Acute Myeloid Leukemia Study Group Research Articles

Analysis of overweight/obese pediatric patients with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study.

The dosage of chemotherapy drugs for overweight/obese children with acute myeloid leukemia (AML) has been empirically reduced based on ideal body weight (BW) in Japan to reduce the risk of adverse events. We investigated the associations between pre-therapeutic body mass index (BMI) and clinical outcomes among children with AML. A total of 280 children were divided into two groups based on the World Health Organization Child Growth Standards: a healthy-weight group (n=254), and an overweight/obese group (n=26). If BW exceeded 1.2 times the standard BW of Japanese children, the dosage of chemotherapy drugs was calculated using 1.2 times the standard BW. The dosage of chemotherapy drugs was reduced during at least one chemotherapy cycle in 24 of 26 patients (92.3%) in the overweight/obese group, compared with zero patients in the healthy-weight group. Overall/event-free survival, cumulative incidence of relapse, and treatment-related mortality (TRM) did not differ between the overweight/obese and healthy weight groups. However, the frequency of bacteremia was higher in the overweight/obese group (80.8 vs. 52.4%, P=0.006). This indicates that TRM may increase when chemotherapy drug dosage is not corrected in overweight/obese patients. Drug reduction is a potential treatment strategy.

High IL2RA/CD25 expression is a prognostic stem cell biomarker for pediatric acute myeloid leukemia without a core-binding factor.

CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p<.001) and event-free survival (p<.001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.

Long-Term Outcome of 1296 Patients with Newly Diagnosed with APL: A Harmony Alliance Study

Background: APL, a rare and aggressive subtype of acute myeloid leukemia (AML), is now curable in 75-90% of patients using targeted agents [All-trans retinoic acid (ATRA)/Arsenic Trioxide (ATO) or ATRA combined with chemotherapy (ATRA+Idarubicin, AIDA-based)]. Despite significant advances in survival, most reports are based on low patient numbers, which limit reliability of data. Aims: to study factors associated with outcome in a large patient cohort diagnosed with APL, and treated according to two European trials (UK AML-17 and GIMEMA APL0406), or recorded in national registries from 6 countries, enrolled in the HARMONY database. Methods: The Harmony platform includes to-date 1868 patients with APL, diagnosed between 2007 and 2020. The present analysis was performed on 1296 patients, who met the data quality requirements, by evaluating the list of variables shown in Table 1. Patients were treated according to APL0406 and AML17 clinical trials, or were included in the Study Alliance Leukemia (SAL), Swedish Cooperative Group or AML study Group (AML-SG) registries. After acquisition from the sources, data were harmonized and transformed using an Observational Medical Outcomes Partnership Common Data Model, and registered in the HARMONY Big Data Platform. Results: Of 1296 patients, 562 were treated with ATRA-ATO (median age 51 yrs, range 16-94; M:F ratio 1), and 605 with ATRA-Idarubicin (AIDA, median age 50 yrs, range 17-86; M:F ratio 1) (p for age groups according to treatment=0.3538). According to Sanz risk-score, 250 patients (44.4%) were low-risk (LR), 258 (45.9%) intermediate-risk (IR), and 50 (8.9%) high-risk (HR) in the ATRA-ATO cohort. The AIDA cohort included 191 LR (31.5%), 235 IR (38.8%), and 171 HR (28.3%) patients (p for risk groups according to treatment: &amp;lt; 0.001). Treatment data were not available in 8 patients (1.3%) The 10-year overall survival (OS) was 90% and 77% in ATRA-ATO vs AIDA groups, respectively (p&amp;lt;0.001, figure 1), while event-free survival (EFS) was 86% and 67%, respectively (p&amp;lt;0.001). At a median follow-up of 4.5 yrs (range 0.02 - 10.2), OS and EFS in patients treated with ATRA-ATO was similar in the three Sanz-risk classes (OS: LR: 94.6%, IR: 91%, HR: 85.6%, p=0.233, EFS: LR: 93.1%, IR: 88.7%, HR: 85.7%, p=0.319). The median follow-up of patients treated with AIDA was 6 yrs (range: 0-14.2). OS was 87.8% in LR, 83.5% in IR, and 74.8% in HR (p=0.004), while EFS was 72% in LR, 74.8% in IR, and 67.2% in HR (p=0.102). OS was significantly associated with age (&amp;lt;50 yrs: n=611, 50-69: n=516, &amp;gt;70: n=169), both overall (p&amp;lt;0.001), and within treatment groups (ATRA-ATO: p&amp;lt;0.001, AIDA: p&amp;lt;0.001). EFS also correlated with age subgroups, both overall (p&amp;lt;0.001) and according to treatment (ATRA-ATO: p&amp;lt;0.001, AIDA: p&amp;lt;0.001). No differences in OS were detected in between de-novo and secondary APL (p=0.746) both in ATRA-ATO (p=0.720) and in AIDA (p=0.766) cohorts. Patients treated outside the clinical trial context had inferior outcomes when compared to clinical trials, with a significant higher rate of early deaths (ED, 10% vs 2.8%, p&amp;lt;0.001), and inferior survival with major differences for the AIDA cohort (8-year OS: 73.6% vs 88.2%, p&amp;lt;0.001, EFS: 69.3% vs 71.7%, p=0.291), versus the ATRA-ATO cohort (8-year OS: 88% vs 93.3%, p=0.010, 8-years EFS: 80.6% vs 92.4%, p&amp;lt;0.001). The multivariate analysis for OS showed that age (50-69 vs &amp;lt;50 years, p&amp;lt;0.001, HR 4.2; &amp;gt;70 vs &amp;lt;50 years p&amp;lt;0.001, HR 8.9), Sanz-risk score (High vs Low/Intermediate p&amp;lt;0.001, HR 2), treatment type (AIDA vs ATRA-ATO p=0.001, HR 1.9) and treatment context (clinical trial vs non-clinical trial p=0.005, HR 1.7) were independent predictors of OS. The multivariate analysis for EFS showed an independent correlation with type of treatment (AIDA vs ATRA-ATO, p&amp;lt;0.001 HR 2.6), age (50-69 vs &amp;lt;50 years, p&amp;lt;0.001, HR 2.1; &amp;gt;70 vs &amp;lt;50 years p&amp;lt;0.001, HR 4.8) and Sanz-risk score (High vs Low/Intermediate p=0.005, HR 1.5), but not with treatment context. In multivariate analysis treatment type was the only predictive factor for early deaths (AIDA vs ATRA-ATO, p=0.047 HR 2.04). Summary/Conclusions: The analysis at long-term of the Harmony APL registry confirmed that patients treated with the ATRA-ATO chemo-free regimen present a significant survival advantage vs the AIDA regimen, with reduced ED rates and prolonged OS, independent of Sanz-risk score. Patients enrolled in clinical trials presented improved survival both in AIDA and in ATRA-ATO cohorts.

