ALBERT

Description: Key Points Daratumumab is effective against T-ALL in human xenograft models. CD38 is a novel target with broad potential in the treatment of T-ALL.

Description: Introduction: Primitive extranodal lymphomas are a heterogeneous group of malignant lymphoid hematological developed from the mucosa-associated lymphoid tissue (MATL) or sites that have acquired MALT after repeated stimulation. The particularity of this type of affection reside: the access to diagnosis which is difficult and therapeutic approach which respond to the ATB, antiviral, surgery and RT. They represent 24-48% of lymph node lymphomas and they are increasing. The incidence of lymphoma is growing in the world, it is approximately 16.8 / 105inhabitants. In Algeria in 2012, the incidence of lymph node lymphomas in adults was 2.24 / 100,000. Lymphomas Diffuse large B-cell phenotype (DLBCL) represent 50-60% of lymphomas, it is the most common histological type. Goals of the study: 1-analyze the epidemiological characteristics (gender, age, geographical distribution, annual incidence). 2- Identify anatomical sites. 3- Specify the clinical and prognostic features Patients and methods: It's is a multicenter, retrospective study over a period between 2010-2014. The study population included all pts over 15 years and having an extranodal DLBCL at 18 hematology centers and 4 cancer centers. Data were collected on data sheets distributed to the various services involved in the study. The diagnosis is made on the histological examination of a biopsy of the affected organ. The clinical, biological and imaging results allowed us to classify and identify prognostic factors for pts. Results: Among 1057 sheets of extranodal lymphomas, the type DLBCL is specified in 562 (53%) cases, distributed in 325 men and 237 women (sex ratio M/F: 1.36). The average age at diagnosis is 51 years (16-88) with a peak in the age group 50-60 years. The overall annual incidence of 0.31/105 inhabitants/year and the specific incidence for patients over 15 years is 0.42 / 105inhabitants/year. PS 0-1: 323 / 543pts (60%). Number of pts (pts) by place of care: Annaba 65, Sétif: 60, CAC Constantine: 53, Tizi Ouzou: 49, Blida Cac: 41, CMPC-hematology: 40, Tlemcen: 30, Beni- Méssous- hematology: 29, CAC CPMC: 24, EHUOran: 23, hematology CAC Batna: 22, CHU Oran: 19, HMRUO: 17, Blida-hematology: 16, HCA:16, SBA: 15, CAC Béni-Messous: 14, EPH Mascara: 10, HMRU Oran: 9, Bejaia: 7, hematology CHU Batna: 2, hematology Cne:1. Number of cases according to anatomical localisation: Stomach: 180, Intestine: 31, Colon 12, Tonsils: 70, Cavum: 31, nasal cavities: 11, Bones: 43, mediastinum: 41, SNC: 29, Skin: 25, Rate / MO :15, Thyroid: 12, soft Parties: 10, Breast: 6, lung / pleural: 5, Liver: 5, Others: 36. The clinical symptomatology is very heterogeneous, specifically of the affected organ. Clinical stage is specified in 549 cases, according to Ann Arbor: SCIE: 272 (49%), SCIIE: 149 (27%), SCIIIE: 31 (6%), SCIV: 97 (18%). The International Prognostic Index adjusted for age (IPIaa) include: for pts less than 60 years: Low (F): 70 (23%), lower intermediate (IF): 130 (43%), intermediate high (IE) : 69 (23%), high (H): 32 (11%); for over 60 years Topics: F: 33 (23%), MI: 53 (37%) IE: 41 (28%), E: 17 (12%). Comments: As with other types of lymphoma, there is a male predominance and a peak incidence in the age group 50-60 years. The higher number of pts in the center and east of the country is probably related to a denser population in these regions. The histological type DLBCL at 53% is in agreement whith what it is conventionally reported. The incidence of 0.31/105inhabitants/year extranodal DLBCL is lower than the overall nodal DLBCL, however, the incidence of extranodal NHL is rarely determined. The number of cases of extranodal lymphomas described in this study is certainly below the actual number because this group of disorders is supported by various specialties related to the location of lymphoma. Extranodal lymphomas has a clinical polymorphism, but it is recognized that gastric and tonsillar locations are the most common, the other despite their rarity, require attention from management. This type of lymphoma is characterized by a preponderance of localized stages unlike ganglion lymphomas where the extended stages predominate. Likewise distribution by IPIaa not exceeding one pejorative factor is more common. Conclusion: Extranodal DLBCL are rare, they are characterized by a diversity clinicopathological that challenges us to homogenization of their treatment in multidisciplinary level. Disclosures No relevant conflicts of interest to declare.

