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1
Haddad, Monoem, Anis Chaouachi, Del Wong, Carlo Castagna, and Karim Chamari. "Heart Rate Responses and Training Load During Nonspecific and Specific Aerobic Training in Adolescent Taekwondo Athletes." Journal of Human Kinetics 29, no. 1 (September 1, 2011): 59–66. http://dx.doi.org/10.2478/v10078-011-0040-y.
Abstract:
Heart Rate Responses and Training Load During Nonspecific and Specific Aerobic Training in Adolescent Taekwondo AthletesThe efficacy of replacing generic running with Taekwondo (TKD) specific technical skills during interval training at an intensity corresponding to 90-95% of maximum heart rate (HRmax) has not yet been demonstrated. Therefore, the purpose of this study was to compare the HR responses and perceived exertion between controlled running and high-intensity TKD technical interval training in adolescent TKD athletes. Eighteen adolescent, male TKD athletes performed short-duration interval running and TKD specific technical skills (i.e. 10-20 [10-s of exercise interspersed with 20 s of passive recovery]) in a counterbalanced design. In both training methods, HR was measured and expressed as the percentage of HR reserve (%HRres). Rating of perceived exertion (RPE, Borg's category rating-10 scale), Banister's training impulse (TRIMP) and Edwards' training load (TL) were used to quantify the internal training load. Recorded cardiovascular responses expressed in %HRresin the two training methods were not significantly different (p > 0.05). Furthermore, the two training methods induced similar training loads as calculated by Banister and Edwards' methods. Perceived exertion ranged between "hard" and "very hard" during all interval training sessions. These findings showed that performing repeated TKD specific skills increased HR to the same level, and were perceived as producing the same training intensity as did short-duration interval running in adolescent TKD athletes. Therefore, using specific TKD kicking exercises in high-intensity interval training can be applied to bring more variety during training, mixing physical and technical aspects of the sport, while reaching the same intensity as interval running.
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Haddad, Monoem, Anis Chaouachi, Carlo Castagna, Del P. Wong, David G. Behm, and Karim Chamari. "The Construct Validity of Session RPE During an Intensive Camp in Young Male Taekwondo Athletes." International Journal of Sports Physiology and Performance 6, no. 2 (June 2011): 252–63. http://dx.doi.org/10.1123/ijspp.6.2.252.
Abstract:
Purpose:The session rating of perceived exertion (RPE) is a practical and non-invasive method that allows a quantification of the internal training load (TL) in individual and team sports, but no study has investigated its construct validity in martial arts. Therefore, the purpose of this study was to examine the convergent validity between the session-RPE method and two objective HR-based methods for quantifying the similar TL during a high-TL camp in young Taekwondo (TKD) athletes.Methods:Ten young TKD athletes (mean ± SD: age, 13.1 ± 2.4 y; body mass, 46.1 ± 12.7 kg; height, 1.53 ± 0.15 m; maximum heart rate (HRmax), 201.0 ± 8.2 bpm) participated in this study. During the training period, subjects performed 35 TKD training sessions, including two formal competitions during which RPE and HR were recorded and analyzed (308 individual training sessions). Correlation analysis was used to evaluate the convergent validity between session-RPE method and the two commonly used HR-based methods for assessing TL in a variety of training modes.Results:Significant relationships were found between individual session-RPE and all the HR-based TLs (r values from 0.55 to 0.90; P < .001). Significant correlations were observed in all mode of exercises practiced in TKD.Conclusions:This study shows that session-RPE can be considered as a valid method to assess TL in TKD.
3
Hegde, Pranay S., Georgia Andrew, Gege Gui, Niveditha Ravindra, Devdeep Mukherjee, Zoe Wong, Jeffery J. Auletta, et al. "Persistence of FLT3-TKD in Blood Prior to Allogeneic Transplant Is Associated with Increased Relapse and Death in Adults with AML in First Remission." Blood 142, Supplement 1 (November 28, 2023): 2941. http://dx.doi.org/10.1182/blood-2023-180121.
Abstract:
Introduction: Next-generation sequencing (NGS) represents a promising modality for measurable residual disease (MRD) testing in patients with acute myeloid leukemia (AML), but systematic efforts are required to define the appropriate targets, test characteristics, and clinical implications. We recently reported that detection of persistent NPM1 or FLT3 internal tandem duplication (ITD) mutations in adults with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death compared with those testing negative (JAMA 2023, PMID: 36881031). FLT3 tyrosine kinase domain (TKD) variants are present in 7-10% of adult patients with AML but the utility of this target for AML MRD testing in CR1 prior to alloHCT was previously unknown. Methods: Patients aged 18 or older who underwent alloHCT for AML in CR1 between 2013 and 2019 reported to have a FLT3-TKD variant at diagnosis and a pre-conditioning remission blood sample available in the CIBMTR biorepository were eligible for this study. Single-amplicon NGS (SA-NGS) library generation utilizing UMI-tagged primers targeting the D835 and I836 codons of FLT3 was performed on 400ng genomic DNA sequenced with unique dual indices, with error-corrected variant calling. Primary outcomes were overall survival (OS) and cumulative incidence of relapse (CIR). Secondary outcomes were relapse-free survival (RFS) and non-relapse mortality (NRM), with NRM being considered as a competing risk. Results: A total of351 patients met inclusion criteria for this study, and 342 (97.4%) had sufficient DNA for SA-NGS and were analyzed for clinical outcomes. Of these patients, 81 (23.7%) experienced relapse at a median of 5 months post-alloHCT. Using the current ELN-recommended variant allele fraction (VAF) threshold of 0.1% for NGS-based AML MRD, 14 patients (4.1%) tested positive. Patients with FLT3-TKD MRD VAF≥0.1% experienced higher rates of relapse (73.8% vs. 20.5%, p < 0.0001) and decreased OS (11.4% vs. 66.8%, p < 0.001) compared to VAF<0.1%. The highly sensitive SA-NGS method allowed for exploration to determine if a deeper VAF threshold of 0.01% (previously validated for NPM1 and FLT3-ITD in the Pre-MEASURE study) was prognostic for FLT3-TKD as an MRD target. This led to an additional 20 patients being reclassified as positive (n = 34 with VAF above 0.01%, =9.9%). However, there was no significant difference in CIR (33.6% vs. 19.7%, p = 0.089) or OS (65.2% vs. 66.9%, p = 0.267) between patients with 0.01%≤VAF<0.1% and VAF<0.01% ( Figure). Out of 28 SA-NGS positive calls, 6 could not be validated by orthogonal digital droplet PCR testing, and interestingly, none of those 6 patients experienced relapse. Site-reported pre-transplant remission multiparametric flow cytometry (MFC) was available for 335 patients (98%). Results of MFC were not associated with differences in CIR (HR 1.2, 95% CI 0.52 - 2.76, p = 0.67) or OS (HR 0.78, 95% CI 0.34 - 1.77, p = 0.551).In multivariable analysis, FLT3-TKD NGS-MRD VAF≥0.1% remained prognostic for CIR (HR 6.1, 95% CI 3.1 - 12.0, p < 0.001) and OS (HR 3.2, 95% CI 1.7 - 5.9, p < 0.001). Conclusions: Detectable persistence of FLT3-TKD variants in blood from AML patients in first remission prior to first alloHCT is rare, but at a VAF level of 0.1% was strongly associated with increased relapse and death after transplant compared to those testing negative. In contrast to FLT3-ITD NGS-MRD, no evidence was found to support lowering the NGS-MRD VAF threshold from 0.1% to 0.01% for FLT3-TKD. Alternative methodology may further improve NGS-MRD test performance. Site-reported MFC prior to alloHCT did not stratify for post-transplant relapse or survival. Optimal NGS-MRD testing for patients with AML will likely require a multi-target approach and testing for persistence of FLT3-TKD MRD is shown here to represent an important component of this strategy.
4
Ernould, Clément, Benoît Beausir, Jean-Jacques Fundenberger, Vincent Taupin, and Emmanuel Bouzy. "Global DIC approach guided by a cross-correlation based initial guess for HR-EBSD and on-axis HR-TKD." Acta Materialia 191 (June 2020): 131–48. http://dx.doi.org/10.1016/j.actamat.2020.03.026.
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Ernould, Clément, Benoît Beausir, Jean-Jacques Fundenberger, Vincent Taupin, and Emmanuel Bouzy. "Characterization at high spatial and angular resolutions of deformed nanostructures by on-axis HR-TKD." Scripta Materialia 185 (August 2020): 30–35. http://dx.doi.org/10.1016/j.scriptamat.2020.04.005.
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Du, Juan, Richard F. Schlenk, Andrea Corbacioglu, Marianne Habdank, Claudia Scholl, Stefan Frohling, Lars Bullinger, Arnold Ganser, Hartmut Dohner, and Konstanze Dohner. "RAS, KIT and FLT3 Gene Mutations in inv(16)/t(16;16)-Positive Acute Myeloid Leukemia (AML): Incidence and Relevance on Clinical Outcome." Blood 108, no. 11 (November 1, 2006): 2303. http://dx.doi.org/10.1182/blood.v108.11.2303.2303.
Abstract:
Abstract Inversion or translocation of chromosome 16 inv(16)/t(16;16) [hereafter abbreviated inv(16)] represent common cytogenetic abnormalities in adult acute myeloid leukemia (AML). At the molecular level inv(16) result in the generation of the CBFb-MYH11 fusion protein that is known to interfere with the heterodimeric transcription factor RUNX1/CBFb and thereby contributes to impaired differentiation of hematopoietic cells. Patients (pts.) with inv(16) are considered to have a favorable outcome, in particular when treated with cytarabine-based consolidation regimens. However, a significant proportion of these pts. relapse and survival after 5 years is about 60%. These findings together with studies from murine models suggest that additional genetic lesions are underlying the clinical heterogeneity of inv(16)-positive AML. The recently described mutations in the signaling molecules FLT3, KIT and RAS represent potential secondary genetic lesions that might contribute to leukemic transformation through constitutive activation. In this study we determined the incidence of KIT (exons 8, 10, 11, and 17), FLT3 (ITD; TKD at D835/I836,) and RAS (NRAS/KRAS exon1, exon2) mutations in 94 adult AML pts. (16 to 60 years; median age 41 years) with inv(16) and evaluated their prognostic impact on clinical outcome. KIT and RAS mutation screening was performed using a sensitive DHPLC-based assay; samples with abnormal profile were confirmed by direct sequencing. FLT3 mutations were identified as previously described. Pts. were entered on 3 AMLSG treatment trials [AML HD93, AML HD98A, AMLSG 07–04]. Postremission therapy implied cytarabine-based (HiDAC n=57) regimens as well as autologous (n=23) or allogeneic (n=13) stem cell transplantation (SCT) in first CR. Mutations were identified in 84% of inv(16) AML with highest frequencies in NRAS (47%) followed by KIT (26%) and FLT3-TKD (15%); 10/24 KIT mutations affected exon17. KRAS and FLT3-ITD mutations were detected in 10% and 3%, respectively. Complete remission (CR) rate was 90% for the whole group. In univariable analyses, FLT3-TKD mutations were associated with a significant inferior relapse-free survival (RFS) (p=0.01). For the other mutations there was no significant difference in RFS when comparing mutated and unmutated pts. Multivariable analysis adjusted for postremission therapy revealed FLT3-TKD (HR 2.39, p=0.04) and in trend KIT exon17 mutations (HR 2.8, p=0.06) as adverse prognostic factors. Therefore, an explorative subgroup analysis was performed for KIT exon17 mutations for the different postremission strategies. In pts. treated with HiDAC, KIT exon17 mutations were associated with a significant inferior RFS (p<0.0001), in contrast to pts. receiving SCT (p=0.70). For overall survival (OS) none of the tested variables were significantly associated with prognosis. KIT, FLT3, or RAS gene mutations can be detected in 84% of inv(16)-positive AML further sustaining the model of cooperating gene mutations. Although the numbers are still quite small, FLT3-TKD and KIT exon17 mutations are of prognostic relevance; the prognostic impact of KIT exon17 mutations seems to be abrogated by SCT strategies. Thus, KIT and FLT3 mutation status might reach clinical importance with regard to the availability of specific inhibitors and the type of postremission therapy.
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Paschka, Peter, Juan Du, Richard F. Schlenk, Verena I. Gaidzik, Lars Bullinger, Andrea Corbacioglu, Daniela Späth, et al. "Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG)." Blood 121, no. 1 (January 3, 2013): 170–77. http://dx.doi.org/10.1182/blood-2012-05-431486.
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Abstract In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log10(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).
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Yu, Hongbing, Junliang Liu, Phani Karamched, Angus J. Wilkinson, and Felix Hofmann. "Mapping the full lattice strain tensor of a single dislocation by high angular resolution transmission Kikuchi diffraction (HR-TKD)." Scripta Materialia 164 (April 2019): 36–41. http://dx.doi.org/10.1016/j.scriptamat.2018.12.039.
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Attar, Eyal C., Kati Maharry, Krzysztof Mrózek, Michael D. Radmacher, Susan P. Whitman, Peter Paschka, Christian Langer, et al. "Increased Expression of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 Is Associated with Inferior Outcome in Younger Patients (Pts) with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) Study." Blood 114, no. 22 (November 20, 2009): 1616. http://dx.doi.org/10.1182/blood.v114.22.1616.1616.
Abstract:
Abstract Abstract 1616 Poster Board I-642 CD74 is a type II integral membrane protein receptor that binds its ligand MIF to induce phosphorylation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) and drive cellular proliferation via nuclear factor-kappa B (NF-kB) activation. CD74 expression has been identified in human solid tumors, and its expression is associated with adverse prognosis in advanced pancreatic cancer. As CD74 is expressed and NF-kB constitutively activated in myeloblasts, we hypothesized that CD74 expression might also be associated with adverse outcome in AML. To investigate the prognostic impact of CD74 expression in the context of other predictive molecular markers in CN-AML, we assessed CD74 expression levels by Affymetrix HG-U133 Plus 2.0 microarray in 102 younger [<60 years (y)] adults with primary CN-AML, treated on the front-line CALGB 19808 trial with an induction regimen containing daunorubicin, cytarabine, etoposide and, in some cases, the inhibitor of multidrug resistance valspodar, and consolidation with autologous stem cell transplantation. Microarray data were analyzed using the Robust Multichip Average method, making use of a GeneAnnot chip definition file, which resulted in a single probe-set measurement for CD74. At diagnosis, CD74 expression, when assessed as a continuous variable, was significantly associated only with extramedullary disease involvement (P=.006) among clinical features, and with none of the molecular prognostic variables tested, including NPM1, WT1, CEBPA, FLT3 (FLT3-ITD and FLT3-TKD) mutations, MLL partial tandem duplication, or differential BAALC and ERG expression levels. Although CD74 expression levels were not associated with achievement of complete remission (CR; 83% vs 81%), higher levels of CD74 were associated with shorter disease-free survival [DFS; P=.046, hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.12-3.08] and with shorter overall survival (OS; P=.02, HR 1.32, CI 1.04-1.67). In multivariable analyses, higher CD74 expression was independently associated with shorter DFS (P=.045, HR 1.98, CI 1.16-3.40), after adjusting for WT1 mutations (P<.001) and FLT3-TKD (P=.04), and shorter OS (P=.01, HR 1.58, CI 1.11-2.25) after adjusting for FLT3-TKD (P=.02), WT1 mutations (P=.007), BAALC expression levels (P=.02), white blood counts (P=.007), and extramedullary involvement (P=.04). As quartiles 2-4 had similar expression levels distinct from the lowest quartile, to display the impact of CD74 expression levels on clinical outcome only, pts were dichotomized into low (the lowest quartile) and high (the top three quartiles) CD74 expressers. The Kaplan-Meier curves for DFS and OS (Figures 1 and 2) are shown below. In conclusion, our study identifies elevated CD74 expression as associated with adverse prognosis in younger CN-AML pts. Since we previously reported that higher CD74 expression was favorably associated with achievement of CR in AML patients receiving chemotherapy plus bortezomib, an inhibitor of the proteasome and NF-kB (Attar et al., Clin Cancer Res, 2008;14:1446-54), it is possible that in future studies elevated CD74 levels can be used not only for prognostication, but also to stratify CN-AML pts to study of bortezomib-containing chemotherapy regimens. Figure 1 Disease free survival Figure 1. Disease free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures No relevant conflicts of interest to declare.
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Mohamedali, Azim M., Robert K. Hills, Erick E. Nasser, Atiyeh Abdallah, Sneha Shinde, Austin G. Kulasekararaj, Amanda Gilkes, Nicholas Lea, Alan K. Burnett, and Ghulam J. Mufti. "Single Nucleotide Polymorphism Array (SNP-A) Karyotype Is the Best Predictor of Prognosis In Normal Cytogenetics Acute Myeloid Leukaemia (AML)." Blood 118, no. 21 (November 18, 2011): 411. http://dx.doi.org/10.1182/blood.v118.21.411.411.
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Abstract Abstract 411 The herald of next generation sequencing has ushered an era for the discovery of frequent novel mutations such as DNMT3a, IDH1/2 and ASXL1 in acute myeloid leukaemia with a normal karyotype (AML-NK). The frequency of these mutations has been extensively documented; however, there is inconclusive evidence for their prognostic significance. Furthermore, whilst having a ‘normal' cytogenetic karyotype, AML-NK has been characterized by SNP-A karyotyping revealing multiple cryptic genomic aberrations. To predict prognosis, mutations of FLT3, NPM1 and CEBPA as well as gene expression profiles have been used as biomarkers. Using 454 next generation sequencing (NGS), we sought to determine the prognostic significance of mutations in ASXL1, DNMT3a, FLT3, IDH1/2, NPM1 and TP53 as well as detect cryptic genomic aberrations using 250K SNP microarrays in 92 AML-NK patients (pts) uniformly treated from the UK MRC/NCRI AML clinical trials, excluding pts with induction deaths. We demonstrate the presence of 54 cryptic genomic aberrations in 37 pts consisting of 11 deletions (del) (8 pts), 10 gains (10 pts) and 33 regions of UPD (29 pts). Aberrations were excluded as CNV's if there was >50% overlap with variants from the DGV and an internal cohort of 91 healthy subjects. The median size of del was 1.6Mb(0.18Mb-3.4Mb) with chromosome (chr) 4(q24) and 17(q11.2 and q22.1) deleted in two pts. One pt had micro del on chr12p13.2-p12.3 and 21q22.11-q22.12 affecting the ETV6 and AML1 genes, respectively, that was confirmed by FISH. Gains (median 0.37Mb(0.26–0.71Mb)) were identified on chr8 (4 pts). The median size of UPD's was 83.3Mb(20.5Mb-158Mb) with interstitial UPD <20Mb excluded from the analysis. Chromosome 13 (q12.11-q34) and 6(p25.3-p22.1) were the most frequently affected with UPD observed in 15 and 5 pts, respectively. Of the 15 pts with UPD of chr13, 11 pts had this occurrence in small clones. Additional regions affected by UPD included chromosomes 1, 2, 4, 5, 7 and 11. NPM1, DNMT3a, FLT3-ITD, IDH2, FLT3-TKD, IDH1, TP53 and ASXL1 mutations occurred in 64%, 49%, 22%, 5%, 3%, 2% and 1% of patients, respectively with 13 cases having no detectable mutations. The R882 mutation hotspot of DNMT3a occurred in 33/45 cases with clone size ranging from 34–65% and occurred concurrently with mutations in NPM1 (31 pts), FLT3-ITD/TKD (30 pts) and IDH2 (9 pts). IDH1 (R130H) and IDH2 (R140Q and R172K) mutations were mutually exclusive and occurred in 23 pts, with 4 pts having concurrent FLT3, NPM1 and DNMT3a mutations. Only 1 patient had an ASXL1 mutation with a concurrent IDH2 mutation and 2 cases had mutation of TP53. FLT3-TKD/ITD mutations were exclusive of each other. Not all pts with FLT3-ITD mutation had UPD of chromosome 13. There was no correlation between genomic aberrations and mutations of any other assayed genes. The median duration of follow-up from time of diagnosis of the study group was 44 months (range 2–160). There were no significant correlations between the presence of genomic aberrations and age, sex, WBC, secondary disease or mutations in IDH1/2, FLT3-ITD or DNMT3a. Patients with FLT3-TKD were likely to have gains (2/5) compared to those with wild type (8/85, p=0.04). Patients with genomic aberrations had worse overall survival (OS) compared to pts without aberrations, (5 year OS 12% vs 40%, hazard ratio (HR) adjusted for other prognostic variables 2.56 (1.43–4.60), p=0.001); this was also seen when considering UPD on OS ((8% for those with UPD compared to 37% for those without UPD (adjusted HR 2.52(1.40–4.54) p=0.002) and cumulative incidence of relapse (CIR) (78% in pts with UPD compared to 54% for those without UPD (adjusted HR 4.04(1.84–8.90) p=0.0003). Adjusted analysis showed a dose effect for the number of UPD's on OS (p=0.007) and relapse (p=0.001). In a model building analysis, adjusted for age, WBC, sex, secondary disease, performance status and mutations of IDH1, IDH2, FLT3-ITD/TKD, DNMT3a and NPM1, only UPD proved independently prognostic for relapse and survival. We conclude that cryptic genomic aberrations in uniformly treated AML-NK pts provide better prognostic value and outcome prediction than metaphase cytogenetics and mutation detection, thereby, helping to identify patient groups with poor prognosis and requiring specific therapeutic strategies. Disclosures: No relevant conflicts of interest to declare.
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Heinicke, Thomas, Myriam Labopin, Didier Blaise, Jaime Sanz, Ibrahim Yakoub-Agha, Thomas Cluzeau, Marco Ladetto, et al. "Outcome of Allogeneic Stem Cell Transplantation in FLT3-TKD-Mutated AML - a Study on Behalf of the Acute Leukemia Working Party of the EBMT." Blood 142, Supplement 1 (November 28, 2023): 4976. http://dx.doi.org/10.1182/blood-2023-174233.
Abstract:
Introduction The overall prognostic impact of point mutations in the tyrosine-kinase domain 1 of FLT3 (FLT3-TKD mut) in patients (pts) with acute myelogenous leukemia (AML) remains controversial. Furthermore, co-occurrence of FLT3-TKD mut and mutated nucleophosmin-1 (NPM1 mut) was shown to have a favorable prognostic impact on AML pts receiving conventional chemotherapy. However, little is known about the outcome of AML pts with FLT3-TKD mut with or without co-occurring NPM1 mut treated with allogeneic stem cell transplantation (alloSCT). Patients and Methods This is a retrospective study of the acute leukemia working party (ALWP) of the European Society for Blood and Marrow transplantation (EBMT) investigating the outcome of adult AML pts with FLT3-TKD mut with or without NPM1 mut after first alloSCT using matched sibling (MSD), unrelated (UD) or haploidentical (haplo) donors between 2005 and 2022. All patients were in first or second complete remission (CR1 of CR2). Information on cytogenetic risk was necessary for inclusion. No ex-vivo T-cell depletion (TCD) was allowed. The primary endpoint was leukemia-free survival (LFS) at two years after alloSCT. Secondary endpoints were overall survival (OS), cumulative incidence of relapse (RI), non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) and GVHD-free, relapse free survival (GRFS). One hundred and eighty-two adult AML pts with FLT3-TKD mut were identified, of which 74 (40.7%) had a co-occurring mutation in NPM1. Median age was 55.1 years (range 18.6-79.1) and 46.7% were male. Median follow-up was 21.4 months [IQR 13.6-28.1]. 78% of the pts were in CR1. Cytogentic risk was favorable, intermediate and adverse in 12.6%, 75.3% and 12.1% of pts, respectively. Additional FLT3 internal tandem duplication (FLT3-ITD) was present in 25.8% of pts. Information on measurable residual disease (MRD) was available for 68.7% of pts, being positive in 48% of these. Karnofsky performance score was < 90% in 21.1%, and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was >=3 in 28.1% of pts. 69.6% of pts were cytomegalovirus (CMV) positive. Conditioning was myeloablative in 52.8% and reduced intensity in 47.2% of pts. Stem cell donors were MSD, UD and haplo in 25.8%, 55.5% and 18.7% of cases. Stem cell source was bone marrow in 10.4%, peripheral blood in 87.4% and both in 2.2%. In-vivo TCD was performed in 59.2% of pts. GVHD prophylaxis was calcineurin inhibitor-based in 92.2% of pts. Results Engraftment was achieved in 99.4% of pts with a day-60 absolute neutrophil count (ANC) >0.5 x 10 9/L of 97.7% [95% CI: 93.7-99.2]. Day-180 rates of acute GVHD (aGVHD) grade II-IV and grade III-IV were 26.2% (95% CI:19.9-32.9) and 8.1% (95% CI:4.6-12.8), respectively. At two years, rates of total chronic GVHD (cGVHD) and extensive cGVHD were 30% (95% CI: 22.5-38) and 16.6% (95% CI:10.6-23.7), respectively. Two-year LFS and OS were 66.1% (95% CI: 57.6-73.2) and 74% (95% CI: 65.4-80.8), respectively. Two-year RI, NRM and GRFS were 22.5% (95% CI:16-29.8), 11.4% (95% CI: 7-17), and 51.1% (95% CI: 42.4-59.1), respectively. Cause of death was original disease in 47.5%, infection in 27.5%, GVHD in 22.5% and non-SCT related in 2.5% of cases. In univariate analysis the only factor with significant impact on LFS was donor type (haplo [n=34] vs. others, p=0.006). For GRFS, patient CMV negativity (p=0.014) and in-vivo TCD (p=0.01) were significant. Interestingly, co-occurring mutations in FLT3 (FLT3-ITD) or NPM1 were not identified as having a significant impact on LFS or GRFS. Moreover, MRD status before alloSCT was also not shown to have a significant impact on these outcomes. In multivariate analysis of LFS and GRFS, only donor type (haplo [n=34] vs. others) was shown to be significant for both endpoints, hazard ratio (HR) 2.54; 95% CI: 1.4-4.6; p=0.002, and HR 2.01; 95% CI: 1.18-3.41; p=0.01, respectively. Conclusion Acknowledging the limitations of our retrospective study in this rare entity results are encouraging given the high-risk population (median age 55.1 years, CR2 in 22%, co-occurring FLT3-ITD in 25.8%, positive MRD in 48%, HCT CI >=3 in 28.1%). LFS, OS and GRFS rates were 66.1%, 74% and 51.1%, respectively, and both RI and NRM were comparably low with rates of 22.5% and 11.4%, respectively. No positive prognostic impact of co-occurring mutations in FLT3-TKD and NPM1 was detected, unlike what was found for conventional chemotherapy.
