ALBERT

Description: Early response to induction chemotherapy is a predictor of outcome in acute myeloid leukemia (AML). We determined the prevalence and significance of postinduction residual disease (RD) by multidimensional flow cytometry (MDF) in children treated on Children's Oncology Group AML protocol AAML03P1. Postinduction marrow specimens at the end of induction (EOI) 1 or 2 or at the end of therapy from 249 patients were prospectively evaluated by MDF for RD, and presence of RD was correlated with disease characteristics and clinical outcome. Of the 188 patients in morphologic complete remission at EOI1, 46 (24%) had MDF-detectable disease. Those with and without RD at the EOI1 had a 3-year relapse risk of 60% and 29%, respectively (P 〈 .001); the corresponding relapse-free survival was 30% and 65% (P 〈 .001). Presence of RD at the EOI2 and end of therapy was similarly predictive of poor outcome. RD was detected in 28% of standard-risk patients in complete remission and was highly associated with poor relapse-free survival (P = .008). In a multivariate analysis, including cytogenetic and molecular risk factors, RD was an independent predictor of relapse (P 〈 .001). MDF identifies patients at risk of relapse and poor outcome and can be incorporated into clinical trials for risk-based therapy allocation. This study was registered at www.clinicaltrials.gov as NCT00070174.

Description: Introduction. Myeloid leukemia in children with Down syndrome (ML-DS) is a unique subtype of acute myeloid leukemia, distinguished by an earlier age of onset (under 4 years of age); somatic mutations of GATA1; hypersensitivity of leukemic blasts to cytarabine and other chemotherapeutic agents; lack of CNS involvement; and superior event-free survival (EFS, 85-90% at 5 years). Due to these excellent outcomes, successive protocols by the Children's Oncology Group (COG) have aimed for a reduction of treatment intensity but continue to include a course containing high-dose cytarabine (HD-AraC) for all patients, which is associated with the bulk of infectious toxicity. COG AAML1531 is the first study to evaluate differential treatment for ML-DS patients based on risk-stratification. We report the outcomes for patients with Standard Risk (SR) ML-DS enrolled on AAML1531, who were treated without inclusion of HD-AraC (https://clinicaltrials.gov/ct2/show/NCT02521493?term=AAML1531&rank=1). Methods. Patients older than 90 days and younger than 4 years of age with ML-DS were eligible, including those presenting with myelodysplastic syndrome (〈 20% blasts in the bone marrow) and trisomy 21 mosaicism. Pathological and cytogenetic data were reviewed centrally. All patients received the same first course of induction therapy (cytarabine 200 mg/m2/24h IV as continuous infusion, day 1-4; daunorubicin 20 mg/m2IV, day 1-4; thioguanine 50 mg/m2/dose PO twice daily, day 1-4; and a single dose of age-based intrathecal cytarabine on day 1). After this first course, measureable residual disease (MRD) in the bone marrow by multi-dimensional flow cytometry in a reference laboratory was used for risk stratification. Patients with negative MRD (0.05%) after the first course were assigned to the High Risk (HR) Arm and received intensified therapy (equivalent to that used for non-DS AML). Accrual to the HR arm is ongoing. Results. Interim analysis of SR therapy was performed after 50% of expected EFS events had occurred as of June 30, 2018. The observed EFS was 89.3 +/- 6.1% at 2 years from study entry and significantly lower than expected for comparable MRD-negative patients whose treatment in predecessor study AAML0431 included a course of HD-AraC/E. coliasparaginase (p=0.0002). OS at 2 years was 88.7 +/- 6.8%. Among a total of 114 SR ML-DS patients, 11 developed a relapse, all within the first year from study entry (range 136-327 days). OS at 1 year from relapse was 9.1 +/- 17.3%. Based on the results of interim analysis, the SR arm of AAML1531 was closed to accrual due to lack of efficacy. Cytogenetic analysis showed that complex karyotypes (defined as 〉3 independent abnormalities including 〉1 structural one) were significantly more frequent in SR patients who relapsed (40%, n=10) compared to SR patients who did not (9%; n=100; p=0.017). The most common abnormalities were trisomies (61% of cases) of chromosomes 3 and 8, and a gain of a fourth copy of chromosome 21. Monosomy 7 was present in 20% of relapsed vs. 5% of patients without a relapse (p=0.122). Conclusions. MRD measured by multi-dimensional flow cytometry is insufficient to identify a subset of ML-DS patients for whom HD-AraC/E.coliasparaginase can be eliminated from treatment. Cytogenetic profiling may aid in further refining risk-based subsets of ML-DS patients. Additional approaches to risk stratification of ML-DS should be pursued, which take into account the emerging genetic events that co-operate with mutant GATA1 in the development of ML-DS. At this time, HD-AraC/E.coli asparaginase should be included in the treatment of ML-DS, regardless of MRD. Disclosures Druley: Washington University: Employment; ArcherDX Inc.: Employment, Equity Ownership. Loken:Hematologics, Inc: Employment, Equity Ownership. Eidenschink Brodersen:Hematologics, Inc: Employment.

