Adult Acute Lymphoblastic Leukemia Research Articles

IKZF1deletions Coupled with CD20 Expression Represents a Novel High-Risk Subtype in Adult B-Cell Progenitor Acute Lymphoblastic Leukemia

Genetic deletions of IKZF1 are associated with poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Here we investigated the effect of IKZF1 deletions (IKZF1 del) plus with immunotype in adult B-ALL in PDT-ALL-2016 cohort. This cohort study involved 161 patients with B-ALL from 2016 to 2019, with detailed information about IKZF1 del and CD20 expression. Validation cohort consists N= patients from TARGET cohort. IKZF1 del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.2±6.7% and overall survival (OS) of 51.1±7.3%, compared to IKZF1 wild-type (IKZF1 wt) with EFS 55.4±5.1% (P<0.01) and OS 74.6±4.5% (P<0.05), respectively. CD20 expression was also associated with inferior EFS than CD20-negative group (P<0.05). Furthermore, IKZF1 del coupled with CD20 expression, termed as IKZF1 del/CD20+, comprised 12.4% of patients with 3-year EFS of 25.0±9.7% compared with IKZF1 wt (P<0.05 ) and IKZF1 del/CD20- (P<0.05 ) groups, respectively. Multivariable analyses demonstrated independence of IKZF1 del/CD20+ with highest hazard ratio for EFS and OS. Furthermore, the prognostic strength of IKZF1 del/CD20+ was confirmed in TARGET validation cohort. Eighty-one patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notably, neither IKZF1 del(P=0.6288), CD20 (P=0.0705) or IKZF1 del/CD20 (P=0.3410) groups were identified as poor outcome in allo-HSCT cohort. Collectively, our data demonstrate that IKZF1 del/CD20+ represents a very high-risk subtype in adult B-ALL; and particularly, allo-HSCT could overcome the poor outcome of IKZF1 del and IKZF1 del/CD20+. DisclosuresNo relevant conflicts of interest to declare.

Heterogeneity of Minimal/Measurable Residual Disease (MRD) Practices in Adult B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) in the United States

Background: MRD testing in BCP-ALL is critical for appropriate patient management, but little is known regarding sample acquisition and testing heterogeneity across clinical practice settings. These factors may impact the quality and reliability of MRD assessment.Methods: Thirty-minute online surveys were conducted in May 2021 with hematologists/oncologists (HEME/ONCs) in the United States in both academic (acad) and community (comm) settings. Respondents were licensed physicians board certified in oncology and/or hematology who treated ≥2 BCP-ALL patients/year or ≥10 patients in the past 5 years, with over 25% of time spent in the clinical setting; pediatric HEME/ONCs were excluded. Survey enrollment is ongoing, with interim results presented here; a related survey for pathologists (PATHs) is underway.Results: HEME/ONC respondents (acad n=40, comm n=57, from 29 states) had been practicing as specialists for a median of between 11-15 years (choices were ranges, eg 6-10, 11-15, min-max was 1-34 years), and typically spent over 75% of their time in the clinic; 94% of respondents had ≥5 BCP-ALL patients/year and 92% ordered MRD tests for ≥5 patients/year. Typical timepoints for MRD testing included the end of induction/suspected complete remission, the end of consolidation, and at suspected disease progression; testing after the end of consolidation was infrequent in both groups (Table). Testing for MRD at the end of consolidation was notably more frequent in the academic setting. In both settings, the HEME/ONC ordering the MRD test generally also performed the bone marrow collection procedure (acad: 78%, comm: 56%). Resources consulted on bone marrow collection best practices included UpToDate (21%), ASH and ASCO (13%), NCCN guidelines (13%), and hematology/oncology journals. About half of practices had defined institutional protocols for bone marrow collection (acad: 55%, comm: 47%), nearly all of which were developed internally. The amount of bone marrow sample collected showed high variability, ranging from 1-10 draws (median=3) and 1-30 mL sample per draw (median=5 mL). While 49% of HEME/ONCs performed <5 draws and extracted ≤6 mL per draw, 22% collected 10 mL/draw, and 10% collected 20 mL/draw; the remaining 18% reported >5 draws and/or >6 mL per draw. In both settings, the first pull was identified and labeled in 35% of procedures; in those cases, the first-pull samples were used primarily for MRD testing in 60% of cases as recommended by NCCN guidelines (vs for morphology assessment and cytogenetic studies). HEME/ONCs typically relied on the expertise of pathologists to choose MRD testing methodology.Survey results indicate that external labs (both national clinical reference labs and commercial labs) were most commonly used for MRD assessments (63%); comm HEME/ONCs were more likely to use external reference labs and acad HEME/ONCs were more likely to use in-house labs. When asked to estimate the frequency with which different MRD methods were used, mean responses were 54% flow cytometry and 40% next-generation sequencing. While all HEME/ONCs indicated that MRD results were presented clearly in lab reports, there was a desire to include more guideline information about MRD interpretation and BCP-ALL treatment.Conclusion: Interim results identified broad heterogeneity in clinical practices affecting sample collection for MRD assessment in Ph- BCP-ALL in the US, indicating several opportunities for harmonization of routine MRD assessment in BCP-ALL. These opportunities include optimization of bone marrow sample collection techniques (volume/draw and identification/use of first pull for MRD), timing/frequency of specimen collection, serial MRD surveillance after consolidation, MRD method chosen, and standardizing reports to include guideline information. There were gaps in awareness of FDA-approved methods of MRD testing for BCP-ALL. Initiatives supporting provider education and harmonization of best practices from professional guideline committees/organizations are needed to optimize outcomes of BCP-ALL patients. [Display omitted] DisclosuresHidalgo-Lopez: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Roboz: Janssen: Research Funding; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Borowitz: Amgen, Blueprint Medicines: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Velasco: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Elkhouly: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Adedokun: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Zaman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Iskander: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding.