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Santos, F. P., W. Qiao, J. E. Cortes, D. Jones, F. Ravandi, D. Verma, H. Kantarjian, and G. Borthakur. "Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia (AML)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 7015. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7015.
Abstract:
7015 Background: Mutations of the FLT3 gene (in special internal tandem duplication -ITD) are common in normal karyotype AML (NK-AML) and are associated with shorter relapse free and overall survival (OS). The frequency of FLT3 mutations is lower in other cytogenetic subgroups and the impact on outcome is unclear. Methods: The records of patients (pts) with newly diagnosed AML (from 2003 to 2007) were reviewed. Pts were divided among three cytogenetic subgroups: Good-risk (t(8;21), Inv(16)/t(16;16)) Intermediate-Risk (Diploid,-Y) and Poor Risk (-5,-7, 11q abnormalities). FLT3 ITD and tyrosine kinase domain (TKD) mutations were determined on baseline DNA samples by a PCR based method with 1% sensitivity. Since the frequencies of FLT3 mutations were lower in good- and poor-risk subgroups, ITD/TKD mutations were considered together in the analysis, while in the intermediate risk group they were analyzed separately. Survival curves stratified by FLT3 mutation were estimated by Kaplan Meier plots and compared by logrank test. A Cox model was fit for OS, and non-significant variables were eliminated in a step-down fashion with a p- value cut-off of p = .10. Results: A total of 481 pts were included (65 pts=good risk, 272 pts=intermediate risk and 144 pts= poor risk). Prevalence of FLT3 mutations is shown in the Table. No difference was found in median OS between FLT3-mutated and FLT3- wild type pts in the good risk group (not reached (NR) vs NR, P = 0.57) nor in the poor risk group (55 vs 24 weeks, P = 0.44). In intermediate risk, OS was worse in FLT3-ITD positive pts (33 vs 89 weeks, P < 0.0001) but not in FLT3-TKD positive pts (77 vs 70 weeks, P = 0.89). In the Cox model, FLT3 mutations were prognostic for OS only in intermediate risk pts with FLT3-ITD (HR 2.63, P < 0.0001). Conclusions: In our cohort of pts, FLT3 mutations did not have a prognostic impact in AML with good and poor risk karyotype. [Table: see text] No significant financial relationships to disclose.
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Schlenk, Richard F., Andrea Corbacioglu, Jürgen Krauter, Lars Bullinger, Michael Morgan, Daniela Späth, Irina Schäfer, et al. "Gene Mutations as Predicitive Markers for Postremission Therapy in Younger Adults with Normal Karyotype AML." Blood 108, no. 11 (November 16, 2006): 4. http://dx.doi.org/10.1182/blood.v108.11.4.4.
Abstract:
Abstract Background: Mutations in the genes encoding NPM1, FLT3 (FLT3 ITD, FLT3 TKD), CEBPA, MLL (PTD) and NRAS have been identified as molecular markers in acute myeloid leukemia (AML) exhibiting a normal karyotype. Most recent studies focused on the prognostic value of single markers not taking into account their potential interactions. In addition, little is known about the predictive value of these markers on postremission therapy. Aims: To evaluate the prognostic impact of NPM1, FLT3, CEBPA, MLL and NRAS gene mutations on response to induction therapy, relapse-free (RFS) and overall survival (OS) as well as the predictive impact of these mutations on RFS and OS following different postremission therapies. Methods: Patients [16 to 60 years of age] were entered on four AMLSG treatment trials [AML-2/95, AML-1/99, AML HD93, AML HD98A]. As a consistent feature, in all four trials a genetic randomization was performed assigning all patients with an HLA-matched family donor (MRD) to allogeneic stem cell transplantation (SCT) in first complete remission (CR). Leukemia cells were analyzed for mutations in the above genes as previously described. Results: Between 1993 and 2004, 872 patients exhibiting a normal karyotype were registered. Median age was 48 years; median follow-up time was 49 months. Mutations were identified as follows (total number of samples analyzed; incidence of mutations): NPM1 (n=526; 53%), FLT3-ITD (n=531; 31%), FLT3-TKD (n=617; 11%), CEBPA (n=509; 14%), MLL-PTD (640; 8%), and NRAS (641; 13%). CR rate was 76%. In a logistic regression model, the NPM1+/FLT3-ITD- (p<.0001) and the CEBPA+ genotypes (p=0.05) were associated with induction success. Of 666 patients achieving a CR after induction therapy, 171 had a MRD and 143 (84%) of these received an allogeneic SCT in first CR. In survival analyses, the variable “availability of a MRD” was included on a strict intent-to-treat basis. Cox proportional hazard models for RFS and OS revealed age <48 years (hazard ratio (HR) 0.72 and 0.62, respectively), availability of a MRD (HR 0.62 and 0.75), the CEBPA+ (HR 0.42 and 0.36) and the NPM1+/FLT3-ITD- (HR 0.34 and 0.43) genotype as prognostic factors. To better define the role of allogeneic SCT in first CR, subgroup analyses were performed according to the combined FLT3-ITD and NPM1 mutation status (NPM1+/FLT3-ITD- versus all other combinations). These analyses revealed a marked difference in HR estimation for the variable “availability of a MRD”. In the NPM1+/FLT3-ITD- subgroup, HR for RFS and OS were 0.89 (95%-CI 0.49–1.64) and 0.93 (95%-CI 0.51–1.67) translating into a nearly equivalent RFS after 4 years of 61% (MRD) and 57% (no MRD). In contrast, in the subgroup defined by all other combinations of FLT3-ITD and NPM1 mutations, HR for RFS and OS were 0.56 (95%-CI 0.39–0.81) and 0.69 (95%-CI 0.48–0.98) translating into a marked difference in 4 years RFS of 47% (MRD) and 23% (no MRD). Conclusions: Specific genotypes emerge as highly significant prognostic factors for response to induction therapy and for survival in AML patients exhibiting a normal karyotype. The genotypic marker constellation NPM1+/FLT3-ITD- also fulfils the criteria of a predictive marker indicating a strong beneficial effect of allogeneic SCT in first CR only in the subgroup of patients without the NPM1+/FLT3-ITD- marker constellation.
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Du, Juan, Richard F. Schlenk, Andrea Corbacioglu, Marianne Habdank, Claudia Scholl, Stefan Frohling, Lars Bullinger, Arnold Ganser, Hartmut Dohner, and Konstanze Dohner. "Detection of RAS, KIT and FLT3 Gene Mutations in t(8;21)-Positive Acute Myeloid Leukemia (AML): Evaluation of the Clinical Relevance." Blood 108, no. 11 (November 1, 2006): 2301. http://dx.doi.org/10.1182/blood.v108.11.2301.2301.
Abstract:
Abstract Acute myeloid leukemia (AML) with translocation t(8;21)(q22;q22) creating the AML1-ETO fusion gene is a distinct type of AML generally associated with a favorable prognosis. However, a significant proportion of these patients (pts.) relapse and survival after 5 years is approximately 50%. These findings together with studies from murine models suggest that additional genetic lesions are underlying the clinical heterogeneity of t(8;21)-positive AML. The recently described mutations in the signaling molecules FLT3, KIT and RAS represent potential secondary genetic lesions that might contribute to leukemic transformation through their constitutive activation. In this study we determined the incidence of KIT (exons 8, 10, 11, and 17), FLT3 (internal tandem duplications, ITD; tyrosine kinase mutations at D835/I836, TKD) and RAS (NRAS and KRAS exon1 and exon2) mutations in 65 adult pts. (median age 49 years) with t(8;21)-positive AML and evaluated their prognostic impact on clinical outcome. KIT and RAS mutation screening was performed using a sensitive DHPLC-based assay; samples with abnormal profile were confirmed by direct sequencing. FLT3 mutations were identified as previously described (Fröhling et al., Blood 2002). Pts. were entered on 3 AMLSG treatment trials [AML HD93, AML HD98A, AMLSG 07–04]. Postremission therapy was high-dose cytarabine-based (Ara-C) in all trials. Mutations were identified in 51% of the t(8;21)-positive AML, with highest frequencies in NRAS (18%) followed by KIT (17%) and FLT3 (ITD; 9%;); 10/11 KIT mutations affected exon17. FLT3-TKD and KRAS mutations were detected in 3% and 1.5%, respectively. Complete remission (CR) rate was 88% for the entire group. In univariable analyses, KIT exon 17 mutated pts. had a significantly inferior event-free (EFS) (p=0.04), overall (OS) (p=0.05), but not relapse-free survival (RFS) (p=0.43). In addition, the presence of FLT3-ITD mutations was in trend associated with a shorter EFS (p=0.09) and OS (p=0.07), and significantly with a shorter RFS (p=0.04). For the other mutations there was no significant or in trend difference in EFS, OS and RFS when comparing mutated and unmutated pts. Multivariable analysis for OS and RFS revealed FLT3-ITD (HR 3.16, p=0.04) and KIT exon17 mutations (HR 2.89, p=0.03) as adverse prognostic factors for OS, whereas only FLT3-ITD showed a significant prognostic impact on RFS (HR 3.32, p=0.04). Since FLT3-ITD and KIT exon 17 mutations both represent potential targets for tyrosine kinase inhibitors, an explorative analysis combining both gene mutations versus unmutated patients was performed revealing a significant inferior RFS (p=0.04) and OS (p=0.006). Mutations in the genes KIT, FLT3 or RAS were detected in 51% of t(8;21)-positive AML. Univariable and multivariable analyses showed a significant or in trend negative prognostic impact for FLT3 and KIT mutations on clinical outcome. Thus, information on the mutation status might reach clinical importance for identifying pts. who are eligible for molecular targeted therapies.
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Xu, Yang, Zhen Yang, Hong Tian, Huiying Qiu, Aining Sun, Suning Chen, and Wu Depei. "Hematopoietic Stem Cell Transplantation (HSCT) Benefits the Survival of Acute Myeloid Leukemia (AML) Patients with IDH1, NRAS and DNMT3A Mutations." Blood 120, no. 21 (November 16, 2012): 1981. http://dx.doi.org/10.1182/blood.v120.21.1981.1981.
Abstract:
Abstract Abstract 1981 Background: Gene mutations may serve as potential markers to extend the prognostic parameters in acute myeloid leukemia (AML) patients. In this study, we detected distribution of mutations in the nucleophosmin gene (NPM1), C-KIT, the fms-related tyrosine kinase 3 gene (FLT3), Isocitrate dehydrogenase gene 1 and 2 (IDH1, IDH2), the neuroblastoma RAS viral oncogene homolog (NRAS) and DNA methyltransferase 3A gene (DNMT3A) in 442 newly diagnosed AML patients (none-APL). Associations of gene mutations with clinical outcomes in these patients followed HSCT treatment or chemotherapy were further evaluated. Methods: Between February 2005 and December 2011, 442 newly diagnosed AML (none-APL) patients in our centre were retrospectively analyzed. There are 248 males and 194 females, and the median ages were 40 (16–60) years. 393 patients (88.9%) of patients were with single or normal karyotype and 49 patients (11.1%) were with complex abnormal karyotype. In addition to MICM examination, direct sequencing was employed to access the distribution of mutations in of FLT3-ITD (exon14), FLT3-TKD (exon 20), NPM1 (exon12), C-KIT (exon8, 17), IDH2 (exon 4), NRAS (exon1, 2), DNMT3A (exon23) of 445 AML patients. Complete remission (CR) was achieved in 258 patients (58.4%) followed the standard induction therapy, 128 patients received HSCT (Allo-HSCT: 121 vs. Auto-HSCT: 7) therapy after first remission or second remission while 258 patients received consolidation chemotherapy contained 4–6 cycles high dose Ara-C (HD-Ara-C). Overall survival (OS) and Event-free survival (EFS) were measured at last follow-up (censored), and Kaplan-Meier analysis was used to calculate the distribution of OS and EFS. Results: In 442 AML (None-APL) patients, 44 patients (9.7%) had C-KIT mutations, 97 patients (21.9%) had NPM1 mutations, 95 patients (21.5%) had FLT3-ITD mutations, 26 patients (5.9%) had FLT3-TKD mutations, 23 patients (5.2%) had IDH1 mutations, 48 patients (10.9%) had IDH2 mutations, 31 patients (7.0%) had DNMT3A mutations, and 40 patients (9.0%) had NRAS mutations. Using COX regression, we found that mutations in FLT3-ITD (HR:2.113; 95%CI: 1.1420 to 3.144),IDH1 (HR:3.023; 95%CI: 1.055 to 3.879), NRAS (HR:1.881; 95%CI: 1.021 to 2.945), and DNMT3A (HR: 2.394; 95%CI: 1.328 to 4.315) were independent unfavorable prognostic indicators of overall survival of AML patients. We further compared the outcomes of AML patients with such gene mutations followed different therapy (HSCT vs. HD Ara-C), and results shown that patients with mutations in IDH1, NRAS and DNMT3A received HSCT therapy had better survival. The median OS and EFS of patients with FLT3-ITD, IDH1, NRAS and DNMT3A in the two groups (HSCT vs. HD Ara-C) were as follows: IDH1 (OS: 35 months vs. 11 months, p=0.016; EFS: 34 months vs. 8 months, p=0.012), NRAS (OS: 27months vs. 8 months, p=0.008; EFS: 23 months vs. 4 months, p=0.049), DNMT3A (OS: 66 months vs. 19 months, p=0.008; EFS: 54 months vs. 13 months, p=0.002). Conclusions: Taken together, our data proved that mutant FLT3-ITD, IDH1, NRAS, and DNMT3A might serve as poor prognostic markers and hematopoietic stem cell transplantation as first-line treatment could favor the outcome of AML patients carrying IDH1, NRAS, and DNMT3A mutations. Disclosures: No relevant conflicts of interest to declare.
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Takahashi, Koichi, Elias J. Jabbour, Xuemei Wang, Hady Ghanem, Naveen Pemmaraju, Farhad Ravandi, Jorge E. Cortes, et al. "Very High Rate of Leukemic Transformation and Poor Survival in Patients with Lower Risk Myelodysplastic Syndrome (MDS) Who Dynamically Acquire FLT3 Molecular Alteration (FLT3m): Study of 290 MDS Patients with Sequential Mutation Analysis." Blood 120, no. 21 (November 16, 2012): 3802. http://dx.doi.org/10.1182/blood.v120.21.3802.3802.
Abstract:
Abstract Abstract 3802 Background and Aims: Molecular alterations of FLT3, in particular internal tandem duplication (ITD) in the juxtamembrane domain or point mutation in the tyrosine kinase domain (TKD), are found in approximately 30% of acute myeloid leukemia (AML). In contrast, FLT3 molecular alteration (FLT3m) is not commonly detected in MDS patients with reported incidence of 0.6–6%. Limited data is available for its prognostic significance in MDS, especially when it is dynamically acquired during the follow up. The aims of this study were to evaluate: 1) the incidence of dynamic acquisition of FLT3m in lower risk MDS patients; 2) the association between FLT3m acquisition and other molecular/cytogenetic aberrations and 3) the prognostic impact of dynamic FLT3m acquisition on AML transformation and survival. Methods: We analyzed 290 patients with low and intermediate-1 (Int-1) risk MDS by IPSS (lower risk MDS), who were tested for FLT3m by semi-quantitative DNA-based PCR capillary electrophoresis assay on at least two occasions (at time of diagnosis and at least once thereafter) between 1/2000 and 1/2010. Result: Median age of the analyzed cohort was 64 years (range, 23–91), and 62% were female. Seventy five (26%) patients were IPSS low risk and 215 (74%) were int-1 risk. RAEB was the most frequent WHO diagnosis (N = 107, 37%), followed by RCMD (N = 78, 27%) and RA (N = 74, 26%). Sixty three percent (N = 183) of the patients had diploid cytogenetics at diagnosis. FLT3m was detected in total of 15 (5%) patients, of which 4 (1%, ITD = 3 and TKD = 1) were detected at initial diagnosis and 11 (4%, ITD = 9 and TKD = 2) were acquired during the follow up. Median time to FLT3m acquisition was 10 months (range, 1–53). Positive statistical association was observed between acquisition of FLT3m and NPM1 mutation (P = 0.004), while negative association was observed against RAS mutation (P = 0.013). Statistical association was not observed between FLT3m acquisition and other covariates that include: age, WHO classification, initial bone marrow blast, cytogenetics, cytogenetic evolution, and molecular mutations other than NPM1 and RAS. Eight (73%) patients with FLT3m acquisition had diploid cytogenetics at diagnosis while 3 had abnormal karyotype at the beginning: inv(3)(q21q26.2), del(11)(q13q23) and dup(2)(p15p23), respectively. Of those 8 patients whose initial cytogenetics were diploid, 4 acquired cytogenetic evolution (of which 3 acquired trisomy 8) concomitantly with FLT3m acquisition. Other 2 patients acquired NPM1 mutation and another patient acquired NRAS mutation in addition to FLT3m. There was only 1 patient whom we could not identify any other genetic alterations accompanied by FLT3m acquisition. After median follow-up duration of 31 months (range, 2–147), 75 [26%] patients transformed to AML in the entire cohort. Median transformation free survival (TFS) and OS of the entire cohort were 34 months (range; 1–147) and 36 months (range; 2–147), respectively. Strikingly, all 11 patients who acquired FLT3m experienced AML transformation (100%), with a median time to transformation of 11 months (range; 4–53). Acquisition of FLT3m was detected prior to transformation in 3 patients and at the time of transformation in 7 patients. One patient acquired FLT3m after the transformation. Log-rank test showed that median TFS and OS were both significantly shorter in the FLT3m acquired group than in the non-acquired group (Figure: TFS = 11 vs. 35 months; OS = 13 vs. 38 months, both P < 0.001). By fitting FLT3m acquisition and cytogenetic evolution as time-dependent covariates, Cox proportional hazard regression showed that age > 60 years (vs. ≤ 60, HR = 1.5, P = 0.008), having cytogenetic evolution (vs. no, HR = 5.3, P < 0.001), and FLT3m acquisition (vs. no, HR = 3.4, P < 0.001) independently predicted worse TFS. Conclusion: Approximately 4% of patients with lower risk MDS acquired FLT3 molecular alteration during their follow-up, and acquisition of such alteration was strongly associated with AML transformation (100%), with significant impact on TFS. Additionally, in 88% of the patients who acquired FLT3m and transformed to AML, other molecular and cytogenetic aberrations were accompanied, that may account for the classical “2-hit” model of AML transformation. This result supports the importance of monitoring for FLT3 mutation in lower risk MDS patients upon or even before disease progression, especially in the new era of FLT3 inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Paschka, Peter, Juan Du, Richard F. Schlenk, Verena I. Gaidzik, Lars Bullinger, Andrea Corbacioglu, Manuela Zucknick, et al. "Type and Number of Secondary Molecular Lesions Improve Outcome Prediction in Acute Myeloid Leukemia (AML) with inv(16) or t(16;16): A Study of the German-Austrian AML Study Group (AMLSG)." Blood 114, no. 22 (November 20, 2009): 824. http://dx.doi.org/10.1182/blood.v114.22.824.824.
Abstract:
Abstract Abstract 824 Background: Although acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) [hereafter referred to as inv(16)] is considered as a favorable AML subset, 30-40% of the patients (pts) are not cured by the current treatment strategies. Various genetic markers have been assessed to identify pts who are at high risk to fail therapy. However, the results among the different studies were not fully consistent. Methods: We studied diagnostic bone marrow and/or blood specimens from 179 adult AML pts with inv(16) for secondary chromosome abnormalities and gene mutations in FLT3 [internal tandem duplications (ITD) and tyrosine kinase domain mutations (TKD)], KIT, JAK2 (V617F) and in N-and K-RAS. All pts were treated on one of 7 prospective protocols of the German-Austrian AML Study Group (AMLSG) including anthracycline- and cytarabine-based induction therapy, and consolidation therapy incorporating higher doses of cytarabine in various settings, but also autologous and allogeneic stem cell transplantation. Multivariable analyses were performed to assess the prognostic value of gene mutations on relapse-free (RFS) and overall survival (OS) and were stratified for treatment protocols. Results: At least one gene mutation was found in 84% of the pts with 21% of the pts having multiple mutations. Pts with gene mutations ≥2 showed no significant differences in WBC, incidence of trisomy 22 and age. Mutations were most frequent in RAS (53%), followed by mutations in KIT (37%) and FLT3 (17%) [FLT3-TKD (15%) and FLT3-ITD (4%)] genes. No mutations were detected in JAK2. Concurrent mutations of KIT and RAS in the same leukemia sample were less likely to occur (P=0.003) than expected based on their frequencies as single markers; no other significant interactions between the gene mutations were observed. Median age of the cohort was 41 years (yrs; range, 18-74 yrs), and median white blood count (WBC) was 38.3 × 109/l (range, 1.1 to 294.9 × 109/l). Median follow-up for survival according to Korn was 4.9 yrs [95%-confidence interval (CI), 4.3-6.0 yrs]. While one multivariable model was constructed using the mutations in KIT, FLT3 and RAS as covariates (model I), the other included the number of mutated genes (≥2 vs <2; model II) as single variable. Additional covariates included in the multivariable models were age, log10(WBC) and presence of trisomy 22. Model I revealed mutated KIT [Hazard ratio (HR), 1.85, P=0.04] and mutated FLT3 (HR, 2.03, P=0.04) as adverse factors for RFS, and mutated FLT3 (HR, 2.39, P=0.03) and older age (HR for 10 yrs change, 1.62, P=0.003) as significant factors for shorter OS. Model II revealed number of mutated genes ≥2 (HR, 2.38, P=0.004) and higher WBC (HR for change of one unit on log10 scale, 1.94, P=0.03) as adverse factors, and trisomy 22 (HR, 0.46, P=0.05) as favorable factor for RFS. In addition, number of mutated genes ≥2 (HR, 1.99, P=0.04) and older age (HR for 10 yrs change, 1.57, P=0.004) predicted for a shorter OS. Additional univariable analyses also revealed that pts with KIT mutations had a worse RFS compared with KIT wild-type (P=0.03; 5-yr RFS rates, 42% vs 60%), and that pts with FLT3 mutations had in trend a shorter OS compared with FLT3 wild-type pts (P=0.08; 5-yr OS rates, 58% vs 70%). Importantly, in univariable analysis, pts with number of mutations ≥2 had a worse RFS (P=0.009; 5-yr RFS rates, 36% vs 58%), but their OS was not significantly shorter (P=0.16; 5-yr OS rates, 58% vs 71%) than in pts with number of mutations <2. However, once pts with trisomy 22 were excluded, the group with number of mutations ≥2 had a worse OS (P=0.02) than the group with number of mutations <2. Conclusions: In this large cohort of genetically well defined inv(16)-positive AML we show that KIT and FLT3 mutations are independent factors for RFS and OS, respectively. Even more important, we demonstrate for the first time that harboring ≥2 secondary molecular lesions is an independent predictor for a worse RFS and OS. Thus, comprehensive genetic characterization may improve outcome prediction for AML with inv(16). Pts with multiple mutations may be candidates for a more aggressive treatment in combination with therapies targeting the mutated tyrosine kinases and GTPase proteins. Disclosures: No relevant conflicts of interest to declare.
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Cocciardi, Sibylle, Nina Weiß, Maral Saadati, Sabrina Skambraks, Daniela Weber, Isabelle Schneider, Annika Meid, et al. "The Genomic Landscape and Its Clinical Implication in NPM1-Mutated AML Patients: A Study within the AMLSG 09-09 Clinical Trial." Blood 142, Supplement 1 (November 28, 2023): 4311. http://dx.doi.org/10.1182/blood-2023-185566.