Description: Introduction: The Children's Oncology Group (COG) conducted a randomized, Phase III study evaluating Gemtuzumab Ozogamicin (GO), a humanized anti-CD33 antibody, for children with de novo AML. This analysis describes longer term outcomes for patients assigned to GO as well as relapse risk factors and subsequent outcome for patients experiencing relapse after AAML0531 therapy. Methods: AAML0531 enrolled 1,022 evaluable patients ages 0-29 to receive either standard five-course chemotherapy with or without 2 doses of GO. All high risk and those intermediate risk patients with family donors received stem cell transplant rather than the last 2 chemotherapy cycles and the 2nd GO dose. Analysis of characteristics impacting cumulative incidence to relapse and overall survival from relapse were performed (data cutoff 3/31/16). Results: Updated outcome analyses demonstrated GO improved 5 year (yr) event-free survival (EFS) of 51.4 ± 4.5% vs 48.5 ± 3.2% p=0.055, but no benefit in 5 yr overall survival (OS), 64.9 ± 4.4% v 64.1 ± 3.1% p=0.406. A 5-yr cumulative incidence to relapse (REL) from complete remission (CR) (N= 849) was seen in 37.8% of patients, with significantly less among those receiving GO vs no-GO (33.6% vs 42.2% p=0.01). In Univariate analysis, children with NPM and CEPBA mutations, low risk cytogenetics, and higher CD33 expression had lower relapse risk (RR). Those with extramedullary disease (EMD) at diagnosis, FLT3/ITD mutations, CNS3 disease, and minimal residual disease at end of induction 1 and 2 predicted higher RR (Table 1). Multivariate analysis determined that EMD at diagnosis (HR 1.68, 95% CI 1.10-2.56, p=0.016) and minimal residual disease (MRD) at end of induction 1 (EOI1) (HR 1.61, 95% CI 1.13-2.30, p= 0.008) predicted significantly higher RR, while low risk cytogenetics predicted lower RR (HR 0.48 95% CI 0.33-0.70, p

Description: Abstract 271 MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have been implicated in the pathogenesis of human cancer. Most current studies utilize array-based or quantitative reverse-transcription-polymerase chain reaction (RT-PCR) approaches to measure miRNA expression. However, these approaches do not interrogate all known (or predicted) miRNAs and are unable to detect mutations in miRNAs. Herein, we use “next generation” sequencing approaches to comprehensively assess miRNA expression and to identify genetic variants of miRNA genes in a patient with AML. This patient (UPN 933124) was a 56 year old female with FAB M1 AML. Routine cytogenetics revealed a normal 46 XY karyotype, and high-resolution comparative genomic hybridization studies revealed no somatic copy number alterations at a resolution of ∼5kb. We previously reported the sequence of genic regions in the cancer genome of this patient (Nature 456:66, 2008). Massively-parallel sequencing of small RNAs isolated from the myeloblasts of patient 933124 was performed using the ABI SOLiD sequencing platform. As a control, we also analyzed pooled RNA isolated from CD34+ bone marrow cells of 4 healthy volunteers. In each case, RNA was size fractionated (corresponding to RNAs of 19-26 nucleotides in length) to enrich for miRNAs prior to sequencing. A total of 28 ×106 sequence reads from AML 933124 and 20×106 reads from the pooled normal CD34+ cells were obtained. Expression of 498 and 458 known miRNAs were detected in AML 933124 and CD34 cells, respectively. MiR-233 was the most highly expressed miRNA in both AML 933124 and CD34; remarkably, it represented 47.3% of all miRNA reads in AML 933124. To determine if extremely high miR-223 expression is a consistent feature of AML, we performed real time RT-PCR for miR-223 in an additional 23 AML samples and in CD34+ cells from 4 healthy donors. Of note, to avoid underestimating miR-233 expression, significant dilution of the RNA samples was required to ensure that the RT-PCR assay for miR-223 was in the linear range. Compared with normal CD34+ cells, miR-223 expression in AML 933124 was increased 6.8-fold. However, increased miR-223 expression was not a common feature of AML, with only 2 of 23 AML samples (both therapy-related AML) showing increased miR-223 expression. A large number of sequence reads mapped to unannotated regions of the genome. Using an in-house program developed to view predicted RNA structure, more than 10 novel putative miRNAs were identified, some of which were differentially expressed in AML 933124 compared with normal CD34+ cells. To detect genetic variants of miRNA genes, we designed 454-amplification and sequencing primers to sequence all 695 miRNA