scholarly journals Potential and pitfalls of whole transcriptome-based immunogenetic marker identification in acute lymphoblastic leukemia; a EuroMRD and EuroClonality-NGS Working Group study

Leukemia ◽  
2021 ◽  
Author(s):  
Vincent H. J. van der Velden ◽  
◽  
Monika Brüggemann ◽  
Giovanni Cazzaniga ◽  
Blanca Scheijen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Working Group ◽  
Lymphoblastic Leukemia ◽  
Whole Transcriptome ◽  
Marker Identification

scholarly journals Asparaginase-Associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Report on Clinical Presentation and Outcome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 585-585
Author(s):  
Wolthers Benjamin Ole ◽  
Thomas Leth Frandsen ◽  
Andre Baruchel ◽  
Andishe Attarbaschi ◽  
Shlomit Barzilai ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Acute Lymphoblastic Leukemia ◽  
Diagnostic Criteria ◽  
Working Group ◽  
Lymphoblastic Leukemia ◽  
Pancreatic Enzyme ◽  
Older Age ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
First Episode

Abstract Background: Asparaginase-associated pancreatitis (AAP) is a well-known and frequent toxicity of childhood acute lymphoblastic leukemia (ALL) therapy. Diagnostic criteria have varied among international ALL study groups, impairing international comparison of incidence, severity and complications, and limiting the knowledge on the risk of re-exposure to asparaginase. Objectives and Methods: This questionnaire study reports AAP data from 19 collaborative groups on children (1.0-17.9 years) treated with ALL from 1/2000-4/2015. To define AAP, the Ponte di Legno toxicity working group (PTWG) consensus definition was used: At least two of i) amylase, pancreatic amylase, or pancreatic lipase >3x upper normal limit (UNL), ii) abdominal pain, iii) imaging compatible with AAP (Lancet Oncology, 2016; 6: 231-239). AAP was graded as mild or severe (persisting abdominal pain and pancreatic enzymes ≥3xUNL more than 72 hours after AAP diagnosis and/or pseudocyst, abscess, or hemorrhagic APP at imaging). Results: Of 633 patients registered with AAP, 459 patients fulfilled the PTWG criteria for AAP; 96% had abdominal pain, 92% had a rise in at least one pancreatic enzyme >3xUNL, and 75% had imaging (72 MRI, 239 CT, 320 ultrasound) compatible with AAP. Of the remaining 174 patients, 29 had >35 days from injection of asparaginase to diagnosis of pancreatitis, 41 fulfilled only one diagnostic criteria, and 104 had insufficient data in the groups' registries. The median age was 8.3 years (75%-range: 4.2-13.3), 53% were male, and 80% had B-cell precursor ALL. At AAP diagnosis, 41% presented with fever, 68% had tachycardia, 29% had hypotension, and 77% presented with systemic inflammatory response syndrome (SIRS) defined as fulfilling a minimum of two of four criteria: i) body temperature >38 ◦C or <36 ◦C; ii) heart rate >90 beats per minute; iii) respiratory rate >20 breaths per minute or PaCO2 <4.2 kPa; iv) white blood cell count >12 x 109/L or <4 x 109/L. Seven percent required mechanical ventilation, including 5 of the 7 patients who died due to AAP. Twenty-six percent of the 459 study patients developed pseudocysts. These patients were older than those who did not (median age 10.8 years vs 7.1 years; p=0.0003), and more frequently presented with SIRS (30% with SIRS vs 16% without SIRS; p=0.015). Five percent of patients with abdominal pain that ceased within 72 hours developed pseudocysts vs 33% of patients with pain persisting >72 hours (p<0.0001). Twenty percent required insulin within ten days of AAP diagnosis, and 6% still received insulin at last follow-up (median: 5 years from diagnosis of AAP). Persisting need of insulin therapy was associated with older age (median: 13 years vs 7.6 years; P=0.001) and presence of pseudocysts (13% vs 3% for those without pseudocysts; p=0.0001). Five percent of all patients had recurrent abdominal pain at last follow-up. 103 patients (22%) were re-exposed to asparaginase, and 45% of these developed a second AAP. 24% were re-exposed after a mild AAP, and no difference in risk of second AAP was found among mild and severe first AAP episodes (47% vs 45%, P=1). Risk of a second AAP was not significantly associated with presence of SIRS at first AAP episode (56% vs 30%; P=0.1), CRP level, or pancreatic enzyme levels at diagnosis of first AAP. Of the 43 patients who developed a second AAP, this was graded as a mild second AAP in 48%. Severity of second AAP was not associated to SIRS or severity of first AAP. Conclusion: AAP is associated with a high frequency of both acute and persisting complications. The risk of complications was associated with older age and presence of SIRS at diagnosis of AAP. Almost half of those re-exposed to asparaginase developed a second episode of AAP, however the risk of recurrent AAP was not predictable based on characteristics of the first episode. To improve prediction of AAP, exploration of other risk factors, including host genome variants, is indicated. Disclosures Inaba: Arog: Research Funding. Moricke:JazzPharma: Honoraria, Other: financial support of travel costs.

