Improving survival of childhood acute myeloid leukemia: through global collaborative research efforts

The first part of this thesis addresses the pediatric AML subtype with KMT2A rearrangement, for which there is no comprehensive international consensus on risk-group stratification. We assembled the most extensive cohort of KMT2A-r pediatric AML to date, including 1,256 children diagnosed between 2005 and 2016, which enabled us to conduct two retrospective studies. We are the first to reveal that measurable residual disease (MRD)-positivity at the end of induction 2 (EOI2) is an independent adverse prognosticator in KMT2A-r pediatric AML, alongside the high-risk fusion-based group. This group includes t(4;11)(q21;q23)/KMT2A::AFF1, t(6;11)(q27;q23)/KMT2A::AFDN, t(10;11)(p12;q23)/KMT2A::MLLT10, t(10;11)(p11.2;q23)/KMT2A::ABI1, and t(11;19)(q23;p13.3)/KMT2A::MLLT1. Both EOI2 MRD-positivity and high-risk fusion-based group should be integrated into risk-group stratification algorithms of KMT2A-r pediatric AML. Our study also indicates that allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR1) is associated with reduced relapse risk within the high-risk fusion-based group, though it does not improve overall survival (OS), underscoring the need for new treatment approaches. Additionally, our findings suggest that t(1;11)(q21;q23)/KMT2A::MLLT11, previously classified as favorable risk, should be reclassified as intermediate risk. We also refined risk-group stratification for the most common KMT2A rearrangement, t(9;11)(p22;q23)/KMT2A::MLLT3, based on French-American-British (FAB)-M5 morphology and trisomy 6. Further, we defined three additional recurring fusion-based groups, two of which with good outcomes, namely t(X;11)(q24;q23)/KMT2A::SEPT6 and t(1;11)(p32;q23)/KMT2A::EPS15, and we identified add(12p) and del(9q) as specific structural additional cytogenetic aberrations as independently associated with adverse prognosis. The second part of this thesis focuses on antibacterial prophylaxis during pediatric AML treatment. There is no international consensus on the routine use of antibacterial prophylaxis, leading to variations in regimens. We retrospectively evaluated the effects of different antibacterial prophylaxis regimens in two Dutch centers from 1998 to 2021 on febrile neutropenic (FN) episodes and bacterial blood stream infections (BSIs). We demonstrate that significantly fewer FN episodes (43% vs. 90% and 75%) and bacterial BSIs (4% vs. 63% and 33%) occurred with teicoplanin plus ciprofloxacin prophylaxis compared to single-agent ciprofloxacin and the combination of penicillin and ciprofloxacin. Importantly, BSIs caused by Gram-negative rods and viridans group streptococci (VGS) did not occur with this regimen. Further, we present the results of the safety run-in phase of the ongoing Pro-Teico study, an open-label, randomized controlled trial on teicoplanin prophylaxis in pediatric AML. We demonstrate that teicoplanin administered at a dose of 20 mg/kg/once daily at three times a week with a 2-3 days interval is safe and well-tolerated. The third part of this thesis addresses treatment outcomes of children with AML in low- and middle-income countries (LMICs), particularly focusing on Kenya. A systematic review of pediatric AML treatment in LMICs revealed considerable disparities in outcomes compared to high-income countries. Contributing factors include high rates of abandonment, early death (ED), treatment-related mortality, and poor salvage rates after relapse. Our retrospective study of Kenyan children diagnosed with AML between 2010 and 2018 at the Moi Teaching and Referral Hospital (MTRH) highlighted the dismal survival prospects in Kenya, with a CR rate of 33%, abandonment rate of 22%, and ED rate of 46%. The 2-year probabilities of event-free survival (pEFS) and pOS were 4% and 7%, respectively. The main causes of ED were hemorrhages and infections. In 2019, MTRH implemented a pediatric AML-specific, resource-adapted treatment guideline. We compared outcomes before and after its implementation and observed a decrease in the abandonment rate (from 19% to 3%) and relapse rate (from 57% to 17%). However, there was no significant improvement in 2-year pEFS (from 5% to 15%; P = .53) or pOS (from 8% to 16%, P = .93) due to high ED rates from sepsis. The findings emphasize the need for better infection prevention and control and optimized treatment.