genes that were in the Sanger miR database (version 12.0). We sequenced approximately 200 bp flanking the mature miRNA (total ∼400 bp per miRNA gene) to ensure that mutations affecting the primary miRNA were detected. To differentiate germline polymorphisms from somatic mutations, genomic DNA from both leukemic blasts and a skin biopsy from this patient were sequenced. Average sequence coverage depth was 52.2X, and 95% of miRNAs had at least one supporting read. Thirteen single nucleotide variants and 3 Indels in miRNA genes were detected. All were present in the skin DNA sample, suggesting that they represent germline polymorphisms. Finally, we analyzed the previously generated whole genome sequence for this AML genome for genetic variants in the 3'-untranslated region of all coding genes. A single somatic mutation in the 3'-UTR of TNFAIP2 was detected. This mutation is predicted to disrupt the binding of several expressed miRNAs. However, no recurrent mutations in the 3'-UTR of TNFAIP2 were detected in an additional 180 patients with AML. Thus, the contribution of this somatic mutation to the pathogenesis of AML is unclear. These data demonstrate the feasibility of ‘next generation' sequencing technologies to identify novel miRNAs, accurately measure mature miRNA expression, and identify both somatic and germline genetic variants of miRNA genes in primary cancer. Using this platform, studies are underway to comprehensively characterize miRNAs in additional human AML samples. Disclosures: No relevant conflicts of interest to declare.

Description: Background: CD33 is variably expressed on leukemia blasts in most patients with acute myeloid leukemia (AML). Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. Qualification for GO therapy has been determined by expression of CD33 by multidimensional flow cytometry (MDF); patients with positive CD33 expression receive GO. Previous studies from the AAML0531 protocol demonstrated that the cell surface intensity expression of CD33, determined by MDF, predicts the response to treatment with GO, and that in part this expression is regulated by a pair of CD33 single nucleotide polymorphisms (SNPs) in linkage disequilibrium that also, independently, predict response to therapy. Patients with CC genotype for rs12459419 have lower relapse risk and improved disease-free survival, compared to CT and TT genotypes. Because GO therapy is associated with treatment-related toxicity, it is important to identify biologic variables associated with benefits and risks. To date, there has been no report associating SNP status among CD33 positive versus CD33 negative patients that could assess how the combination of these biomarkers for determining administration of GO therapy could improve patient outcomes. Objective: In an effort to determine which children would benefit most from GO treatment in future prospective pediatric AML protocols, we aimed to elucidate if CD33 SNP genotype status should be combined with quantitative CD33 cell surface antigen expression on the diagnostic leukemia cells (CD33+ versus CD33-) to determine GO eligibility, with a retrospective analysis of children enrolled in Children's Oncology Group AAML0531. Methods: Of 1022 newly diagnosed pediatric patients with de novo AML enrolled on protocol AAML0531, 666 satisfied two criteria for this study: (1) submission of a blood or bone marrow sample for MDF at diagnosis with corresponding CD33 SNP genotype data available, and (2) proper consent for specimen testing. CD33 Expression Levels on Leukemic Blasts The diagnostic AML leukemia population was identified by gating on CD45 versus log-side scatter and CD33 expression levels were determined by measuring the mean fluorescence intensity (MFI) by flow cytometry. For a patient to be considered CD33+ two criteria were required: intensity of CD33 on blasts was at minimum four times the MFI of its correspondent autofluorescent control, and at least 80% of the total blasts were greater than this minimum. Genotyping CD33 SNPs CD33-coding SNP rs12459419-Ala14Val and linked promoter SNP rs3865444 were genotyped using the Sequenome (San Diego, CA) platform at the Biomedical Genomics Center, University of Minnesota. Both SNPs had a call rate of 0.98 and were in Hardy-Weinberg equilibrium (P=0.05). Results: Association of Genotype and cell surface expression of CD33 for AAML0531 patients Of 666 patients, 84% (560/666) were CD33+. CC genotype was observed in 54.5% (305/560) of CD33+ cases, 37.5% (210/560) had CT genotype and 8% (45/560) TT genotype. Of the 16% (106/666) of patients who were CD33 negative, 