scholarly journals Common Genetic Variants in Trypsin Regulating Genes Are Associated with AsparAginase-Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 885-885
Author(s):  
Benjamin Ole Wolthers ◽  
Thomas Leth Frandsen ◽  
Andishe Attarbaschi ◽  
Shlomit Barzilai ◽  
Antonella Colombini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Variants ◽  
Working Group ◽  
Risk Allele ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Minor Allele ◽  
European Ancestry ◽  
Common Genetic Variants ◽  
Increased Risk

Abstract Background: Asparaginase-associated pancreatitis (AAP) is a well-known toxicity of childhood acute lymphoblastic leukemia (ALL) therapy. Recent multi-trial group phenotyping of 465AAP caseshas documented severe complications to AAP, including 8% risk of needing assisted mechanical ventilation, 26% risk of developing pancreatic pseudocysts and 9% risk of developing persisting diabetes (Wolthers et al. Lancet Oncology, 2017) . Investigation of host genome variation associated with AAP has been limited by varying phenotype definition, inclusion criteria and small study sizes. Objectives and Methods: To investigate genetic variants associated with risk of developing AAP, this genome-wide association study reports data on 1544 children (1.0−17.9 years) from 10 ALL trial groups treated with ALL from January 2000−January 2016. The Ponte di Legno toxicity working group consensus definition (Schmiegelow et al. Lancet Oncology, 2016) was used to diagnose AAP: At least two of i) amylase, pancreatic amylase, or pancreatic lipase &gt;3x upper normal limit (UNL), ii) abdominal pain, iii) imaging compatible with AAP. Controls included children treated for ALL with verified completion of intended asparaginase therapy, 78% of whom (1024/1320) received at least 8 injections of PEG-asparaginase without developing AAP. Germline DNA obtained after clinical remission was genotyped on Illumina Infinium Omni2.5exome-8 BeadChip arrays. Association analyses were done in PLINK and annotation in Ensembl. Results: Of 1564 patients passing genotype quality control, 244 had AAP. 205 of 244 (84%) of cases and 1185/1320 (90%) of controls were of European ancestry. Median age was 8.1 years (IQR 4.3−13.1) and 5 (IQR: 3−9) for cases and controls, respectively. After filtering, 1401908 single nucleotide polymorphisms (SNPs) with a minor allele frequency above 1% were analyzed. In logistic regression analysis, adjusting for age and ancestry, the variant rs62228256 (reference allele=C, minor allele=T (C&gt;T)) on 20q13.2 had the strongest association to AAP (OR=3.75; 95% CI 2.33−6.04; p=5.2∙10-8). rs62228256 is located in a non-coding region without known regulatory effects. rs13228878 (A&gt;G; OR=0.61; 95% CI 0.5−0.76; p=7.1∙10-6) and rs10273639 (C&gt;T; OR=0.62; 95% CI 0.5−0.77; p =1.1∙10-5) were among the top 30 SNPs most significantly associated to AAP. They are in high linkage disequilibrium (R2=0.94) and located in the PRSS1-PRSS2 locus on chromosome 7. The rs13228878 A risk allele was not associated with level of amylase (p=0.1) or lipase (p=0,68) at diagnosis of AAP, age at diagnosis of AAP (p=0.63), or risk of pseudocysts (p=0.78). Using identical diagnostic criteria for pancreatitis, the major C allele in rs10273639 has been associated with pancreatitis risk in adults (Whitcomb et al. Nature Genetics, 2012; Masson et al. Gut, 2017) with identical risk allele and similar odds ratios. PRSS1 and PRSS2 encode cationic and anionic trypsinogen, respectively. rs10273639 is an expressive quantitative locus for PRSS1 and the C risk-variant is associated with elevated expression of trypsinogen in pancreatic tissue. Gain of function mutations in PRSS1, known from hereditary pancreatitis, lead to increased autoactivation, increased intra-acinar trypsin levels, and increased risk of auto-digestion leading to pancreatitis. Further investigation of previously validated SNPs known to regulate trypsin activation gave the following results for associations with AAP; rs17107315 in pancreatic secretory trypsin inhibitor (SPINK1; OR=2.87; 95% CI 1.36−5.8; p=4∙10-3), rs10436957 in chymotrypsin C (CTRC ; OR=0.69; 95% CI 0.53−0.89; p=5∙10-3) and rs4409525 in Claudin-2 (CLDN2 ; OR=1.41; 95% CI 1.08−1.83; p=1∙10-2). In total, 207 out of 244 cases were homozygous for the risk allele in rs13228878 (n=104), rs17107315 (n=1), rs10436957 (n=165) and/or rs4409525 (n=16). However, no significant additive effect of having more than one risk allele was found. Conclusion: Children who develop AAP possess the same pancreatitis risk variants as adults with non-asparaginase associated pancreatitis. This shared genetic disposition may facilitate research into pathogenesis and identification of effective interventions towards AAP. Disclosures No relevant conflicts of interest to declare.