Outcomes in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia Patients Using Tyrosine Kinase Inhibitors Combined with the Modified University of Southern California (USC ALL) Regimen without Pegaspargase in the Era of Novel Agents; A Retrospective Study

Introduction:Prior to the introduction of tyrosine kinase inhibitors (TKIs), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukemia (ALL). We published in 2017 in Br J Haematology our analysis comparing the survival of Ph-Positive (Ph+) and Ph-negative ALL during the period when TKIs were universally available in the United States for Ph+ ALL using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic stem cell transplant (allo-HSCT) to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease (MRD) the best approach is yet to be determined. In this study we present data from our institution with incorporation of TKIs in our modified USC ALL pediatric-based regimen without pegaspargase (PEG) (Table 1).Methods:This retrospective, single institution chart review included adults aged >18 with newly diagnosed Ph+ ALL between 2016 and 2020. Primary objectives were Overall survival (OS) and event-free survival (EFS) at 3 years for Ph+ ALL patients and secondary objectives were rates of complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry and presence of BCR-ABL1 fusion transcript by real time polymerase chain reaction. Descriptive statistics of patients were reported and evaluated using Fisher's exact test. OS and EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant.RESULTS: 26 Ph+ ALL patients were identified. Median age at diagnosis was 42.5 years, with 42.3% males and 57.7% females. Median BMI was 31.1 kg/m 2, 42.3% had hepatic steatosis and 34.6% had CNS disease pre-induction.After induction 1, 91.3% of patients achieved CR/CRi, 8.7% were refractory, and 64.3% were MRD flow negative with 24% of patients with undetectable BCR-ABL1. After induction 2, 94.1% had achieved CR/CRi, 64.3% were MRD flow negative with 44.4% of patients with undetectable BCR-ABL1. After consolidation I, 78.6% were MRD flow negative. 50% of patients had received blinatumomab for MRD flow positivity early in the course and 34.6% underwent allo-HSCT. Of note, 65.4% of patients received Dasatinib only and 30.8% received at least 2 TKIs. Overall, 11.5% had known relapse, 12.5% died. 3-year OS was 83.3% and 3-year EFS was 86.6% (Table 2).When survival was stratified by transplant status, 3-year OS with allo-HSCT was 100% versus 70% without allo-HSCT (p=0.15) and 3-year EFS with allo-HSCT was 100% compared to 77.9% without allo-HSCT (Table 3).CONCLUSIONS: The use of the modified USC ALL regimen without PEG for the treatment of newly diagnosed Ph+ ALL combined with TKI at our institution led to an excellent 3-year OS (83.3%) and 3-year EFS (86.6%). All patients received TKI, half of the patients received blinatumomab and at least one third received allo-HSCT which likely led to higher OS even without PEG. We also observed a trend towards improved OS in recipients of allo-HSCT compared to patients who did not receive allo-HSCT (100% vs. 70%, p=0.15) although statistically not significant, it highlights the role of allo-HSCT in the management of Ph+ ALL patients. [Display omitted] DisclosuresChaudhary: TCR2: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Allogene: Current equity holder in publicly-traded company. Douer: Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy; Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Yaghmour: Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.

Diagnostic Utility of Multimodal Genomic Profiling for Molecular Classification and MRD Assessment in Adult B-Cell Acute Lymphoblastic Leukemia