Description: Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) occurs in 5-30% of children and adolescents/young adults (AYAs) with B-ALL, is driven by genetic alterations that induce constitutive cytokine receptor and kinase signaling, and is associated with poor clinical outcomes across the older pediatric-to-adult age spectrum (Tasian Blood 2017c, Reshmi Blood 2017, Roberts Blood 2018). Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of Ph-like ALL cases with frequently co-occurring JAK2 or JAK1 point mutations or IL7R indel mutations. This study reports the clinical outcomes of children and AYAs with newly-diagnosed National Cancer Institute (NCI) standard-risk (SR) or high-risk (HR) CRLF2+ ALL without Down syndrome treated on four successive Children's Oncology Group (COG) phase 3 clinical trials from 2003 to 2018. Methods: We retrospectively assessed demographic characteristics, laboratory data, and clinical outcomes of 3757 patients with B-ALL treated on COG trials AALL0331 and AALL0932 (SR) and AALL0232 and AALL1131 (HR) whose diagnostic leukemia specimens were analysed by low-density microarray (LDA), fluorescence in situ hybridization, polymerase chain reaction (PCR), and/or anchored multiplex PCR testing (Harvey and Tasian Blood Advances 2020). Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at the end of consolidation for a subset of EOI MRD+ patients. Results: We identified 77/1541 (5.0%) SR and 244/2216 (11.0%) HR patients with CRLF2+ B-ALL in this cohort. Amongst those with diagnostic leukemia specimens analysed by LDA, 57/72 (79.2%) of SR CRLF2+ and 175/213 (82.2%) of HR CRLF2+ patients were positive for the Ph-like gene expression profile with an 8-gene score ≥0.5. P2RY8-CRLF2 fusions and IGH-CRLF2 translocations were detected in 64/77 (83.1%) and 10/77 (13.0%) of SR CRLF2+ patients and in 98/244 (40.2%) and 103/244 (42.2%) of HR CRLF2+ patients, respectively. CRLF2 rearrangements or F232C mutations were not found in the remaining 3 SR and 43 HR CRLF2+ patients, although other Ph-like alterations were discovered in some (n=3 IGH-EPOR fusions, 1 IL7R indel). Importantly, CRLF2+ vs non-CRLF2-overexpressing (CRLF2-) status was associated with older age (10.8 ±6.5 vs 7.8 ±5.8 years [mean ±SD], p

Description: Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal; the primary goal of T-ALL/T-LL treatment is to prevent relapse. AALL1231 was a COG phase 3 clinical trial that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone +/- the proteasome inhibitor bortezomib during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). Bortezomib was tested in frontline therapy based on strong preclinical data and data in relapse on COG AALL07P1. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphologic and minimal residual disease (MRD) at end induction and end consolidation (T-ALL) and radiographic response (T-LL). To eliminate cranial radiation (CXRT) in all pts, (except VHR: Day 29 M3 marrow or EOC MRD 〉0.1% or pts with overt CNS leukemia at diagnosis, CNS3), the aBFM backbone was modified to use dexamethasone (dex) as the sole corticosteroid and an extra pegaspargase dose was added in both induction and DI, following the MRC strategy. IR pts received a second interim maintenance (IM) phase (one Capizzi MTX; one HD-MTX). Following consolidation, VHR pts received 3 BFM high-risk intensification blocks in lieu of IM. Results: AALL1231 accrued 847 patients (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure in 2017 when COG AALL0434 established that nelarabine (NEL) improved DFS in T-ALL (AALL1231 did not include NEL). The 3-year EFS for Arm A (no bortezomib) vs Arm B (bortezomib) were 81.7±2.4% and 85.1±2.2 % (HR=0.782, p=0.074) (3/31/20 data cut-off; see Table 1 for additional outcomes). SR and IR pts, who account for 95% of pts, had significantly improved EFS on Arm B as compared with Arm A. Yet, VHR patients had improved EFS on Arm A. Patients with T-LL had improved EFS and OS with bortezomib: 3-year EFS (76.5±5.9% vs 88.3±4.5%; p = 0.01); 3-year OS (78.0±5.8% vs 89.5±4.2%, p = 0.007). A similar improvement in EFS and OS was not seen in T-ALL; however, with longer follow-up this may change. No excess toxicity was seen on Arm B. A dex-based Induction did result in lower MRD rates; more T-ALL pts on AALL1231 had Day 29 MRD

Description: The authors report the interaction between Down syndrome, a major genetic leukemia predisposition condition, and inherited genetic alleles associated with increased susceptibility to childhood acute lymphoblastic leukemia.

