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Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial
Madita Uffmann1, Mareike Rasche2, Martin Zimmermann1
1Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Insights
Reducing treatment intensity for children with myeloid leukemia associated with Down syndrome (ML-DS) did not impact survival outcomes. Poor early response and chromosome 8 gain are key prognostic factors in pediatric ML-DS.
Area of Science:
- Pediatric Hematology and Oncology
- Cancer Genomics
- Clinical Trial Design
Background:
- Children with myeloid leukemia associated with Down syndrome (ML-DS) have a favorable prognosis but increased susceptibility to cytotoxic drugs.
- Previous treatment protocols often involved high-intensity therapy, potentially leading to increased toxicity in ML-DS patients.
Purpose of the Study:
- To evaluate the efficacy and safety of a reduced-intensity treatment protocol (ML-DS 2006 trial) for pediatric ML-DS patients.
- To identify prognostic factors influencing treatment outcomes in this specific patient population.
Main Methods:
- Analysis of 170 pediatric ML-DS patients enrolled in the prospective, multicenter ML-DS 2006 trial.
- Comparison of outcomes with a historical control arm (AML-BFM 98 trial) using a reduced-intensity protocol.
- Reduced cumulative etoposide dose, modified intrathecal prophylaxis, and omitted maintenance therapy were implemented.
Main Results:
- The ML-DS 2006 trial showed comparable 5-year overall survival (89%) and event-free survival (87%) to the historical control (90% and 89%, respectively).
- Cumulative incidence of relapse/nonresponse was similar between the groups (6%).
- Poor early treatment response and gain of chromosome 8 were identified as independent negative prognostic factors for event-free survival.
Conclusions:
- Reducing treatment intensity in pediatric ML-DS patients did not compromise excellent survival outcomes.
- Early treatment response and specific cytogenetic abnormalities (gain of chromosome 8) are crucial prognostic markers.
- This study supports de-escalation of therapy in ML-DS without sacrificing efficacy, highlighting the importance of risk stratification.
Abstract:
Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%; PGray = .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% ± 16% vs 88% ± 3%; Plog rank = .0008) and gain of chromosome 8 (CIR/NR, 16% ± 7% vs 3% ± 2%, PGray = .02; 5-year EFS, 73% ± 8% vs 91% ± 4%, Plog rank = .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2.