Abstract:
Background: Mutations in the Nucleophosmin 1 gene ( NPM1 mut ) represent one of the most common genetic lesions in acute myeloid leukemia (AML).Based on its characteristic clinico-pathologic features, NPM1 mutAML has been recognized as a distinct entity among the category “AML with recurrent genetic abnormalities”. According to the ELN 2022 genetic risk-stratification, NPM1 mut AML, in the absence of FLT3-ITD mutation, is associated with a favorable prognosis. However, a significant proportion of these patients (pts) relapse after intensive therapy suggesting that other co-mutations may have an impact on outcome. Aims: To comprehensively characterize the genomic landscape and leukemogenic trajectoriesin a large cohort of NPM1 mut AML pts and to investigate its prognostic and predictive impact on outcome. Methods: Targeted DNA sequencing (mean read depth: 1817) on the entire coding region of 263 genes was performed in 568 NPM1 mut AML pts (median age: 58.7 years; 18-60 years, n=317; >60 years, n=251). All pts were enrolled in the randomized open-label Phase 3 AMLSG 09-09 trial [NCT00893399; Döhner H et al. Lancet Haematol 2023]. In this trial, pts were assigned to intensive chemotherapy plus all- trans retinoic acid with or without gemtuzumab ozogamicin; none of the pts received midostaurin. Results: In total n=3,058 variants (variant allele frequency of ≥1%) were identified in 195/263 genes. The median number of co-mutations was 3 (range 0-11). The most common co-mutated genes were DNMT3A (49.5%), FLT3-TKD (42.8%) PTPN11 (24.8%), NRAS (22.7%) TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3-ITD (17.3%). DNMT3AR882 hotspot mutations occurred more frequently in younger pts (36.6% vs 17.1%), while there was no difference for DNMT3AnonR882 mutations between the two age groups (21.8% and 21.9%). An age-dependent difference was also identified for mutations in myelodysplasia-related genes ( ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) as defined by the ICC, occurring with a higher incidence in older pts (30.3% vs 12.3% in younger pts). Analyzing the mutational pattern of co-mutations, we found statistically significant tertiary gene-gene interactions: e.g., NPM1- NFE2- STAG2 (p<.001), NPM1- IDH2- SRSF2 (p<.001), NPM1- CEBPA- TET2 (p<.001), NPM1- DNMT3AR882- NRAS (p=.002), and NPM1- ASXL1- SRSF2 (p=.004); mutual exclusivities were identified for NPM1- DNMT3AR882- DNMT3AnonR882 (p<.001), NPM1- IDH2- TET2 (p<.001), NPM1- DNMT3AR882- SRSF2 (p<.001), NPM1- IDH1- TET2 (p<.001), and NPM1- FLT3-ITD- KRAS (p<.002). Correlating co-mutation data with outcome, we found that DNMT3AR882 hotspot mutations confer inferior event-free (EFS) and overall survival (OS) only in younger pts (EFS, p<.001 vs p=.11, Figure 1a; OS, p=.003 vs p=.8), whereas DNMT3AnonR882 mutations did not impact prognosis within the two age groups. We also found a negative prognostic impact of IDH1 mutations which was restricted to younger pts (EFS, p=.05), whereas IDH2 mutations were associated with superior EFS in older pts (p=.04) and superior OS in both groups (p=.05 and p=.03). Of note, co-mutations occurring in one or more of the myelodysplasia-related genes did not impact EFS or OS (Figure 1b). In multivariable analysis (all pts) including age, WBC, LDH, allogeneic transplantation in CR1, and mutations with an incidence of at least 3% as covariables, age (HR,1.03; p<.001), DNMT3AR882 (HR, 1.86; p<.001), FLT3-ITD (HR, 1.54; p=.012), IDH1 (HR, 1.48; p=.009), MYC (HR, 1.83; p=.032), and WT1 (HR, 1.73; p=.012), were associated with an inferior EFS, while SMC3 mutation showed favorable EFS (HR, 0.44; p=.019). To further study the leukemogenic trajectories, we used an oncogenetic tree modeling algorithm, which yielded a tree with several main branches including DNMT3AR882, DNMT3AnonR882, FLT3-TKD , IDH1, IDH2, PTPN11, and TET2. These mutations might represent initiating events which predispose to additional events with further distinct branches. Conclusions: Our study provides comprehensive data on the genomic landscape and its clinical impact in pts with NPM1mut AML fit for intensive chemotherapy. The co-mutational pattern clearly differs between younger and older NPM1 mutAML pts. Using this large dataset allowed the identification of secondary and tertiary gene-gene interactions with significant impact on outcome. Further data analysis is ongoing and will be presented at the meeting.
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Yoon, Jae-Ho, Hee-Je Kim, Byung Sik Cho, Seung-Ah Yahng, Seung-Hwan Shin, Sung-Eun Lee, Ki-Seong Eom, et al. "High Post-Remission WT1 Expression Is a Predictive Marker for Subsequent Molecular Relapse and Poor Survival Outcome in Adult Patients with Acute Promyelocytic Leukemia (APL)." Blood 126, no. 23 (December 3, 2015): 3842. http://dx.doi.org/10.1182/blood.v126.23.3842.3842.
Abstract:
Abstract Background: Acute promyelocytic leukemia (APL) is classified into favorable-risk group and long-term overall survival (OS) is estimated at around 80%. Relapse rate of APL is relatively lower than another acute myeloid leukemia (AML) subtypes, but we still confront relapse in 10-20% and some relapsed cases are hardly cured even after hematopoietic cell transplantation (HCT). Therefore, it is important to find out patients with high-risk of relapse and early intervention should be considered. In APL, PML-RARa RQ PCR is used as a marker for residual disease, but the marker is not useful for pre-emptive management for relapse prevention because its positivity directly indicates relapse of disease. WT1 expression is a well-known marker in AML, and the expression is higher in APL than the other AML subtypes (Cilloni et al., leukemia, 2002). We monitored WT1 decrement along the treatment courses to identify its significant role as a marker for relapse prediction. Methods: In this study, 117 APL patients with a median follow-up duration of 38.5 months (range, 9.7-81.3) from 2008 to 2014 were analyzed. APL was diagnosed by RT-PCR method for detection of PML-RARa and all patients were available with cytogenetic results. All except 5 with normal karyotype was identified with t(15;17)(q22;q21) and 33 (28.2%) showed combination of additional chromosomal abnormalities. Our treatment protocol was based on LPA99 trial using ATRA and idarubicin monotherapy (Sanz et al., Blood, 2004). In relapsed patients, we applied ATO and some high-risk patients were treated with HCT (n=3). PML-RARa and WT1 expression in the BM samples were quantified by RQ-PCR method, and we used WT1 ProfileQuant¢â kit (Ipsogen) for WT1 monitoring. We measured RQ-PCR levels at diagnosis, post-induction and each of the 3 post-consolidation chemotherapies, and 3 months interval after starting maintenance therapy. FLT3- ITD/TKD mutation was evaluated by multiplex allele-specific PCR and concomitantly analyzed. Significant cut-off level of PML-RARa and WT1 expression was calculated by ROC curve analysis. According to the level, we calculated OS, disease free survival (DFS), and cumulative incidence of relapse (CIR). Results: Hematological complete remission (CR) was identified in 117 (100.0%) patients but complete molecular remission (CMR) was identified in 68 (42.7%) after induction. Among 49 patients who failed to achieve CMR, 44 patients achieved CMR after 1st consolidation and 5 patients after 2nd consolidation. Three-year OS and EFS was 92.5% and 82.0%, and CIR rate was 14.7% (n=13). Three patients showed clonal evolution to therapy-related AML and 1 patient died in CR due to lung cancer. FLT3 -TKD and FLT3 -ITD mutation was identified in 6 (5.1%) and 25 (21.4%) patients, and PML-RARa BCR3 and BCR1 subtype was identified in 32 (27.4%) and 85 (72.6%) patients, respectively. For relapse prediction, we analyzed WT1 expression at several time points in association with CMR after induction, FLT3 -ITD/TKD mutation, BCR subtype, and hyperleukocytosis at diagnosis and during first chemotherapy. High WT1 expression (>120 copies/104ABL1) in early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR was not detected except one sample with early relapse after 3rd consolidation. Patients with high post-maintenance WT1 expression (n=40) showed significantly higher CIR rate (30.7% vs. 4.2%, p=0.0003) and inferior 3-year OS (86.1% vs. 97.9%, p =.0103) and DFS (62.8% vs. 94.1%, p<.0001). Multivariate analysis revealed high leukocyte counts [HR=9.2, 95%CI=2.2-38.5, p =.002], WT1 at 3 months post-maintenance [HR=8.7, 95%CI=1.9-38.9, p =.0051], and FLT3 mutation [HR=5.4, 95%CI=1.5-19.4, p =.0092] were significant factors for relapse prediction. However, even in the BCR3 or FLT3 -positive subgroup (n=48), low WT1 at post-maintenance 3 months was associated with lower CIR rate (13.4% vs. 50.8%, p<.0001) and better DFS (95.2% vs. 49.2%, p<.0001). Conclusion: High post-remission WT1 expression was a reliable marker for the prediction of subsequent relapse in APL, even when PML-RARa was not detected at 3 months post-maintenance. In this high-risk group, early intervention with ATRA±ATO, WT1 vaccination or WT1 -specific cytotoxic cell therapy may be used for relapse prevention. The role of WT1 expression needs to be validated by prospective studies in a large cohort. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Knapper, Steven, Robert K. Hills, James D. Cavenagh, Lars Kjeldsen, Ann E. Hunter, Richard E. Clark, Michael Dennis, et al. "A Randomised Comparison of the Sequential Addition of the FLT3 Inhibitor Lestaurtinib (CEP701) to Standard First Line Chemotherapy for FLT3-Mutated Acute Myeloid Leukemia: The UK Experience." Blood 124, no. 21 (December 6, 2014): 3736. http://dx.doi.org/10.1182/blood.v124.21.3736.3736.
Abstract:
Abstract Activating mutations of the receptor tyrosine kinase FLT3 are seen at diagnosis in one-third of younger adults with acute myeloid leukemia (AML) and are associated with an increased risk of relapse. FLT3 remains the subject of intense clinical interest as a therapeutic target. To date FLT3-targeted monotherapy has produced only transient clinical responses with no prospective trial producing an overall survival benefit. Here we report the results of the first randomised trial of a FLT3 inhibitor (Lestaurtinib, CEP701) given sequentially to chemotherapy as first line treatment for newly-diagnosed AML. FLT3-mutated patients entering the UK MRC AML15 and UK NCRI AML17 trials between January 2007 and October 2012 were randomised to receive either oral Lestaurtinib 80mg bid, or placebo, for up to 28 days after each of 4 courses of chemotherapy. Based on early pharmacokinetic data provision was made for dose reduction to 40mg bid for patients on concomitant azole anti-fungal drugs. 500 patients were randomised (175 AML15, 325 AML17). Median age was 49yrs (5-68, only 5 were <16yrs.). 94% patients had de novo AML, 5% secondary AML and 1% high risk MDS. The majority of patients (89%) had cytogenetically intermediate risk disease with 6% favourable and 5% adverse risk. Median presenting WBC was 28.0x109/l (0.2-363); 381 patients (74%) had FLT3-ITD mutations, 127 (23%) FLT3-TKD point mutations and 12 (2%) both types; 207 patients (41%) had concomitant mutated NPM1. All characteristics were balanced between the arms. Results: No difference in remission rate was seen between the arms (CR/CRi: Lestaurtinib 92% vs Control 94%. OR 1.37 [0.68-2.78] p=0.4). The respective 5-year RFS was 40% vs 37%, HR 0.87 (0.68-1.12) p=0.3; cumulative incidence of relapse 52% vs 54%, HR 0.87 (0.67-1.13) p=0.3 and OS at 5 years 46% vs 43%, HR 0.89 (0.68-1.13) p=0.3 did not differ between arms. Figure 1 Figure 1. 43% of patients were transplanted in both Lestaurtinib and control arms (130/300 and 85/200 respectively); 133 transplants were in CR1, 63 in CR2; 188 were allografts. When the data were censored at SCT the lack of difference in clinical outcome persisted (HR 0.97 [0.71-1.33] p=0.8). Stratified analyses involving age, sex, diagnosis (de novo/secondary/MDS), cytogenetic group, performance status, ITD vs TKD, ITD allelic %, NPM1 status, Gemtuzumab ozogamicin (GO) or not in induction and concomitant use of azoles were undertaken to identify evidence of subgroup benefit with Lestaurtinib. No significant interactions were seen, with some evidence of survival benefit in patients receiving GO (p=0.09 for interaction). In patients receiving concomitant azole treatment there was a significant survival benefit with Lestaurtinib (HR 0.57 (0.36-0.92) p=0.02) although the test for interaction was not significant (p=0.2). Course 1 day 14 plasma trough Lestaurtinib levels were significantly higher in azole-treated patients than in those not receiving azoles (median 4517 vs 3085ng/ml, p=0.03). In AML17 patients treated with GO and azoles, survival with Lestaurtinib at 4 years was 61% compared to 28% in the control arm (p=0.02) Minimal difference in toxicity was seen between the 2 arms, with the exception of slight excess nausea/diarrhea with Lestaurtinib in course 2. Supportive care requirements were slightly increased with Lestaurtinib with a borderline-significant 1-day increase in median time to platelet recovery following course 2 (p=0.05). Conclusion: Lestaurtinib may be safely combined with intensive chemotherapy in younger patients with newly-diagnosed FLT3-mutated AML. No overall clinical improvement was seen with Lestaurtinib, although there was a suggestion of benefit in patients also receiving GO in induction: in Lestaurtinib-treated patients receiving both GO and azoles, survival was 61%. The potential clinical benefit of GO with adequate FLT3 inhibition requires prospective validation. (We are grateful to Cephalon for the provision of Lestaurtinib for this study) Disclosures Knapper: Cephalon: Consultancy, Research Funding. Off Label Use: Tyrosine kinase inhibitor Lestaurtinib (CEP701) used off-label in a randomised controlled trial in FLT3-mutated acute myeloid leukemia.
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Paschka, Peter, Guido Marcucci, Amy S. Ruppert, Susan P. Whitman, Krzysztof Mrózek, Kati Maharry, Christian Langer, et al. "Wilms’ Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study." Journal of Clinical Oncology 26, no. 28 (October 1, 2008): 4595–602. http://dx.doi.org/10.1200/jco.2007.15.2058.
Abstract:
PurposeTo analyze the prognostic impact of Wilms’ tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML).Patients and MethodsWe studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.ResultsTwenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITDnegative/NPM1mutatedas low risk v FLT3-ITDpositiveand/or NPM1wild-typeas high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.ConclusionWe report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.
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Silva, Wellington F., Fernanda Rodrigues Mendes, Marco Sartori, Maria Isabel A. Madeira, Katia B. Pagnano, Ana Beatriz F. Gloria, Elenaide C. Nunes, et al. "Real-World Data for FLT3-Mutated Acute Myeloid Leukemia Patients Treated in Resource-Constrained Settings." Blood 142, Supplement 1 (November 28, 2023): 5839. http://dx.doi.org/10.1182/blood-2023-187902.
Abstract:
Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a well-established prognostic marker in acute myeloid leukemia (AML), whereas the impact of mutations in the Tirosine-Kinase Domain (TKD) is controversial. The association of TK inhibitors (TKIs) with intensive chemotherapy improved the overall survival (OS) of FLT3-mutated AML patients in randomized clinical trials and is recommended by the European LeukemiaNet panel of experts. Nevertheless, TKIs are not available for most patients treated in Low- and Middle-Income Countries (LMIC) and there is a scarcity of data concerning the outcome of treatment in these resource-constrained settings nowadays. Methods: This is a real-world study encompassing newly diagnosed adults with FLT3-mutated AML intensively treated at public hospitals in Brazil between January 2015 and December 2020, who were registered in the International Consortium on Acute Leukemias (ICAL) ICAML2015 Study. No patient received TKIs as part of the treatment. FLT3 mutation was tested in diagnostic samples by fragment analysis method. We used the Adapted Genetic Risk (AGR) score reported by Silveira et al. (2020), which is an adaptation of the European Leukemia Net (ELN) 2017 classification. The primary endpoints were event-free survival (EFS) and OS, calculated by Kaplan-Meier method. Relapse rate was calculated through competing risk analysis. Results: Overall, 350 pts (median age: 51y; 52.8% females) were included. FLT3-ITD and -TKD mutations were detected in 17.5% and 7.2% of the patients, respectively. Ninety patients (35.1%) were classified in the favorable risk group, 110 (42.9%) in the intermediate, and 56 (21.9%) in the adverse risk group, according to the AGR. The most frequent co-mutation was in the NPM1 gene. The remaining features are summarized in Table 1. Seventy-eight patients underwent allogeneic stem-cell transplantation (HSCT) in first complete remission (22.2%), of whom 27 had FLT3-ITD (i.e. 43.9% of patients harboring FLT3-ITD underwent HSCT). With a median follow-up period of 3.5 years, the median 4-year OS rate was 24.2% (95% CI 19.8-30.1), and the 4-y EFS 22.9% (95% CI 18.6-28.2). When only patients with FLT3-ITD mutations were analyzed, the 4-y OS rate was 14.4% which was inferior to that of patients with wild-type FLT3 (27.5%; p=0.057) (Figure 1). The cumulative incidence of relapse at four years was 39.4% for patients with FLT3-ITD and 43.9% for those with wildtype FLT3 (p=0.5), while the non-relapse mortality (NRM) at four years was 28.1% and 32.4%, respectively. The four-year OS rate for patients with FLT3-ITD mutations who underwent HSCT was 49.1% (95% CI 38.9-62.1). Patients with FLT3-ITD were further subdivided according to the allelic ratio (AR) in those with low (<0.5) and high (³ 0.5), and no significant difference in OS was detected between the two groups. Of note that patients harboring FLT3-TKD mutations showed a better overall survival rate compared to those with wild-type FLT3 (HR 0.49, 95% CI 0.26-0.93, p=0.029), but this result needs to be interpreted cautiously due the small size of the cohort. Conclusion: our results show that the frequency of FLT3-ITD mutations and their association with worse prognosis was similar to those described in high-income countries previously to the introduction of TKI as the standard of care. Therefore, allogeneic HSCT remains a valid consolidation strategy for FLT3-mutated patients. However, less than half of the patients for whom HSCT was indicated were actually transplanted. Additionally, the allelic ratio of FLT3-ITD should no longer be considered a prognostic marker for intensively treated patients not receiving FLT3 inhibitors.
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Grossmann, Vera, Claudia Haferlach, Susanne Schnittger, Ulrike Bacher, Franziska Poetzinger, Sandra Weissmann, Andreas Roller, et al. "Acute Erythroid Leukemia (AEL) Can Be Separated Into Distinct Prognostic Subsets Based On Cytogenetic and Molecular Genetic Characteristics." Blood 120, no. 21 (November 16, 2012): 1394. http://dx.doi.org/10.1182/blood.v120.21.1394.1394.
Abstract:
Abstract Abstract 1394 Background: Acute erythroid leukemia (AEL) is characterized by a predominant erythroid population and is comprising <5% of adult AML cases. Because of the relative rarity of AEL, few large studies have examined underlying clinical and genetic features. Aims: Molecular and cytogenetic characterization of AEL and identification of genes with prognostic impact. Patients and Methods: We studied an unselected cohort of 94 AEL patients including 32 female and 62 male cases; median age was 69.0 yrs (range: 21.3–88.3 yrs). Survival data was available in 73 cases; median survival was 15.9 months. First, chromosome banding analysis (n=94) was performed. In addition, all cases with normal karyotype (NK) were investigated by CGH arrays (n=32) (Human CGH 12×270K Whole-Genome Tiling Array, Roche NimbleGen, Madison, WI). Further, mutation screening for ASXL1 (n=87), CEBPA (n=94), DNMT3A (n=94), FLT3 (both internal tandem duplication (ITD) (n=93), and tyrosine-kinase domain (TKD) mutations (n=85)), IDH1 (n=93), IDH2 (n=65), NRAS (n=91), KRAS (n=93), MLL-PTD (n=79), NPM1 (n=94), RUNX1 (n=94), TP53 (n=94), and WT1 (n=90) was performed by 454 amplicon deep-sequencing (Roche, Branford, CT), Sanger sequencing or melting curve analyses. CGH array data analysis was performed using Nexus Copy Number 6.0 (BioDiscovery Inc, El Segundo, CA). Results: Cytogenetic data was available for all cases: 48 cases (51.1%) presented an intermediate-risk and 46 (48.9%) cases an unfavorable cytogenetic category according to the MRC Classification. By CGH array analysis 30/32 cases retained a NK, whereas in two cases small aberrations were detected: case 1: deletion of the CEBPA gene, case 2: duplication 11q13.3 to 11q25 including the ATM and MLL gene. Molecular mutations were detected in 85/94 patients (90.4%). 63.5% (54/85) of mutated patients carried one, whereas 36.5% (31/85) of cases harbored two (n=22) or more (n=9) mutations. In detail, TP53 was the most frequently mutated gene (41 cases, 43.6%). Other alterations were detected in NPM1 (15/94; 16.0%); DNMT3A (12/94; 12.8%); ASXL1 (8/87; 9.2%); MLL-PTD (7/79; 8.9%); RUNX1 (8/94; 8.5%); IDH1 (6/93; 6.5%); WT1 (5/90; 5.6%); IDH2 (3/65; 4.6%); NRAS (3/91; 3.3%); KRAS (3/93; 3.2%); FLT3-ITD (3/93, 3.2%), FLT3-TKD (3/85, 3.5%), and CEBPA (1/94). First, we were interested in any correlation with the respective karyotype and observed that NPM1, RUNX1, and WT1 mutations correlated with an intermediate-risk karyotype (NPM1: 15/48 vs 0/46, P<0.001; RUNX1: 8/48 vs 0/46, P=0.006; WT1: 5/46 vs 0/44, P=0.056), whereas TP53mut correlated with the unfavorable karyotype (38/46 vs 3/48, P<0.001). Within the cytogenetically adverse subset TP53mut were associated with complex karyotype (36/38 vs 2/8, P<0.001). In addition, NPM1mut correlated with lower age (56±15 vs 67±13 yrs, P=0.002), whereas mutations in ASXL1, DNMT3A, and TP53 correlated with higher age (73±4 vs 64±15, P=0.001; 71±6 vs 65±14, P=0.015; 71±8 vs 61±15, P<0.001). NPM1mut were associated with longer, and RUNX1mut and TP53mut with shorter OS (OS after 2 yrs: NPM1mut vs wt: 85.1% vs 28.3%, P=0.001; RUNX1mut vs wt: 0% vs 45.2%, P=0.007; TP53mut vs wt: 9.4% vs 61.6%, P=0.001). In the univariable Cox regression analyses mutations in NPM1 (HR 0.12; P=0.004), RUNX1 (HR 3.99; P=0.013), TP53 (HR 3.19; P=0.001), age (HR 4.24, P=0.001) and adverse cytogenetics (HR 2.98, P=0.002) were significantly associated with OS. Independent prognostic factors in multivariable Cox regression analysis were: age (HR 2.6, P=0.047) and RUNX1mut (HR 6.3, P=0.006). Of note, when separating MRC intermediate from MRC adverse cases, we confirmed the longer OS of NPM1 and shorter OS of RUNX1 mutated cases in comparison to NPM1, RUNX1 wt cases (OS after 2 yrs: NPM1mut vs wt: 85.1% vs 46.3%, P=0.027; RUNX1mut vs wt: 0% vs 69.0%, P<0.001). Conclusions: (1) The frequency of cases with complex or other adverse karyotypes within the AEL cohort is very high (48.9%), (2) 93.7% of cases with NK also showed a NK using high-resolution CGH arrays. (3) Overall, a remarkably high mutation frequency of 90.4% was found. (4) NPM1 and RUNX1mut were exclusively detected in the cytogenetically intermediate-risk MRC, TP53 mut predominantly in the MRC adverse group and mainly in cases with complex karyotype. (5) In addition to chromosome banding analysis mutation screening of RUNX1 and NPM1 in cases with intermediate-risk karyotype should be considered for better prognostication. Disclosures: Grossmann: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Bacher:MLL Munich Leukemia Laboratory: Employment. Poetzinger:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Roller:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Zenger:MLL Munich Leukemia Laboratory: Employment. Staller:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.
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Sanford, David, Jorge E. Cortes, Farhad Ravandi, Wei Qiao, Keyur P. Patel, Thuyvan Hoang, Tapan Kadia, Hagop M. Kantarjian, and Gautam Borthakur. "Prognostic Impact of Kinase Mutations and Minimal Residual Disease in Core-Binding Factor Leukemia." Blood 126, no. 23 (December 3, 2015): 3828. http://dx.doi.org/10.1182/blood.v126.23.3828.3828.