Description: Key Points Ph-like ALL is characterized by a diverse array of genetic alterations activating cytokine receptor and tyrosine kinase signaling. Pediatric patients with Ph-like ALL can be identified in real time for effective treatment stratification.

Description: Introduction. Prior studies have described a subset of B-progenitor ALL cases with a distinct gene expression profile and/or deletions involving ERG (encoding the ETS family member v-ets avian erythroblastosis virus E26 oncogene), however the relationship of these alterations and their role in leukemogenesis are poorly understood. We performed integrated genomic and epigenetic analyses, biochemical studies and leukemogenesis assays to define the genetic basis of this form of ALL. Methods. We studied 1674 childhood, adolescent and young adult B-progenitor ALL cases with microarray gene expression profiling and/or RNA-sequencing data to enable the identification of ERG ALL by unsupervised clustering and predictive analysis of microarrays. Detailed genomic analysis was performed for 144 ERG ALL cases, including whole genome (N=38), exome (n=46) and/or RNA-sequencing (n=57) cases, and single nucleotide polymorphism array analysis. Epigenetic profiling, including whole genome bisulfite sequencing, chromatin immunoprecipitation and sequencing for ERG and histone modifications and ATAC-sequencing were performed for a subset of 8 xenografted ERG tumors and reference cell lines. ERG transcript expression was measured by analysis of RNA-seq analysis and quantitative RT-PCR assays, and by interrogation of TCGA and PCGP RNA-seq data. The function of ERG isoforms was evaluated by EMSA and transcriptional reporter assays, immunofluoresence, colony forming assays and retroviral bone marrow transplant assays. Results. One hundred and forty four cases (8.6%) of B-ALL cases exhibited a distinct gene expression profile and lacked known chromosomal rearrangements (ERG ALL). Such cases had favorable outcome. Eighty cases (55.6%) had focal deletions of ERG with no evidence of oncogenic or chimeric ERG fusions. The deletions were most commonly heterozygous and involving exons 3-7 (n=27) or 3-9 (n=22) of 10 coding exons, and less commonly involving exon 1, or a larger region of the gene. No ERG deletions were identified in non-ERG ALL. Two cases harbored missense mutations in the ETS domain. Analysis of whole genome and exome sequencing data of 71 cases identified a high frequency of alterations of lymphoid transcription factors (46.5%; IKZF1 36.7%, PAX5 11.3%); mutation of transcription factors otherwise uncommon in ALL (21%; MYC, MYCBP2, MGA, ZEB2, GATA3); activation of signaling pathways, most commonly NRAS or KRAS (35.2%); cell cycle regulation (22.5%); and epigenetic modifiers (56.3%), most commonly KMT2D, SETD2, ARID2 and NCOR1. Notably, the five year event-free survival of ERG ALL cases with IKZF1 alterations exceeded 85% in both St Jude and Children's Oncology Group cohorts. We observed striking transcriptional deregulation at the ERG locus. Most (51/56) ERG- deleted cases expressed an ERG isoform encoded by a novel exon in intron 6 that splices in frame to distal exons, resulting in expression of a truncated C-terminal ERG protein that lacks the pointed and central regulatory domains, but retains the ETS and transactivation domain (ERGalt). ERGalt was also present in most (36/44) cases lacking an ERG deletion, and was strongly associated with presence of ERGalt protein in leukemic cells. We also identified expression of an Antisense Long non-coding RNA associated with the ERG locus (ALE) in ERG ALL. ERGalt and ALE were absent, or uncommonly expressed at very low levels in non-ERG ALL. ERGalt was absent, and ALE rarely expressed in non-ALL PCGP and TCGA samples. ERGalt and point mutant ERG were retained in the nucleus, bound DNA targets and acted as competitive inhibitors of wild type (WT) ERG in transcriptional reporter assays. Lineage-negative Arf -null bone marrow cells transduced with ERG WT induced an aggressive erythro-megakaryoblastic leukemia; in contrast ERGalt induced an immature lymphoid progenitor leukemia. Conclusions. Genomic alterations drive aberrant transcription of ERG, resulting on expression of a truncated, C-terminal oncogenic ERG protein. This represents a novel mechanism of transcription factor deregulation in leukemia. As a subset of ERG ALL cases lack ERG deletion, and as IKZF1 alterations are not associated with inferior outcome in this form of ALL, diagnostic approaches must incorporate gene expression profiling in addition to identification of ERG and IKZF1 alterations to accurately identify this form of leukemia. Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Voorhees:Oncopeptides: Consultancy; Onyx Pharmaceuticals: Research Funding; GSK: Consultancy; Oncopeptides: Research Funding; Janssen: Research Funding; A Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon Pharmaceuticals, Inc.: Research Funding; Novartis: Consultancy; Array BioPharma: Consultancy; GSK: Research Funding; Celgene: Research Funding. Hunger:Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Merck: Equity Ownership. Mullighan:Incyte: Consultancy; Amgen: Honoraria.