Genomic markers define molecular subtypes and measurable residual disease (MRD) targets in B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) and are essential determinants of treatment. Current diagnostic approaches typically involve serial multi-step testing utilizing conventional cytogenetics (CC)/FISH and molecular genetic (RT-qPCR, MLPA, clonality PCR, NGS panel) techniques which are time and sample consuming and ultimately may not adequately identify genomically complex B-ALL subtypes. In contrast, single-step comprehensive genomic profiling by whole genome and whole transcriptome sequencing (WGS/WTS) may be more efficient for the molecular classification of established and newly described entities which are of increasing therapeutic relevance. We have instituted a multimodal platform for molecular testing in B-ALL performing WGS/WTS in parallel with deep NGS-based immunoglobulin (IG) rearrangement MRD and exploratory DNA-breakpoint based MRD assays. We aimed to determine the utility of this approach for subtype classification compared to a standard-of-care diagnostic approach of CC/FISH testing.Forty-two consecutive adult patients underwent both standard-of-care diagnostic testing and WGS/WTS. 20/42 (48%) patients had an abnormal CC/FISH result supporting classification into recognized molecular subgroups. WGS/WTS assessment incorporating somatic coding and non-coding mutations, structural variants, fusions, copy number abnormalities and gene expression subtype prediction (ALLSorts, https://github.com/Oshlack/ALLSorts) was performed with concordant results in all 20 patients. 16/22 patients that were unclassified by CC/FISH were successfully reclassified by WGS/WTS including subtypes enriched for cryptic rearrangements (Ph-like, DUX4, MEF2D) and groups characterized by heterogeneous genomic alterations or a distinctive gene expression signature (PAX5alt, ZEB2/CEBP). A low hypodiploid karyotype was observed in two cases with an apparently normal karyotype by CC. The six patients who remained without a subtype defining driver genetic alteration after comprehensive testing frequently harbored novel IGH translocations or a Ph-like expression signature but without a described fusion.In order to understand the relative contribution from WGS versus WTS, analysis of 36 patients was performed using a truth classification. WGS and WTS produced equivalent classifications for 22 cases. Two cases were based solely on WGS findings (iAMP21 and ZEB2/CEBP) and three cases were based solely on WTS findings (DUX4). Importantly the combination of both WGS and WTS was critical to correctly classify nine cases (Ph-like and PAX5alt).MRD was assessed by a sensitive NGS assay to IG rearrangements (Adaptive Biotechnologies) and by quantitative probe-based droplet digital PCR (ddPCR) assays designed to structural rearrangement DNA breakpoints from genome data (analytical sensitivity 10 -4). Patient-specific ddPCR assays were designed to eight structural variants (KMT2A and IGH translocations, and IKZF1 deletions) in seven patients and assessed in 36 remission samples with parallel testing by multiparametric flow cytometry (MFC). Concordant MFC and ddPCR was observed in 30/36 samples (19 MRD pos, 11 MRD neg). Discordances included two MRD pos by MFC-only and four MRD pos by ddPCR-only; the latter often occurring in the setting of antigen directed therapy or in ALL with a less informative immunophenotype, demonstrating the additional utility of non-MFC based MRD assessment in specific clinical settings. 27/42 patients in our cohort had ≥1 genomic structural rearrangement identified by WGS that could be used for patient-specific MRD monitoring to complement existing MRD assessment.In conclusion WGS/WTS provided a molecular subtype classification in 86% of our cohort compared to 48% by standard-of-care diagnostic testing highlighting that CC/FISH alone is inadequate for contemporary molecular classification of B-ALL, which may have implications for treatment decisions. Importantly, the combination of WGS and WTS was superior to WGS-only or WTS-only for correct molecular subtype assignment. This approach has the potential to improve risk assessment in adult B-ALL and the routine feasibility, improvement in clinical outcomes and health economic impact warrant further assessment. DisclosuresBajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Dickinson: Janssen: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tiong: Servier: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Consultancy.

The Clinical Outcomes and Genomic Landscapes of Acute Lymphoblastic Leukemia Patients with E2A-PBX1: A 10-Year Retrospective Study