scholarly journals T-Cell Acute Lymphoblastic Leukemia Can be Subdivided into Six Genetically Distinct Subtypes with Prognostic Impact By Combination of Whole Genome and Whole Transcriptome Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Janine Müller ◽  
Claudia Haferlach ◽  
Henning Ruge ◽  
Heiko Müller ◽  
Irene Fuhrmann ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Older Age ◽  
The Other ◽  
Whole Genome ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Group 5 ◽  
Whole Transcriptome

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a rare aggressive neoplasm accounting for ∼20% of all ALL cases. It is more common in adults than in children, although the incidence decreases with older age. Subclassification of T-ALL cases according to WHO is so far solely based on the immunophenotype. Although a number of common molecular aberrations have been described in T-ALL, a molecular classification of T-ALLs so far is missing. Aim: (1) Molecular subclassification of T-ALL cases based on whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) data. (2) Analysis of correlations between aberrations, subgroups and other parameters. Methods: WGS and WTS were performed in 114 patients. For WGS, 151bp paired-end reads were generated on NovaSeq 6000 and HiSeqX machines (Illumina, San Diego, CA). For WTS, 101 bp paired-end reads were produced on a NovaSeq 6000 system with a yield between 35 and 125 million paired reads per sample. SPSS (version 19.0.0, IBM Corporation, Armonk, NY) was used for statistical analysis. Results: The cohort comprised 114 T-ALL cases (29% female, 71% male) with a median age of 37 years (range 1 - 91 years). Based on mutations (mut), translocations and gene expression, the cases were subdivided into six different groups: group 1 (n=20) was defined by overexpression (oex) of TLX1 (by t(10;14)(q24;q11)/TRAD-TLX1, n=17; t(7;10)(q34;q24)/TRB-TLX1, n=2; inv(10)(q23q24), n=1) and was correlated to a high frequency of mut in NOTCH1 (19/20, 95%, p=0.011 compared to the other T-ALL cases), PHF6 (11/20, 55%, p=0.04) and BCL11B (5/20, 25%, p=0.004). Group 2 (n=9) showed TLX3 oex by t(5;14)(q35;q32)/BCL11B-TLX3 (n=8) or t(5;8)(q35;q24) (n=1). Mut in WT1 (5/9 = 56%, p&lt;0.001) and PHF6 (7/9 = 78%, p=0.005) were frequently detected. Groups 1/2 were further characterized by male predominance (18/20 = 90%, p=0.04 and 8/9 = 89%) and a cortical immunophenotype (20/20 = 100% and 7/9 = 78%). Group 3 (n=23) was defined by oex of HOXA genes, caused by inv(7)(p15q34)/TRB-HOXA (n=6), other HOXA rearrangements (n=2), SET-NUP214 (n=6), NUP98-RAP1GDS1 (n=3) and fusions involving MLLT10 (n=6). Group 4 (n=7) was defined by oex of TAL1 due to the fusion STIL-TAL1 (n=3), t(1;14)(p33;q11)/TRA-TAL1 (n=1), mut in MYB enhancers (n=2) and a MYB-translocation (n=1), and was correlated to the absence of PHF6 mut (p=0.045). The remaining 55 cases did not show oex of TLX1, TLX3, HOXA or TAL1 and were subdivided based on the presence of NOTCH1 aberrations (group 5, n=29, NOTCH1+; group 6, n=26, NOTCH1-). 