Abstract:
Abstract Background Core-binding factor (CBF) acute myeloid leukemia (AML) is characterized by recurrent cytogenetic abnormalities t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), amenable for minimal residual disease (MRD) monitoring by quantitative reverse transcription polymerase chain reaction (RT-PCR). Kinase mutations (KIT, RAS, FLT3) have been reported to carry adverse prognostic implication. Promising results using FLAG-based treatment (fludarabine/Ara-C/G-CSF) in CBF leukemia in phase 2 [Borthakur G, Am J Hematol, 10, 89 (2014)] and phase 3 [Burnett AK, JCO, 27, 31 (2013)] clinical trials prompted us to review the prognostic impact of MRD evaluation and mutations. Methods The primary aim was to assess the prognostic impact of kinase-activating mutations (KIT, FLT3-TKD, FLT3-ITD, KRAS and NRAS) and MRD in CBF leukemia treated with FLAG-based regimens. Newly diagnosed patients were treated in 2 consecutive phase 2 clinical trials (clinicaltrials.gov identifier: NCT00801489) and received FLAG during induction (1 cycle) and consolidation (up to 6 cycles) in combination with either gemtuzumab (for 3 cycles) or idarubicin (for 2 cycles). Mutation analysis was performed at baseline on bone-marrow aspirates and MRD was measured on serial bone marrow aspirates using RT-PCR to detect RUNX1-RUNX1T1 and CBFB-MYH11 fusion transcripts, normalized to ABL1 transcript. The Kaplan-Meier method was used to estimate unadjusted overall survival (OS) and relapse-free survival (RFS). The Cox-proportional hazards model was used to estimate the association of covariates with OS and RFS. Landmark survival analysis was used to determine the association between OS/RFS and MRD, to account for time-dependent nature of this covariate. Results: One hundred and seven patients were included [t(8;21)=54, inv(16)=53]. Forty-eight were treated with FLAG + gemtuzumab and 59 were treated with FLAG + idarubicin. The 3 year OS and RFS for the cohort was 79% (95% CI, 71-89%) and 82% (95% CI, 74 - 91%) respectively with comparable outcomes with both regimens. The incidence of mutations in KIT, FLT3-ITD, FLT3-TKD and NRAS/KRAS was 13%, 7%, 10% and 38.5% respectively. In univariate analysis, the presence of mutations in KIT, FLT3 and NRAS/KRAS individually or together were not associated with OS or RFS. A 3-log or greater reduction in RT-PCR level at 1 month and 3-4 months was associated with improved RFS. A 3-log or greater reduction in RTPCR level at 6-9 months was also significantly associated with improved OS (HR 0.19, 95% CI 0.03 -1.0, p=0.05) and there was a trend towards improved OS with 3-log reduction at 1 month (HR 0.39, 95% CI 0.14 - 1.06, p=0.06). Conclusion: In contrast to some reports, mutations in KIT, FLT3 and RAS were not prognostic for RFS or OS in our study. Favorable outcomes using FLAG-based therapy in CBF leukemia may abrogate adverse impact of kinase mutations and this hypothesis needs to be clinically tested. The incidence of KIT mutations was slightly lower in our cohort in comparison to most previous reports, which may relate to differences in sensitivity of detection. Significantly, quantitative detection of MRD by PCR early on appears to be a broadly applicable predictor of relapse and may be the most relevant prognostic factor for clinical management of CBF leukemia patients. Table 1. Univariate analysis showing hazard of relapse for all patients HR 95% CI p-value Age 1.00 0.97 - 1.04 0.89 Performance status (ECOG 1,2 vs. 0) 3.59 1.3 - 9.95 0.01 Therapy related (Y vs. N) 0.38 0.05 - 2.93 0.36 CBF Type - [inv(16) vs. t(8;21)] 0.95 0.34 - 2.62 0.92 Treatment (FLAG-ida vs. FLAG-GO) 1.59 0.56 - 4.51 0.38 Mutated KIT (Y vs. N) 1.55 0.35 -6.91 0.56 FLT3-ITD (Y vs. N) 0.7 0.09 - 5.39 0.73 FLT3-TKD (Y vs. N) 2.07 0.46 - 9.32 0.34 RAS - NRAS/KRAS (Y vs. N) 0.79 0.24 - 2.63 0.7 Any mutation -KIT/FLT3/ RAS (Y vs. N) 1.17 0.42 - 3.22 0.76 MRD - 3 log reduction at 1 month (Y vs. N) 0.23 0.06 - 0.81 0.02 MRD - 3 log reduction at 3-4 months (Y vs. N) 0.18 0.05 - 0.61 <0.01 MRD - 3 log reduction at 6-9 months (Y vs. N) 0.29 0.06 - 1.41 0.12 MRD - negative at 6-9 months (Y vs. N) 0.3 0.06 - 1.47 0.13 Figure 1. Outcomes by mutation status (KIT or FLT3 or RAS). (a) Overall survival; (b) Relapse free survival. Figure 1. Outcomes by mutation status (KIT or FLT3 or RAS). (a) Overall survival; (b) Relapse free survival. Disclosures Cortes: Teva: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.
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Eisfeld, Ann-Kathrin, Guido Marcucci, Kati Maharry, Sebastian Schwind, Michael D. Radmacher, Deedra Nicolet, Heiko Becker, et al. "MiR-3151, a Novel MicroRNA Embedded in BAALC, Is Only Weakly Co-Expressed with Its Host Gene and Independently Impacts on the Clinical Outcome of Older Patients (Pts) with De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)." Blood 118, no. 21 (November 18, 2011): 1462. http://dx.doi.org/10.1182/blood.v118.21.1462.1462.
Abstract:
Abstract Abstract 1462 Despite progress made in understanding the biology and risk-adapted treatment of AML, prognosis of older pts [age ≥60 years (y)] remains poor. We have shown that high expression of the BAALC gene bestows worse outcome in older CN-AML pts. Yet, the mechanism(s) by which BAALC affects response to therapy remain unknown. MicroRNAs (miRs) are small noncoding RNAs that hybridize to target mRNAs and inhibit their translation or promote degradation, resulting in downregulation of the corresponding proteins. Recently, miR-3151 was discovered embedded in intron 1 of BAALC. We thus hypothesized that miR-3151 might be co-expressed with BAALC and contributes alone or in concert with its host to poor prognostic impact in older CN-AML. MiR-3151 and BAALC expression were measured by quantitative real time (RT) PCR in pretreatment blood of 179 older CN-AML pts enrolled on Cancer and Leukemia Group B (CALGB) cytarabine/daunorubicin-based protocols. The expression values of miR-3151 and BAALC were normalized to the internal controls SNORD44 and RN18S1, respectively. MiR-3151 expression correlated only weakly with the expression of BAALC (Spearman correlation r= 0.3). For clinical and prognostic analyses pts were dichotomized into high and low miR-3151 and BAALC expressers at the median miR and gene transcript expression values and analyzed for other molecular prognosticators (FLT3 -ITD, FLT3 -TKD, CEBPA, IDH1, IDH2, NPM1, TET2, WT1 mutations and ERG expression). Gene (GEP) and microRNA (MEP) expression profiles associated with miR-3151 expression were derived, using Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays, respectively. At diagnosis, higher miR-3151 expression was associated with lower % blood blasts (P =.02), FAB types M4 and M5 (P =.05), and wild-type NPM1 (P<. 001). High miR-3151 expressers had a lower complete remission (CR) rate (62% v 81%, P=. 005), and, with a median follow-up of 5.1 y for pts alive, shorter disease-free (DFS; hazard ratio [HR]=1.76, P=. 003; 3y rates, 7% v 26%; Figure 1A) and overall survival (OS; HR=1.86, P <.001; 3y rates, 10% v 32%; Figure 1B) than low expressers. In multivariable analyses (MVA), higher miR-3151 expression no longer remained in the model for CR after adjusting for BAALC expression and white blood count (WBC), but higher miR-3151 expression remained associated with shorter DFS (HR=2.32, P <.001), after adjusting for FLT3 -TKD, ERG expression status and WBC, and shorter OS (HR=1.77, P=. 003), after adjusting for ERG and BAALC expression status. To gain biological insights of miR-3151 -associated AML, we derived a GEP comprising 377 annotated genes and a MEP comprising 14 miRs. High miR-3151 expressers exhibited upregulation of genes associated with immature differentiation stage and adverse outcome (eg, MN1, ID1), downregulation of genes involved in hematopoietic differentiation (eg, MEIS1, PDCD4, PBX3) and transcriptional regulators (ZNF s, E2F3), including predicted targets of miR-3151 (eg, MEIS1). In the MEP, high miR-3151 expressers showed downregulation of let-7a/b/c that play crucial roles in cell cycle and proliferation regulation. While miR-3151- associated GEP/MEP shared genes with BAALC expression-associated GEP/MEP (eg, upregulated MN1 and DNTT and downregulated MEIS1, let-7b, miR-10a/b), other genes were unique to miR-3151- associated GEP/MEP (eg, upregulated ID1 and downregulated ZNFs, miR-206 and let-7a/c), suggesting biologic mechanisms distinct from those directly connected with BAALC upregulation operating in miR-3151- associated leukemia. In conclusion, high miR-3151 expression is independently associated with worse survival in older CN-AML pts. The weak correlation between expression of miR-3151 and its host gene BAALC, the independent impact of each on outcome endpoints (BAALC was a strong predictor of CR but did not predict DFS while miR-3151 was not independently associated with CR, but remained in the DFS MVA) and differences in GEP/MEP suggest that miR-3151 and BAALC are deregulated and contribute to disease outcome differently. We surmise that determining the expression levels of miR-3151 at diagnosis might help to improve the risk-stratification of older CN-AML. Development of therapies targeting miR-3151 upregulation with synthetic inhibitors may provide novel, effective strategies for personalized treatment of older CN-AML pts. Disclosures: No relevant conflicts of interest to declare.
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Aly, Mai M. M., Mahesh Swaminathan, Katherine G. Akers, Seongho Kim, Harry Ramos, Jaroslaw P. Maciejewski, and Suresh Kumar Balasubramanian. "A Systematic Review and Meta-Analysis Comparing Type I and II FLT3 Inhibitors in Relapsed/ Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome." Blood 138, Supplement 1 (November 5, 2021): 1249. http://dx.doi.org/10.1182/blood-2021-148902.
Abstract:
Abstract Background: Acute myeloid leukemia (AML) is frequently characterized by mutations in FMS-like tyrosine kinase 3 (FLT3). FLT3 is mutated in one-third of de novo AML patients and recurrent in relapsed/refractory (R/R) AML. More frequent FLT3 internal tandem duplications (ITD) and less frequent tyrosine kinase domain (TKD) point mutations are prognostically important in AML and are associated with an inferior outcome. Although targeted therapy with FLT3 inhibitors improves prognosis in FLT3 mutated AML patients, there is a lack of evidence regarding the superiority of efficacy of various FLT3 inhibitors in clinical practice and the therapeutic pipeline. Broadly grouped as type 1 (targets ITD and TKD, e.g., midostaurin) and type 2 (targets only ITD, e.g., quizartinib) inhibitors, there is no consolidated summary of the difference in efficacy between these two classes of FLT3 inhibitors in R/R AML and high-risk myelodysplastic syndrome (HR-MDS). Hence, we conducted a systematic review and meta-analysis of various type 1 and 2 FLT3 inhibitors tested in clinical trials to compare their clinical effectiveness in treating R/R AML and HR-MDS. Methods: PubMed and EMBASE databases were searched for clinical trials published between 1/1/2000 and 5/26/2021 using a combination of keywords and subject headings related to FLT3 inhibitors and AML. Two independent reviewers screened titles/abstracts and full texts, with a third reviewer resolving conflicts. Studies were included if they were (1) full-length published journal articles that (2) reported the results of single-arm or double-arm phase I/II/III clinical trials in patients with R/R AML or HR-MDS. Outcomes of interest were composite response rate (CRc=complete response + complete response with incomplete count recovery) and overall response rate (ORR). Results: Record screening resulted in the initial inclusion of 30 studies for qualitative analysis (Fig. 1). Due to poor representation of R/R AML patients and post-transplant FLT3 inhibitor outcomes, two studies were excluded from quantitative analysis, leaving 28 studies for the final analysis. The studies had a total of 1927 R/R AML and HR-MDS patients with a median age of 61.5 years (range, 13-91) and a median of three (range, 0-10) prior lines of treatment. Giltertinib (n=3 studies) was the most frequently studied type 1 inhibitor, and quizartinib (n=6) and sorafenib (n=5) were the most frequently studied type 2 inhibitors. Heterogeneity testing using Cochran's Q test and I 2 values showed the presence of heterogeneity for both CRc (p<0.01 and I 2=87% for both type 1 and 2) and ORR (p<0.01 for both type 1 and 2, I 2=88% and 92% for type 1 and type 2, respectively) and. Hence, random-effects models were used. Asymmetry tests performed using Egger's linear regression test suggested publication bias only for type 2 (p=0.005) for ORR and type 1 and 2 for CRc (p=0.017 and 0.002, respectively). Thus, the trim-and-fill method was used to adjust for publication bias for type 2 for ORR and type 1 and 2 for CRc. Pooled ORR was 37% (95% CI, 25-51%) for type 1 and 58% (95% CI, 43-71%) for type 2. The highest ORR was for gilteritinib (68%; 95% CI, 61-73%) among type 1 and sorafenib (99%; 95% CI, 81-100%), linifanib (99%; 95% CI, 89-100%), and tandutinib (100%; 95% CI, 93-100%) for type 2 (Fig. 2). Pooled CRc was 35% (95% CI, 21-52%) for type 1 and 38% (95% CI, 27-50%) for type 2. The highest CRc was for midostaurin (98%; 95% CI, 79-100%) among type 1 and sorafenib (97%; 95% CI, 68-100%), tandutinib (98%; 95% CI, 72-100%), and semaxinib (98%; 78-100%) among type 3 (Fig. 3). Conclusion: Both type 1 and 2 inhibitors are effective as monotherapy in R/R AML and HR-MDS patients. Though not statistically significant, better ORR for type 2 than for type 1 inhibitors in the R/R setting provides a background to explore the biological heterogeneity of response and preferential sensitivity to ITD-targeted therapy alone rather than the dual inhibitor. More prospective randomized study designs comparing type 1 and 2 inhibitors in the R/R and de novo setting are needed. Figure 1 Figure 1. Disclosures Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy; Novartis: Consultancy. Balasubramanian: Servier Pharmaceuticals: Research Funding.
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Whitman, Susan P., Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Dean Margeson, Kelsi B. Holland, Heiko Becker, et al. "Adverse Prognostic Impact of FLT3 Internal Tandem Duplication (ITD) Is Age-Associated in Older [≥60 Years (Y)] De Novo cytogenetically Normal Acute Myeloid Leukemia (CN-AML) Patients (Pts): a Cancer and Leukemia Group B (CALGB) Study." Blood 114, no. 22 (November 20, 2009): 1579. http://dx.doi.org/10.1182/blood.v114.22.1579.1579.
Abstract:
Abstract Abstract 1579 Poster Board I-605 While the prognostic role of FLT3 ITD has been validated in younger CN-AML adults (<60 y), its association with outcome has not been fully investigated in older pts. We studied the frequency and the clinical impact of FLT3 ITD in a cohort of older pts ≥60 y ([n=243; 111 (46%) aged ≥70 y] with de novo CN-AML. Pts were treated on CALGB protocols [10201, 9720, 9420, 8923 and 8525] with cytarabine/anthracycline-based induction and cytarabine-based consolidation. Diagnostic samples were assessed by quantitative fluorescence-based PCR capillary electrophoresis for FLT3 ITD and tyrosine kinase domain (TKD) mutations, and by DHPLC/sequencing analysis for NPM1 and WT1 mutations. Of the 243 pts, 78 (32%) presented with FLT3 ITD, 24 (10%) with FLT3 TKD and 6 (2%) had both. Outcome analyses were restricted to comparison of FLT3 wild-type (WT) pts (n=147) with those with FLT3 ITD alone (n=72). Of these pts, 121 (55%) had NPM1 mutations and 15 (7%) had WT1 mutations. Unfortunately, only a subset of these pts also had available material for BAALC and ERG measurements, thereby preventing analysis of the prognostic significance of FLT3 ITD in the context of a panel of variables that included these markers. Compared with FLT3 WT pts, FLT3 ITD pts had higher WBC counts and % bone marrow and blood blasts (P<.001, all), and higher frequencies of NPM1 (74% v 46%; P<.001) and WT1 mutations (15% v 3%; P=.001). Complete remission (CR) rates were similar, but disease-free (DFS) and overall survival (OS) were shorter in FLT3 ITD v FLT3 WT pts (Table 1). In multivariable analyses (MVA), FLT3 ITD associated with shorter DFS and OS (Table 2). The FLT3 ITD prognostic impact was associated with age. FLT3 ITD pts aged 60-69 y had shorter DFS and OS than FLT3 WT pts, whereas clinical outcomes were not different for ≥70 y FLT3 ITD v FLT3 WT pts (Table 1). In MVA for the 60-69 y subgroup, pts with FLT3 ITD had shorter DFS and OS (Table 2). The reasons for this age-associated effect remain to be explained. In previous studies of younger CN-AML, a higher (≥ median) FLT3 ITD:WT allelic ratio (AR) was associated with worse clinical outcome. In the current study, FLT3 ITD had an adverse prognostic impact on the 60-69 y pts and no significant impact on the ≥70 y pts regardless of the AR levels. However, a 27-microRNA (miR) signature differentiating between FLT3 ITD and FLT3 WT pts and characterized by >2-fold higher miR-155 expression in FLT3 ITD pts, was associated with shorter DFS and OS in the 60-69 y pt subgroup (P=.001, each) but not in the ≥70 y subgroup (P=.26 and P=.89, respectively), suggesting an age-associated prognostic role of the miRs. In summary, our data show FLT3 ITD is an independent marker for poor outcome in CN-AML pts aged 60-69 y but not in those aged ≥70 y. Although the ≥70 y pts with FLT3 ITD had a seemingly better prognosis than the corresponding 60-69 y pts, the outcome for both groups is poor and novel treatment approaches are needed in older pts. Table 1 Outcomes in older CN-AML pts with and without FLT3ITD Overall 60-69 y Pts ≥70 y Pts FLT3 ITD (n=72) FLT3 WT (n=147) P FLT3 ITD (n=41) FLT3 WT (n=78) P FLT3 ITD (n=31) FLT3 WT (n=69) P % achieving CR 67% 70% .64 71% 75% .67 61% 65% .82 DFS % disease-free at 3 y 10% 18% .007 7% 19% <.001 16% 18% .94 OS % alive at 3 y 14% 23% <.001 10% 26% <.001 19% 20% .71 Table 2 Variables in Final MVA Models for DFS and OS Overall 60-69 y Pts DFS OS DFS OS HR* P HR* P HR* P HR* P FLT3 ITD, positive v negative 2.10 <.001† 1.97 <.001 2.94 <.001† 2.79 <.001 NPM1, mutated v wild-type 0.59 .005 0.54 <.001 – – 0.62 .021 WBC, continuous, 50 unit increase 1.44 .028† – – – – – – Hemoglobin, continuous 1.27 .045† – – 1.50 .018† – – * HRs <1 (>1) indicate lower (higher) risk for an event for the first category listed for the dichotomous variables and for the higher values of the continuous variables. Variables considered in the models were those significant at á=0.20 in univariable analyses. † Variable did not meet the proportional hazards assumption, a covariate was used to account for time dependence. Disclosures Stone: Cephalon: ad hoc consultancy; Novartis: Research Funding, ad hoc consultancy.
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Mosquera Orgueira, Adrian, Manuel Perez Encinas, Jose Angel Diaz Arias, Rebeca Rodriguez Veiga, Juan Miguel Bergua Burgues, Jesús Lorenzo Algarra, Carmen Botella, et al. "The FLT3-like Gene Expression Signature Predicts Response to Quizartinib in Wild-Type FLT3 Acute Myeloid Leukemia: An Analysis of the Pethema Quiwi Trial." Blood 142, Supplement 1 (November 28, 2023): 974. http://dx.doi.org/10.1182/blood-2023-180482.
Abstract:
Background The identification of predictive biomarkers is crucial for guiding treatment decisions in acute myeloid leukemia (AML). Previously, we identified a FLT3-like gene expression signature in FLT3 wild-type AML patients, which clustered a variable proportion of FLT3 wild-type patients with FLT3-ITD and TKD mutated patients. The QUIWI trial was a randomized, placebo-controlled, phase II study preliminary showing a significant increase in overall survival (OS) in wild-type FLT3 AML patients treated with the FLT3 inhibitor quizartinib (Quiza) plus standard chemotherapy. This preplanned correlative study was designed to assess the value of the FLT3-like signature to predict responses to Quiza. Methods We performed RNA sequencing (RNAseq) analysis on a subset of patients from the clinical trial. RNA was extracted using standard methods, followed by assessment of nucleic acid integrity (TapeStation) and quantification (Qubit). Total mRNA sequencing was performed using polyA RNAseq with TruSeq technology. A total of 206 adequate samples from bone marrow and peripheral blood were sequenced (161 from FLT3-ITD negative enrolled in QUIWI; and 55 from FLT3-ITD positive patients who were screen failure of the QUIWI trial by this reason). The sequences were aligned to the GRCh37 reference genome using the Hisat algorithm. Gene expression quantification was performed using the Bioconductor workflow, and gene expression estimates (FPKM) were obtained. The gene expression estimates were log2 normalized. Finally, those genes mapping to the original FLT3-like signature (595 genes) were selected for downstream analysis. Clustering was based on the hierarchical method, using standard euclidean distance metrics. OS was defined as time from start of screening to death. Event-free survival (EFS) was defined as time from randomization to failure to achieve CR/CRi after 1 or 2 cycles, death in CR/CRi, or relapse (whichever occurred the first). Relapse-free survival was defined as time from randomization to disease relapse or death by any cause. Results Among the total 206 patients, a cluster of 54.37% (N=112) was enriched in FLT3-mutant cases (71.11% of cases, Figure 1A). This subgroup comprised 49.67% of wild-type FLT3 cases (N=80), hereafter FLT3-like patients. In the group of not FLT3-like patients, no differences were identified between the placebo and Quiza group in the total number of deaths (Fisher's p-value, 0.63), EFS (cox p-value, 0.83; HR 1.07 [0.56-2.06]), RFS (cox p-value 0.76; HR 0.88 [0.38-2.01]) and OS (cox p-value, 0.62; HR 1.22 [0.55-2.67]). Among FLT3-like patients, significant differences were identified in the total number of deaths (Fisher's p-value, 0.004), EFS (cox p-value, 0.009; HR 0.45 [0.25-0.82], RFS (cox p-value 0.01, HR 0.37 [0.18-0.79]) and OS (cox p-value 0.01, HR, 0.41 [0.20-0.84]) ( Figure 1B). No statistically significant association was observed between the FLT3-like pattern and the ELN-17 classification: 30.4% were low risk, 40.5% intermediate risk, 29.1% high risk. Conclusion The FLT3-like gene expression signature successfully identified a subset of patients who derived the most benefit from Quiz, while patients without the FLT3-like signature did not demonstrate a benefit compared with placebo. These findings support the use of the FLT3-like signature as a potential biomarker to identify those wild-type FLT3 AML patients who may benefit from Quiz, providing a valuable insight for personalized treatment in AML.
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Deneberg, Stefan, Michael Grövdal, Monika Jansson, Verena I. Gaidzik, Andrea Corbacioglu, Hareth Nahi, Sofia Bengtzen, et al. "Different Incidence and Implications of DNA Hypermethylation in De Novo AML Compared to High-Risk MDS and AML Following MDS." Blood 112, no. 11 (November 16, 2008): 3337. http://dx.doi.org/10.1182/blood.v112.11.3337.3337.
Abstract:
Abstract AML and high risk MDS are two myeloid malignancies with poor prognosis. Epigenetic changes such as silencing of tumor suppressor genes by promoter hypermethylation play a role in pathogenesis and disease progression. There is no consensus regarding the prognostic implications of epigenetic alterations in AML. We analyzed 108 de novo AML (median age 62 years, range 23–85), and 47 patients with MDS-related disease (19 MDS with IPSS INT-2 or High, 28 MDS-AML, median age 77 years, range 54–83), with respect to clinical and prognostic parameters and hypermethylation of the promoter region of three tumor suppressor genes; HIC, CDKN2b(p15) and CDH. All patients were eligible for and received standard induction chemotherapy. Methylation analysis was performed by Denaturing Gradient Gel Electrophoresis (DGGE) following bisulfite treatment and promoter specific PCR. A complete remission (CR) was achieved by 81 and 43 percent in the de novo AML group and the MDS group respectively. Hypermethylation of CDH or of multiple genes has previously been reported to correlate negatively to the probability of CR after intensive chemotherapy in the MDS cohort (p=0.008 and p=0.05, respectively). This was not true for the de novo AML patients (p=0.748 and p=0.681, respectively). The incidence of hypermethylation was significantly higher in de novo AML where 89% had at least one methylated gene compared to 66% in MDS (p=0.006). The mean number of methylated genes were 1.8 in de novo AML compared to 1.0 in MDS (p=0.002). In de novo AML the number of methylated genes decreased with increasing age (p=0.041) and an opposing trend was seen in MDS (p=0.15). Hypermethylation of all three genes was associated with higher age in MDS (p=0.040) whereas a trend towards the opposite was seen in de novo AML (p=0.084). In de novo AML the occurrence of FLT3-TKD was associated with hypermethylation of all three genes (p=0.011). Kaplan-Meier curves showed that hypermethylation of CDH and p15 together was associated with better overall survival (OS) in the de novo AML patients (p=0.001) (fig 1A). Median OS was 1.4 months for cases with no methylated genes and 13.5 and 14.5 months for those with one or two methylated genes, respectively. In contrast, in the MDS cohort, hypermethylation of CDH and p15 was a negative prognostic factor (p=0.002) (fig 1B). Median OS was 2.9 months for cases with two methylated genes and 12.7 and 9.4 for 0–1 methylated genes, respectively. The significance of these findings were retained after correction for age in a Cox regression analysis, HR 0.20 (p=0.001) for de novo AML and HR 2.96 (p=0.015) for MDS. We conclude that de novo AML and high risk MDS/MDS-AML show significant differences with respect to DNA promoter hypermethylation. Also, the correlation between hypermethylation and age as well as the effect on OS and complete remission rate differs between the de novo AML and the MDS cohort, respectively. This indicates epigenetic differences that may explain some of the clinical and morphological differences between the diseases. We also for the first time describe a relationship between FLT3-TKD and hypermethylation in AML. Fig 1A: Kaplan Meier curve showing the effect of methylation of p15 and CDH on OS (months) in de novo AML. Fig 1B: Kaplan Meier curve showing the effect of methylation of p15 and CDH on OS (months) in high risk MDS. Fig 1A:. Kaplan Meier curve showing the effect of methylation of p15 and CDH on OS (months) in de novo AML. . / Fig 1B: Kaplan Meier curve showing the effect of methylation of p15 and CDH on OS (months) in high risk MDS.