33% (35/106) had CC genotype, 47% (50/106) CT genotype, and 20% (21/106) had TT genotype. Comprehensively, 340/666 (51%) had CC genotype (51%) and 10% were CD33 negative (35/340). Conversely, out of a total of 66 patients with TT genotype, 45 (68%) were CD33+ and 32% (21/66) were CD33 negative. Conclusions: These results clarify the relationship between the amount of CD33 expressed on AML at diagnosis as measured by MDF and CD33 SNP genotype status. While correlation with clinical outcome analysis is ongoing, these data support inclusion of CD33 SNP genotyping for eligibility of GO therapy. Therefore, the current recommendation for future COG AML clinical protocols is that GO will be administered to patients with CD33 expression as determined by MDF and CC genotype patients regardless of CD33 expression. Disclosures Pardo: Hematologics, Inc: Employment. Eidenschink Brodersen:Hematologics, Inc: Employment. Paine:Hematologics, Inc: Employment. Loken:Hematologics, Inc: Employment, Equity Ownership.

Description: The MLLT10 gene, a known fusion partner for KMT2A, encodes AF10 protein, a transcription factor that binds unmodified histone H3 and regulates DOT1L expression. KMT2A-MLLT10 fusion portends adverse outcome, but MLLT10 function and prognostic implications in partnership with other genes has not been defined. In comprehensive transcriptome and karyotype evaluation of 2226 children and young adults (0-30 years), we defined the full spectrum of MLLT10 fusions, identified new fusion partners, and correlated MLLT10 structural variants with clinical outcome. We also evaluated transcription and methylation profiles to identify genes dysregulated in MLLT10 fusions with and without KMT2A. 2226 patients treated on Children's Oncology Group (COG) trials AAML0531 and AAML1031 were evaluated by transcriptome profiling and/or karyotyping to identify leukemia associated fusions and copy number changes associated with prognosis. Collectively, 127 patients (5.7%) had primary fusions involving MLLT10: 104 (82%) involving KMT2A (KMT2A-MLLT10), and 23 patients (18%) revealed other fusion partners (MLLT10-X). Alternate, recurrent fusion partners included PICALM (n=13), DDX3X (n=2), and TEC (n=2), while fusions with 6 other partner genes (DDX3Y, CEP164, NAP1L1, SCN2B, TREH, and XPO1) were each identified in single patients. Given the known association of KMT2A-MLLT10 fusions with adverse outcome, we sought to determine whether MLLT10-X had distinct characteristics and comparable outcomes. Initial comparison of disease characteristics in patients with and without KMT2A as fusion partner showed significant differences in age at diagnosis. Those with KMT2A-MLLT10 had a median age of 1.7 years (range 0-21.3), compared to 12.7 years (range 1.4-18.9) in those with MLLT10-X (p ≤ 0.001). There was no significant difference in gender, race, mutational status, or white blood cell count between these two cohorts. MLLT10 rearranged patients (n=127) demonstrated adverse outcomes, with 5-year event-free survival (EFS) of 18.6% vs. 49% in non-MLLT10 rearranged patients (N=1953, p6 logFC, or over 400x higher on average in MLLT10 rearranged patients. To determine if patients with MLLT10 fusions had distinct epigenetic profiles, we performed differential methylation analyses on samples from normal bone marrow and patients with 4 high-risk molecular features: MLLT10 rearranged, KMT2A rearranged, NUP98-NSD1 fused, and FLT3-ITD, across nearly 1 million CpG sites on the Infinium EPIC array (Illumina, CA). After fitting a multivariate model with all of the interacting molecular features, the 250 most discriminative regions were extracted and plotted (ComplexHeatmap) (Fig 1D). Strikingly, patients with MLLT10-X fusions cluster discretely with ultra-high-risk NUP98-NSD1 fusion patients, showing a broadly hypermethylated profile, while KMT2A-MLLT10 patients cluster within the larger KMT2A category and show far fewer hypermethylated regions. We identified patients with MLLT10 fusion partners not previously described, and compared them to other AML patients, as well as patients with known MLLT10 partners KMT2A and PICALM. All MLLT10-aberrant cases had poor EFS and OS, high RR, overexpressed HOXA genes, and distinct DNA methylation profiles, while patients with MLLT10-X fusions tend to be older children. Regardless of fusion partner, patients with MLLT10 fusions exhibit very high risk, and should be prioritized for alternative therapeutic intervention. Disclosures Farrar: Novartis: Research Funding. Deshpande:A2A Pharmaceuticals: Consultancy; Salgomed Therapeutics: Consultancy.