▪IntroductionPatients with E2A-PBX1 fusion are expected to have an aggressive disease course. Because of the rarity of this genotype (nearly 5% of pediatric and 3% of adult B-cell acute lymphoblastic leukemia (B-ALL) cases), a consensus on the clinical and prognostic characteristics of adult E2A-PBX1-positive B-ALL patients, especially in adult patients, has not yet been reached.Patients and MethodsWe retrospectively summarized our clinical findings from 137 B-ALL patients diagnosed with E2A-PBX at our centers from 2009 to 2019, including 56 adolescents/adults (≥15 years old) and 81 children (<15 years old). Genomic investigated analysis was performed on sufficient bone marrow at diagnosis, relapse and remission as well as matched hair follicle cells using somatic copy number variation detection (n=25), whole-exome sequencing (n=29), the next-generation sequencing pane (tumor only, n=14) and RNA sequencing (n=22).ResultsThe proportions of E2A-PBX1-positive B-ALL in our centers were 5.3% (81/1526) in children, 4.6% (43/925) in AYA and 2.1% (15/713) in older adults. The complete remission rate among all E2A-PBX1-positive B-ALL patients in this study was 94.9% (129/136) after one course of induction chemotherapy. The 5-year overall survival (OS) and disease-free survival (DFS) rates of the whole cohort were 68.6% and 61.0%, respectively.Allo-HSCT at CR1 in adolescents/adults could dramatically improve the 5-year prognoses (OS: 80.8% vs. 25.7%, P<0.001; DFS: 73.3% vs. 15.5%, P<0.001; cumulative incidence of relapse (CIR): 20.0% vs. 80.5%, P<0.001) (Figure 1A). Haploidentical-HSCT decreased the CIR compared with HLA-matched-HSCT in adolescents/adults (12.5% vs 58.3%, P=0.017) (Figure 1B).A total of 12 patients received CD19-targeted CAR-T cell therapy for disease progression (Figure 1C), and 91.7% (11/12) of patients achieved remission. Two patients died of relapse, and 3 patients died of complications (One died of grade 4 CRS, one died of cerebral hemorrhage after transfusion, and the other one died of infection after 14 months). Three patients received CAR-T bridging to allo-HSCT, and all of them remained in remission within the follow-up period.Univariate and multivariate analysis showed that t(1;19)(q23;p13) only (OS: P=0.020, HR=0.387, 95% CI: 0.174-0.862; DFS: P=0.004, HR= 0.375, 95% CI: 0.193-0.729; CIR: P=0.009, HR= 0.400, 95% CI: 0.200-0.799), Age (DFS: P=0.037, HR=1.009, 95% CI: 1.001-1.018; CIR: P=0.005, HR=1.025, 95% CI: 1.008-1.044) and the level of minimal residual disease (MRD) after induction chemotherapy (OS: P=0.020, HR=2.971, 95% CI: 1.185-7.452; DFS: P=0.002, HR= 3.218, 95% CI: 1.510-6.861; CIR: P=0.006, HR= 3.190, 95% CI: 1.406-7.246) were independent risk factors in E2A-PBX1-positive B-ALL (Figure 1D).In the diagnosis samples, mutations in PBX1, PAX5, CTCF and SETD2, amplification of AKT3, and deletion of CDKN2A/B were common in the total cohort, while transcriptome differences were found in the cell cycle, NGF signaling pathway and transcriptional regulation by TP53 between adolescents/adults and children (Figure 2A,B). More DNA repair gene mutations were detected in the relapse samples (7.9% vs. 57.1%, P<0.001). The median number of subclones in E2A-PBX1-positive B-ALL at diagnosis was 2 (range 1-4). Patients with multiple subclones at diagnosis tended to have unfavorable 3-year prognoses (DFS: P=0.010; CIR: P=0.021). Leukemia clones with DNA repair gene mutations showed aggressive and treatment-refractory phenotypes in this subtype of ALL (Figure 2C).ConclusionsOur study indicated that age, the level of MRD and DNA repair gene mutations were associated with E2A-PBX1-positive B-ALL outcomes. Allo-HSCT, especially haploidentical-HSCT, could improve the prognosis of adolescent/adult patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genomic Data Improves Prognostic Stratification in Adult T-Cell Acute Lymphoblastic Leukemia Patients Enrolled in Measurable Residual Disease-Oriented Trials

Background:Genetic information has become critical to understand the development of T-cell acute lymphoblastic leukemia (T-ALL) and to elucidate the origin of disease relapse. Several genetic markers, together with measurable residual disease (MRD), are considered strong predictors of patient outcome. However, the prognostic significance of genetic markers can varie according to treatment.Aim: We used targeted deep sequencing to analyze the genetic profile of 125 T-ALL patients enrolled in three consecutive MRD-oriented trials from the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genomic information was analyzed together with the main clinical and biologic data in a subset of 111 patients with detailed clinical and outcome data to determine the prognostic significance for overall survival (OS) and cumulative incidence of relapse (CIR).Methods: Genetic mutations were detected using a custom gene panel and sequenced on a MiSeq platform. Alignment, variant calling, filtration and annotation of variants were done using standardized pipelines. OS curves were plotted by the Kaplan-Meier method and compared by the log-rank test. CIR was estimated using cumulative incidence functions by competing risks analysis. A Cox proportional hazard regression model was used to identify predictive factors for OS. Statistical significance was set at (two-sided) p-values <0.05.Results: Recurrently mutated genes found in ≥4/125 patients involved transcription factor tumor suppressor genes (PTEN, BCL11B, RUNX1, GATA3, ETV6), epigenetic regulators (PHF6, DNMT3A, EP300, KMT2C, EZH2, TET2), DNA mismatch repair genes (MSH2), ribosomal (RPL5) and RNA splicing (U2AF1) genes, and genes involved in the RAS/MAPK (NRAS), WNT (FAT1, FAT3), IL7R-JAK-STAT (JAK3, JAK1, IL7R) and NOTCH1 signaling pathways, respectively. Mutations in the latest pathway (NOTCH1 & FBXW7) was found in 88/125 (70%) patients.Clinical-genetic correlations revealed that patients with mutations in JAK3, DNMT3A, N/KRAS, IL7R, MSH2 or in U2AF1 were associated with lower OS (vs unmutated patients). None of the mutated genes had impact on CIR. Upon grouping the mutated genes according to their functional role and potential biological impact on T-ALL, two gene signatures were defined. These included the aging gene signature (DNMT3A and U2AF1) characterized by mutations in genes identified in clonal hematopoiesis of indeterminate potential (CHIP); and the treatment resistance gene signature (JAK3, N/KRAS, IL7R and MSH2), defined by mutations in genes involved in resistance to the ALL therapy. Both clusters identified patients with poorer response to therapy (poorer blast clearance on day 14 of induction treatment and lower CR rates). Therefore, we considered together (worse outcome genetics [WOG] signature) for univariate and multivariate analyses. WOG and MRD level (0.1% cut-off) on day 35 after induction therapy (+35d MRD) showed significant prognostic impact in the univariable and multivariable analyses for OS (3y) with a hazard ratio (95% CI) of 2.4 (1.2; 4.8) and 2.7 (1.4; 5.1), respectively (Table 1). OS according to these two variables allowed risk stratification of T-ALL into low, intermediate- and high-risk (HR) patients with significantly different outcomes (p<0.001) (Figure 1).Conclusion: A genetic signature with independent prognostic significance of MRD has been identified in this cohort of patients included in MRD-oriented trials. This gene signature (WOG) together with MRD could help to improve risk-stratification of adult T-ALL patients and would be of interest in the search for new therapies for HR patientsFunding: Support from AECC (GC16173697BIGA); ISCIII (PI19/01828 and PI19/01183), co-funded by ERDF/ESF, “A way to make Europe”/“Investing in your future”, CERCA/Generalitat de Catalunya SGR 2017 288 (GRC)/ C González-Gil was supported by AGAUR grant (2020 FI_B2 00210). [Display omitted] DisclosuresDiaz-Beyá: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tormo: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau.

