Optimized Cytogenetic Risk-Group Stratification of KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.

Comprehensive international consensus on cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1,256 children with KMT2A-r AML aimed to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs), and secondly, to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared to our previous study, three additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8% to 76.2%; P<0.01). ACAs occurred in 46.8% of 1,200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P<0.01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcome was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate the five adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcome, and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

Golgi satellites are essential for polysialylation of NCAM and expression of LTP at distal synapses.

The complex cytoarchitecture of neurons poses significant challenges for the maturation of synaptic membrane proteins. It is currently unclear whether locally secreted synaptic proteins bypass the Golgi or whether they traffic through Golgi satellites (GSs). Here, we create a transgenic GS reporter mouse line and show that GSs are widely distributed along dendrites and are capable of mature glycosylation, in particular sialylation. We find that polysialylation of locally secreted NCAM takes place at GSs. Accordingly, in mice lacking a component of trans-Golgi network-to-plasma membrane trafficking, we find fewer GSs and significantly reduced PSA-NCAM levels in distal dendrites of CA1 neurons that receive input from the temporoammonic pathway. Induction of long-term potentiation at those, but not more proximal, synapses is severely impaired. We conclude that GSs serve the need for local mature glycosylation of synaptic membrane proteins in distal dendrites and thereby contribute to rapid changes in synaptic strength.

Treatment outcomes of pediatric acute myeloid leukemia in Western Kenya before and after the implementation of the SIOP PODC treatment guideline.

PURPOSE: The Pediatric Oncology in Developing Countries (PODC) committee of the International Society of Pediatric Oncology (SIOP) published a pediatric acute myeloid leukemia (AML)-specific adapted treatment guideline for low- and middle-income countries. We evaluated the outcomes of children with AML at a large Kenyan academic hospital before (period 1) and after (period 2) implementing this guideline. PATIENTS AND METHODS: Records of children (≤17 years) newly diagnosed with AML between 2010 and 2021 were retrospectively studied. In period 1, induction therapy comprised two courses with doxorubicin and cytarabine, and consolidation comprised two courses with etoposide and cytarabine. In period 2, a prephase with intravenous low-dose etoposide was administered prior to induction therapy, induction course I was intensified, and consolidation was adapted to two high-dose cytarabine courses. Probabilities of event-free survival (pEFS) and overall survival (pOS) were estimated using the Kaplan-Meier method. RESULTS: One-hundred twenty-two children with AML were included - 83 in period 1 and 39 in period 2. Overall, 95 patients received chemotherapy. The abandonment rate was 19% (16/83) in period 1 and 3% (1/39) in period 2. The early death, treatment-related mortality, complete remission, and relapse rates in periods 1 and 2 were 46% (29/63) versus 44% (14/32), 36% (12/33) versus 47% (8/17), 33% (21/63) versus 38% (12/32), and 57% (12/21) versus 17% (2/12), respectively. The 2-year pEFS and pOS in periods 1 and 2 were 5% versus 15% (p = .53), and 8% versus 16% (p = .93), respectively. CONCLUSION: The implementation of the SIOP PODC guideline did not result in improved outcomes of Kenyan children with AML. Survival of these children remains dismal, mainly attributable to early mortality.

Treating CD33-Positive de novo Acute Myeloid Leukemia in Pediatric Patients: Focus on the Clinical Value of Gemtuzumab Ozogamicin.

Although survival in pediatric acute myeloid leukemia (AML) has increased considerably over the past decades, refractory disease and relapse rates remain high. Refractory and relapsed disease are difficult to treat, with overall survival rates less than 40-50%. Preventing relapse should, therefore, be one of the highest priorities. Current conventional chemotherapy regimens are hard to intensify due to associated toxic complications, hence more effective therapies that do not increase toxicity are needed. A promising targeted agent is the CD33-directed antibody-drug conjugate gemtuzumab ozogamicin (GO). Because CD33 is highly expressed on leukemic cells in the majority of AML patients, GO can be useful for a broad range of patients. Better relapse-free survival (RFS) after therapy including GO has been reported in several pediatric clinical trials; however, ambiguity about the clinical value of GO in newly diagnosed children remains. Treatment with GO in de novo AML patients aged ≥1 month, in combination with standard chemotherapy is approved in the United States, whereas in Europe, GO is only approved for newly diagnosed patients aged ≥15 years. In this review, we aimed to clarify the clinical value of GO for treatment of newly diagnosed pediatric AML patients. Based on current literature, GO seems to have additional value, in terms of RFS, and acceptable toxicity when used in addition to chemotherapy during initial treatment. Moreover, in KMT2A-rearranged patients, the clinical value of GO was even more evident. Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.

Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group.

PURPOSE: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

Effect of Antibacterial Prophylaxis on Febrile Neutropenic Episodes and Bacterial Bloodstream Infections in Dutch Pediatric Patients with Acute Myeloid Leukemia: A Two-Center Retrospective Study.

Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial prophylaxis regimens on the incidence of febrile neutropenic (FN) episodes and bacterial BSIs. Medical records of children (0−18 years) diagnosed with de novo AML and treated at two Dutch centers from May 1998 to March 2021 were studied. Data were analyzed per chemotherapy course and consecutive neutropenic period. A total of 82 patients had 316 evaluable courses: 92 were given with single-agent ciprofloxacin, 138 with penicillin plus ciprofloxacin, and 51 with teicoplanin plus ciprofloxacin. The remaining 35 courses with various other prophylaxis regimens were not statistically compared. During courses with teicoplanin plus ciprofloxacin, significantly fewer FN episodes (43 vs. 90% and 75%; p < 0.0001) and bacterial BSIs (4 vs. 63% and 33%; p < 0.0001) occurred than with single-agent ciprofloxacin and penicillin plus ciprofloxacin, respectively. GNR and VGS BSIs did not occur with teicoplanin plus ciprofloxacin and no bacterial BSI-related pediatric intensive care unit (PICU) admissions were required, whereas, with single-agent ciprofloxacin and penicillin plus ciprofloxacin, GNR BSIs occurred in 8 and 1% (p = 0.004), VGS BSIs in 24 and 14% (p = 0.0005), and BSI-related PICU admissions were required in 8 and 2% of the courses (p = 0.029), respectively. Teicoplanin plus ciprofloxacin as antibacterial prophylaxis is associated with a lower incidence of FN episodes and bacterial BSIs. This may be a good prophylactic regimen for pediatric AML patients during treatment.

Prognostic significance of chromosomal abnormalities at relapse in children with relapsed acute myeloid leukemia: A retrospective cohort study of the Relapsed AML 2001/01 Study.

BACKGROUND: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. METHODS: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. RESULTS: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. CONCLUSION: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.

Outcomes of pediatric acute myeloid leukemia treatment in Western Kenya.

BACKGROUND: Pediatric acute myeloid leukemia (AML) is a challenging disease to treat in low- and middle-income countries (LMICs). Literature suggests that survival in LMICs is poorer compared with survival in high-income countries (HICs). AIMS: This study evaluates the outcomes of Kenyan children with AML and the impact of sociodemographic and clinical characteristics on outcome. METHODS AND RESULTS: A retrospective medical records study was performed at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya, between January 2010 and December 2018. Sociodemographic and clinical characteristics, and treatment outcomes were evaluated. Chemotherapy included two "3 + 7" induction courses with doxorubicin and cytarabine and two "3 + 5" consolidation courses with etoposide and cytarabine. Supportive care included antimicrobial prophylaxis with cotrimoxazole and fluconazole, and blood products, if available. Seventy-three children with AML were included. The median duration of symptoms before admission at MTRH was 1 month. The median time from admission at MTRH to diagnosis was 6 days and to the start of AML treatment 16 days. Out of the 55 children who were started on chemotherapy, 18 (33%) achieved complete remission, of whom 10 (56%) relapsed. The abandonment rate was 22% and the early death rate was 46%. The 2-year probabilities of event-free survival and overall survival were 4% and 7%, respectively. None of the sociodemographic and clinical characteristics were significantly associated with outcome. CONCLUSION: Survival of Kenyan children with AML is dismal and considerably lower compared with survival in HICs. Strategies to improve survival should be put in place including better supportive care, optimization of the treatment protocol, and reduction of the abandonment rate and time lag to diagnosis with sooner start of treatment.

Outcome of pediatric acute myeloid leukemia (AML) in low- and middle-income countries: a systematic review of the literature.