Description: Key Points Single-agent IL-15/IL-15Rα-Fc (ALT-803) therapy was well tolerated and resulted in clinical responses in patients who relapsed post-HCT. First-in-human use of ALT-803 promoted NK and CD8+ T-cell expansion and activation in vivo without stimulating regulatory T cells.

Description: Key Points A gene expression profile consistent with activated JAK2 signaling is seen in all MPN patients, including in patients with CALR mutations. Transcriptional profiling discriminates subsets of MPNs based on JAK2V617F allele burden and on the presence of CALR and TET2 mutations.

Description: Abstract 3604 Background: Clofarabine is a nucleoside analog that potently inhibits ribonucleotide reductase and DNA polymerase α. The biochemical modulation of cytarabine by clofarabine via inhibition of ribonucleotide reductase is well established, and this combination has been studied in adults with relapsed AML1, 2. We have previously reported the toxicity profile of the Phase I portion of AAML05233. Here, we report the Phase II portion of AAML0523 in children with relapsed AML. Study Design: Clofarabine and cytarabine were administered on days 1–5. Cytarabine (1 gm/m2) was given 4 hours after the start of clofarabine to optimize the biochemical modulation of ara-CTP. Patients were encouraged to receive 2 cycles of induction therapy, based on previous trials demonstrating response after a second cycle in those without response after the first4. The Phase I portion of AAML0523 determined that clofarabine at a dose of 52 mg/m2/day can be given safely in combination with cytarabine3. Results: 47 eligible AML patients were enrolled at the dose of 52 mg/m2 of clofarabine. One patient did not have bone marrow evaluation after course 1 and therefore was not evaluable for response. The median age at study entry was 14.1, the median length of CR1 was 306 days (range 35–2212), 44 patients were in first relapse, and 3 were primary refractory. Only 4 had prior stem cell transplant. The most common toxicities grade 3 or higher were: febrile neutropenia (36%), diarrhea (12%), nausea (11%), infection (51%), and hypokalemia (24 %). Four patients had capillary leak syndrome after the first cycle. There were no treatment-related deaths in AML patients. Response was measured as best response after up to 2 cycles of Induction. Of the 46 patients evaluable for response, 16 (35%) had complete response (CR), 5 (11%) CR with incomplete platelet recovery (CRp), 14 stable disease (SD), and 11 had progressive disease (PD). Of the 21 responders, 11 had SD after induction course 1 but then achieved CR or CRp after course 2. However, 8 non-responders who achieved SD after course 1 were then taken off study, mostly at physician's discretion to pursue other therapy. Four patients met conventional criteria for CRi (complete response with incomplete count recovery) and then received stem cell transplant, but this was not included among the study response definitions. Among all responders, median time to relapse was 374.5 days (range 42–2212), 16 went on to HSCT, and 3-year overall survival was 51±34%. Conclusions: The overall response rate (ORR) of 46 % (21 patients) did not meet the statistical threshold for efficacy of 50% (23 patients) developed for this study. Factors involving study compliance (8 SD patients did not receive course 2; 4 CRi patients did not await count recovery) may have affected the ORR. However, this non-anthracycline salvage regimen may be effective as a bridge to potentially curative HSCT in this high risk patient population. Disclosures: Off Label Use: Clofarabine is approved for use in ALL in second relapse. This presentation will discuss a clinical trial using clofarabine for children with AML in first relapse.