The Comparison of Kte-X19 to Current Standards of Care: A Pre-Specified Synthetic Control Study Utilizing Individual Patient Level Data from Historic Clinical Trials (SCHOLAR-3)

Background: The ZUMA-3 trial of KTE-X19 in relapsed/refractory (r/r) adult B-cell precursor acute lymphoblastic leukaemia (B-ALL) utilizes a single arm design. To contextualize these results, a synthetic control (SC) study derived from individual patient-level data (IPD) sampled from historical clinical trials (CTs) was constructed.Aims: To compare the overall survival (OS) and objective complete response rate at week 24 (OCR24) results of the ZUMA-3 pivitol study using a matched (SC) derived from IPD from CTs.Methods:This study had two distinct phases: firstly, CTs from which patients were sampled were identified using the medidata enterprise data store (MEDS). The second phase of this study constructed SCs to the ZUMA-3 population, one SC for patients naïve to blinatumomab (blin) or inotuzuamab (ino) therapy (SCA-1) and one in blin or ino pre-treated patients (SCA-2). All analysis were pre-specified and conducted by an external third party to Kite Pharma.For the trial identification phase, the MEDS database was searched to identify CTs that had inclusion and exlusion criteria congruent with ZUMA-3 and treatment assignments representative of current standards of care inclusive of blin, ino or chemotherapy regimens. Once appropriate CTs had been identified the endpoints were re-engineerd to match the same defintions as the ZUMA-3 trial.For the SC construction phase, propensity score (PS) matching was used. The PS was derived as a function of the number of previous lines of therapy, prior allo-SCT, age, sex, ECOG, Philadelphia chromosome status, percentage bone marrow blasts and extramedullary disease.For outcomes analysis, time-to-event endpoints of interest were analyzed using the Kaplan-Meier method and compared using a Cox proportional hazard regression model. OCR rate was described through crude incidence rates and corresponding 95% CI. ln addition, an odds ratio together with associated 95% CI and 2-sided p-value were estimated from a logistic regression model.ResultsA total of 20 SCA-1 patients were matched to 20 patients from ZUMA-3 and a total 20 SCA-2 patients were matched to 29 patients from ZUMA-3.Analysis of the SCA-1 cohort shows an OCR24 of 85% (95% CI 62.1%, 96.8%) in the Zuma-3 patients and 35.0% (95% CI 15.4, 59.2) among propensity matched controls. This corresponds to an OR of 10.5 (95% CI 2.3, 48.7; p-value 0.0031). No OCR24 data was available for SCA-2.A post hoc analysis was conducted in order to further contextualize the OCR24 rate. ZUMA-3 patients irrespective if they had been pre-treated with blin or ino were matched to patients from HCTs who were previously naïve to blin or ino therapy (SCA-3). The OCR24 rate in the ZUMA-3 arm was 69.8% (95% CI 55.7%, 81.7%) while for SCA-3 patients was 35.8% (95% CI 23.1%, 50.2%) meaning that ZUMA-3 patients had 4.1 times higher odds of achieving OCR in comparison to SCA-3 patients (95% CI 1.8, 9.3) p-value 0.0009.The comparison of overall survival (OS) between all matched ZUMA-3 and all SCA patients demonstrated a significantly higher median OS of 18.20 months (95% CI 12.22, NE months) for patients in ZUMA-3 versus 5.49 months (95% CI 3.32, 9.23 months) in SCA-3. A cox regression model showed that ZUMA-3 patients had a 64% lower risk of death with a hazard ratio 0.36 (95% CI 0.20, 0.66) p-value 0.0005.Conclusion: This comparative study demonstrated a clinically relevant improvement of OCR24 and OS following KTE-X19 vs available therapies and provides strong evidence for its use in adult patients with R/R B-ALL DisclosuresShah: Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Precision Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy. Faghmous: Kite A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Whitmore: Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Masouleh: GSK: Current equity holder in publicly-traded company; Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company; Immatics: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment.