Risk Stratification of Patients with RUNX1-mutated Acute Myeloid Leukemia

Mutations in RUNX1 ( RUNX1mut) occur in ~15% of intensively treated AML cases. RUNX1mut have no specific hotspot and various types of alteration are observed. The European LeukemiaNet (ELN) risk stratification assigns adverse prognosis to RUNX1mut if they do not co-occur with favorable-risk genotypes. Considering the biological complexity of RUNX1 it seems implausible that all alterations have similar consequences. Using clinical and genetic variables, we developed a prognostic risk stratification model for ELN adverse-risk RUNX1mut AML patients. We combined data from five groups, totaling 609 patients with intensively treated RUNX1mut AML, to develop the model. Our training set included 448 patients treated on trials of the AML Cooperative Group (AMLCG; Herold et al, Leukemia, 2020; (n=178)), AML Study Group (Gerstung et al, NEJM, 2016; (n=116)) and Study Alliance Leukemia (n=154). Patients from the Munich Leukemia Laboratory (MLL; (n=107)) and of the Alliance group (trials NCT00048958, NCT00899223, NCT00900224; Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; (n=54)) served as independent validation cohorts. Additionally, 955 patients without RUNX1mut treated on AMLCG trials served as controls. Patients with t(15;17), prior treatment, or RUNX1mut with co-occurring favorable-risk genotypes according to ELN 2017 were excluded. Differences between RUNX1mut patients and controls were investigated using univariate logistic regression. Testing was performed using likelihood ratio tests and adjusted for study group. Univariate analyses were adjusted for multiple testing using the Benjamini-Hochberg procedure. We obtained risk prediction models using multivariate Cox regression. Missing values were imputed using the missForest approach. Model selection was performed using forward selection based on the Bayesian information criterion. Cut-offs were based on the 25 th- 50 th- and 75 th-percentile score values obtained in the training data. Performance was evaluated using Kaplan-Meier curves. For internal validation Harrell's C index was estimated using cross-study validation. For external validation, the final risk prediction models were separately applied to the external datasets. RUNX1mut were more common in older, male patients and sAML (table). White blood cells, lactate dehydrogenase and bone marrow blasts were lower in RUNX1mut patients. Mutations in several myelodysplasia-related genes were enriched in RUNX1mut patients ( ASXL1, BCOR, BCORL1, EZH2, KMT2A, PHF6, and STAG2, SF3B1, SRSF2, and U2AF1), whereas DNMT3A, NPM1 and FLT3 were more frequently altered in controls. A strong association with mutations of the splicing factor complex was identified (49% vs. 13%, p&amp;lt;0.0001). Contradicting previous reports, we found no association with IDH mutations. The risk prediction score we obtained for OS is as follows: 0.03054 x age (y) + 0.74996 x adverse MRC + 0.43779 x FLT3-ITD + 0.00317 x WBC count (10^9/L) - 0.00158 x platelet count (10^9/L) + 0.37401 x NRAS-mutation, where the obtained cut-off values are: &amp;lt;1.592 (low risk); 1.592 to 2.303 (moderate risk) &amp;gt;2.303 (high risk). Binary variables are coded as 0 or 1. Harrell's C index estimated using internal validation was 0.6. Kaplan-Meier curves estimated using the training set suggest strong differences in survival between the risk categories. Median overall survival (OS) was 2.5, 1.0 and 0.6 years for low-, intermediate-, and high-risk. External validation using the Alliance cohort shows similar results (Figure). Results obtained for the MLL cohort show smaller differences. However, we still observe clear separation of risk groups with a significant difference between low- and high-risk groups (adjusted p-value: 0.0266). Scores for relapse-free survival (RFS) as well as for OS and RFS censored for allogeneic transplant show similar results. We analyzed a large collection of intensively treated RUNX1mut AML patients and observed heterogenous outcomes that could be predicted by applying few variables (age, MRC-score, FLT3/NRAS mutation-status, and WBC/platelet count). The OS of RUNX1mut high-risk patients is discouraging, highlighting the unmet need of these patients. In addition, our work demonstrates that ELN risk groups can be further stratified and that integrated approaches using routinely available variables can further advance risk prediction.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial

Analysis of Patient-Level Data from 3 Cooperative Group Trials Confirms a Survival Advantage for NPM1m Patients Achieving MRD-Negative CR after Intensive Induction

Background:NPM1 mutations (NPM1m), predominantly tetra-nucleotide insertions in exon 12, are clonal driver events in acute myeloid leukemia (AML) and are found exclusively in leukemic cells, making them ideal for sensitive detection of measurable residual disease (MRD) using quantitative polymerase chain reaction (qPCR)- or next generation sequencing (NGS)-based methods. Over 50 peer-reviewed publications across multiple cooperative group trials have shown that NPM1m AML patients in complete remission (CR), CR with incomplete count recovery (CRi), or CR with partial hematologic recovery (CRh) have significantly better survival if they are MRD negative compared to MRD positive. Based on this body of evidence, the European LeukemiaNet recommends monitoring molecular MRD in NPM1m AML patients during treatment to help guide treatment decisions. Purpose: To provide further evidence for the value of NPM1 MRD as a surrogate endpoint for prospective, randomized trials in patients receiving novel agents in combination with intensive chemotherapy by evaluating the relationship between MRD negativity in patients with CR after 2 cycles of chemotherapy and event-free survival (EFS) and overall survival (OS) in a pooled analysis of patient-level data from 3 large cooperative group trials. MRD in all 3 studies was assessed using reverse transcriptase-mediated qPCR (RT-qPCR) of NPM1m transcripts normalized to ABL transcripts. Methods: Deidentified patient data for a total of 1,128 patients who achieved CR, CRi, or CRh, and who had MRD data after 2 cycles of chemotherapy, were provided by the UK National Cancer Research Institute AML Study Group (SG) for the AML17 (N = 539), the AMLSG for the AMLSG 09-09 (N = 497), and the Study Alliance Leukemia (SAL) for the AML2003 (N = 105) trials and standardized using Standard Data Tabulation Models. Data included demographic information, disease history, induction and consolidation treatment received, morphologic response, MRD data after 2 cycles of treatment, relapse, and survival. Cutoffs for MRD negativity were defined according to the definitions used in the individual studies (Ivey A, et al. N Engl J Med. 2016; Kapp-Schwoerer S, et al. Blood. 2020; Shayegi N, et al. Blood. 2013). In addition, sensitivity analyses were conducted using a range of cutoff values. CR was defined as <5% blasts in the bone marrow (BM) with count recovery, occurring within 42 days of the start of the last induction cycle; only these patients were included in the MRD analysis. EFS and OS were estimated using the Kaplan-Meier method and defined according to FDA criteria. Briefly, EFS was measured from day 1 of randomization to the date of treatment failure, hematologic relapse from CR or death from any cause; treatment failure was defined as not achieving CR after two cycles of chemotherapy. OS was measured from day 1 to the date of death from any cause. The absolute risk difference among MRD response status groups in EFS/OS at the 2-month, 1-year, 2-year, 3-year, and 5-year landmarks and their corresponding 95% confidence intervals (CI) were calculated using complementary log-log transformation. Hazard ratios (HR) were fitted using a Cox regression model with EFS/OS as the dependent variable and with MRD-response status and study as independent variables. Results: Among the 515 patients who achieved a CR within 42 days at the start of chemotherapy Cycle 2, MRD negativity confers a substantial survival advantage with EFS HR (95% CI) = 1.6 (1.1-2.3) when measured in BM and 1.8 (1.4-2.4) in peripheral blood (PB) using the study-defined cutoffs for positive and negative. This advantage is also observed using cutoff definitions of MRD negativity ranging from <10 to <1,000 NPM1m/104ABL transcripts. A survival advantage for OS was also observed with HR (95% CI) = 1.5 (1.0-2.4) and 1.7 (1.2-2.3) in BM and PB, respectively. Analysis of the predictive value of MRD negativity in the 613 patients who achieved CRi/CRh within 42 days of the start of Cycle 2 is underway. Conclusions: Analysis of pooled patient-level data confirms the survival advantage of achieving MRD-negative CR as previously reported in 3 independent, cooperative group trials using different induction regimens. The prognostic value of MRD negativity in NPM1m AML is consistent across a broad range of cutoff definitions in both BM and PB providing further evidence for the value of NPM1 MRD as a surrogate endpoint for clinical trials.