Description: The range of genomic drivers of leukemogenesis and clonal nature of the disease illustrate the heterogeneity of the mutational spectrum in AML. Genomic interrogation of the evolution of AML has begun to highlight the scope of somatic changes that occur between diagnosis and relapse. A total of 1,214 patients were treated on the Children's Oncology Group trials AAML03P1 and AAML0531, of which 398 had relapse after initial remission. Of this cohort, 201 patients had matching diagnostic and relapse specimens for molecular profiling for the most common somatic mutations in pediatric AML (FLT3/ITD, FLT3/ALM, NPM1, CEBPA, WT1, NRAS, and KIT). Sequencing techniques included PCR with Sanger sequencing for detection of point mutations and indels and fragment length analysis for FLT3/ITD. In the cohort, FLT3/ITD was detected in 31/201 (15%) cases at diagnosis. Of the cases with diagnostic ITD, 22 (71%) relapsed with FLT3/ITD. Conversely, of the 28 cases with FLT3/ITD detected at relapse, 6 (21%) did not have detectable ITD at diagnosis. Overall, there were 37 patients (18%) with FLT3/ITD mutations detected at either time point. Of the 37 patients, 22 (59%) demonstrated stability of the mutation from diagnosis to relapse. Discordant mutation status was observed in 15 patients (41%). Among the discordant patients, 9 had FLT3/ITD detected at diagnosis only. Conversely, 6 patients were ITD-positive at relapse only, demonstrating disease evolution with continued mutational acquisition (Table 1). In every discordant case, ultra sensitive PCR analysis confirmed absence of an ITD. The median ITD allelic ratio (AR) for patients with concordant status was 0.47 (range 0.03-2.67) vs. 0.24 (range 0.04-0.47) for those with disappearance of the ITD at relapse, suggesting an association of diagnostic AR with mutation stability. NPM1 mutations were detected in 8 patients at diagnosis and 100% concordance was observed in the cohort. CEBPA mutations were detected in 6 patients at diagnosis, and in 5 cases remained at relapse. One patient had a CEBPA mutation detected at diagnosis only. FLT3/ALM mutations were detected in 7 patients at either time point. Seven patients had an ALM at diagnosis, however concordance was observed in 2 cases, whereas 4 patients had detection at diagnosis only. There were 22 patients (11%) with NRAS mutations detected at either time point. Diagnostic NRAS mutations were detected in 18 patients, while only 3 (17%) had the identical mutation detected at relapse, as one patient had a distinct mutational sequence present at relapse. NRAS mutations were detected at diagnosis only in 13 patients (59%), where as 5 patients (23%) had a mutation detected at relapse only. NRAS was the most discordant mutations analyzed, with only 3/22 patients (14%) demonstrating stability of the mutation from diagnosis to relapse (Table 1). WT1 exon 17 indels were observed in 24 patients (12%) at either time point. Nineteen patients had diagnostic mutations, with 18 patients demonstrating stability at relapse. Five patients had mutations detected at relapse only. Overall, concordance was observed in 18 patients (75%). Only 1 alteration was detected at diagnosis in all patients, however 6 patients with concordant WT1 status had multiple indels detected at relapse, demonstrating continued mutational acquisition. KIT mutations (missense and indels) in exons 8 (n=11) and 17 (n=7) were detected in 17 patients. Mutational concordance was observed in 7 patients. Eight patients had mutations detected at diagnosis only, while 2 patients had mutations detected at relapse only (Table 1). We demonstrate the complexity of the evolving somatic landscape from diagnosis to relapse in pediatric AML. The stability of NPM1 mutations, considered an early leukemogenic event, is in contrast to the discordant NRAS and KIT mutations. There was evolution of FLT3/ITD status, and we observed overall higher ARs in the concordant cohort, perhaps suggesting mutations in this cohort served as stronger leukemic drivers. Further investigation on the biologic implications and clonal prevalence is critical to determine a mutation's significance in leukemogenesis, timing of acquisition, and if appropriate for therapeutic targeting and disease monitoring. Table 1 Mutational concordance from diagnosis to relapse. Legend: Discordant D+/R-: Discordant status with diagnostic only positive Discordant D-/R+: Discordant status with relapse only positive Table 1. Mutational concordance from diagnosis to relapse. / Legend:. / Discordant D+/R-: Discordant status with diagnostic only positive. / Discordant D-/R+: Discordant status with relapse only positive Disclosures No relevant conflicts of interest to declare.