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Jentzsch, Madlen, Marius Bill, Julia Schulz, Juliane Grimm, Stefanie Beinicke, Karoline Schubert, Janine Haentschel, et al. "High Blood BAALC Copy Numbers Determined By Digital Droplet PCR at Timepoint of Allogeneic Transplantation in Complete Remission Predicts Relapse in Patients with Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 517. http://dx.doi.org/10.1182/blood.v128.22.517.517.
Abstract:
Abstract Allogeneic hematopoietic cell transplantation (HSCT) is a powerful consolidation option for acute myeloid leukemia (AML) patients (pts) in hematologic complete remission (CR). Disease recurrence after HSCT remains a major clinical problem & early identification of AML pts at risk of relapse is crucial to improve outcomes. High expression of the AML associated gene BAALC (Brain and acute leukemia, cytoplasmic) at diagnosis adversely impacts on outcomes in AML pts. Little is known about its prognostic capacity during disease course & as a marker of residual disease. Here we adopted digital droplet polymerase chain reaction (ddPCR) for absolute quantification of BAALC copy numbers in peripheral blood (PB) prior to HSCT in AML pts in hematologic CR. We identified 82 AML pts with PB in first (60%) or second CR (23%) or CRi (17%) up to 28 days prior to HSCT available. Median age at HSCT was 63.9 (range 50.8-76.2) years (y). All pts received non-myeloablative (NMA) conditioning (fludarabine 3x30 mg & 2 Gy total body irradiation). At diagnosis, mutation status (mut) of the NPM1, CEBPA, IDH1, IDH2,& DNMT3A gene & presence of FLT3-ITD or FLT3-TKD were assessed. In pre-HSCT PB, absolute quantification of BAALC copy numbers was performed by ddPCR & results were normalized to ABL1 copy numbers.Additionally, absolute BAALC copy numbers wereassessedin PB of healthy controls (n=7) with a median age of 62.7 (range 39.6-82.0) y. Pts were grouped according to the European LeukemiaNet (ELN) classification in 21% favorable, 23% intermediate-I, 24% intermediate-II, 23% adverse & 9% unknown. Pts & healthy control were evenly matched in age (P=1) & sex (P=1). BAALC/ABL1 copy numbers did not differ between AML pts at HSCT (median 0.03 [range 0.01-2.48]) & the healthy controls (median 0.04 [range 0.03-0.10], P=.34, Figure 1). A cut-off point of 0.14absolute BAALC/ABL1 copies was determined using the R package 'OptimalCutpoints' & used to define pts with high (26%) & low (74%) pre-HSCT BAALC/ABL1 copy numbers. The copy number at this cut-off point was higher than the two-fold standard deviation over the median of the healthy controls (0.10 BAALC/ABL1). Pts with high & low pre-HSCT BAALC/ABL1 copy numbers did not differ significantly in pre-treatment characteristics (i.e. hemoglobin, white blood count, platelets, blasts in bone marrow or PB, ELN genetic group, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, DNMT3A, IDH1 or IDH2 mut) or remission status at HSCT (CR1 vs. CR2 vs. CRi). However, pts with high pre-HSCT BAALC/ABL1 copy numbers had a significantly higher cumulative incidence of relapse (CIR, P=.02, Figure 2a) & shorter overall survival (OS, P=.02, Figure 2b). High pre-HSCT BAALC/ABL1 copy numbers especially impacted on CIR when we restricted our analysis to pts with normal cytogenetics (P=.003). In multivariate analysis for the entire cohort, high pre-HSCT BAALC/ABL1 copy numbers retained the prognostic impact on CIR (Hazard Ratio [HR] 3.6, Confidence Interval [CI] 1.6-8.2, P=.002) after adjustment for disease status at HSCT (P=.006) & the prognostic impact on OS (HR 2.2, CI 1.1-4.3, P=.02). In conclusion, ddPCR is a feasible method for absolute quantification of BAALC copy numbers in PB, which may indicate residual disease burden in AML pts. High PB BAALC/ABL1 copy numbers (>0.14) in AML pts in hematologic CR at HSCT associated with higher CIR & shorter OS in univariate & multivariate models. AML pts with high PB BAALC/ABL1 copy numbers at HSCT should be closely monitored for relapse in the post-transplant period. In the future prospective studies will be required to validate the absolute PB BAALC/ABL1 copy number cut-off point & to evaluate whether AML pts with high BAALC/ABL1 copy numbersmight benefit from additional treatment before HSCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Poenisch: Mundipharma: Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.
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Paschka, Peter, Juan Du, Richard F. Schlenk, Lars Bullinger, Verena I. Gaidzik, Andrea Corbacioglu, Axel Benner, et al. "Mutations in the Fms-Related Tyrosine Kinase 3 (FLT3) Gene Independently Predict Poor Outcome in Acute Myeloid Leukemia (AML) with t(8;21): A Study of the German-Austrian AML Study Group (AMLSG)." Blood 114, no. 22 (November 20, 2009): 825. http://dx.doi.org/10.1182/blood.v114.22.825.825.
Abstract:
Abstract Abstract 825 Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) is considered as a prognostically favorable subgroup of AML. However, outcome is heterogeneous and almost half of adult patients (pts) cannot be cured by current treatment. Candidate molecular markers have been assessed in an effort to predict outcome in AML with t(8;21) at the time of diagnosis and to potentially guide the development of genotype-specific approaches. In most, but not all studies, KIT mutations were associated with adverse prognosis in AML with t(8;21). However, no larger study has elucidated the independent prognostic impact of various gene mutations in a comprehensive molecular analysis. Methods: Bone marrow and/or blood specimens from 146 adult pts diagnosed with de novo (n=137), therapy-related (n=5) or unknown history (n=4) t(8;21) AML were studied for the presence of additional chromosome abnormalities and for mutations in FLT3 [internal tandem duplications (ITD) and tyrosine kinase domain mutations (TKD)], N-/K-RAS, KIT and JAK2 (V617F) genes. All pts were treated on one of 7 prospective protocols of the German-Austrian AML Study Group (AMLSG). For induction pts received anthracycline-and cytarabine-based therapy regimens; pts achieving a complete remission (CR) were assigned to postremission therapy incorporating higher doses of cytarabine in various settings or to autologous stem cell transplantation. Multivariable analyses were performed to assess the prognostic value of gene mutations on relapse-free (RFS) and overall survival (OS) and were stratified for treatment protocols. Results: Mutations were identified in 56% of the pts with the highest frequency observed in KIT (30%), followed by mutations in RAS (21%), FLT3 (13%) [ITD (9.5%) and TKD (3.5%)] and JAK2 (3.5%) genes. When correlating gene mutations with clinical features, pts with RAS mutations had a higher WBC (P=0.003) and a lower frequency of the most common secondary chromosome abnormality represented by the loss of a sex chromosome (LOS; P=0.03) when compared to pts with wild-type RAS; for the other genes studied no differences in pretreatment characteristics were observed. The median age of the study cohort at diagnosis was 46 years (yrs; range, 17-73 yrs), and the median white blood count (WBC) was 8.7 × 109/l (range, 0.9-152 × 109/l). Median follow-up for survival according to Korn was 3.4 yrs [95%-confidence interval (CI), 2.6.-5.2 yrs]. The CR rate in the entire study cohort was 89% and none of the gene mutations impacted as single marker on the CR rate. In univariable and multivariable analyses, only FLT3 mutations significantly affected relapse-free survival (RFS) and overall survival (OS). No significant difference in RFS and OS was observed with respect to the mutational status of KIT, RAS and JAK2 genes. In univariable analyses, pts with FLT3 mutations relapsed more frequently (P=0.03; 3-yr RFS rates, 22% vs 58%) and had a shorter survival time (P=0.006; 3-yr OS rates, 26% vs 63%) than those without FLT3 mutations. Multivariable analyses revealed the mutational status of FLT3 as independent prognostic variable for RFS and OS. Age was a significant risk factor for OS. Additional variables that were also included in multivariable models were mutational status of KIT and RAS, log10(WBC), and presence of LOS. Pts harboring FLT3 mutations relapsed more frequently (HR, 3.20, P=0.01) than pts with FLT3 wild-type. In addition, the risk of death in pts with FLT3 mutations was more than four times higher (HR, 4.24, P=0.004) than in pts lacking these mutations. Conclusions: In conclusion, we show here in a large group of adult AML pts with t(8;21) that the presence of activating FLT3 mutations independently predicts for poor outcome within this favorable subset of AML. Thus, adults with t(8;21)-positive AML and FLT3 mutations require alternative treatment strategies. Our data support the rationale of evaluating FLT3 tyrosine kinase inhibitors in these pts. Disclosures: No relevant conflicts of interest to declare.
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Schroeder, Thomas, Christian Saure, Ingmar Bruns, Fabian Zohren, Akos G. Czibere, Nelly Nancy Safaian, Roland Fenk, Rainer Haas, and Guido Kobbe. "Clinical Efficacy of Sorafenib in Patients with Acute Myeloid Leukemia (AML) and Activating FLT3-Mutations." Blood 114, no. 22 (November 20, 2009): 2057. http://dx.doi.org/10.1182/blood.v114.22.2057.2057.
Abstract:
Abstract Abstract 2057 Poster Board II-34 Introduction: Patients with acute myeloid leukemia (AML) and activating mutations in the Fms-like tyrosine-3 (FLT3) gene have an abysmal prognosis. Together with other groups we have recently demonstrated the clinical activity of the multikinase and FLT3 inhibitor sorafenib in patients with FLT3+ AML (Safaian et al., 2008; Zhang et al., 2008; Metzelder et al., 2009). We here present clinical results of 8 AML FLT3+ patients treated with sorafenib either prior or after allogeneic stem cell transplantation (allo-SCT) on an off-label basis. Patients, Treatment and Response Evaluation: Between February 2007 to August 2009 eight patients with AML (7 female, 1 male, median age: 47 years, range 23-63 years) were treated with sorafenib 800 mg daily (dose range 400-800 mg daily) for a median duration of 37 days (range 5-225 days). Six patients had an internal tandem duplication mutation (ITD), while 2 patients carried a tyrosine kinase domain (TKD) mutation. One patient received sorafenib at diagnosis before remission induction while all other patients had relapsed and/or refractory disease. Response and toxicity were evaluated regularly and defined according to established criteria. Results: Two of four patients who received sorafenib for refractory relapse after allo-SCT (median time to relapse 78 days, range 59-84 days) achieved complete remission (CR) (1 CR, 1 complete molecular remission (CMR) with disappearance of extramedullary chloromas) and survived 164 and 594 days, respectively. One of these patients died after another systemic relapse, while the other died as result of a CNS-chloroma being still in CMR in bone marrow (BM). In the 2 other patients sorafenib induced a hematological response (HR) and these patients survived 188 and 329 days before they died of progressive disease. Of the 4 patients treated prior allo-SCT, 2 had relapsed during consolidation after a previous CR, 1 had refractory disease and 1 was treated at diagnosis. Both patients with relapse showed response to sorafenib treatment thereby permitting allo-SCT. While one achieved HR, the other had regression of multiple isolated cutaneous relapse manifestations. Both patients are still alive at day +81 and day +16 in CMR and CR, respectively. The patient, who was primary refractory to double induction and high-dose cytarabine had a reduction of BM-blasts. She discontinued sorafenib because of neurotoxicity after 13 days. This patient reached a CR after allo-SCT, but died on day + 379 of another relapse. At the time of AML diagnosis the fourth patients had a WBC of 377.000/ul. Despite treatment with hydroxyurea, cytarabine and leukapheresis WBC could not be lowered <100.000/ul within 5 days and the patient developed pulmonary leukostasis syndrome. At this point of time FLT3 TKD mutation was detected and sorafenib was started promptly. Within the next 5 days WBC (peripheral blasts %) declined from 119.700/μl (98%) to 5.300/μl (28%) without tumor lysis syndrome facilitating induction therapy with cytarabine, daunorubicin and etoposide. Sorafenib therapy was continued in parallel and led to a CMR without increased toxicity. In general, sorafenib treatment was well tolerated. Besides neurotoxicity in one patient extrahematological side effects were almost limited to transient dermatological symptoms in two patients, which resolved after discontinuitation of sorafenib. Four Patients developed neutropenia grade IV and thrombopenia grade IV, which was not exclusively attributable to sorafenib, but also to the underlying AML. Conclusion: Our results add to the growing evidence that sorafenib is highly active in patients with FLT3+ AML. In view of the clinical course of our patients we suggest that sorafenib can achieve temporary disease control, but should be integrated into induction and consolidation regimens to achieve curative treatment. Recent data on synergistic effects between sorafenib and cytarabine and the CXCR4 inhibitor AMD3100 suggest these combinations for new clinical trials. Disclosures: Off Label Use: individual treatment approach of patients with refractory FLT3+ AML with multikinase inhibitor sorafenib, which is approved by EMEA + FDA for renal cell carcinoma.
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Perl, Alexander E., Jessica K. Altman, Naoko Hosono, Pau Montesinos, Nikolai A. Podoltsev, Giovanni Martinelli, Catherine C. Smith, et al. "Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib." Blood 136, Supplement 1 (November 5, 2020): 22–23. http://dx.doi.org/10.1182/blood-2020-136395.
Abstract:
Background: Gilteritinib is a FLT3 inhibitor with demonstrated efficacy and safety in patients with FLT3-mutated relapsed or refractory (R/R) AML. The efficacy of gilteritinib in patients with prior tyrosine kinase inhibitor (TKI) therapy is not clearly defined. The phase 1/2 CHRYSALIS trial demonstrated the safety and antileukemic activity of gilteritinib in a FLT3-mutation-enriched R/R AML population (Perl AE, et al. Lancet Oncol. 2017). The phase 3 ADMIRAL trial demonstrated the superiority of gilteritinib to salvage chemotherapy (SC) in FLT3-mutated patients based on longer median overall survival (OS) with gilteritinib (9.3 vs 5.6 months; hazard ratio [HR]=0.64 [95% CI: 0.49, 0.83]; P<0.001) (Perl AE, et al. N Engl J Med. 2019). We sought to determine whether prior TKI therapy affected response and survival in these two trials. Methods: We retrospectively analyzed clinical outcomes in patients with R/R AML previously treated with TKIs midostaurin or sorafenib, before receiving 120- or 200-mg gilteritinib in the CHRYSALIS trial, or before receiving 120-mg gilteritinib in the ADMIRAL trial. Patients randomized to SC in the ADMIRAL trial were also assessed. Patients in the CHRYSALIS trial had received at least one line of prior AML therapy; patients in the ADMIRAL trial received only one line of prior AML therapy. Results: Of the 145 FLT3-mutation-enriched patients who received 120- or 200-mg gilteritinib in the CHRYSALIS trial, 33 (23%; 120 mg, n=15; 200 mg, n=18) had received a prior TKI (all received sorafenib). Baseline characteristics among patients who received (n=33) or did not receive prior TKIs (n=112) were similar; median age was 56 and 61 years, respectively. Across both dose groups, FLT3 mutation types in prior TKI-treated and non-treated patients were: FLT3-ITD (88% vs 84%, respectively), FLT3-TKD (0 vs 8%, respectively), FLT3-ITD and -TKD (12% vs 6%, respectively), and unknown or missing (0 vs 2%, respectively). Rates of composite complete remission (CRc) were similar in patients who received prior TKIs (42%; n=14/33) and in those who did not (43%; n=48/112). Among patients who received prior TKIs, rates of CRc were 53% (n=8/15) in the 120-mg dose group and 33% (n=6/18) in the 200-mg dose group (Table 1); rates of CRc in patients who did not receive prior TKIs were similar across both the 120- and 200-mg dose groups (44% [n=18/41] and 42% [n=30/71], respectively). Among patients treated with prior TKIs across the 120- or 200-mg dose groups (n=33), most (73%; n=24) had received ≥3 lines of any prior AML therapy. In the phase 3 ADMIRAL trial, 31 of 247 (13%) R/R FLT3-mutated AML patients in the gilteritinib arm and 14 of 124 (11%) patients in the SC arm had received prior TKIs. Demographic and baseline characteristics were well balanced between treatment arms and were also similar between prior TKI-treated (n=45) and non-treated patients (n=326); median age was 57 and 62 years, respectively. Among prior TKI-treated and non-treated patients, FLT3 mutation types in gilteritinib and SC arms were: FLT3-ITD (71% vs 93% and 89% vs 91%, respectively), FLT3-TKD (16% vs 7% and 7% vs 8%, respectively), and FLT3-ITD and -TKD (13% vs 0 and 1% vs 0, respectively). FLT3 mutation type was unconfirmed in 5 of 326 (2%) patients who did not receive prior TKIs (gilteritinib vs SC, 2% vs 1%, respectively). In the gilteritinib arm, CRc rates were comparable in patients who received (48%; n=15/31) and did not receive prior TKIs (55%; n=119/216); lower CRc rates were observed in the SC arm in both TKI-treated and non-treated groups (21% [n=3/14] and 22% [n=24/110], respectively) (Table 2). Median OS in patients treated with prior TKIs, albeit not statistically significant, remained high in patients treated with gilteritinib compared with those treated with SC (6.5 vs 4.7 months, respectively; HR=0.671 [95% CI: 0.328, 1.376]) (Table 2). In patients who did not receive prior TKIs, median OS was 9.6 months in the gilteritinib arm and 6.0 months in the SC arm (HR=0.625 [95% CI: 0.474, 0.824]). Conclusions: Patients with R/R AML who received prior TKIs (midostaurin or sorafenib) were able to achieve remission with gilteritinib. High response rates with gilteritinib were observed in heavily pre-treated FLT3-mutation-enriched patients in the CHRYSALIS trial who received prior TKIs. Higher response rates with gilteritinib than with SC were observed in prior TKI-treated patients with FLT3 mutations in the ADMIRAL trial. Disclosures Perl: Takeda: Honoraria, Other: Travel costs for meeting; Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Agios: Consultancy, Honoraria, Other; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Novartis: Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; New Link Genetics: Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Jazz: Honoraria, Other; Biomed Valley Discoveries: Research Funding. Altman:Cancer Expert Now: Consultancy; ASH: Consultancy; PeerView: Consultancy; Bristol-Myers Squibb: Consultancy; Fujifilm: Research Funding; AbbVie: Other: advisory board, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Theradex: Other: Advisory Board; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Janssen: Consultancy; Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy. Montesinos:Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau. Podoltsev:Blueprint Medicines: Consultancy, Honoraria; Astellas Pharma: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Daiichi Sankyo: Research Funding; Genentech: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Consultancy, Honoraria; Kartos Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daichii Sankyo: Consultancy, Research Funding; Incyte: Consultancy; Jazz: Consultancy. Smith:FujiFilm: Other: Research support, Research Funding; Abbvie: Other: Research Support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding. Levis:Amgen: Honoraria; Menarini: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Röllig:Abbvie, Novartis, Pfizer: Consultancy, Research Funding; Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy. Groß-Langenhoff:Astellas: Current Employment. Hasabou:Astellas Pharma: Current Employment. Lu:Astellas: Current Employment. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months.
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Stone, Richard M., Sumithra Mandrekar, Ben L. Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, et al. "The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance])." Blood 126, no. 23 (December 3, 2015): 6. http://dx.doi.org/10.1182/blood.v126.23.6.6.
Abstract:
Abstract Background: Midostaurin (M) is a multi-targeted small molecule FLT3 inhibitor which has single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant FLT3 AML. The objective of this global rand phase III trial was to determine if the addition of M to ind and consol therapy followed by one year of maint would improve overall survival (OS) compared to standard chemotherapy in younger adults with activating FLT3 muts. Methods: Between May 2008 and October 2011, 3279 previously untreated AML pts age 18-60 (exclusive of acute promyelocytic leukemia) in 225 sites/17 countries were screened for FLT3 muts at one of 7 academic labs (subject to extensive assay cross-validation). Hydroxyurea was allowed for up to 5 d prior to beginning ind therapy while awaiting results of mut testing. Pts were rand for the duration of therapy to M or P stratified by FLT3 mut subtype (TKD v ITD high allelic mut fraction (>0.7) vs low mut fraction (0.05-0.7). Ind therapy consisted of D 60 mg/m2 IV d1-3 and C 200 mg/m2 d1-7 CIV plus M or P (50 mg po bid, d 8-22). Re-treatment with a second blinded course was allowed if residual AML was noted on a d 21 marrow exam. Pts achieving complete remission (CR) received 4 cycles of C 3g/m2 over 3h q 12h on days 1, 3, and 5 plus M or P (50 mg po bid, d 8-22) followed by a year of maint therapy with M or P (50 mg po bid). Transplantation (SCT) was allowed. With a sample size of 717 pts, the trial was powered to detect an improvement from 16.3 (P) to 20.9 (M) months in median OS (HR = 0.78) using a one-sided alpha of 0.025 and power of 84%. The final analysis was to occur after 509 deaths, but given the slow rate of events (359 deaths by April 2015), the trial was amended to change the timing of the OS analysis, and promote event free survival (EFS, defined as the earliest of death, relapse, or no CR within 61 d of the start of ind) as a key secondary endpoint. The critical value for this primary analysis is set at 0.02286 (1-sided) accounting for the alpha spent at the interim analysis (0.5%). Support: U10CA180821, U10CA180882, CA31946, Novartis Results: 717 pts (341 FLT3 ITD-Low, 214 FLT3 ITD-High; 162 FLT3 TKD) were rand to either M (n=360) or P (n=357). There were no significant differences between the arms in age (median, 48y), race, FLT3 subtype, or baseline CBC except for gender (M, 48.2% male; P, 40.6% male; p=.04). All pts are off active treatment, with a median follow-up of 57 months for surviving pts. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic or non-hematologic adverse events (AEs) between M and P (regardless of attribution). A total of 37 grade 5 AEs were reported (M, 5.3%; P, 5.0%; p=1.0). No differences in treatment-related grade 5 AEs were observed (M, 3.1%; P, 2.5%; p=0.82). CR rate is 59% (M) and 54% (P) (p=0.18). The HRs comparing M to P for OS is 0.77 (one-sided p = 0.007; Figure 1), and for EFS is 0.80 (one-sided p = 0.004; Figure 2). 402/717 (57%) pts received an allogeneic SCT (M, 58%; P, 54%) at any time; 177/717 (25%) in CR1 (M, 27%; P, 22%). Median time to allogeneic SCT was similar on each arm (M, 5.0 months; P, 4.6; p=0.23). Secondary analyses for OS and EFS censoring at the time of SCT provided similar results (Table). The benefit of M was consistent across all FLT3 subgroups for both EFS and OS (Figure 3). Conclusions: The C10603 trial demonstrated that a prospective trial in a pre-therapy genetically defined subgroup of AML pts was feasible and that the addition of the multi-kinase inhibitor M to standard chemotherapy and for one year of maint therapy significantly improved EFS and OS (in both uncensored and censored for transplant analyses) in pts whose blasts had a TKD or ITD (low or high FLT3 mut burden). These findings may lead to improved outcomes through the use of M as a component of therapy in younger adults with mutant FLT3 AML. Table.ArmMedian, mos (95% CI)p-value 15-year Event rate% (95% CI)HR2(95% CI)OSM74.7 (31.5, * )0.00750.8 (45.4-55.9)0.77 (0.63, 0.95)P26.0 (18.5, 46.5)43.1 (37.6-48.4)OS, SCT censoredM* (*,*)0.04762.6 (54.6-69.7)0.77 (0.56,1.05)P* (36.9, *)54.9 (46.2-62.8)EFSM8.0 (5.3, 10.6)0.004426.7 (22.2-31.5)0.80 (0.67, 0.95)P3.0 (1.9, 5.8)19.1 (15.1-23.6)EFS, SCT censoredM8.2 (5.5, 10.7)0.02524.2 (18.9-29.8)0.84 (0.70, 1.0020)P3.0 (1.9, 5.8)21.8 (16.8-27.3)1Stratified on FLT3 subtype; one-sided, log-rank p-value.2Cox model stratified on FLT3 subtype.*= not attained Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Stone: Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Amgen: Consultancy; Agios: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Celator: Consultancy; Juno: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy. Off Label Use: midostaurin- FLT 3 inhibitor. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding. Larson:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy, Research Funding; Pfizer: Consultancy.
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Mushtaq, Muhammad Umair, Sibgha Gull Chaudhary, Guru Subramanian Guru Murthy, Aric C. Hall, Ehab L. Atallah, and Ryan J. Mattison. "Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Relapsed/Refractory Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5246. http://dx.doi.org/10.1182/blood-2018-99-112204.
