remission (CR1) as co-variates were used for multivariate analyses.

Relapse occurred in 190 patients. Distributions of sex and age were comparable for patients with relapse after treatment on the 2012 and 2004 protocols. AML harbouring KMT2A-rearrangements was more common in patients with relapse after 2012 therapy (18% vs. 7%, P=0.003), whereas t(8;21) was less common (8% vs. 17%, P=0.01) compared to the 2004 protocol.

There was no difference in 3-year OS between relapsed patients treated on the 2012 (45%; CI 38-53) and 2004 protocols (43%; CI 34-51, P=0.9). Patients with CBF AML performed exceptionally well with an OS of 85% (CI 65-94) in the 2012 cohort. Patients with non-CBF AML had an OS of 37% (CI 30-45). Patients with early relapse (<12 months from primary diagnosis) had a significantly lower OS (31%; CI 22-40) than those with late relapse (62%; CI 50-72, P<0.001). Patients who underwent SCT in CR1 had a significantly lower OS (26%; CI 12-43) compared to patients who received chemotherapy only (48%; CI 40-56, P=0.004).

Patients who were multiparameter flow cytometrymeasurable residual disease (MRD) positive (≥0.1% leukemic blasts) after first course of therapy at initial AML diagnosis showed an OS of 36% (CI 25-48) compared to 50% (CI 40-60) in MRD negative patients (P=0.08).

Data on relapse treatment was available for 184 of 190 patients. Curative treatment was initiated in 175 (95%) patients with relapse, 119 (65%) patients received a fludarabine and high-dose cytarabine (FLA)-based regimen including an anthracycline (84/119; 69%), 44 (25%) patients received other myelosuppressive regimens, and 12 (7%) received experimental therapy as first relapse therapy. Second complete remission was achieved in 120 (69%) patients of whom 107 (89%) proceeded to SCT with an OS of 69% (Cl 59-77).

MRD after first reinduction course was available for 106/171 (62%) patients with bone marrow relapse. MRD negative patients showed a higher OS of 68% (CI 52-80) compared to MRD positive patients (OS 34%; CI 22-45, P=0.0009). MRD before SCT was available for 77 (72%) patients and demonstrated an improved OS in MRD negative patients compared to MRD positive patients (75%; CI 60-85 vs 36%; CI 18-54, P=0.003).

MRD negativity after first reinduction course (Hazard ratio (HR) 0.47; CI 0.26-0.85, P=0.01), late relapse (HR 0.29; CI 0.17-0.52, P<0.001), and CBF AML (HR 0.06; CI 0.01-0.47, P=0.007) were significant predictors of higher OS.

With the exception of CBF AML, OS after relapse has not improved in the last decades in our experience. In addition to established prognosticators, we identify MRD during reinduction therapy as a significant predictor of outcome.

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