Detection of CSRP2 Transcript Levels By Real-Time Quantitative PCR May be a Useful Tool for Monitoring Minimal Residual Disease in B-Cell ALL

Introduction Cysteine and glycine-rich protein 2 (CSRP2) is gaining increasing attention as a therapeutic target due to its high expression in acute leukemias and its involvement in the development of cancer. However, whether it can be used as a reliable marker for minimal residual disease (MRD) remains unknown.Methods A total of 155 adult B-cell acute lymphoblastic leukemia (ALL) patients who received at least two cycles of consolidation chemotherapy were enrolled. Their leukemia-associated aberrant immune phenotypes (LAIPs) and CSRP2 transcript levels at the second consolidation chemotherapy (CON2) were detected by flow cytometry (FCM) and real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR). According to our published work, 1.80% and 0.01% were set as the positive threshold of CSRP2 transcript level and the FCM test for diagnosis, respectively. Pearson correlation coefficient was calculated to describe the relationship between the CSRP2 transcript level and the FCM test. Competing risk model and Cox proportional hazard regression model were conducted to estimated associations between the CSRP2 transcript level at CON2 and the prognosis.Results The median CSRP2 transcript level of all 155 patients was 0.2% (0.02%-108.17%). Among them, 108 patients were negative for both FCM and CSRP2, and 8 patients were positive for both FCM and CSRP2. The coincidence rate was 74.84%. There was a significant positive correlation between FCM and CSRP2 (r=0.73, 95% CI 0.64-0.79; P <0.001)(Figure 1a).Patients were divided into a high CSRP2 group (N=17) and a low CSRP2 group (N=138) based on the transcript level of 1.00% settled by the ROC curve. Nine of 17 patients with high transcript level of CSRP2 suffered from leukemia relapse during the follow-up. Moreover, among the nine relapse patients, three patients had positive CSRP2 and negative FCM at CON2. In univariate analysis, patients with high CSRP2 transcript level showed a significantly lower 5-year leukemia-free survival (LFS) (33.0% vs. 48.6%, P =0.014) and 5-year survival (OS) (28.6% vs. 72.5%, P <0.001), higher 5-year cumulative incidence of relapse (CIR) (60.6% vs. 47.3%; P =0.042) (Figure 1b-d). Variates with P-value lower than 0.1 including BCR-ABL1(Y/N), treatment (chemotherapy only vs. allo-HSCT), CSRP2 transcript level (high vs. low), WBC (≥ vs. < 53.6×10E+9/L [settled by ROC curve]), were put into multivariate analysis. In multivariate analysis, no BCR-ABL1 (LFS, HR 0.43, 95% CI 0.26-0.71, P =0.001; OS, HR 0.41, 95% CI 0.21-0.81, P =0.010; CIR, HR 0.39, 95% CI 0.22-0.68, P =0.001), allo-HSCT (LFS, HR 0.29, 95% CI 0.17-0.51, P < 0.001; OS, HR 0.21, 95% CI 0.11-0.42, P <0.001; CIR, HR 0.29, 95% CI 0.17-0.50, P <0.001), and low CSRP2 (LFS, HR 0.37, 95% CI 0.19-0.74, P =0.005; OS, HR 0.21, 95% CI 0.10-0.44, P <0.001; CIR, HR 0.44, 95% CI 0.21-0.93, P =0.031) were independently associated with higher LFS, OS and lower CIR.Conclusions Our study suggested that patients with a high CSRP2 transcript level at CON2 had poor survival and was an independent risk factor for relapse. The transcript level of CSPR2 at CON2 may be a valuable marker to complement the MRD assessment system and improve the number of evaluable patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of genetic polymorphism of TPMT and NUDT15 on the tolerance of 6-mercaptopurine therapy in adult acute lymphoblastic leukemia