Abstract:
Abstract Background The inflammatory and immune response in tumor microenvironment plays a critical role in cancer progression. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor in solid and lymphoid malignancies. We explored the association of NLR with response to chemotherapy and overall survival (OS) in patients with relapsed/refractory acute myeloid leukemia (RR-AML). Methods A single-center retrospective study was conducted, including 63 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. Refractory AML was defined as failure to achieve remission and <50% reduction in myeloblasts after one or more courses of induction chemotherapy according to the Center for International Blood and Marrow Transplant Research (CIBMTR) reporting criteria. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and Kaplan-Meier analyses, using log-rank test, were performed. Cox regression analyses were conducted to correlate factors with OS. Hazard ratios (HR) and adjusted HR (aHR) with 95% confidence intervals (CI) were obtained. Statistical significance was considered at P<0.05. Results The study included 63 patients with relapsed (57%) or refractory (43%) AML. Median age was 58 years and 59% of patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (25%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (6%) and AML not otherwise specified (43%). Cytogenetics were good (5%), intermediate (68%) and poor (27%) with normal (46%), complex (17.5%) and trisomy (14%) being common karyotypes. Frequent molecular abnormalities were NPM1 (21%), FLT3-ITD (17.5%), FLT3-TKD (8%), DNMT3A (6%) and CEBPA (5%). AML risk status was good (19%), intermediate (36.5%) and poor (44.5%), based on cytogenetic and molecular abnormalities as defined by the ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 11% of patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% of patients. Median values for clinical factors were: hemoglobin 9.2 g/dL, platelets 43 K/uL, leukocytes 1.7 K/uL, neutrophils 262 /uL, lymphocytes 820 /uL and LDH 211 U/L. Median bone marrow cellularity was 50% with 35% myeloblasts. Median NLR was 0.22 (mean 1.54) and 11% patients had NLR of 3 or more. Salvage chemotherapy included MEC (71%), CLAG-M (24%) and CLAG (5%). Complete remission (CR) was noted in 36.5% patients, 8% of patients had CR with incomplete hematologic recovery (CRi) and 55.5% patients were refractory. Thirty patients (48%) received HSCT, of which 40% (n=12/30) were refractory or relapsed. After index salvage regimen, about half of patients received one (33%) or two (16%) lines of further chemotherapy. At last follow-up, 32% of patients were in CR and 62% had relapsed or refractory disease. Nineteen (30%) patients were alive at last follow-up with a median OS of 8.1 months (95% CI 5.0-11.1). Significant correlates of poor OS included MDS-related AML (HR 2.19, 95% CI 1.13-4.27, P=0.021) and therapy-related AML (HR 4.02, 95% CI 1.16-13.90, P=0.028) compared to de-novo AML, poor-risk AML (HR 3.09, 95% CI 1.18-8.10, P=0.022) compared to good-risk AML, refractory to salvage chemotherapy (HR 7.04, 95% CI 3.51-14.14, P<0.001) and high NLR (HR 1.13, 95% CI 1.04-1.23, P=0.003) while HSCT (HR 0.25, 95% CI 0.13-0.48, P<0.001) predicted better OS. Relapsed vs refractory AML was not associated with OS. In age- and gender-adjusted multivariate model, MDS-related AML (aHR 3.85, 95% CI 1.68-8.87, P=0.002), therapy-related AML (aHR 4.72, 95% CI 1.10-20.31, P=0.037), refractory to salvage chemotherapy (aHR 12.93, 95% CI 4.95-33.78, P<0.001), HSCT (aHR 0.12, 95% CI 0.05-0.27, P<0.001) and high NLR (aHR 1.14, 95% CI 1.05-1.25, P=0.004) independently predicted OS. Median OS in patients with NLR of 3 or more was 3.4 months (95% CI 3.2-3.7) versus 9.2 months (95% CI 7.1-11.3) in those with NLR <3 (P=0.040). Conclusion High NLR independently predicts poor OS in RR-AML patients. Our findings warrant further studies with a large prospective cohort to explore the prognostic significance of NLR and incorporate it in AML risk assessment. Disclosures Atallah: BMS: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy.
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Wang, Jianxiang, Bin Jiang, Jian Li, Ligen Liu, Xin Du, Hao Jiang, Jianda Hu, et al. "Gilteritinib Versus Salvage Chemotherapy for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Phase 3, Randomized, Multicenter, Open-Label Trial in Asia." Blood 138, Supplement 1 (November 5, 2021): 695. http://dx.doi.org/10.1182/blood-2021-145436.
Abstract:
Abstract Background: Due to poor prognosis, treatment options for patients with FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) who are refractory to therapy or have relapsed (R/R) are needed globally. Gilteritinib is approved in multiple countries, including Japan, and has recently received conditional approval in China for the treatment of R/R FLT3mut+ AML; in the phase 3 ADMIRAL trial, superior survival benefit and a favorable safety profile were shown for patients receiving gilteritinib compared to those receiving salvage chemotherapy (SC) (HR 0.64 [95% CI: 0.49, 0.83]; P<0.001) in the R/R FLT3mut+ AML setting. While data from the Asian subpopulation of ADMIRAL have been evaluated, larger randomized, controlled trials of outcomes for treatments in a predominantly Asian population are lacking. Aim/Objective: To evaluate the efficacy and safety/tolerability of gilteritinib compared with SC in Asian patients with R/R FLT3mut+ AML after first-line therapy. Methods: In this phase 3, open-label, multicenter COMMODORE (NCT03182244) trial, adult patients in China, Russia, Singapore, Thailand, and Malaysia with R/R FLT3mut+ AML were randomized 1:1 to gilteritinib 120 mg orally per day or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor) over continuous 28-day cycles. Patients must have had an ECOG performance status score ≤2; those with acute promyelocytic leukemia, BCR-ABL-positive leukemia, clinically active central nervous system disease, or secondary AML were excluded. The primary endpoint was overall survival (OS), and key secondary efficacy endpoints were event-free survival (EFS) and complete remission (CR). Additional secondary endpoints included duration of remission, composite CR (CRc), and safety/tolerability. OS and EFS were analyzed with stratified Cox proportional hazard models, and response rates were analyzed with the Cochran-Mantel-Haenszel test. Results of the interim analysis are presented here. Results: As of June 30, 2020, a total of 234 patients were randomized (gilteritinib, n=116; SC, n=118). Median age was 51.5 and 49.5 years in the gilteritinib and SC groups, respectively; most patients had not previously received FLT3 inhibitors (87.9% and 93.2%, respectively). Baseline FLT3 mutations in the gilteritinib vs SC groups were: FLT3-ITD (91.4% vs 83.1%), FLT3-TKD (6.0% vs 11.9%), and both FLT3-ITD and FLT3-TKD (2.6% vs 5.1%). Median follow-up duration for OS was 11.1 months for gilteritinib and 6.9 months for SC. Median OS was significantly longer in the gilteritinib group (9.0 months) compared with the SC group (4.7 months; HR 0.549 [95% CI: 0.379, 0.795]; P=0.00126; Figure); 1-year survival rates were 33.3% and 23.2%, respectively. Patients on gilteritinib had significantly longer EFS than those receiving SC (median EFS 2.8 vs 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; P=0.00004). A higher proportion of patients achieved CR on gilteritinib (16.4%) compared with SC (10.2%; P=0.17690); CRc rates were 50.0% and 20.3% (P<0.00001). Grade ≥3 adverse events (AEs) in the gilteritinib (97.3%) vs SC (94.2%) groups were comparable; rates for serious AEs were higher for gilteritinib (73.5%) vs SC (61.5%). When adjusted for treatment exposure, AE rates were lower with gilteritinib (grade ≥3, 55.56 events/patient-year [E/PY]; serious, 6.19 E/PY) than with SC (grade ≥3, 164.00 E/PY; serious, 12.40 E/PY). The most common AEs occurring in the gilteritinib group were anemia (76.1%), thrombocytopenia (46.9%), pyrexia (41.6%), and increased blood lactate dehydrogenase (41.6%); for SC, the most common AEs were anemia (64.4%), decreased white blood cell count (41.3%), and thrombocytopenia (38.5%). AEs leading to death occurred in 22 (19.5%) and 15 (14.4%) of patients receiving gilteritinib or SC, respectively. Conclusions: Gilteritinib significantly prolonged OS and EFS compared with SC in patients with R/R FLT3mut+ AML in Asia. When adjusted for treatment exposure, safety/tolerability was favorable for gilteritinib compared with SC. The results of the COMMODORE trial further validate and affirm the clinical efficacy and safety data from the ADMIRAL trial, reinforcing the significant benefit of gilteritinib in R/R FLT3mut+ AML. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Li: Astellas Pharma, Inc.: Research Funding. Liu: Astellas Pharma, Inc.: Research Funding. Du: Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Hu: Astellas Pharma, Inc.: Research Funding. Yuan: Astellas Pharma, Inc.: Current Employment. Sakatani: Astellas Pharma, Inc.: Current Employment, Current equity holder in publicly-traded company. Kadokura: Astellas Pharma, Inc.: Current Employment. Takeuchi: Astellas Pharma, Inc.: Current Employment. Izuka: Astellas Pharma, Inc.: Current Employment. Girshova: Astellas Pharma, Inc.: Research Funding. Tan: Astellas Pharma, Inc.: Research Funding. Wong: Astellas Pharma, INc.: Research Funding. Khuhapinant: Astellas Pharma, Inc.: Research Funding. Martynova: Astellas Pharma, Inc.: Research Funding. Hasabou: Astellas Pharma, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.
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Marcucci, Guido, Kati Maharry, Klaus H. Metzeler, Stefano Volinia, Yue-Zhong Wu, Krzysztof Mrózek, Deedra Nicolet, et al. "The Clinical Role of Micrornas (miRs) in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML): miR-155 Upregulation Independently Identifies High-Risk Patients (Pts)." Blood 120, no. 21 (November 16, 2012): 1387. http://dx.doi.org/10.1182/blood.v120.21.1387.1387.
Abstract:
Abstract Abstract 1387 miR-155 is upregulated in aggressive subtypes of solid tumors and leukemia. In AML, higher miR-155 expression is associated with FLT3-ITD. However, whether miR-155 upregulation impacts on clinical outcome independently from FLT3-ITD and other prognosticators is unknown. We evaluated the prognostic impact of miR-155 in 363 CN-AML pts (153 age <60 y; 210 age ≥60 y) that were treated with cytarabine-daunorubicin-based regimens and had a median follow-up of 7.9 y (range, 2.3–12.9). miR-155 levels were measured in pretreatment marrow or blood by the NanoString nCounter assay quantifying expression of the encoding gene MIR155HG; other molecular markers were assessed centrally. High miR-155 expressers (miR-155) had higher WBC (P<.001) and were more often FLT3-ITD-positive (pos; P<.001), RUNX1-mutated (mut; <.001), WT1-mut (P=.03), ↑ ERG (P=.02) and ↑ BAALC (P=.002), and less often CEBPA-mut (P=.003), IDH2-mut (P=.004) and FLT3-TKD-pos (P=.08) than low expressers (↓ miR-155). ↑ miR-155 had lower CR rates (P<.001), shorter DFS (P=.001) and OS (P<.001), than ↓ miR-155. In multivariable analyses (MVA; Table), ↑ miR-155 was associated with lower CR rates (P=.007) and shorter OS (P<.001). Among younger pts, ↑ miR-155 had lower CR rates (P=.03) and shorter DFS (P<.001) and OS (P<.001) than ↓ miR-155. In MVA (Table), ↑ miR-155 status remained associated with worse CR rate (P=.06), shorter DFS (P=.003) and OS (P=.01). Among older pts, ↑ miR-155 had lower CR rates (P=.008) and shorter OS (P<.001); in MVA (Table), ↑ miR-155 remained associated with worse CR (P=.03) and shorter OS (P=.05). In the European LeukemiaNet classification, younger ↑ miR-155 in the Favorable (Fav) Genetic Group (GG; CEBPA-mut and/or NPM1-mut without FLT3-ITD) had lower CR rates (P=.03) and shorter DFS (P=.04) and OS (P=.02) than ↓ miR-155. In the younger Intermediate-I (Int-I) GG pts (with wild-type CEBPA, NPM1-mut with FLT3-ITD, or wild-type NPM1), miR-155 expression did not impact independently on outcome. In older pts, ↑ miR-155 had a shorter OS both in the Fav (P=.06) and Int-I GGs (P=.05) than ↓ miR-155. To gain biologic insights, we derived an Affymetrix gene-expression signature that comprised 196 mRNAs significantly correlated with miR-155 expression. Consistent with previous mechanistic studies, Gene Ontology analysis revealed that the ↑ miR-155-associated signature was enriched for genes involved in anti-apoptotic, proliferative and inflammatory activities (FDR<0.05). ↑ miR-155 was not significantly correlated with that of any other microRNAs (miRs) thereby supporting the unique role of miR-155 among the miRs in AML. In summary, miR-155 expression is independently associated with clinical outcome in CN-AML and may allow for better evaluation of molecular risk, especially in pts lacking FLT3-ITD, like those in the ELN Fav GG. Moreover, given its role in deregulation of fundamental mechanisms of cell homeostasis and the emergence of miR inhibitors, miR-155 may become a novel therapeutic target. Table. MVA in pts with primary CN-AML Group CR DFS OS OR P HR P HR P All pts miR-155 expression not significantly associated with DFS a miR-155, ↑ v ↓ 0.46 .007 1.62 <.001 NPM1, mut v wt 2.42 .005 BAALC, ↑ v ↓ 0.37 .002 2.16 <.001 WBC, each 50 units 0.65 <.001 Age group, older v younger 0.43 .003 2.38 <.001 FLT3-ITD, pos v neg 1.78 <.001 Race, white v nonwhite 1.62 .03 Pts age < 60 y miR-155, ↑ v ↓ 0.39 .06 2.13 .003 1.84 .01 RUNX1, mut v wt 0.21 .01 Age, each 10 y increase 0.45 .004 WBC, each 50 units 1.49 <.001 FLT3-ITD, pos v neg 2.82 <.001 1.82 .01 FLT3-TKD, pos v neg 3.27 <.001 BAALC, ↑ v ↓ 2.66 <.001 2.33 <.001 Race, white v nonwhite 2.81 .02 CEBPA, mut v wt 0.47 .02 WT1, mut v wt 2.25 .005 Pts age ≥ 60 y miR-155 expression not significantly associated with DFS miR-155, ↑ v ↓ 0.46 .03 1.36 .05 NPM1, mut v wt 2.45 .03 BAALC, ↑ v ↓ 0.32 .004 2.18 <.001 WBC, each 50 units 0.65 .005 Age, each 10 y increase 0.48 .02 FLT3-ITD, pos v neg 1.56 .006 ↑, high expression; ↓, low expression; CR, complete remission; DFS, disease-free survival; HR, hazard ratio; mut, mutated; neg, negative; OR, odds ratio; OS, overall survival; pos, positive; WBC, white blood count; wt, wild-type. Odds ratios > (<) 1.0 mean higher (lower) CR rate and HRs > (<) 1.0 mean higher (lower) risk of relapse or death (DFS) or death (OS) for the higher values of continuous variables and the 1st category listed for categorical variables. Disclosures: No relevant conflicts of interest to declare.
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Schnittger, Susanne, Christiane Eder, Tamara Alpermann, Frank Dicker, Madlen Ulke, Alexander Kohlmann, Sabrina Kuznia, Wolfgang Kern, Torsten Haferlach, and Claudia Haferlach. "WT1 Mutations Are Secondary Events In AML and Show Varying Frequencies Within Genetic Subgroups and Different Impact On Prognosis." Blood 122, no. 21 (November 15, 2013): 2542. http://dx.doi.org/10.1182/blood.v122.21.2542.2542.
Abstract:
Abstract Background Mutations (mut) in the WT1 gene belong to the first genetic aberrations described in AML. In contrast to recurrent fusion genes or NPM1mut WT1mut do not seem to be disease defining. Also in contrast to other mutations in AML, for most of which a certain prognostic value has been established, the impact of WT1mut still is discussed controversially. Aim Analyze the frequency and prognostic impact of WT1 mutations in comparison to other genetic aberrations. Patients and Methods 3,157 unselected AML patients (pts) were analyzed (de novo: n=2,699, s-AML: n=234, t-AML: n=224). 1,708 pts were male and 1,449 female. Median age was 67.1 years (y) (range: 17.8-100.4 y) with 1,108 pts <60 y and 2,049 ≥60 y. The mutational hot spot regions of WT1 (exons 7 and 9) were analyzed by direct Sanger sequencing with a sensitivity of ∼10%. Karyotype and WT1 mutation status was available in all cases. Other mutations were assessed in subsets: ASXL1 (n=1,951), CEBPA (n=2,670), DNMT3A (n=1,293), FLT3-ITD (n=3,149), FLT3-TKD (n=3,004), IDH1R132 (n=2,431), IDH2R140 (n=2,380), IDH2R172 (n=2,412), KRAS (n=1,409), NRAS (n=1,780), NPM1 (n=3,003), MLL-PTD (n=2,961), RUNX1 (n=2,390), TET2 (n=1,016) and TP53 (n=1,215). Results A total of 189 WT1 mutations were detected (exon 7: n=151, exon 9: n=38). The total frequency of WT1mut pts was 175/3,157 (5.5%). 11 pts were double to quadruple mutated. The frequency was heterogeneous with respect to AML subtypes. Compared to all others, significantly higher frequencies were detected in biallelic CEBPAmut (15/110; 13.6%; p=0.001), followed by t(15;17)/PML-RARA (18/164; 11.0%, p=0.004), and FLT3-ITD (58/682; 8.5%, p<0.001). Lower frequencies were observed in DNMT3Amut (18/412; 4.3%, p=0.014, ASXL1mut (6/355; 1.7%, p<0.001), IDH2R140 (5/286; 1.7%, p=0.001), and IDH1R132 (2/222; 0.9%, p<0.001). WT1mut were never detected in pts with complex karyotypes (0/175; p=0.047) or those with IDH2R172 (0/68; p=0.020). Further, WT1mut were more frequent in females (95/1,449, 6.6%) than in males (80/1,708, 4.7%) (p=0.014) and in younger pts (<60 y: 102/1,108, 9.2% vs ≥ 60 y: 73/2,049, 3.6%; p<0.001). Median age of pts with WT1mut was 55.5 y compared to 63.6 in WT1wt (p<0.001). Further, WT1mut were associated with lower platelet count (58.4 vs 84.7 x109/L; p<0.001) and lower hemoglobin level (8.8 vs 9.3 g/dL, p=0.001). There was no association to the history of the disease or white blood cell count. Stability of WT1mut was analyzed in 35 paired diagnostic and relapse samples (median time of relapse after diagnoses: 11.1 months (m); range: 2.6-60.6 m). In 23 cases (65.7%) the WT1mut was retained at relapse and in 12 cases (34.3%) it was lost. In 5 cases a sample at 2nd relapse was available (median time from 1st relapse: 8.5 m, range: 6.0-18.0 m). 3 of these cases retained and 2 lost the WT1mut. Analysis of prognostic impact was restricted to intensively treated pts (n=1,936, WT1mut: n=132, 6.8%). In the total cohort, there was no impact of WT1mut on prognosis. In pts ≥60 y there was a trend to shorter event free survival (EFS) for WT1mut (9.3 vs 12.3 m, p=0.052). In the two prognostically favorable groups with high WT1mut incidences (biallelic CEBPAmut and PML-RARA) no effect on outcome was seen. When restricting the analysis to normal karyotype AML (WT1mut: n=85, WT1wt: n=1,093) WT1mut pts had shorter EFS (10.8 vs 17.9 m, p=0.008). This was true for the younger (12.2 vs 29.0 m, p=0.007) as well as for the older pts (9.3 vs 13.9 m, p=0.016). In a multivariate analysis all parameters with significant impact on EFS in univariate analysis were included: age (p<0.001, HR: 1.24), ASXL1mut (p<0.001, HR: 1.36), FLT3-ITD (p<0.001, HR: 1.55), NPM1mut/FLT3-ITD wild-type (p<0.001, HR:1.55), RUNX1 (p=0.019, HR: 1.23, and WT1mut (p=0.009, HR: 1.64). In multivariate analysis WT1mut was found to have independent adverse impact on EFS (p=0.002, HR: 1.64) besides FLT3-ITD status (p<0.001, HR: 1.71) and age (p<0.001, HR: 1.28). Conclusions WT1 mutations are 1) more frequent in females and younger AML, 2) more frequent in t(15;17)/PML-RARA, biallelic CEBPAmut, FLT3-ITD mutated AML, and nearly mutually exclusive of ASXL1, IDH1, IDH2 and complex karyotype. 3) The distribution pattern in different genetic subtypes and the instability during follow-up as shown by paired sample analyses clearly emphasize a secondary character of this mutation. 4) For AML with normal karyotype an independent adverse impact of WT1mut on EFS was shown. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Ulke:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kuznia:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Liévin, Raphaël, Nicolas Duployez, Loïc Vasseur, Juliette Lambert, Mael Heiblig, Mathilde Hunault, Claude Gardin, et al. "Hyperleukocytosis Increases the Risk of Early Relapses Independently of Genetics in AML." Blood 142, Supplement 1 (November 28, 2023): 4322. http://dx.doi.org/10.1182/blood-2023-173614.
Abstract:
Background. Higher white blood cell (WBC) count at diagnosis is associated with specific gene lesions and higher early death rates in AML patients (pts) treated intensively. Whether higher WBC count at diagnosis affects outcome beyond remission independently of genetics is unknown. Methods. 1,371 AML pts treated intensively in 3 ALFA trials (0702 18-60y, 0701 50-70y, 1200 60y+) with centralized genetics were studied. Genetic alterations found in >5% of pts (n=22) were analyzed. Hyperleukocytosis (HL) was defined as WBC > 50 x10 9/L. NPM1 MRD was stratified as published (Balsat, J Clin Oncol 2017). All prognostic analyses were stratified on trial. Time-dependent effects were introduced in multivariable Cox models when the proportional hazard (PH) assumption was violated. Results. The median WBC count at diagnosis was 7.1 x10 9/L (range 0.3-546.6), and 235 pts (17.1%) had HL. HL pts had poorer performance status (p<0.001), lower platelet counts (p=0.003), higher frequency of de novo AML (p=0.006) and more favorable genetic risk (ELN 2022 criteria, p<0.001). In a multivariable model, HL was independently associated with more frequent NPM1, FLT3-ITD and -TKD mutations, and less frequent STAG2 and -17/17p- alterations (all p<0.05, Figure 1A). Complete remission (CR [including CR with incomplete platelet recovery, CRp]) and early death (ED) rates were 77.4 vs 80.0% (p=0.38) and 8.9 vs 5.0% (p=0.03) in pts with and without HL, respectively (resp). In a multivariable model accounting for ELN22 risk and age, HL was independently associated with more frequent ED (OR =2.20, 95%CI 1.26-3.75, p=0.004), and a trend to more frequent primary induction failure (OR=1.40, 95%CI 0.95-2.05, p=0.08). In the 1,091 pts achieving CR/CRp (182 and 909 with and without HL resp), 1-y and 2-y cumulative incidence of relapse were 39.0% vs 26.1% and 44.0% vs 40.2% resp, suggestive of a time-dependent effect of HL on post-remission outcome ( Figure 1B). Considering relapse and death as competing events, a multivariable model revealed a significant impact of HL on relapse (subdistribution hazard ratio, sHR=1.59, p=0.0003), independent of ELN22 risk and age, but not on non-relapse mortality (sHR=0.69, p=0.23). HL violated the PH assumption in a univariable Cox model for DFS (p=0.0003). We thus performed multivariable Cox models for DFS separating early (< 1 year from CR) and late (≥1 year) effects for HL. In a multivariable time-dependent model, HL significantly impaired early (HR=1.89, p<10 -4), but not late (HR=0.79, p=0.29) DFS, independently of ELN risk and age. These results were confirmed considering WBC count as a (log-transformed) continuous variable, accounting for all differentially represented genetic lesions instead of ELN22 risk or censoring at allogeneic HCT. In a validation cohort of 1,089 pts <60y reaching CR after intensive chemotherapy in the BIG-1 trial (NCT02416388) where median WBC was 7.7 x10 9/L and 16.1% of pts were HL, the adverse risk of HL on CIR (sHR=1.39, p=0.007) but not NRM (sHR=1.02, p=0.95) and on early (HR=1.42, p=0.01), but not late (HR=1.24, p=0.23) DFS independent of ELN22 risk and age was validated. Finally, to explore the mechanism underlying the higher early relapse rate of HL pts, we analyzed NPM1 MRD (n=152) and LSC17 (n=504) data from the 0702 trial. A higher WBC count was predictive of suboptimal MRD (OR=1.97, p=0.05) independently of FLT3-ITD status. A higher WBC count was significantly correlated to lower LSC17 score (Spearman rho=0.23, p<10-5). Conclusion. A high WBC count at diagnosis predicts higher rates of early, but not late relapse, independent of genetic risk. Our results strengthen the hypothesis that distinct biological mechanisms underpin early vs late chemoresistance in AML.
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Balsat, Marie, Aline Renneville, Xavier Thomas, Alice Marceau, Stéphane De Botton, Olivier Nibourel, Emmanuel Raffoux, et al. "NPM1 Minimal Residual Disease As Prognostic and Predictive Factor in Young Adults with Acute Myeloid Leukemia: a Study By the French ALFA Group." Blood 126, no. 23 (December 3, 2015): 2581. http://dx.doi.org/10.1182/blood.v126.23.2581.2581.