Description: Current risk stratification for COG ALL patients (pts) relies on National Cancer Institute (NCI) risk group (RG) at diagnosis, somatic genetics, and early response to therapy as measured by specific thresholds of minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). NCI RG is defined as age 1-10 years (yrs) and white blood cell count (WBC)

Description: Background: Patients with Down syndrome (DS) have an approximately 10-fold increased risk of developing ALL, and the spectrum of genetic alterations differs from that of non-DS ALL. Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of DS ALL, compared to only 5-10% CRLF2+ cases in non-DS children and adolescents. JAK2 or JAK1 mutations co-occur in about half of CRLF2+ cases in both DS and non-DS ALL. The prognostic significance of CRLF2+ ALL also appears to differ in the limited data reported to date, with less adverse impact in patients with DS compared to non-DS ALL. Here, we report the clinical characteristics and prognostic significance of B-ALL with CRLF2 overexpression and JAK alterations in children and adolescents/young adults (AYA) with DS who were treated on Children's Oncology Group (COG) clinical trials from 2003-2016. Methods: We analyzed clinical, laboratory, and outcome data for 317 patients with DS B-ALL treated on standard risk (SR) trials AALL0331 and AALL0932 and high risk (HR) trials AALL0232 and AALL1131, for whom CRLF2 status and rearrangement partners (IGH or P2RY8) were ascertained by flow cytometric assessment of surface expression; fluorescence in situ hybridization; and/or polymerase chain reaction (PCR) testing. JAK mutations were ascertained in a subset by PCR and sequencing. Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at end of consolidation (EOC) for a subset of EOI MRD+ patients. Results: We identified 168/317 (53.0%) CRLF2+ cases, and among those assessed for CRLF2 partner, 17/73 (23.3%) were IGH-CRLF2 and 56/73 (76.7%) were P2RY8-CRLF2. In the subset of 165 cases tested for JAK mutations (85 CRLF2- and 80 CRLF2+), 42/165 (25.4%) had JAK mutations, all of which co-occurred in CRLF2+ cases. CRLF2 positivity was significantly associated with younger age at diagnosis: 140/168 (83.3%) of CRLF2+ cases were under 10 years old, versus 106/149 (71.1%) of CRLF2- cases, p