Development of a Standardized, DNA-Based Next Generation Sequencing Assay for Assessment of Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML) As the Primary Endpoint in the Agility Study

Background:NPM1 mutations (NPM1m) are a well-characterized biomarker for minimal residual disease (MRD) detection in acute myeloid leukemia (AML). Based on our retrospective meta-analysis across multiple trials and prior published studies, we are evaluating the utility of MRD complete response as a surrogate biomarker for clinical benefit in the AGILITY study (NCT05020665) to support a potential accelerated approval. Currently, measurement of NPM1m RNA transcripts (relative to ABL1) using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is considered the gold standard for monitoring of MRD; however, DNA-based next generation sequencing (NGS) provides several logistical and technical advantages over RT-qPCR in a global registrational trial setting. NGS allows for detection of all NPM1m variant alleles in a single assay (more closely approximating the variant allelic fraction [VAF] from leukemic cells vs NPM1m transcripts). Furthermore, longer stability of DNA during transit alleviates logistical challenges related to sample processing across different labs and transport from sites worldwide to a central testing site. Purpose: To develop a standardized and highly sensitive DNA-based NGS assay for detection of MRD in NPM1m AML patients at the end of 2 cycles of chemotherapy in the AGILITY study and to assess its performance against an established RT-qPCR method. Methods: Assay performance was assessed by serially diluting NPM1 synthetic DNA or NPM1m genomic DNA (gDNA) extracted from OCI/AML3 cells in a background of wild-type bone marrow (BM) gDNA (range: 0.008%-0.0005% VAF) using a fixed sample input of 400,000 gene copies. DNA sequencing (median read depth: 5.5×106) analysis based on the Inivata MRD platform was performed on the Illumina NextSeq 550 instrument using a proprietary bioinformatic pipeline. A set of follow-up AML samples consisting of peripheral blood (N = 31) and BM (N = 55) from patients enrolled in the UK NCRI AML Study Group AML-19 trial (ISRCTN 2014-002195-90) were tested for comparison of MRD status by NGS with an orthogonal NPM1 RT-qPCR method. This sample cohort included both negative (n = 16) and positive (n = 70) samples as defined by RT-qPCR analysis. To assess the level of agreement between both platforms, we use Pearson's correlation statistics including 95% CIs. Assay performance was evaluated by determining the area under the receiver operating characteristic curve (ROCAUC). RT-qPCR was performed as previously described (Ivey A. N Engl J Med. 2016). NGS results are expressed as percent variant allele frequency (%VAF) and RT-qPCR results as NPM1m transcript copies per 10e4ABL transcripts (normalized copy number [NCN]). Results: The NPM1m NGS assay demonstrated high sensitivity and specificity with a limit of detection with 95% confidence (LoD95) of 0.002% VAF when using serially diluted NPM1 synthetic DNA or NPM1m gDNA extracted from OCI/AML3 cells. In the AML19 set, MRD was detectable in 52/70 (74.3%) samples by both platforms. The level of MRD detected by NGS varied between 0.00025%-46% VAF (median: 0.0042%) and by RT-qPCR between 0.01-1.65x105 NCN (median: 8.03), showing a statistically significant correlation when considering all positive samples (R = 0.84, P < 9.8e-15). Despite this agreement, in 18/70 (25.7%) samples NPM1m was not detected by NGS but detected by RT-qPCR, with NCN between 0.03 and 20.5 (median: 0.37), confirming the expected higher sensitivity of RT-qPCR. Conversely, MRD was detected in 5/16 samples by NGS but not detected by RT-qPCR (VAFs were < technical LoD95 in all cases). The NGS assay could reliably detect MRD positivity in almost all samples with an NCN > 10 copies (23/24 samples, 95.8%) and there was a statistically significant correlation (R = 0.78, P < 1.4e-5). Using a cutoff of > 10 copies, ROC analysis was performed, again demonstrating good concordance (AUC: 91.9%) and identifying an optimal cutoff of 0.003% VAF (specificity = 85.5%, sensitivity = 87.5%). Conclusion: Our DNA-based NGS-MRD assay demonstrates high sensitivity and specificity with a technical LoD95 in serial dilution of 0.002% VAF. It is sufficiently robust to reliably identify MRD positive samples above an RT-qPCR threshold of 10 copies / 10e4ABL (ie, 0.01% NPM1/ABL ratio) and notably, this is tenfold below the provisional European LeukemiaNet definition for high-level MRD of > 0.1%.

Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications

AbstractWe conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Guideline for management of non-Down syndrome neonates with a myeloproliferative disease on behalf of the I-BFM AML Study Group and EWOG-MDS.

Not available.

Machine Learning of Genomic Factors in 1,961 Patients with Acute Myeloid Leukemia Identifies Patients with Very Good or Very Poor Prognosis Who Do Not Benefit from Allogeneic Hematopoietic Cell Transplant in First Remission

Genomic profiling contributes to assessment of suitability for allogeneic hematopoietic cell transplant (alloHCT) in Acute Myeloid Leukaemia (AML). The ELN 2017 AML risk classification identifies patients with favorable, intermediate and adverse risk (Döhner 2017). We have used supervised machine learning (ML) to prognostically risk stratify patients with AML and explore whether prognostic groups benefit from alloHCT in first complete remission (CR1) based on pre-treatment stratification.1961 patients were identified across the German Acute Myeloid Leukemia Study Group (AMLSG, n=1315) and National Taiwan University Hospital (NTUH, n=646) who had sufficient cytogenetic and genomic information available including the ELN 2017 cytogenetic and genomic abnormalities, spliceosome, cohesin complex and the fifteen most common genomic alterations from the Cancer Genome Atlas dataset (Ley 2013). A supervised machine learning model within R (version 4.1.0) employed a combination of random forest analysis (utilising the RandomForestSRC module version 2.11.0) and recursive partitioning (utilising the Rpart module version 4.1-15) to identify prognostic groups categorised into quintiles based upon 4-year overall survival (OS) into very poor, poor, intermediate, good and very good prognostic groups (A). Outcome according to alloHCT in CR1 was then determined by a time-dependent analysis comparing patients who in CR1 who did/or did not receive an alloHCT and were alive at 147 days (median time to transplant in the cohort). The prognostic groups were then validated against a separate AML cohort (Montreal Leucegene cohort)Patients defined by ML classification (figure 1A) to have very poor risk included patients with complex karyotype and either -7, del(7q), -17, del(17p), abn(17p) or TP53 mutations; EVI1 abnormalities (inv(3)/t(3;3)) and combined spliceosome and ASXL1 mutations. These patients had a very poor outcome irrespective of alloHCT in CR1 with a 4yr OS of 13% vs 15% (p=0.24) (alloHCT vs no-alloHCT). Patients with the combination of bi-allelic CEBPA and NRAS mutations, or the combination of NPM1, NRAS and Cohesin mutations had very good prognosis and failed to derive survival benefit from alloHCT in CR1 (4yr OS 80% vs 96% (p<0.05)) (figure 1B). Patients with either good, intermediate and poor prognosis all demonstrated improvement in OS with alloHCT in CR1 (good prognosis 90% vs 74% (p<0.05), intermediate 65% vs 50%mo (p<0.05) and poor 50% vs 31% (p<0.05)(figure 1B).ML AML classification defines two groups of patients who may not benefit from an alloHCT in CR1. Patients with very good prognosis may avoid the toxicity associated with transplantation with expectation of equivalent outcomes to those in receipt of alloHCT. Patients with very poor prognosis also fail to derive survival benefit from transplantation and represent candidates for novel post-remission strategies to improve the natural history of their disease. As this data predates the usage of FLT3 inhibitors and other novel therapies such as liposomal cytarabine/daunorubicin the impact of these therapies on patient outcome will warrant future consideration. [Display omitted] DisclosuresFleming: Amgen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Servier: Honoraria. Döhner: AstraZeneca: Honoraria; GEMoaB: Honoraria; Novartis: Honoraria, Research Funding; Helsinn: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Agios: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding. Döhner: Abbvie: Consultancy, Honoraria; Jazz Roche: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Astellas: Research Funding; Agios and Astex: Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Tien: AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Reynolds: Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company; Novartis AG: Current equity holder in publicly-traded company. Wei: Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy.