Introduction: Survival rates of pediatric acute myeloid leukemia (AML) in low- and middle-income countries (LMICs) seem extremely poor, and the available literature on the matter is scarce. Accordingly, there is a limited understanding of poor treatment outcomes seen in this population.Areas covered: We provide an overview of the available literature with respect to treatment outcomes of pediatric AML in LMICs yielding poor outcomes compared to high-income countries. Moreover, treatment outcomes vary markedly between LMICs. In addition, there is a wide variation among studies in how treatment outcomes are reported and analyzed.Expert opinion: The substantially inferior treatment outcomes of pediatric AML in LMICs emphasize the unprecedented importance of global initiatives and international collaborations to improve the survival of these patients. A coordinated approach is necessary to carry out country-specific situational analyses. These analyses will result in operational plans on how to structurally implement childhood cancer registries, align healthcare infrastructure, build on capacities, and provide universal health coverage in LMICs. In addition, we strongly recommend that, in the future, LMICs document, analyze, and publish pediatric AML treatment outcomes in a more structured and uniform manner.

TP53 mutations and relevance of expression of TP53 pathway genes in paediatric acute myeloid leukaemia.

Limited data are available on the incidence and impact of TP53 alterations and TP53 pathway deregulation in paediatric acute myeloid leukaemia (AML). We analysed TP53 alterations in bone marrow samples of 229 patients with de novo paediatric AML, and detected heterozygous missense exon mutations in two patients (1%) and 17p deletions of the TP53 gene in four patients (2%). These patients more frequently had complex karyotype (50% vs. 4%, P = 0·002) or adverse cytogenetic abnormalities, including complex karyotype (67% vs. 17%, P = 0·013), compared to TP53 wild-type. Differential expression of TP53 pathway genes was associated with poor survival, indicating a role for TP53 regulators and effector genes.

Causes of early death and treatment-related death in newly diagnosed pediatric acute myeloid leukemia: Recent experiences of the Dutch Childhood Oncology Group.

BACKGROUND: With the current more effective treatment regimens for pediatric acute myeloid leukemia (AML), research on early death (ED), treatment-related mortality (TRM), and toxicity becomes increasingly important. The aim of this study was to give an overview of the frequency, clinical features, and risk factors associated with ED and TRM in first complete remission (CR1) during the last three consecutive treatment protocols of the Dutch Childhood Oncology Group (DCOG) between 1998 and 2014. METHODS: Incidence and risk factors associated with ED and TRM in CR1 were retrospectively studied in 245 patients treated according to the Dutch ANLL-97/AML-12 (n = 118), AML-15 (n = 60), or DB AML-01 (n = 67) protocols. RESULTS: The incidence of ED was, respectively, 5.1%, 6.7%, and 3.0% excluding deaths before treatment (P = NS), and 7.4%, 11.1%, and 4.4% including deaths before the onset of treatment. Severe underweight at initial diagnosis was significantly associated with more frequent ED. When relapse was included as a competing risk, cumulative incidence of death in CR1 were 5.9%, 5.0%, and 4.6% for ANLL97, AML15, and DB01, respectively (P = NS). The most important cause of TRM included infectious and SCT-related complications. CONCLUSION: We report relatively stable rates of ED and TRM in CR1 in the latest completed DCOG protocols for newly diagnosed AML patients. The most important causes of TRM were SCT- or infection-related, warranting further evaluation and awareness.

Differences in infection prophylaxis measures between paediatric acute myeloid leukaemia study groups within the international Berlin-Frankfürt-Münster (I-BFM) study group.

Prevention of infections is of obvious relevance in paediatric patients with acute myeloid leukaemia (AML). However, recommendations are often non-specific and supported by low-quality evidence, resulting in divergent infection preventive regimens. Using a web-based survey, we investigated the infection prophylaxis guidelines of 22 paediatric AML study groups affiliated to the international Berlin-Frankfürt-Münster study group. In order to evaluate differences in daily practice among hospitals, representatives (n = 27) from the Nordic Society for Paediatric Haematology and Oncology-Dutch-Belgium-Hong Kong - AML study group participated in a slightly modified survey. Seven study groups (32%) advise gram-negative antibiotic prophylaxis, mainly with fluoroquinolones (n = 6). Gram-positive prophylaxis is prescribed by eight groups (36%). Over 60% of the study groups prescribe food and social restrictions, but the specific topics and strictness differ widely. According to the hospital-based survey, sites roughly comply with common study group guidelines. However, the use of any gram-negative antibiotic prophylaxis, the specific prophylactic antifungal agent and the strictness of the food and social restrictions differ substantially between the hospitals. Despite a long history of close collaboration, many differences are still present between the affiliated groups. The results of this survey provide an appropriate baseline measure to study the emergence and impact of future guidelines on infection prophylaxis in paediatric AML.

Clinical challenges in de novo pediatric acute myeloid leukemia.

INTRODUCTION: Although the prognosis of pediatric acute myeloid leukemia (pAML) has improved, with current survival rates up to 75%, relapse rates remain high. Areas covered: The low number of patients, the heterogeneous genomic landscape of AML, novel diagnostic techniques, divergent available treatment protocols, and dose-limiting toxicity of conventional agents all contribute to the complexity of AML treatment. This review gives an overview of the current clinical challenges with respect to diagnostics, treatment, and supportive care in pAML. Expert commentary: Due to intensified treatment regimens and improved supportive care measures, the outcome for pAML patients has improved substantially over the past years. However, most treatment protocols still rely on conventional chemotherapeutic agents with significant toxicity. Although targeted therapies promise to reduce the need for high doses of conventional agents with a subsequent decrease in toxicity, the effectiveness of these strategies remains unsatisfactory today. International collaborations are needed in order to address the ongoing therapeutic challenges of reducing toxicity while increasing effectivity. Consensus on risk-group classification, a common chemotherapy backbone and evidence-based supportive care guidelines are necessary in this context, at the same time enabling intergroup studies on new agents in subgroups.

Clinical and prognostic significance of eosinophilia and inv(16)/t(16;16) in pediatric acute myelomonocytic leukemia (AML-M4).

BACKGROUND: The cytogenetic aberrations inv(16)(p13.1q22)/t(16;16)(p13.1;q22), frequently detected in acute myelomonocytic leukemia with eosinophilia (FAB type M4eo), are generally considered a prognostically favorable subgroup. M4eo comprises a distinct morphology compared to M4 without eosinophilia (M4eo-) and therefore may be indicative for a different pathogenesis. PROCEDURES: Morphology and cytogenetic/molecular analyses of a Dutch cohort of pediatric acute myelomonocytic leukemia (AML-M4) patients were performed and studied in order to analyze the association between the presence of eosinophilia morphology (M4eo+), inv(16)/t(16;16) (inv(16)+), clinical features, and outcome. RESULTS: Of the 119 included patients with available combined morphological and cytogenetic results, 60% had M4eo- without inv(16) (inv(16)-), 10% had M4eo-/inv(16)+, 13% had M4eo+/inv(16)-, and 17% had M4eo+/inv(16)+. M4eo+ was significantly associated with the presence of inv(16)/t(16;16) (P < 0.001). Patients with M4eo+ had no significantly superior outcome compared with patients with M4eo-, whereas patients with inv(16)+ had significantly superior probabilities of event-free survival and probabilities of overall survival compared with patients without inv(16)-. Patients with M4eo+/inv(16)+ had no significantly better outcome than those with M4eo-/inv(16)+. CONCLUSION: The prognostically favorable impact of distinct morphology with eosinophilia probably relies on its association with inv(16)/t(16;16). Simultaneous presence of both eosinophilia and inv(16) was not associated with superior outcome in our study. These results may be relevant for risk-group classification and risk-group adapted treatment and underline the importance of accurate cytogenetic analysis.

Glucocorticoid-Induced Proliferation in Untreated Pediatric Acute Myeloid Leukemic Blasts.

We evaluated the in vitro glucocorticoid (GC) responsiveness of 117 pediatric acute myeloid leukemia cells by considering GC resistance, GC-induced proliferation, and GC-induced differentiation. None of the samples was highly GC sensitive, and only 15% were intermediately sensitive. GC-induced differentiation was not observed, while GC-induced proliferation was observed in 27% of the samples. Samples with French-American-British classification (FAB) type M5 or activating Fms-like tyrosine kinase 3 (FLT3) mutations were significantly more prone to this phenomenon. Although we could not confirm this in our study, if induced proliferation in vitro is paralleled in vivo, GCs during consolidation may have adverse effects on minimal residual leukemic cells, which might increase relapse risk.

Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group.

PURPOSE: This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. RESULTS: Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival. CONCLUSION: Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.