目的探讨TPMT*2 rs1800462、TPMT*3B rs1800460、TPMT*3C rs1142345和NUDT15 rs116855232基因多态性对成人急性淋巴细胞白血病（ALL）患者6-巯基嘌呤（6-MP）耐受性的影响。方法选取2015年9月至2019年12月于中国医学科学院血液病医院确诊并接受环磷酰胺、阿糖胞苷和6-MP（CAM方案）治疗的216例成人ALL患者，利用Taqman SNP基因分型方法检测患者的TPMT、NUDT15基因型。结合临床资料，分析基因多态性对ALL治疗中含6-MP方案耐受性的影响。结果216例患者中B-ALL 185例（85.65％）、T-ALL 31例（14.35％）。TPMT*2 rs1800462 CC型216例（100.00％）；TPMT*3B rs1800460 CC型216例（100.00％）；TPMT*3C rs1142345 TT型209例（96.76％）、TC型7例（3.24％），等位基因突变频率为1.62％。NUDT15 rs116855232 CC型166例（76.85％）、CT型48例（22.22％）、TT型2例（0.93％），等位基因突变频率为12.04％。TPMT*3C rs1142345突变型组（TC+CC型）悬浮红细胞的输注量少于野生型组（CC型）（P＝0.036）；TPMT*3C rs1142345突变型组出现肝损害（天冬氨酸转氨酶升高）的风险高于野生型组（OR＝9.559, 95％CI 1.135～80.475, P＝0.038）。NUDT15 rs116855232突变型组（CT+TT型）WBC<1×109/L和中性粒细胞绝对计数<0.5×109/L的持续时间均长于野生型组（CC型）（P＝0.005，P＝0.007）；突变型组单采血小板的输注量多于野生型组（P＝0.014）。结论TMPT、NUDT15基因多态性可以影响成人ALL患者对6-MP的耐受性。治疗前检测患者基因型，进而优化6-MP使用剂量，有助于缩短骨髓抑制时间和减少血制品输注量。临床试验注册：中国临床试验注册中心（ChiCTR-TNC-09000397）

Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of CDX2 and IDH1/2 mutations

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph−) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.

Comparative study of therapy-related and de novo adult b-cell acute lymphoblastic leukaemia.

SummaryWe report a comparative analysis of patients with therapy‐related acute lymphoblastic leukaemia (tr‐ALL) vs de novo ALL. We identified 331 patients with B‐ALL; 69 (21%) were classified as tr‐ALL. The most common prior malignancies were breast (23·2%) and plasma cell disorders (20·3%). Patients with tr‐ALL were older (median 63·2 vs. 46·2 years, P < 0.001), more often female (66·7% vs. 43·5%, P < 0·001), and more likely to have hypodiploid cytogenetics (18·8% vs. 5·0%, P < 0·001). In multivariable analysis, patients with tr‐ALL were less likely to achieve complete remission [odds ratio (OR) = 0·16, P < 0·001] and more likely to be minimal residual disease‐positive (OR = 4·86, P = 0·01) but had similar OS after diagnosis and allo‐haematopoietic cell transplantation.

Improved survival after allogeneic transplantation for acute lymphoblastic leukemia in adults: a Danish population-based study

We investigated trends of survival in a population-based cohort study of all 181 adults who received HCT for ALL in Denmark between 2000–2019. Patients had a median (min–max) age of 36 (18–74) years at HCT and were followed for a median of eight years. Overall survival (OS) improved over time with an estimated 2-year OS of 49% (CI 27–66%) in year 2000 versus 77% (CI 59–88%) in year 2019. More patients achieved cure over time (OR for cure per year 1.07, CI 1.00–1.15), while the rate of death in non-cured patients remained stable (HR of excess mortality per year 0.99, CI 0.93–1.06). Relapse decreased over time (HR 0.92 per year, CI 0.87–0.98), whereas non-relapse mortality did not change notably (HR 0.98 per year, CI 0.93–1.04). In conclusion, survival after HCT in adults with ALL has improved over the past two decades, primarily due to more patients achieving cure.

An MRD-stratified pediatric protocol is as deliverable in adolescents and young adults as in children with ALL

AbstractPediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children's Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.

Cognitive interference processing in adult survivors of childhood acute lymphoblastic leukemia using functional magnetic resonance imaging

Background Childhood acute lymphoblastic leukemia (ALL) is associated with cognitive impairment in adulthood. Cognitive interference processing and its correlated functional magnetic resonance imaging (fMRI) activity in the brain have not yet been studied in this patient group. Material Twenty-six adult childhood ALL survivors (median [interquartile range {IQR}] age, 40.0 [37.0–42.3] years) were investigated at median age (IQR), 35.0 (32.0–37.0) years after treatment with intrathecal and intravenous chemotherapy as well as cranial radiotherapy (24 Gy) and compared with 26 matched controls (median [IQR] age, 37.5 [33.0–41.5] years). Methods Cognitive interference processing was investigated in terms of behavioral performance (response times [ms] and accuracy performance [%]) and fMRI activity in the cingulo-fronto-parietal (CFP) attention network as well as other parts of the brain using the multisource interference task (MSIT). Results ALL survivors had longer response times and reduced accuracy performance during cognitive interference processing (median [IQR] interference effect, 371.9 [314.7–453.3] ms and 6.7 [4.2–14.7]%, respectively) comparedwith controls (303.7 [275.0–376.7] ms and 2.3 [1.6–4.3]%, respectively), but did not exhibit altered fMRI activity in the CFP attention network or elsewhere in the brain. Conclusion Adult childhood ALL survivors demonstrated impaired behavioral performance but no altered fMRI activity when performing cognitive interference processing when compared with controls. The results can be used to better characterize this patient group and to optimize follow-up care and support for these individuals.