25/29 NOTCH1+ cases showed at least 1 mut in NOTCH1 (range: 1-3), 2/29 had a t(7;9)(q34;q34)/TRB-NOTCH1, 2/29 showed NOTCH1 deletions. Group 5 correlated to mut in DNMT3A, NRAS and ASXL1 (p=0.001; p=0.006; p&lt;0.001) and comprised a high number of female patients (15/29 = 52%, p=0.004). NOTCH1- cases lacked mut in FBXW7 and DNM2 (p=0.02) and comprised a high number of cases with Pre-T-ALL and mature T-ALL immunophenotype. Other findings include: (1) detection of two cases with a novel type of NOTCH1 mut, termed NOTCH1-ITD, characterized by a duplication event in the NOTCH domain. (2) Mut in DNMT3A, TET2 and ASXL1 were exclusively detected in groups 5 and 6, causing correlation to older age (p=0.011 and p=0.001), whereas the HOXA group was correlated to younger age (p=0.001) (3) NRAS mut were associated with females (6/10 = 60% vs. 27/104 = 26%, p=0.023). (4) Oex of BCL11B and RAG1 was predominantly detected in groups 1 and 4. (5) Mut in DNM2 occurred concomitantly with NOTCH1 mut (p&lt;0.001); NOTCH1 and PHF6 mut were correlated with each other (p=0.008). (6) Female patients were significantly older than male patients (55 vs. 36 years, p=0.005). (7) Finally, analysis of OS (total cohort median: 36 months (m)) in the six groups revealed a significantly more favorable outcome of groups 1 (TLX1; n.r.) and 3 (HOXA; n.r.) compared to the other groups (see table), which might be linked to the high number of cases with cortical immunophenotype. Conclusions: (1) The combination of WGS and WTS successfully subclassified T-ALL cases on a molecular level into six different groups, by oex of TLX1, TLX3, HOXA or TAL1 and presence/absence of NOTCH1 mut. (2) We identified a novel so far unknown type of NOTCH1 aberrations, termed NOTCH1-ITD. (3) Molecular sub-classification of T-ALL cases also impacts on prognosis (TLX1 and HOXA group, longer OS; NOTCH1+ and TAL1 group, shorter OS). Figure Disclosures No relevant conflicts of interest to declare.

Treatment of Czech children with acute lymphoblastic leukemia: A report of the Czech working group for pediatric hematology

2002 ◽  
Vol 39 (2) ◽  
pp. 125-127 ◽  
Author(s):  
Jan Starý ◽  
Petr Gajdoš ◽  
Hana Hrstková ◽  
Bohumír Blažek ◽  
Zdeněk Slavík ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Working Group ◽  
Lymphoblastic Leukemia ◽  
Pediatric Hematology
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