Abstract:
Abstract Introduction Therapy decision in young adults with acute myeloid leukemia (AML) is mostly guided by pre-therapeutic risk assessment based on cytogenetical and molecular characterizations. Mutations in the nucleophosmin 1 (NPM1 m) gene represent one of the most common gene mutations, found in around one third of AML and associated with normal karyotype in 85% of cases. Because of their homogeneous mutation pattern and their clonal stability, NPM1 mutations are an effective tool for monitoring MRD. The aim of this study was to assess the prognostic impact of post-induction NPM1 MRD in homogeneously treated patients and to address the question of whether NPM1 MRD may be used as a predictive factor of allogeneic stem cell transplantation (SCT) benefit in this subgroup of patients. Materiel and methods Among 196 NPM1 m patients treated in the ALFA-0702 trial, 172 achieved complete remission (CR). A MRD was available in 152 patients, on peripheral blood (PB) in 135 patients and on bone marrow (BM) in 135 patients. MRD levels were reported as the normalized values of NPM1 m copy number/ABL copy number x 100 (%). Patients were also screened for FLT3-TKD, FLT3-ITD, CEBPA, DMT3A, IDH1, IDH2, WT1 and TET2 mutations. Patients that did not belong to ELN-favorable group were eligible for allogeneic SCT (N=71). Results The median follow-up was 3.5 years (95%CI: 3.1-3.9). The karyotype was normal in 122 patients (80.3%), and a FLT3-ITD was found in 59/150 (39.3%) with a median FLT3-ITD allelic ratio of 0.385 (range: 0.02-8.0). Fifty out of the 71 patients eligible for SCT were allografted in first CR. The 3-year CIR and OS censored at SCT were 29.3% (95%CI: 21.5-39.4) and 78.6% (95%CI: 69.3-85.5) respectively. At diagnosis, NPM1 baseline levels did not differ between PB and BM (p=.20). However, after induction, the median MRD log reduction was 4.5 in PB (range: 1.7-5.8) and 3.8 in BM (range: 0.01-5.5) (p<.0001). We focused here on the value of PB-MRD log reduction. Patients with a high WBC (>50 G/L) or FLT3-ITD had higher NPM1 baseline but also PB-MRD levels. However, no correlation between PB-MRD log reduction and age, WBC, karyotype, or any of the gene mutations was observed. Patients who did not achieve a 4-log reduction in NPM1 PB-MRD were exposed to a higher risk of relapse and had a shorter survival (3-year CIR censored at ASCT: 65.8% vs. 20.5%, SHR 5.83, 95%CI: 2.78-12.23, p<.001; 3-year OS censored at SCT: 92.3% 40.8%, HR 10.99, 95%CI: 3.97-30.39, p<.001). In multivariable analysis of CIR and OS censored at ASCT, abnormal karyotype, FLT3-ITD, and PB-MRD reduction < 4 log were significantly associated with a higher risk of event. Among the 59 patients with FLT3-ITD, a PB-MRD reduction < 4 log was also predictive of a higher risk of relapse and a shorter survival (SHR 3.74, 95%CI: 1.47-9.53, p=.006; HR 3.26, 95%CI: 1.43-7.44, p=.005) along with age, logWBC, and FLT3-ITD allelic ratio. In multivariable analysis of CIR and OS, only age, logWBC, and PB-MRD reduction < 4 log were significantly associated with a higher risk of relapse or death. Considering allogeneic SCT as a time-dependent variable, DFS but also OS were significantly improved by SCT in non-favorable ELN patients with PB-MRD reduction <4 log (DFS, HR 0.25, 95%CI: 0.06-0.98, p=.047; OS, HR 0.25, 95%CI: 0.06-0.98, p=.047). This benefit was not observed in patients with a favorable PB-MRD response (DFS, HR 1.62, 95%CI: 0.05-5.17, p=.419; OS, HR 2.11, 95%CI 0.57-7.71, p=.261) with a significant interaction between SCT effect and PB-MRD log reduction (DFS, p=.024; OS, p=.027). Conclusion Our study supports the prognostic significance of early NPM1 PB-MRD, independently of cytogenetical and molecular context. Moreover, NPM1 PB-MRD may be used as a predictive factor of allogeneic SCT benefit in non-favorable ELN population. Figure 1. DFS (A) and OS (B) according to PB-MRD log reduction and post-remission therapy (SCT) in ELN non-favorable patients (Simon Makuch plots). Figure 1. DFS (A) and OS (B) according to PB-MRD log reduction and post-remission therapy (SCT) in ELN non-favorable patients (Simon Makuch plots). Disclosures De Botton: Agios Pharmaceuticals: Research Funding. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Cappelli, Luca Vincenzo, Manja Meggendorfer, Constance Baer, Niroshan Nadarajah, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach, and Alexander Höllein. "NPM1 Mutated AML Is Characterized By Pre-Leukemic Mutations and the Persistence and Acquisition of Co-Mutations in Molecular Remission Leads to Inferior Prognosis." Blood 132, Supplement 1 (November 29, 2018): 996. http://dx.doi.org/10.1182/blood-2018-99-118286.
Abstract:
Abstract Background: In AML patients (pts), pre-leukemic mutations in DNMT3A, TET2 and ASXL1 (DTA) were shown to persist in remission, which was not associated with survival (Jongen-Lavrencic et al. NEJM 2018). On the other hand Abelson et al. (Nature 2018) recently identified a specific pre-leukemic mutational spectrum in pts that eventually develop AML. NPM1 mutation (NPM1mut) identifies a WHO AML entity which accounts for about 30% of all AML. The absence of NPM1 transcripts following treatment defines complete molecular remission (CMR). We aimed to dissect the clonal hierarchy of co-mutations at diagnosis of NPM1mut AML and analyze the role of persistent mutations in this well-defined CMR setting. Methods: We investigated 136 pts with diagnosis of NPM1mut AML (from 2006 to 2016) who attained a CMR (absence of NPM1 transcripts, sensitivity 0.001%) after intensive treatment. The mean follow-up was 40 months (2-96). Next-generation sequencing of 39 genes associated with myeloid malignancies was performed for all pts in paired samples at diagnosis and at CMR. The median coverage was 5200x. FLT3-ITD was analyzed by gene scan. Results: At diagnosis, a total of 375 mutations were detected, with an average of 2.8/pt (range 1-6); at least one mutation other than NPM1 was present in 123/136 pts (90%). DTA-genes DNMT3A (39% of pts) and TET2 (15%) were among the most frequently mutated, while no ASXL1 mutation was observed. Mutated non-DTA genes included: FLT3-ITD (35%), IDH2 (27%), IDH1 (21%), NRAS (18%), FLT3-TKD (14%) and PTPN11 (13%). The mean variant allele frequency (VAF) was 36% (2.7-94), and was higher for DTA than non-DTA mutations (44% vs 34%, p<0.0001). We established the clonal hierarchy of NPM1mut AML at diagnosis by analyzing the VAF of co-mutations in relation to NPM1 ±5%). In the majority of pts (75/123: 61%) a higher VAF was detected for co-mutations than for NPM1. Specific mutations with higher VAF were DNMT3A (35/52, 67%), IDH1 (21/28: 75%), IDH2 (31/36: 86%), SRSF2 (9/11: 82%) and TET2 (14/21: 67%). Mutations in those genes therefore represent first hits and occur at an earlier phase of AML development. This phenomenon was more frequent in pts ≥60 years (yrs) vs pts <60 yrs (72% vs 52%, p=0.021, OR: 2.4). On the contrary, mutations in FLT3-TKD (10/18: 56%), NRAS (14/23: 61%) and WT1 (4/6: 67%) had a significantly lower VAF than NPM1mut (p<0.0001) indicating that these are second hit mutations. We detected a significant higher rate of persistent mutations in CMR in pts with NMP1mut as 2nd hit vs cases with NPM1 as 1st hit (55% vs 33%, p=0.026, OR=2.4). No difference in OS was detected for pts with NPM1 as 1st or 2nd hit mutation. At CMR, a total of 84 mutations were detected, with an average of 0.6/pt (range 0-3). DTA mutations in DNMT3A and TET2 persisted with the highest frequency (59% and 46%). The most frequently persisting non-DTA mutations were: SRSF2 (42%), IDH2 (28%) and IDH1 (21%). The VAF at CMR was significantly lower than VAF at diagnosis (mean: 16% vs 36%, p<0.0001). In line with previous reports, we confirm in NPM1mut AML that the detection of persistent non-DTA mutations (n=20 pts) at CMR was associated with shorter OS, while this was not true for DTA mutations (5-yrs OS: 46% vs 86% for no persisting and 84% for DTA persisting, p=0.001). Moreover, 15/136 pts (11%) acquired novel mutations at CMR (among which: 2 BCOR, 1 RUNX1, 1 SF3B1 and 2 TP53 mutations) and showed worse prognosis (5-yrs OS: 52% vs 84%, p=0.036; 5-yrs EFS: 17% vs 65%, p=0.04) than those who did not (121/136, 89%). By multivariate analysis including known risk factors such as: age, bone marrow blast levels and karyotype, we found that both persistence (HR: 2.8, CI=1.3-6, p=0.007) and acquisition (HR: 3.3, CI=1-11, p=0.05) of non-DTA mutations are independent predictors of outcome. Conclusions. Here we challenge the notion that in NPM1mut AML the NPM1 mutation is generally the first hit. We show that especially in older patients NPM1 is a frequent 2nd hit mutation and that the corresponding 1st hit mutations are more likely to persist in CMR. We also show for the first time in NPM1mut AML that the persistence of non-DTA gene mutations and the acquisition of further hits at CMR impacts prognosis. These findings suggest that the longitudinal assessment of pts at CMR will potentially aid prognostic stratification of NPM1mut AML pts and eventually lead to therapeutic strategies aimed at eradicating a pre-leukemic/relapse state in this subset of patients. Disclosures Cappelli: MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Baer:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Höllein:MLL Munich Leukemia Laboratory: Employment.
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Agrawal, Mridul, Andrea Corbacioglu, Peter Paschka, Daniela Weber, Verena I. Gaidzik, Nikolaus Jahn, Andrea Kündgen, et al. "Minimal Residual Disease Monitoring in Acute Myeloid Leukemia (AML) with Translocation t(8;21)(q22;q22): Results of the AML Study Group (AMLSG)." Blood 128, no. 22 (December 2, 2016): 1207. http://dx.doi.org/10.1182/blood.v128.22.1207.1207.
Abstract:
Abstract Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) results in the formation of the RUNX1-RUNX1T1 fusion transcript which can be used to monitor minimal residual disease (MRD) by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Early identification of patients (pts) with a high risk of relapse will allow pre-emptive therapy including allogeneic hematopoietic cell transplantation (alloHCT). Recent studies in AML with NPM1 mutation or the CBFB-MYH11 gene fusion revealed that MRD persistence is significantly associated with a high risk of relapse. However, the prognostic impact of MRD assessment in RUNX1-RUNX1T1-positive AML is not well established. Aims: To assess the prognostic impact of qRT-PCR-based MRD monitoring in bone marrow (BM) of pts with t(8;21)/RUNX1-RUNX1T1-positive AML obtained at defined time-points (diagnosis, first and second cycle of chemotherapy, end of treatment). Methods: In total, 120 pts were included based on the availability of a diagnostic BM sample and at least two subsequent BM samples obtained during therapy and at the end of treatment; 106 pts were enrolled in one of six AMLSG treatment trials: AML HD93 (n=1), AML HD98A (NCT00146120; n=13), AMLSG 06-04 (NCT00151255; n=4), AMLSG 07-04 (NCT00151242; n=43), AMLSG 11-08 (NCT00850382; n=31), AMLSG 21-13 (NCT02013648; n=14); 14 pts were treated outside clinical trials. All pts received anthracycline- and cytarabine-based intensive induction followed by subsequent high-dose cytarabine consolidation cycles. For MRD assessment, qRT-PCR from BM specimens was performed using TaqMan technology; RUNX1-RUNX1T1 transcript levels (TL) were reported as the normalized value of RUNX1-RUNX1T1 per 106 transcripts of the housekeeping gene beta2-microglobulin. The maximum sensitivity of the assay was 10-6. Results: The median age of the pts was 47 years (yrs; range, 18-73 yrs); at the time of diagnosis there was a broad range of RUNX1-RUNX1T1 TL (18490 to 14440000) with a median of 227800. RUNX1-RUNX1T1 TL did not correlate with clinical features (age, WBC, platelets, LDH, BM blasts) or associated gene mutations such as KIT, FLT3-ITD/TKD, NRAS or ASXL2. However, pts with additional FLT3 mutation showed higher TL compared to wild-type pts (median, 412955 vs 219052). Cox regression analysis using RUNX1-RUNX1T1 TL as a log10 transformed continuous variable showed that higher RUNX1-RUNX1T1 TL were significantly associated with a higher cumulative incidence of relapse (CIR), inferior event-free survival (EFS) and shorter overall survival (OS) for the two time points "after first treatment cycle" and "at end of treatment" (CIR: HR, 1.84, p=0.001; HR, 1.60, p=0.03; EFS: HR, 1.59, p=0.01, HR, 1.74, p=0.01; OS: HR, 1.63, p=0.02, HR 2.13, p=0.009, respectively). In univariate analyses achievement of MRD negativity (n=35) at the end of treatment was significantly associated with a superior 4-yr OS (93% vs 67%; p=0.007) and 4-yr EFS (81% vs 61%; p=0.04) whereas achievement of MRD negativity after the first (1/85) and second (20/89) treatment cycle was low not reaching significance for any of the clinical endpoints. Separation of the RUNX1-RUNX1T1 TL according to quartiles of distribution showed significant differences in OS (p=0.04), and remission duration (p=0.006) "after first cycle" whereas "at end of treatment" significant differences were only found for OS (p=0.009). Finally, we evaluated the impact of concurrent KIT mutations on the kinetics of RUNX1-RUNX1T1 TL. Following the first treatment cycle, the median RUNX1-RUNX1T1 TL were significantly lower in the KIT wildtype group compared with the KIT mutated group (p=0.02); the same was true "at the end of treatment" (p=0.02). Conclusions: In our study, achievement of MRD negativity at the end of treatment was significantly associated with a better outcome in t(8;21)-positive AML. The fact that earlier time points did not allow the identification of pts with a high relapse risk is probably due to the high sensitivity of the qRT-PCR assay which is also reflected by the low number of pts achieving qRT-PCR negativity after first and second treatment cycle, respectively. Further analyses are ongoing including multivariable as well as molecular subgroup analyses. *These authors contributed equally to the work: MA, AC MA was supported by the Else-Kröner-Fresenius-Stiftung (EKFS). Disclosures Paschka: Celgene: Honoraria; Pfizer Pharma GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Medupdate GmbH: Honoraria; Novartis: Consultancy; ASTEX Pharmaceuticals: Consultancy. Lübbert:Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Teva: Other: Travel; Kolltan: Research Funding; Ariad/Incyte: Consultancy; Novartis: Consultancy; Gilead: Other: Travel; GSO: Other: Travel; Pfizer: Research Funding. Heuser:Karyopharm Therapeutics Inc: Research Funding; Pfizer: Research Funding; Bayer Pharma AG: Research Funding; Celgene: Honoraria; Tetralogic: Research Funding; BerGenBio: Research Funding; Novartis: Consultancy, Research Funding. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding.
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Hou, Hsin-An, Yuan-Yeh Kuo, Chieh-Yu Liu, Wen-Chien Chou, Ming Cheng Lee, Chien-Yuan Chen, Liang-In Lin, et al. "DNMT3A Mutations in Acute Myeloid Leukemia-Stability During Disease Evolution and the Clinical Implication." Blood 118, no. 21 (November 18, 2011): 409. http://dx.doi.org/10.1182/blood.v118.21.409.409.
Abstract:
Abstract Abstract 409 Background: DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. Materials and Methods: Mutation analysis of DNMT3A exons 2–23 was performed by polymerase chain reaction and direct sequencing in 506 de novo AML patients. Their interaction with clinical parameters, chromosomal abnormalities and genetic mutations were analysed. Results: DNMT3A mutations were identified in 14% of total patients and 22.9% of patients with normal karyotype (CN-AML). 30 different kinds of DNMT3A mutations were identified in 70 patients. Twelve were missense mutations, eight were nonsense mutations, nine were frame-shift mutations and one, in-frame mutation. The most common mutation was R882H (26 patients), followed by R882C (15 patients), R882S (3 patients), R736H (3 patients) and R320X (2 patients). DNMT3A mutations were closely associated with older age, higher white blood cell (WBC) and platelet counts at diagnosis, FAB M4/M5 subtype, intermediate-risk and normal cytogenetics. Among the 70 patients with DNMT3A mutations, 68 (97.1%) showed additional molecular abnormalities at diagnosis. The most common associated molecular event was NPM1 mutation (38 cases), followed by FLT3-ITD (30 cases), IDH2 mutation (16 cases) and FLT3-TKD (9 cases). Patients with DNMT3A mutations had significantly higher incidences of NPM1 mutation, FLT3-ITD, IDH2 and PTPN11 mutations than those with DNMT3A-wild type (54.3% vs. 15.3%, P<0.0001; 42.9% vs. 19.3%, P<0.0001; 22.9% vs. 9.1%, P=0.0016; and 10% vs. 3.5%; P=0.007, respectively). On the contrary, CEBPA was rarely seen in patients with DNMT3A mutations (4.3% vs. 14.7%, P=0.0134). Totally, 40 patients (58.8%) had concurrent both Class I and Class II or NPM1 mutations at diagnosis. With a median follow-up of 55 months (ranges, 1.0 to 160), patients with DNMT3A mutation had significantly poorer overall survival (OS) and relapse-free survival (RFS) than those without DNMT3A mutation (median, 14.5 months vs. 38 months, P =0.013, and medium, 7.5 months vs. 15 months, P=0.012, respectively). In the subgroup of 130 younger patients (less than 60 years) with CN-AML, the differences between patients with and without DNMT3A mutation in OS (median, 15.5 months vs. not reached, P= 0.018) and RFS (median, 6 months vs. 21 months, P=0.004) were still significant. Multivariate analysis demonstrated that DNMT3A mutation was an independent poor prognostic factor for OS and RFS among total patients (HR 2.218, 95% CI 1.333–3.692, P=0.002 and HR 2.898, 95% CI 1.673–5.022, P<0.001, respectively) and CN-AML group (HR 2.303, 95% CI 1.088–4.876, P=0.029 and HR 3.496, 95% CI 1.773–6.896, P<0.001, respectively). Further, a scoring system incorporating DNMT3A mutation and eight other prognostic factors, including age, WBC count, cytogenetics, and gene mutations (NPM1/FLT3-ITD, CEBPA, AML1/RUNX1, WT1, and IDH2 mutations), into survival analysis was proved to be very useful to stratify AML patients into different prognostic groups (P<0.001). DNMT3A mutations were serially studied in 316 samples from 138 patients, including 35 patients with distinct DNMT3A mutations and 103 patients without mutation at diagnosis. Among the 34 patients with DNMT3A mutations who had ever obtained a CR and had available samples for study, 29 lost the original mutation at remission status, but five retained it; all these five patients relapsed finally within a median of 3.5 months and died of disease progression, suggesting presence of leukemic cells. In the 13 patients who had available samples for serial study at relapse, all patients regained the original mutations, including mutant clone was found by TA cloning in one patient. Among the 103 patients who had no DNMT3A mutation at diagnosis, none acquired DNMT3A mutation at relapse, while karyotypic evolution was noted at relapse in 39% of them. Conclusion: DNMT3A mutations are associated with distinct clinical and biological features and poor prognosis in de novo AML patients. Furthermore, the mutation may be a potential biomarker for monitoring of minimal residual disease. Disclosures: No relevant conflicts of interest to declare.
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Strzalka, Piotr, Kinga Krawiec, Dariusz Jarych, Aneta Wiśnik, Michał Soin, Magdalena Góralska, Damian Mikulski, et al. "Assessment of SIRT1-SIRT7 and TP53 Genes Expression in Patients with Acute Myeloid Leukemia." Blood 142, Supplement 1 (November 28, 2023): 6048. http://dx.doi.org/10.1182/blood-2023-187756.
Abstract:
BACKGROUND Sirtuins ( SIRTs) are a family of histone deacetylases with 7 representatives ( SIRT1-7), which affect cell survival and metabolism. They influence gene expression by interacting with histones and transcription factors, or directly modulate pathways associated with cell survival, for instance by downregulating p53, thus potentially contributing to cancerogenesis. On the other hand, SIRTs may function as tumor suppressors depending on cellular context. While the role of SIRTs expression is widely discussed in solid neoplasms, they have not been comprehensively evaluated in acute myeloid leukemia (AML) yet. AIMS To investigate the prognostic importance of initial SIRTs expression in AML patients (pts) and its relationship with the expression of TP53. METHODS The study included 40 newly diagnosed AML pts (19 women, 21 men), with a mean age of 62 years (range: 26-87). Low-, intermediate- or high-risk AML according to European LeukemiaNet (ELN) 2022 stratification was diagnosed in 6 (15%), 13 (32.5%), and 21 (52.5%) of pts respectively. The expression of SIRT1-7 and TP53 was examined by real-time PCR using the TaqMan chemistry and the QuantStudio7 thermal cycler (Applied Biosystems-Thermo Fisher Scientific). The reference genes were selected using GeNorm and NormFinder. The mRNA levels were normalized by the formula ∆Ct = Ct(reference) - Ct(particular mRNA). Group comparisons were performed using Welch's t-test. Pearson correlation evaluated the relationship between individual gene expression. Overall survival (OS) was assessed by the Kaplan-Meier method with the log-rank test. Cox proportional hazard regression of clinical factors and genes expression for predicting OS was performed. RESULTS FLT3 ITDor TKD mutations were present in 10 (25%) of pts, NPM1 in 9 (23%), and IDH1 or IDH2 in 6 (15%). 14 (35%) of the study group were diagnosed with AML with myelodysplasia-related cytogenetic abnormalities, AML progressed from myelodysplastic syndrome, or therapy-related AML (secondary AML, sAML). Standard induction chemotherapy was given in 42.5% of pts, 25% were treated with azacitidine+venetoclax (Aza+Ven), and other non-intensive therapies were administered to 32.5%. SIRT4 expression was detected in 92.5% of pts, while expression of the other genes studied was found in all pts. There were no differences in SIRT 1-7 expression in terms of ELN2022 risk stratification. However, TP53 was downregulated in the high-risk group (fold change - FC=0.6, p=0.004). In pts with FLT3 mutation, SIRT7 was downregulated (FC=0.8, p=0.07), while in both NPM1 and IDH1/2 mutated groups, we showed upregulation of TP53 (FC=1.5, p=0.03, and FC=1.5, p=0.001, respectively). Moreover, in older pts (>60 years old) TP53 was downregulated (FC=0.7, p=0.02). In sAML group SIRT3 and TP53 were downregulated (FC=0.7, p=0.08, and FC=0.7, p=0.05, respectively). Significant positive correlations were shown between the expression of individual SIRTs, and it was most strongly expressed between SIRT2 and SIRT6 (r=0.85, p=0.00), SIRT2 and SIRT7 (r=0.81, p=0.00), and SIRT6 and SIRT7 (r=0.76, p=0.00). The median follow-up was 6.7 months (95% CI: 4.5-9.1). The median OS in the study cohort was not reached. There were no significant differences in treatment response or OS considering each SIRT expression level. However, pts with higher TP53 expression (> median) presented longer OS (median OS not reached vs 5.8 months (95% CI:1.3-5.8, p=0.05) [Figure 1]. In the multivariate Cox proportional hazard model for OS, upregulation of TP53 (HR 0.25, 95%CI: 0.08-0.60, p=0.01), age (HR 1.06, 95%CI: 1.01-1.12, p=0.03), as well as initial albumins (HR 0.01, 95%CI: 0.00-0.07, p=0.01), and LDH levels (HR 1.00, 95%CI: 1.00-1.01, p=0.01) were factors influencing the outcome [Table 1]. CONCLUSIONS The expression of SIRTs in AML presented no evident impact on treatment outcome. However, our study revealed that higher TP53 expression was associated with longer OS. Moreover, TP53 upregulation was found in pts with certain mutational profiles, while downregulation in the elderly and those with sAML. The analysis indicates that SIRTs expression may also vary markedly depending on the clinical and molecular context. The expression of individual SIRTs is closely correlated with each other, but these preliminary results did not show their direct relationship with TP53 expression. Further studies on SIRTs are needed to assess their impact on AML.
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Lachowiez, Curtis A., Christopher A. Eide, Stephen E. Kurtz, Nicola Long, Manoj Rai, Wei Xie, Andy Kaempf, et al. "Acute Myeloid Leukemia Differentiation State and Genotype Influence Anti-Apoptotic Protein Expression, Venetoclax Sensitivity, and Survival in AML." Blood 142, Supplement 1 (November 28, 2023): 978. http://dx.doi.org/10.1182/blood-2023-179527.