Real-World Experience of CPX-351 As First-Line Treatment in 188 Patients with Acute Myeloid Leukemia

Real-World Experience of CPX-351 As First-Line Treatment in 188 Patients with Acute Myeloid Leukemia

MIDOSTAURIN ADDED TO CYTOSINE ARABINOSIDE PLUS IDARUBICIN (“7+3”) IN NEWLY DIAGNOSED FLT3-MUTATED ACUTE MYELOID LEUKEMIA

The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia (AML) for more than four decades. Fetal liver tyrosine kinase 3 (FLT3) mutations are among the most frequently found mutations in newly diagnosed AML. According to the results of RATIFY trial, midostaurin was approved for use together with intensive chemotherapy (cytarabine plus daunorubicin). Recently, idarubicin has been more frequently favored over daunorubicin. Report the outcome of patients with AML and FLT3 mutated treated with a combination of cytosine arabinoside plus anthracycline (“7+3”regimen) and midostaurin. Herein, we retrospectively analyzed the treatment outcome of three patients with newly diagnosed AML and confirmed FLT3-ITD were eligible. The treatment consisted induction with “7+3”regimen and midostaurin (administered at a dose of 50 mg orally twice daily on days 8 through 21). All were male with age between 21 and 38 years old. A normal karyotype was found in all cases. Patients received cytarabine, idarubicin and midostaurin for induction and all experienced febrile neutropenia and two necessitated preemptive liposomal amphotericin B. One patient developed neutropenic enterocolitis. A second course of induction chemotherapy was administered to 2 patients. Relapse was observed in 1 patient (after Allo-HCT). One patient died after allo-HCT due to severe acute GVHD and one patient is alive in CR1. We showed that young patients, who had AML and a FLT3-ITD mutation, can be treated with the combination of cytarabine, idarubicin and midostaurin. The RATIFY study (Stone et al., 2017) and the German-Austrian AML Study Group (Schlenk et al., 2019) used daunorubicin 60 mg/m2 for induction, in combination with cytarabine and midostaurin. The complete remission rates in these trials were 59.8% (CR – Ratify) and 77.9% (CR+Cri - German-Austrian trial). In contrast with these two studies, idarubicin was used for induction in 53.5% of cases and was favored over daunorubicin in a more recent trial (Sierra et al. 2020). Of note, the results of FLT3 are necessary before the day 8 of induction. Hence, some patients may have already received the all three planned doses of anthracycline (idarubicin) before the information on results of FLT3 mutation. The recent approvals of new drugs for treating AML will modify the treatment algorithm and our data indicate that the use of idarubicin in combination with cytarabine and midostaurin is feasible in young patients with FLT3-mutated AML.

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Differences in Infection Prophylaxis between Pediatric AML Study Groups within the International BFM Study Group

BackgroundPediatric patients with acute myeloid leukemia (AML) are at high risk of severe infections. Prophylaxis of infections is of obvious relevance, but recommendations are often non-specific and supported by low-quality evidence. Despite appeals by experts and working groups in the field to harmonize guidelines, many divergent regimens among hospitals and study groups seem to exist. Whereas previous surveys on this matter mainly focused on hospital-based recommendations, the aim of the current study was to gain insight in all nationally available infection prophylaxis guidelines for pediatric AML patients within the international Berlin-Frankfurt-Munster (I-BFM) study group.MethodsUsing a web-based survey, we inquired the infection prophylaxis guidelines of 22 pediatric AML study groups within the I-BFM consortium. The survey included questions on the use of both pharmacological measures, i.e. antibiotics, antifungal medication, antiviral prophylaxis, granulocyte colony stimulating factor (G-CSF), and non-pharmacological measures, e.g. the use of isolation rooms, out-patient clinic visits and food or social restrictions. In order to check for discordant answers or inconsistencies, a copy of the formal study group guidelines (if available) was requested.In order to evaluate differences in daily practice among hospitals within one study group, hospital representatives (n =27) from the NOPHO-DBH AML Study Group participated in a slightly modified survey.Descriptive statistics are presented.ResultsAlmost all participating study groups prescribe Pneumocystis Jiroveci pneumonia prophylaxis with sulfonamides (n =21, 95%). About 32% of the study groups (n =7) advise gram-negative antibiotic prophylaxis, mainly with fluoroquinolones (n =6, 86%). Gram-positive prophylaxis is prescribed by 36% of the study groups (n =8), of whom 2 study groups only prescribe this in specific situations, for example after high-dose cytarabine. The majority of the study groups do not recommend the use of G-CSF (n =10, 46%) or recommend it only in specific cases of severe infections and/or prolonged neutropenia (n =7, 32%).Over 60% of the study group prescribe food and social restrictions, but the specific topics and strictness differed largely between all groups. Most frequently reported food restrictions included consumption of raw meat and raw seafood (n =16, 76%), unpasteurized milk products (n =14, 67%) and dishes with undercooked eggs (n =13, 62%). Frequently reported social restrictions included visiting indoor crowded places (n =13, 62%), using public transportation (n =12, 57%) and visiting daycare/kindergarten/pre-school (n =12, 57%). Study groups who recommend antibiotic prophylaxis were comparable stringent with regard to social or food restrictions and outpatient management.According to the hospital-based survey, sites roughly complied with the 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 differed substantially between the hospitals.ConclusionThis study gives an overview of the currently applied international recommendations on infection prophylaxis for pediatric AML patients. Despite a long history of close collaboration within the I-BFM consortium, many differences are still present between the affiliated pediatric AML study groups. Differences between study groups, as well as the discrepancies between hospital practices, are probably explained by generally formulated guidelines based on conflicting results of previous studies, and the lack of solid clinical evidence. Fortunately major efforts are now being undertaken to answer several of the remaining issues on infection prophylaxis. Furthermore, an update of the international guidelines on management of pediatric oncology patients with fever and neutropenia was recently published. The results of this survey provide an appropriate baseline measure to study the impact of these and emerging guidelines in the future. DisclosuresKaspers:Janssen-Cilag: Research Funding.

Clinical Relevance of Alternatively Spliced Isoform AML1-ETO9a in Adult Patients with t(8;21)(q22;q22.1) Acute Myeloid Leukemia (AML): A Study of the German-Austrian AML Study Group (AMLSG)

Background: AML with t(8;21)(q22;q22.1) defines a distinct disease entity within the WHO category ‘AML with recurrent genetic abnormalities’ and results in the formation of the AML1-ETO (AE) fusion transcript. Recent data showed that alternative splicing generates a truncated variant of AE, namely AML1-ETO9a (AE9a), containing an additional exon 9a. Co-expression of AE and AE9a was shown to induce a more aggressive leukemic phenotype with a rapid onset of AML in a retrovirally transduced mouse model (Yan et al., Nat Med 2006). However, the clinical relevance of the alternatively spliced AE9a isoform in adult patients (pts) with t(8;21) AML is not well determined yet.Aim: We sought to assess the incidence and prognostic significance of AE9a co-expression in the context of clinical and genetic factors in a large clinically well-annotated cohort of pts with t(8;21) AML.Methods: 129 pts were included based on the availability of a diagnostic bone marrow (BM) or peripheral blood (PB) sample; all pts were either enrolled on an AMLSG clinical trial protocol (n=93) or received standard intensive chemotherapy regimens. AE9a mRNA transcript levels (TL) were determined by quantitative reverse transcription PCR (qRT-PCR) using TaqMan technology. Co-expression of AE9a as a fraction of the full-length AE transcript was reported as AE9a / AE ratio (%). ABL gene expression was used as housekeeping control. Additional gene mutation data were available for KIT, FLT3 -ITD/TKD, NRA S, and ASXL2 .Results: The median age of the pts was 49 years (yrs; range, 18-75 yrs); the alternatively spliced isoform AE9a was identified in all pts; the AE9a / AE ratio (range 3%-77%, median 32%) did not significantly differ between BM (n=116, range 8%-77%, median 31%) and PB (n=13, range 3%-66%, median 52%). Median AE9a / AE ratio was not correlated with clinical features (sex, age, WBC, platelets, BM blasts) or gene mutations affecting KIT (p=0.10), FLT3 -ITD/TKD (p=0.77) or ASXL2 (p=1.00); pts with an additional NRAS mutation showed higher AE9a / AE ratios as compared to wild-type pts (median, 44% vs 31%) without reaching statistical significance (p=0.06). Using Cox regression analysis, AE9a / AE ratios were not associated with the clinical endpoints overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR). The same remained true when performing univariate analyses comparing AE9a / AE ratios dichotomized at the median (AE9a / AE>median vs AE9a / AE≤median): AE9a / AE had no impact on 4-yr OS (71% vs 79%; p=0.37), 4-yr EFS (59% vs 67%; p=0.83), and 4-yr CIR (32% vs 33%; p=0.35). Correlation of AE9a / AE ratios according to quartiles of distribution did also not affect OS (p=0.14), EFS (p=0.67), and CIR (p=0.70). Finally, we evaluated a possible correlation between AE9a / AE ratio and NRAS or KIT mutations which frequently co-occur in this AML subtype. In a subgroup analysis according to KIT or NRAS mutation status, no significant differences with regard to the clinical endpoints OS, EFS and CIR were found between AE9a / AE>median and AE9a / AE≤median.Conclusion: Alternative splicing of the AML1-ETO fusion transcript is a common feature in pts with t(8;21) AML. This finding is also supported by a recent collaborative transcriptome study where novel high-throughput sequencing (HTS) technologies were applied (Faber et al., Nat Genet 2016). Using different explorative approaches, AE9a has no impact on clinical outcome which precludes its potential as a novel independent prognostic marker in this AML subtype.MA was supported by the Else Kröner-Forschungskolleg. DisclosuresKindler:Novartis: Membership on an entity's Board of Directors or advisory committees. Lübbert:Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid. Fiedler:Amgen, Pfizer: Research Funding; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Patents & Royalties; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Griesshammer:Gilead: Consultancy, Honoraria, Speakers Bureau; Baxalta: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; AOP Orphan: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Greil:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis, Celgene: Research Funding; Takeda: Honoraria, Research Funding; BMS, Amgen: Honoraria. Döhner:Amgen: Honoraria; Celator: Honoraria; Pfizer: Research Funding; Seattle Genetics: Honoraria; Bristol Myers Squibb: Research Funding; Abbvie: Honoraria; Sunesis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria; Boehringer Ingelheim: Research Funding; Astex Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arog Pharmaceuticals: Honoraria, Research Funding. Döhner:Novartis: Honoraria, Research Funding.

Pharmacodynamic Monitoring of Targeted Therapy with Midostaurin By Plasma Inhibitor Activity (PIA) Analysis in FLT3 -ITD Positive AML Patients Enrolled in the AMLSG16-10 Trial: A Study of the AML Study Group (AMLSG)

Background: The multi-targeted tyrosine kinase inhibitor (TKI) Midostaurin has recently been approved by the FDA for the treatment of newly diagnosed acute myeloid leukemia (AML) with FLT3 -ITD mutation in combination with intensive standard chemotherapy (Stone et al. NEJM 2017). Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome is of major importance. The plasma inhibitor activity (PIA) assay allows to determine the level of dephosphorylation of the target under TKI therapy, which is suggested to correlate, as a marker for activity, with clinical outcome.Aim: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3 -ITD positive AML patients (pts) treated in our AMLSG16-10 trial (NCT: NCT01477606) and to correlate the results with clinical outcome.Methods: Plasma samples from 118 pts (age 18-70 years) with newly diagnosed FLT3 -ITD positive AML were obtained at defined time points during and after therapy for PIA analysis. Pts were enrolled in the ongoing AMLSG16-10 trial (NCT01477606) applying intensive therapy in combination with Midostaurin (continuous dosing except days of chemotherapy). For consolidation therapy, pts proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) as first priority; pts not eligible for alloHSCT were intended to receive 3 cycles of age-adapted high-dose cytarabine (HiDAC) with Midostaurin from day 6 onwards, followed by 12 28-day cycles of Midostaurin maintenance therapy. PIA analyses were performed at day 15 and at the end of each induction and consolidation cycle, monthly during maintenance therapy and every three months during follow-up.Results: So far, 946 plasma samples from 118 pts have been analyzed during (n=116) and after (n=136) 1st and 2nd induction cycle, during (n=104) and after (n=122) consolidation therapy as well as during maintenance therapy (n=346) and the follow-up period (n=122). The strongest reduction of FLT3 phosphorylation (p-FLT3) was observed at the end of 1st induction to 41.3% p-FLT3 (median; range, 0.3-100%). During treatment p-FLT3 levels increased again up to 80.2% (median; range, 32.6-100%), while during maintenance therapy p-FLT3 levels subsequently decreased down to 48.5% (median; range, 15.7-100%). P-FLT3 levels stratified by the median (41.3%) obtained after the 1st induction cycle were not associated with clinical or genetic features and they had no impact on response to induction therapy. So far, pts with a p-FLT3 level below that median showed an in trend better overall survival (OS) (P= .09), while there was no effect on event-free survival (EFS) and the cumulative incidence of relapse (CIR) between pts with p-FLT3 below or above the median level (P= .11 and P= .80, respectively). In addition, we also evaluated if a lower value (20%) for p-FLT3 levels allows to better discriminate pts with regard to their clinical outcome. However, there was no difference for the clinical endpoints OS, EFS and CIR between pts with target inhibition of >80% and <80% (P= .21, P= .75 and P= .58, respectively).Conclusions: In our study of FLT3 -ITD positive AML pts treated with Midostaurin in combination with intensive chemotherapy the strongest target inhibition was reached after the 1st induction cycle indicating the highest TKI activity against FLT3 at that time point. First correlations with clinical outcome suggest that p-FLT3 levels below the median after the 1st induction cycle may correlate with better overall survival. Interestingly, target-inhibition was not maintained during subsequent treatment cycles in most of the pts, while a more sufficient inhibition of p-FLT3 was again achieved during TKI maintenance therapy. It has to be determined if loss of stable target-inhibition during treatment might be triggered by the combination of the TKI and concomitant standard chemotherapy. In addition, effects of Midostaurin maintenance therapy have to be evaluated in larger patient cohorts. DisclosuresSchroeder:Celgene: Consultancy, Honoraria, Other: travel support. Salwender:Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support; Takeda: Honoraria. Fiedler:Amgen, Pfizer: Research Funding; Amgen: Patents & Royalties; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Kindler:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Novartis: Honoraria, Research Funding.

Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy

AbstractTo design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10−4) allelic ratio, DNMT3A (HR, 1.86; P < 10−4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a “go-go” tier with a 2-year OS of 66.1%, 7.6% to the “no-go” group (2-year OS 2.8%), and 3.3% of to the “slow-go” group (2-year OS of 39.1%; P < 10−5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10−5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.

Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD–mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls

Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls

Predisposition to prolonged neutropenia after chemotherapy for paediatric acute myeloid leukaemia is associated with better prognosis in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study.

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P=0·011) and low frequency of relapse (P=0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.