Response to blinatumomab or inotuzumab ozogamicin for isolated extramedullary relapse of adult acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation: a case study.

Isolated extramedullary relapse (EMR) without bone marrow relapse (BMR) after allogeneic hematopoietic cell transplantation (allo-HCT) is a rare condition in patients with acute lymphoblastic leukemia (ALL), and the role of immunotherapeutic agents for these patients remains unclear. We analyzed treatment outcomes of blinatumomab or inotuzumab ozogamicin (INO) as first- or second-line salvage therapy in nine patients with Philadelphia chromosome-negative B-cell precursor ALL presenting with isolated EMR after previous allo-HCT. In seven patients receiving blinatumomab as first-line salvage therapy, 4 (57.1%) achieved complete remission (CR). Among the three patients without remission after blinatumomab, two switched to INO and subsequently showed responses {one CR and one partial response [PR]}, and one switched to multiagent chemotherapy that led to CR. In the two patients receiving first-line salvage therapy with INO, one showed PR and the other achieved CR. Overall, 6 (66.7%) of nine patients achieved CR, and five of them proceeded to allo-HCT in CR. The median overall survival after relapse was 27.8months. In conclusion, both blinatumomab and INO showed good response rates and a safe bridging role to second allo-HCT in patients with isolated EMR. However, clinical differences between isolated EMR and EMR with BMR remain to be elucidated.

Application of Next-Generation Sequencing-Based Mutational Profiling in Acute Lymphoblastic Leukemia.

Recent efforts to characterize hematologic cancers with genetic and molecular detail have largely relied on mutational profiling via next-generation sequencing (NGS). The application of NGS-guided disease prognostication and clinical decision making requires a basic understanding of sequencing advantages, pitfalls, and areas where clinical care might be enhanced by the knowledge generated. This article identifies avenues within the landscape of adult acute lymphoblastic leukemia (ALL) where mutational data hold the opportunity to enhance understanding of disease biology and patient care. NGS-based assessment of measurable residual disease (MRD) after ALL treatment allows for a sensitive and specific molecular survey that is at least comparable, if not superior, to existing techniques. Mutational assessment by NGS has unraveled complex signaling networks that drive pathogenesis of T-cell ALL. Sequencing of patients with familial clustering of ALL has also identified novel germline mutations whose inheritance predisposes to disease development in successive generations. While NGS-based assessment of hematopoietic malignancies often provides actionable information to clinicians, patients with acute lymphoblastic leukemia are left underserved due to a lack of disease classification and prognostication schema that integrate molecular data. Ongoing research is positioned to enrich the molecular toolbox available to clinicians caring for adult ALL patients and deliver new insights to guide therapeutic selection, monitor clinical response, and detect relapse.

Pediatric-inspired regimen with late intensification and increased dose of L-asparaginase for adult acute lymphoblastic leukemia: the KALLA 1406/1407 study.

Background/AimsThe objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology.MethodsData of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib.ResultsA total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events.ConclusionsThe KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.

How I Treat Adult Acute Lymphoblastic Leukemia in India

AbstractSurvival of children with acute lymphoblastic leukemia (ALL) has improved from 10% to 90% over the last six decades. Survival gains in adult ALL have been more modest and confined to the adolescent and young adult population. Age is an important factor in determining outcomes in ALL. Additional factors like adverse biology, less intense treatment regimens, and poorer tolerance to therapy contribute to inferior survival among adults. Indian physicians face unique challenges while managing these patients. These are high infection rates, limited access to high-end investigations, and newer drugs. In this context, the management decisions in an individual patient are highly nuanced. Through a case-based review, we discuss representative scenarios in adult ALL where we detail our current approach to treatment in the context of available evidence.

Cytogenetic aberrations in adult acute lymphoblastic leukemia-A population-based study.

Cytogenetic aberrations are recognized as important prognostic factors in adult acute lymphoblastic leukemia (ALL), but studies seldom include elderly patients. From the population‐based Swedish ALL Registry, we identified 728 patients aged 18–95 years, who were diagnosed with ALL 1997–2015 and had cytogenetic information. Registry data were complemented with original cytogenetic reports. BCR‐ABL1 was the most recurrent aberration, with a frequency of 26%, with additional cytogenetic alterations in 64%. KTM2A rearrangement was the second most frequent aberration found in 7%. Low hypodiploidy‐near triploidy and complex karyotype had negative impact, while t(1;19);TCF3‐PBX1 showed positive impact on overall survival. However, after correction for age only complex karyotype remained significant.

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols.

The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).