Abstract:
Background: Somatic mutations (mut) and acute myeloid leukemia (AML) differentiation state (phenotype) influence sensitivity and response to treatment. However the interaction between genotype and phenotype with respect to sensitivity or resistance to venetoclax (VEN) based therapy has yet to be fully evaluated. Methods: Samples from patients (pts.) with newly diagnosed (ND) AML enrolled in Beat AML with available bulk RNA sequencing (RNAseq), whole exome sequencing, and ex vivo drug sensitivity testing (N=255) were analyzed for correlation between AML phenotype (defined using RNAseq [van Galen et. al. Cell 2019] and surface immunophenotype via multiparameter flow cytometry [MFC]), genotype, and VEN sensitivity. A monocytic score corresponding to monocytic gene expression and myeloid differentiation for each sample was included as previously defined (Bottomly et. al. Cancer Cell 2022). Clinical outcomes were assessed in an independent retrospective patient cohort (N=97) treated with frontline hypomethylating agents (HMA)+VEN at Oregon Health & Science University. Categorical and continuous variables were analyzed using Fisher's or Wilcoxon rank sum testing. Time to event outcomes utilized the log-rank method with cox multivariable regression modeling. Results: Median patient (pt) age at diagnosis in the surveyed cohort was 61 years (range 20-88). AML phenotype determined using proportional deconvolution of RNAseq data was HSC/progenitor (primitive) in 31% (N=78), mixed/intermediate in 31% (N=79), cDC/monocytic (mature) in 29% (N=73), and unknown in 10% (N=25) of pts. Muts frequent in primitive vs. mature AML samples included transcription factor ( RUNX1, CEBPA, GATA2, GATA1, ETV6, IKZF1; 30% vs. 15%, p=0.050), tumor suppressor ( TP53, PHF6, WT1; 21% vs. 7%, p=0.019), and IDH1/2 (27% vs. 12%, p= 0.027). Active signaling mut ( FLT3-ITD/TKD, K/NRAS, PTPN11, BRAF) were more frequent in mature vs. primitive samples (78% vs. 44%, p < 0.0001), underscoring the correlation between genotype and myeloid differentiation (Fig.A). Expression of anti-apoptotic protein and myeloid differentiation markers measured using RNAseq varied by AML genotype and phenotype and corresponded to VEN resistance. The ratios of BCL2A1 (pearson R=0.62, p < 0.0001), CD11b (R=0.65, p < 0.0001), CD14 (R=0.73, p < 0.0001), and CLEC7A (R=0.72, p < 0.0001) to BCL2 positively correlated with VEN resistance (i.e., increasing area under the curve [AUC]). While IDH1/2 and NPM1 mutated samples demonstrated the highest BCL2 expression and lowest BCL2A1: BCL2 ratio and remained largely sensitive to VEN, myeloid differentiation (in particular monocytic differentiation) increased VEN resistance irrespective of genotype. For instance, classification of a primitive vs. mature phenotype further stratified ex vivo VEN sensitivity in pts with IDH1 (median AUC: 61 vs. 195, p: 0.004), IDH2 (median AUC: 61 vs. 185, p: 0.002), or NPM1 (median AUC: 60 vs. 220, p < 0.0001) mut (Fig.B). Overall survival (OS) following HMA+VEN was evaluated based on the presence or absence of surface immunophenotypic markers measured via MFC that correlated with myeloid differentiation. CD117+ AML (HR: 0.30 95% CI: 0.14 - 0.65, p=0.002) associated with improved OS, while inferior OS was observed with CD11b+ (HR: 2.03 95% CI: 1.07 - 3.86, p=0.031) and CD64+ AML (HR:1.86 95% CI: 0.90 - 3.85, p=0.095). When assessing the combined influence of genotype and immunophenotype on OS in CD11b+ or CD64+ AML, IDH1/2 mut (N=8) numerically improved OS compared to IDH1/2 wild-type cases (N=17) (median 12.3 vs. 5.8 months, p: 0.17). In multivariate analysis adjusted for CD11b or CD64 positivity, age, IDH1/2 mut, and secondary or therapy-related AML, CD11b or CD64 positivity (HR: 1.98 95% CI: 1.08-3.66, p=0.028) retained the strongest impact on OS. Conclusions: Genotype and phenotype both modulate VEN sensitivity in AML. Myeloid differentiation is associated with increased alternative anti-apoptotic protein expression and VEN resistance irrespective of genotype; however certain mutations (i.e., IDH1/2) may retain prognostic significance independent of myeloid differentiation. Given both factors influence VEN sensitivity, prognostic models incorporating AML phenotype and genotype may further improve risk stratification and predict response to VEN based therapy in AML.
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Chan, Onyee, Najla Al Ali, Hammad Tashkandi, Austin Ellis, Somedeb Ball, Ling Zhang, Mohammad Hussaini, et al. "Mutations Highly Specific for Secondary AML Are Associated with Poor Outcomes in Patients with NPM1-Mutated ELN Favorable Risk AML." Blood 138, Supplement 1 (November 5, 2021): 686. http://dx.doi.org/10.1182/blood-2021-150759.
Abstract:
Abstract Background: NPM1 is commonly mutated in acute myeloid leukemia (AML) and represents a distinct entity under the WHO 2016 classification. It is one of the few mutations that can potentially support favorable risk by European LeukemiaNet (ELN) 2017 criteria. Mutations that are highly specific for secondary AML including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 (sMut) (Lindsley et al.) have been shown to confer poor prognosis. The impact of these mutations on NPM1-mutated AML warrants further investigation. Objective: In this study, we explore the outcomes in patients with NPM1-mutated AML. Methods: This was a retrospective study of NPM1-mutated AML patients who were diagnosed and treated at the Moffitt Cancer Center from 2013 to March 2021. Inclusion was restricted to NPM1-mutated patients with mutation analysis (NGS) performed at diagnosis (n=159). Kaplan-Meier, univariate, and multivariate analyses were performed. Results: Among 159 patients (78M/81F, median age 63 years at diagnosis), 80.5% had de novo AML. By ELN 2017 criteria, 63.5% (101/159) had favorable risk, 27.7% (44/159) had intermediate risk, and 8.2% (13/159) had adverse risk disease. Almost 90% had intermediate risk cytogenetics at the time of diagnosis. Common co-mutations included DNMT3A (47.2%), FLT3-ITD (35.8%), TET2 (26.4%), IDH1 (17.6%), FLT3-TKD (15.1%), and IDH2 (13.8%). sMut comprised 19.5% (31/159) of patients and 20.8% (21/101) of those with ELN favorable risk. In patients with treatment response data, those with sMut never achieved CR/CRi in 35.7% (10/28) compared to 17.2% (22/128) of patients without sMut (p=0.038). The overall survival (OS) was 43.7 months with a median follow up of 35.5 months. Patients with sMut had worse OS compared to those without sMut (14.7 months vs 57.6 months, p=0.011). Among patients with favorable risk disease, OS was 11.6 months compared to not reached for those with sMut and without sMut, respectively (p<0.0001). Univariate analysis showed sMut and allogeneic hematopoietic cell transplant (HCT) significantly impacted OS (sMut: HR 3.48, 95% CI: 1.80-6.72, p<0.001; HCT: HR 0.17, 95% CI: 0.07-0.44, p<0.001). Multivariate regression using covariates including age, AML type, sMut, and HCT confirmed their prognostic significance on survival (sMut: HR 2.40, 95% CI: 1.17-4.93, p=0.017; HCT: HR 0.26, 95% CI: 0.08-0.56, p=0.002). Conclusions: Our findings suggest NPM1-mutated AML patients with sMut have significantly worse prognosis despite being classified primarily as favorable risk by ELN 2017 at diagnosis. This may have treatment implications altering the need for and/or timing of HCT. These findings should be assessed prospectively and validated in independent datasets. Figure 1 Figure 1. Disclosures Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy. Talati: AbbVie: Honoraria; Pfizer: Honoraria; Astellas: Speakers Bureau; BMS: Honoraria; Jazz: Speakers Bureau. Kuykendall: Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Research Funding; Celgene/BMS: Honoraria; Abbvie: Honoraria; Blueprint: Honoraria; Pharmaessentia: Honoraria. Padron: Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; AbbVie: Consultancy; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Agios: Consultancy; Astellas: Consultancy.
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Yang, Hongbo, Yan Song, James D. Griffin, Manasee V. Shah, Jonathan Freimark, and Andrew Chilelli. "Maintenance Therapy in Patients with FLT3-ITD-Mutation-Positive Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation: Real-World Survival." Blood 138, Supplement 1 (November 5, 2021): 693. http://dx.doi.org/10.1182/blood-2021-145790.
Abstract:
Abstract Background: Patients with FLT3-mutation-positive (FLT3mut+) acute myeloid leukemia (AML) have a poor prognosis, particularly those with a high allelic burden of FLT3-ITD mutations (FLT3-ITD mut+). Further, patients with FLT3-ITD mut+ who have relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) have a 1-year overall survival (OS) rate of less than 20%. While treatment guidelines vary in their recommendations for maintenance therapy after HSCT to prevent relapse, data are emerging on the potential benefits of maintenance therapy for patients with FLT3mut+ AML. Aim/Objective: To examine real-world survival outcomes in adult patients with FLT3-ITD mut+ AML who received maintenance therapy versus those who did not receive maintenance therapy after allogeneic HSCT, including a qualitative comparison with real-world survival outcomes in adults with FLT3mut+ AML. Methods: This was a retrospective chart review wherein hematologists and oncologists from North America, Europe, and Japan extracted data from the medical charts of patients with FLT3mut+ AML who underwent HSCT after achieving complete remission with first-line chemotherapy within the prior 3 years. The index date was the date of HSCT and the study period was from the index date to the date of the last follow-up or death. All patients were grouped into two cohorts based on post-HSCT therapy received (no maintenance therapy or maintenance therapy). In an analysis of a subgroup of patients typically considered to be at high risk of relapse, patients who had both received an allogeneic HSCT and had a high allelic burden of FLT3-ITD mut+ were analyzed; patients with FLT3-ITD and FLT3-TKD co-mutations were also included in this subgroup. Overall survival during the study period was assessed for each cohort in the overall population of patients and in the subgroup. Kaplan-Meier analyses and Cox regression models, including unadjusted models and models with adjustments for baseline covariates, were used to describe and evaluate cross-cohort comparisons of survival. Covariates in the adjusted Cox models were Eastern Cooperative Oncology Group status, risk status, measurable residual disease status, age at index date, sex, extramedullary involvement, race, BMI, time from diagnosis to index month, HSCT type, and country. Results: A total of 1,208 AML patients with FLT3mut+ who received HSCT were included in the general study population; 765 (63.3%) patients received no maintenance therapy and 443 (36.7%) patients received maintenance therapy (including FLT3 inhibitors, hypomethylating agents, cytotoxic chemotherapy, and other targeted therapies). In Kaplan-Meier analyses, OS was longer in patients who received maintenance therapy compared with those who did not receive maintenance therapy (log-rank P<0.001; Figure A). Similar results were seen between maintenance therapy versus no maintenance therapy in an unadjusted Cox regression model (HR 0.52 [95% CI 0.35, 0.76], P<0.001) and adjusted Cox regression model (HR 0.48 [95% CI 0.30, 0.77], P<0.01). In an analysis of the subgroup, data from the charts of 745 patients with FLT3-ITD mut+ who received allogeneic HSCT were reviewed. The mean age at HSCT was 53.2 years; 39.9% and 38.4% of patients had intermediate and poor risk status, respectively. Of this subgroup, 473 (63.5%) patients received no maintenance therapy and 272 (36.5%) patients received maintenance therapy. Kaplan-Meier analyses show that OS was longer in patients receiving maintenance therapy versus no maintenance therapy (log-rank P<0.001; Figure B); the risk of death appeared to plateau after approximately 2 years in patients receiving maintenance treatments. Similar results were seen between maintenance therapy versus no maintenance therapy in an unadjusted Cox regression model (HR 0.39 [95% CI 0.23, 0.65], P<0.001) and adjusted Cox regression model (HR 0.38 [95% CI 0.20, 0.72], P<0.01). Conclusions: In patients with FLT3-ITD mut+ AML, OS was improved in patients that received any type of maintenance therapy compared with patients that received no maintenance therapy after allogeneic HSCT. These improved clinical outcomes in a high-risk subgroup receiving maintenance treatments are consistent with findings in the general population of patients with FLT3mut+ AML. Additional analyses are warranted to statistically verify these results. Figure 1 Figure 1. Disclosures Yang: Astellas Pharma, Inc.: Consultancy. Song: Astellas Pharma, Inc.: Consultancy. Griffin: Astellas Pharma, Inc.: Consultancy; Novartis: Patents & Royalties: Post marketing royalties from midostaurin. Shah: Astellas Pharma, Inc.: Current Employment; University of Michigan School of Public Health Department of Health Management and Policy Alumni Board: Other: Chair-Elect. Freimark: Astellas Pharma, Inc.: Consultancy. Chilelli: Astellas Pharma, Inc.: Current Employment.
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Getta, Bartlomiej M., Sean Devlin, Molly A. Maloy, Abhinita Mohanty, Maria Arcila, Martin S. Tallman, Ross L. Levine, Sergio A. Giralt, and Mikhail Roshal. "Multicolor Flow Cytometry and Multi-Gene Next Generation Sequencing Are Complimentary and Highly Predictive for Relapse in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplant." Blood 128, no. 22 (December 2, 2016): 834. http://dx.doi.org/10.1182/blood.v128.22.834.834.
Abstract:
Abstract Aim: Evaluation of tandem minimal residual disease (MRD) assessment using multi-gene next generation sequencing (NGS) and multi-parameter flow cytometry (MFC) in acute myeloid leukemia (AML) pts undergoing allogeneic hematopoietic stem cell transplant (allo-HCT). Methods: MRD was measured on the same bone marrow aspirate using 10-color MFC and a targeted myeloid specific 28-gene NGS panel pre and post allo-HCT in available samples from 122 consecutive pts with AML transplanted between 2014 and 2015. Any level of MRD measured by MFC in the blast compartment was regarded as positive, while somatic mutations detected above a pre-defined variant allele frequency (VAF) threshold on bulk marrow by multi-gene NGS were regarded as positive. Mutations identified on diagnostic or relapse samples were tracked throughout the disease course. FLT3-ITD and TKD mutations were detected in a stand-alone PCR based assay and VAF was not quantified. Results: NGS (HR: 2.37 (95% CI 1.06-5.28) and HR: 3.23 (95% CI 1.21-8.62)) and MFC (HR: 2.44 (95% CI 1-5.97) and HR: 4.62 (95% CI 1.32-16.09)) predicted overall survival (OS) and time-to-relapse respectively with median observation time of 12 months among survivors. MRD detection using both assays was associated with relapse, with MRD detected by MFC being the most predictive (table 1). NGS was applicable to 85% of tested pts with probable pathogenic mutations seen at diagnosis, while all pts tested at diagnosis had abnormal blasts detected by MFC. Transplant factors including donor source, conditioning intensity, stem cell source and GVHD prophylaxis were not associated with transplant outcomes while complex and monosomal karyotype were associated with OS and time-to-relapse (table 1). Pre allo-HCT concordance rate of MRD detection using the two assays was 70% (table 2). 12 (20%) pts had detectable MRD by MFC and not NGS. Five of these patients had NGS assessment at diagnosis and on manual review of NGS results 3 of these 5 had diagnostic mutations detected on pre allo-HCT samples at VAF below threshold to call mutations. Six (10%) were MFC negative but had detectable mutations by NGS, which were typically clonal hematopoiesis (CH) type mutations with VAF ranging between 3-20%, only 1/6 of these has relapsed post allo-HSCT. MRD pre allo-HCT using both MFC and NGS was associated with relapse; however, the risk was highest in pts who had pre transplant MRD detected concurrently using both techniques and cumulative incidence of relapse was lowest in those who were MRD negative using both techniques (Figure 1A & B). No significant change in mutant DNMT3A, TET2 and JAK2 variant allele frequency (VAF) was seen between assessment at diagnosis and pre transplant, while a significant reduction in NPM1 and IDH VAF was noted. For pts in CR or CRi pre allo-HCT MRD burden quantified using MFC (on blasts) was markedly lower than the corresponding VAF of residual mutations (on bulk marrow) measured in the same sample (Figure 1C) with VAF of residual mutation ranging between 10-20% suggesting that a large bulk of cells at the time of CR were derived from the abnormal clone. We tracked pathogenic mutations identified on diagnostic samples in pts who had marrow MFC and NGS MRD assessment after transplant. In pts who relapsed, multi-gene NGS detected mutations earlier than MFC although at very low allele burden (<1%) (Figure 3D). Low VAF (<2%) DNMT3A mutations were detected after transplant in 10/11 evaluable pts who had these mutations on pre transplant assessment while MFC was negative in 9/10 of those with low VAF DNMT3A mutations detected after transplant. Of the 10 pts with detectable DNMT3A mutations after transplant only 2 have relapsed and both had mutations in TP53. This suggests that the clinical significance of persistent low allelic burden DNMT3A mutations needs further clarification, as they may not be strongly predictive of relapse even if detected after transplant. Conclusion: Despite different assay sensitivity MFC and multi gene NGS had a concordance of 70% for detecting pre allo-HCT MRD in AML.Assessing pre Allo-HCT MRD with MFC and multi-gene NGS improves the ability to predict relapse and OS. MFC had more universal applicability, while NGS could identify residual CH-type mutations with greater sensitivity than MFC and identify MRD at earlier time points than MFC post-HCT. Using a more extensive gene panel is likely to improve the sensitivity of MRD detection and may improve correlation with MFC Disclosures Levine: Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Roshal:BD Biosciences: Consultancy.
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Perl, Alexander, Harry P. Erba, Pau Montesinos, Radovan Vrhovac, Elzbieta Patkowska, Heeje Kim, Pavel Zak, et al. "Quantum-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication ( FLT3-ITD)-Specific Measurable Residual Disease (MRD) Clearance Assessed through Induction (IND) and Consolidation (CONS) Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (nd) FLT3-ITD+ AML Patients (pts)." Blood 142, Supplement 1 (November 28, 2023): 832. http://dx.doi.org/10.1182/blood-2023-186785.
Abstract:
Background Detection of MRD by flow cytometry or gene fusion transcript quantitation increasingly is used to guide treatment decisions in AML. Molecular monitoring of recurrent gene mutations for MRD detection is an alternative strategy but, other than for nucleophosmin 1 ( NPM1) gene quantitation, remains controversial. FLT3-ITD is among the most common recurrent mutations in AML and confers a worse prognosis vs FLT3-wild-type and FLT3-TKD+ AML. Routine use of FLT3-ITD detection in remission as a predictor of relapse risk or OS has been limited by the low sensitivity of both conventional PCR-based detection methods and broad NGS platforms in clinical practice settings. More recently, FLT3-ITD-specific PCR-NGS assays such as getITD (PMID: 31089248) show greater sensitivity and ease of interpretation that point to eventual routine clinical application. However, the clinical value of these measurements has not been evaluated prospectively in large scale randomized controlled trials of FLT3 inhibitors. The phase 3 QuANTUM-First study (NCT02668653) evaluated the novel, potent, and highly selective type II FLT3 inhibitor quizartinib (Quiz) in nd FLT3-ITD+ AML pts and demonstrated that Quiz added to intensive IND and CONS, ± transplant, followed by single-agent continuation (CONT) therapy (Tx) resulted in a significant improvement in OS (PMID: 37116523). We analyzed if FLT3-ITD-specific MRD in QuANTUM-First pts impacted the clinical outcome or the benefits provided by Quiz in nd FLT3-ITD+ AML pts. Methods Genomic DNA, isolated from bone marrow aspirates or peripheral blood from pts after achievement of remission after 1 or 2 courses of IND and at end of CONS (prior to transplant or CONT cycle 1 day 1 [C1D1] for transplant pts and prior to CONT C1D1 for non-transplant pts), was analyzed with a FLT3-ITD PCR-NGS assay specifically developed for this trial (PMID: 31722002). ITD mutations detected after IND were cross-validated against the ITD detected at enrollment for each patient. Using a custom bioinformatics program, ITD mutations were identified, and variant allele frequencies (VAFs) were calculated with a sensitivity of 10 −5. MRD was classified as undetectable (using the 0 cutoff) or detectable above or below a 10 −4 predefined cutoff (based on lower limit of quantification for the assay). Comparisons of complete response (CR), composite complete response (CRc=CR+CRi), and the rate of pts achieving CRc during IND with no MRD between arms were made using a stratified Cochran-Mantel-Haenszel test. Comparison of FLT3-ITD VAF during IND and during CONS between arms was made using Wilcoxon rank sum test. All P-values were not adjusted for multiplicity. Results In QuANTUM-First, 539 nd FLT3-ITD+ AML pts were randomized to Quiz (n=268) or placebo (PBO; n=271). Of the 539 randomized pts, 368 (68.3%) achieved CRc after 1 or 2 courses of IND, and MRD analysis was performed on 321 (87.2%) of these pts (162 pts in Quiz and 159 pts in PBO) using samples collected at the time of response assessment during IND, before further Tx. MRD was also assessed in 337 pts (172 pts in Quiz and 165 pts in PBO) by end of up to 4 cycles of CONS prior to CONT/maintenance Tx. Of these pts, 166 additionally received transplant (87 in Quiz, 79 in PBO). The % of pts in CRc at end of IND with FLT3-ITD MRD of <10 −4 was similar between study arms (25.4% Quiz vs 21.8% PBO, nominal P = 0.3430), however, a greater % of pts in CRc had undetectable MRD with Quiz than PBO (12.3% vs 7.0%, nominal P = 0.0403). Among pts with CRc at end of IND, the median best FLT3-ITD VAF by end of CONS was lower (0% versus 0.0017%; nominal P = 0.0006) with Quiz vs PBO (Fig 1) and, using the 0 cutoff at end of IND, a longer OS was observed with Quiz vs PBO, regardless of MRD status, with a greater effect with Quiz (HR, 0.789 in MRD− pts; HR, 0.749 in MRD+ pts; Fig 2). In MRD+ pts, the median OS was not reached with Quiz and 35.4 months with PBO (Fig 2). Performing this analysis with an MRD cutoff of 10 ‒4 yielded similar findings (HR, 0.696 in MRD− pts; HR, 0.800 in MRD+ pts). Additional data about MRD impact on pts ± transplant in this trial will be presented. Conclusions These findings demonstrate the potential prognostic utility of FLT3-ITD-specific MRD measurements in the clinical management of pts with FLT3-ITD+ AML. Our data suggest that long-term OS benefits conferred by Quiz in part derive from a deep and sustained reduction of the FLT3-ITD+ leukemia burden.
50
Krawiec, Kinga, Piotr Strzalka, Dariusz Jarych, Aneta Wiśnik, Michał Soin, Magdalena Góralska, Damian Mikulski, et al. "Evaluation of Neddylation and Apoptosis-Related Gene Expression in Patients with Acute Myeloid Leukemia." Blood 142, Supplement 1 (November 28, 2023): 5990. http://dx.doi.org/10.1182/blood-2023-181739.
Abstract:
Introduction Regulated cell death (RCD) is a process commonly dysregulated in patients (pts) with acute myeloid leukemia (AML), resulting in the survival of genetically unstable cells. Apoptosis, as the best-known form of RCD, interacts with neddylation, a process that contributes to tumorigenesis and apoptosis resistance. Aims This study was conducted to determine the expression of the selected genes involved in the neddylation pathway and to assess their clinical importance along with selected interacting proapoptotic genes. In addition, we correlated the expression levels of these genes with known prognostic factors in AML and determined their impact on the survival of AML pts. Methods The expression of selected proapoptotic genes BIK, BAX, BAK, BCL2L11, BBC3 , PMAIP1 CASP3, CASP7, and neddylation-related genes: CUL1, CUL2 , CUL4A, CUL5, CUL7, CUL9, NEDD8 was determined in duplicates in bone marrow samples of newly diagnosed AML pts. Real-Time PCR was carried out using the TaqMan chemistry and the QuantStudio7 thermal cycler (Applied Biosystems-Thermo Fisher Scientific). Gene expression was normalized using reference genes selected by the Normirazor tool. The normalization was performed by ∆Ct = Ct (reference) - Ct (mRNA of interest). This approach results in higher values for higher mRNA expression. Differential expression analysis was performed using a Welch t-test. Kaplan-Meier method with the log-rank test was used to assess overall survival (OS). Results In a prospective study, we included 40 newly diagnosed AML pts (mean age 62; range 26-87) with a median (m) follow-up of 6.7 months (95% CI: 4.5-9.1). High-risk AML was present in 52.5%, intermediate-risk in 32.5%, and low-risk in 15% of pts, according to European LeukemiaNet (ELN) 2022 risk stratification. NPM1 mutation was present in 23%, whereas FLT3 ITD or TKD mutation in 25% of pts. Intensive treatment was introduced in 43% of pts, while 25% were treated with azacitidine+venetoclax. Non-intensive treatment with azacitidine in monotherapy was administered to the remaining pts. BAK expression was detected in 70%, BIK in 98%, while expression of the other genes was found in all pts. In the high-risk group, we detected lower expression of both proapoptotic BAX (fold change - FC=0.7, p=0.01) and BIK gene (FC=0.4, p=0.01), as well as lower expression of CUL9 (FC=0.7, p=0.03). Accordingly, in pts with NPM1 mutation we revealed upregulation of BIK (FC=6.1, p=0.001), and CUL9 (FC=1.6, p=0.01). Whereas pts with FLT3 mutation had lower expression of proapoptotic BBC3 (FC=0.5, p=0.01), and neddylation-related CUL1 (FC=0.6, p=0.01). In cases of initial bone marrow blasts infiltration above median value (>49%) BCL2L11 CUL5 , NEDD8 and PMAIP1were downregulated ( p=0.001-0.02), while CUL7 ( p=0.00) and CASP3 ( p=0.04) were upregulated. Patients with initial white blood cell count >20 G/l had lower expression of BCL2L11 ( p=0.005), and CUL4A ( p=0.02), while higher expression of CASP7 ( p=0.04). The mOS in the study cohort was not reached. OS was longer in pts with higher (> -2.061, cutoff was determined with CutOff Finder) BAX expression (log-rank: p=0.03) [Figure 1]. The mOS was not reached in this group, whereas the mOS in pts with lower BAX expression was 1.3 months (95% CI: 0.6-1.3). In univariate Cox regression analysis, higher BAX expression (HR 0.31, 95%CI: 0.11-0.84, p=0.022), higher albumin level (HR 0.13, 95%CI: 0.04-0.41, p=0.0004), and intensive treatment (HR 0.18, 95%CI: 0.04-0.69, p=0.012) were factors influencing the outcome. In the multivariate model for OS, higher expression of BAX (HR 0.03, 95%CI: 0.003-0.33, p=0.004) retained its significant protective effect in the context of established prognostic factors [Table 1]. Conclusions To our knowledge, we were the first to evaluate such a complex spectrum of neddylation and apoptosis-related genes in AML. We revealed dysregulation of these genes in AML. Our data indicate that upregulation of BAX at the diagnosis is associated with longer OS. Moreover, we reported significantly lower BAX expression in ELN high-risk group. Thus, indicating BAX may be a potential prognostic factor in AML. Our preliminary results did not prove significant differences in the effect of neddylation gene expression levels on the prognosis of AML patients. As studies are emerging on the potential of neddylation-targeted therapies, we are conducting further research to verify the effect of neddylation on AML.