Description: Introduction: Although recent studies have refined the classification of B-progenitor and T-lineage acute lymphoblastic leukemia into gene-expression based subgroups, a comprehensive integration of significantly mutated genes and pathways for each subgroup is needed to understand disease etiology. Methods: We studied 2789 children, adolescents and young adults (AYA) with newly diagnosed B-ALL (n=2,322 cases) or T-ALL (n=467) treated on Children's Oncology Group (n=1,872) and St. Jude Children's Research Hospital trials (n=917). The cohort comprised childhood NCI standard-risk (41.8%; age range 1-9.99 yrs, WBC ≤ 50,000/ml), childhood NCI high-risk (44.5%; age range ≥10 to 15.99 yrs) and AYA (9.9%; age range 16-30.7 yrs). Genomic analysis was performed on tumor and matched-remission samples using whole transcriptome sequencing (RNA-seq; tumor only; n=1,922), whole exome sequencing (n=1,659), whole genome sequencing (n=757), and single nucleotide polymorphism array (n=1,909). Results: For B-ALL, 2104 cases (90.6%) were classified into 26 subgroups based on RNA-seq gene expression data and aneuploidy or other gross chromosomal abnormalities (iAMP21, Down syndrome, dicentric), deregulation of known transcription factors by rearrangement or mutation (PAX5 P80R, IKZF1 N159Y), or activation of kinase alterations (Ph+, Ph-like). For T-ALL, cases were classified into 9 previously described subtypes based on dysregulation of transcription factor genes and gene expression. In 1,659 cases subject to exome sequencing (1259 B-ALL, 405 T-ALL) we identified 18,954 nonsynonymous single nucleotide variants (SNV) and 2,329 insertion-deletion mutations (indels) in 8,985 genes. Overall, 161 potential driver genes were identified by the mutation-significance detection tool MutSigCV or by presence of pathogenic variants in known cancer genes. Integration of sequence mutations and DNA copy number alteration data in B-ALL identified 7 recurrently mutated pathways: transcriptional regulation (40.6%), cell cycle and tumor suppression (38.0%), B-cell development (34.5%), epigenetic regulation (24.7%), Ras signaling (33.0%), JAK-STAT signaling (12.0%) and protein modification (ubiquitination or SUMOylation, 5.0%). The top 10 genes altered by deletion or mutation in B-ALL were CDKN2A/B (30.1%), ETV6 (27.0%), PAX5 (24.6%), CDKN1B (20.3%), IKZF1 (17.6%), KRAS (16.5%), NRAS (14.6%), BTG1 (7.5%) histone genes on chromosome 6 (6.9%) and FLT3 (6.1%), and for T-ALL, CDKN2A/B (74.7%), NOTCH1 (68.2%), FBXW7 (21.3%), PTEN (20.5%) and PHF6 (18.2%) (Figure 1A). We identified 17 putative novel driver genes involved in ubiquitination (UBE2D3, UBE2A, UHRF1, and USP1), SUMOylation (SAE1, UBE2I), transcriptional regulation (ZMYM2, HMGB1), immune function (B2M), migration (CXCR4), epigenetic regulation (DOT1L) and mitochondrial function (LETM1). We also observed variation in the frequency of genes and pathways altered across B-ALL subtypes (Figure 1B). Interestingly, alteration of SAE1 and UBA2, novel genes that form a heterodimeric complex important for SUMOylation, and UHRF1 were enriched in ETV6-RUNX1 cases. Deletions of LETM1, ZMYM2 and CHD4 were associated with near haploid and low hypodiploid cases. Deletion of histone genes on chromosome 6 and alterations of HDAC7 were enriched in Ph+ and Ph-like ALL. Mutations in the RNA-binding protein ZFP36L2 were observed in PAX5alt, DUX4 and MEF2D subgroups. Genomic subtypes were prognostic. ETV6-RUNX1, hyperdiploid, DUX4 and ZNF384 ALL were associated with good outcome (5-yr EFS 91.1%, 87.2%, 91.9% and 85.7%, respectively), ETV6-RUNX1-like, iAMP21, low hyperdiploid, PAX5 P80R and PAX5alt were associated with intermediate outcome (5-yr EFS 68.6%, 72.2%, 70.8%, 77.0% and 70.9%, respectively), whilst KMT2A, MEF2D, Ph-like CRLF2 and Ph-like other conferred a poor prognosis (55.5%, 67.1%, 51.5% and 62.1%, respectively). TCF3-HLF and near haploid had the worst outcome with 5-yr EFS rates of 27.3% and 47.2%, respectively. Conclusions: These findings provide a comprehensive landscape of genomic alterations in childhood ALL. The associations of mutations with ALL subtypes highlights the need for specific patterns of cooperating mutations in the development of leukemia, which may help identify vulnerabilities for therapy intervention. Disclosures Gastier-Foster: Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Willman:to come: Patents & Royalties; to come: Membership on an entity's Board of Directors or advisory committees; to come: Research Funding. Raetz:Pfizer: Research Funding. Borowitz:Beckman Coulter: Honoraria. Zweidler-McKay:ImmunoGen: Employment. Angiolillo:Servier Pharmaceuticals: Consultancy. Relling:Servier Pharmaceuticals: Research Funding. Hunger:Jazz: Honoraria; Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Mullighan:Amgen: Honoraria, Other: speaker, sponsored travel; Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel.