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Molecular Markers in Acute Lymphoblastic Leukemia

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Molecular Markers in Acute Lymphoblastic Leukemia 18 th Congress of the European Hematology Association Molecular Markers in acute lymphoblastic Bolzano, 8Ospedale Oncologico A. Businco, Cagliari, 9Ospedale San Raffaele, 10 Ospedale Maggiore Policlinico, Milano, 11 AOU Careggi, Firenze, 12 ASO S. leukemia Croce e Carle, Cuneo, 13 Ospedale San Giovanni Battista, Torino, Italy Background: MRD is the most powerful indicator of the risk of relapse, and is S535 increasingly adopted in ALL for the risk-oriented application of stem cell trans - plantation (SCT) in MRD-positive ( pos ) patients. Retrospective analyses indi - NOVEL AND RECURRENT GENES INVOLVED IN STRUCTURAL AND cated a lesser efficacy of SCT in MRD pos cases, however without defining the SEQUENCE VARIATIONS IN RELAPSED CHILDHOOD HIGH HYPER - quantitative MRD ranges associated with SCT failure. Such a definition could DIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA improve the ability to distinguish MRD pos patients for whom SCT is an appro - U Fischer 1,* , C Bartenhagen 2, M Gombert 1, V Okpanyi 1, V Binder 1, S priate choice from those in whom other treatments should be considered Röttgers 3, J Bradtke 3, A Teigler 3, Jochen Harbott 3, Sebastian Ginzel 1,4 , R instead or prior to SCT. 4 2 5 1 1,5 Thiele , M Dugas , J Hu , A Borkhardt , C Chen Aims: To define which post-induction/consolidation MRD levels can negative - 1Department of Pediatric Oncology, Hematology and Clinical Immunology, Uni - ly affect post-transplantation outcome in adult ALL. versity Children’s Hospital, Medical Faculty, Heinrich Heine University, Dues - Methods: The long-term results of a prospective Northern Italy Leukemia seldorf, 2Institute of Medical Informatics, University of Muenster, Muenster, Group trial conducted between 2000 and 2006 and enrolling a total of 304 con - 3Oncogenetic Laboratory, Department of Pediatric Hematology and Oncology, secutive unselected patients with Ph- ALL were reviewed. In this study, SCT Justus Liebig University, Giessen, 4Department of Computer Science, Bonn- was prescribed only to MRD pos patients, regardless of clinical risk class. MRD Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany, 5Fujian was assessed by RQ-PCR methodology using one-two case-specific sensitive Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China molecular probes, examining the bone marrow at weeks 10, 16 and 22, i.e. after chemotherapy cycles no. 3, 5 and 7. MRD results from all three time-points Background: High hyperdiploid acute lymphoblastic leukemia (HH-ALL) is were pooled, and the highest value registered in individual patients was used characterized by 51-67 chromosomes and nonrandom gains of specific chro - to identify the MRD-negative group (always MRD neg ) and three other subsets mosomes (X, 4, 6, 10, 14, 17, 18, or 21). Occuring in 25-30% of cases, it is the characterized by increasing levels of residual ALL, from low-positive (<10 -4 most frequent numerical cytogenetic alteration in pediatric B-cell precursor [MRD pos1 ]) to positive (10 -4 to <10 -3 [MRD pos2 ]) to strongly positive (≥10 -3 ALL. Pre-leukemic clones are generated already in utero , but cooperating onco - [MRD pos3 ]). MRD neg patients were not offered SCT unless t(4;11)+. For study genic lesions are necessary for overt leukemia. Children suffering from HH-ALL purposes, disease-free survival (DFS) and relapse incidence (RI) were have a good prognosis, but recurrent disease will affect 15-20%. The underly - assessed and compared among different MRD pos groups, specifically in ing genetic mechanisms leading to overt leukemia and relapse remain to be patients selected for SCT at end of consolidation phase after completion of the determined. MRD study as per study design (at least MRD pos2 at week 16 and/or MRD pos1 Aims: The objective of this study was to comprehensively assess and validate at week 22). genetic lesions associated with genesis and relapse of leukemia in a cohort of Results: Of 304 patients treated (median age 35 years, range 16-68; male gen - pediatric patients (n=6) with recurrent HH-ALL. der 57%) 258 (85%) entered complete remission (CR). Sensitive probe(s) were Methods: Whole genome and whole exome next-generation-sequencing was available for 200 (77.5%) CR patients, of whom 141 completed consolidation applied to analyze matched sample sets of six children with recurrent HH-ALL and 59 did not (early SCT 13, relapse 41, toxicity 5). Of 141 evaluable patients, taken at initial diagnosis and/or relapse and remission. Paired-end genomic 136 completed the MRD study, 64 being MRD neg (47%), 21 MRD pos1 (15.5%), libraries were sequenced on a Genome Analyzer IIx or a HiSeq 2000 (Illumi - 17 MRD pos2 (12.5%) and 34 MRD pos3 (25%). With a minimum observation na). Reads were aligned against the human reference genome (GRCh37) using time of 4 years and a maximum close to 12 years, estimated 6-year DFS and BWA. Unique reads were analyzed with GASV to detect translocations and RI were 57% and 32% in MRD pos1 , 46% and 50% in MRD pos2 and 15% and inversions. Somatically acquired variations not present in the Database of 76% in MRD pos3 cohorts, respectively (all P’s <0.0001). Of all 72 MRD pos Genomic Variants were reported. FREEC was employed to detect copy num - patients, 44 (61%) underwent SCT as per protocol design (allogeneic SCT 26, ber alterations. Targeted enrichment of whole exomic regions was carried out “hypercycles” with autologous blood stem cell rescue 18). Although 6-year DFS employing SeqCap EZ libraries (Roche) and 100 bp single reads were rate was improved after allogeneic SCT (42% vs 20% with autologous SCT, sequenced on a HiSeq 2000. Mutations were called and LOH detected using P=0.09), MRD level was highly influential for post-transplantation outcome an in-house bioinformatic pipeline. Putative somatically acquired mutations (DFS 48% in MRD pos1-2 group [n=25] vs 16% in MRD pos3 group [n19], P=0.025; were validated by PCR, Sanger sequencing and FISH analysis. RI 42% vs 69%, P=0.13), and the best overall result was obtained with allo - Results: We detected and validated 11 interchromosomal translocations affect - geneic SCT in MRD pos1-2 group (DFS 60% [n=15] vs 18% in MRD pos3 group ing genes coding for proteins (ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, [n=11], P=0.08; RI 23% vs 64%, P=0.09). KIAA1467, ELMO1) and several miRNAs (e.g. miR1200), lincRNAs and nuclear Summary / Conclusion: In this prospective study, about one half of MRD pos1- RNAs involved in splicing (U6, U13). A MACROD2/KIAA1467-fusion potential - 2 patients were salvaged by SCT, mainly by allogeneic rather than autologous ly encoded a novel chimeric protein. All other rearrangements presented loss- SCT (DFS 60%). Because of the poorer SCT results in MRD pos3 group, patients of-function or -expression alterations. Most translocations were associated with with post-induction/consolidation MRD ≥10 -3 should receive further/experimen - copy number alterations. One case showed oscillating copy numbers at clus - tal therapy and not proceed to SCT until the MRD signal is brought below the tered breakpoints indicative of shattering/rejoining of chromosomal fragments, 10 -3 cutoff. termed chromothripsis. Furthermore, deletions, inversions and loss-of-het - erozygosity were detected. Exome sequencing revealed recurring mutations of CREBBP and members of the Ras family of small GTPases. One patient S537 expressing wildtype NRAS and KRAS harbored mutated PAR4, a tumorsup - pressor that is downregulated by oncogenic RAS for efficient transformation. COMPARISON OF NEXT-GENERATION SEQUENCING AND ASO-PCR Further mutations (non synonymous coding, splice site mutations or gained METHODS FOR MRD DETECTION IN ACUTE LYMPHOBLASTIC stop codons) were detected and validated in various transcription factors and LEUKEMIA 1 2 2 2 1,* signaling molecules involved in differentiation, cell cycle regulation and apop - G Malnassy , V Carlton , M Moorhead , M Faham , W Stock 1 2 tosis. Relapse was associated with partial chromosomal gain (1q), loss (4q), a University of Chicago, Chicago, Sequenta, Inc., South San Francisco, Unit - novel translocation (t(4;7)), deletions (IKZF1), increasing dominance of a chro - ed States mothriptic clone and selection for RAS and CREBBP alterations. Summary / Conclusion: Our data indicate a central role for RAS and CREBBP Background: The clinical management of patients with acute lymphoblastic regulated pathways as assisting oncogenic lesions in pathogenesis and relapse leukemia (ALL) relies on accurate prediction of relapse risk to inform treatment of HH-ALL. Additional mutations indicate disturbance of B-cell differentiation, decisions (Pui et al , JCO 2011). The measurement of minimal residual disease enhanced proliferation, suppression of cell death and a possible role of regu - (MRD) has emerged as the most important predictor of outcome in ALL (Cam - latory RNAs in HH-ALL. pana, Hematology Am Soc Hematol Educ Program 2010). Allele-specific oligonucleotide (ASO)-PCR can be used to assess MRD; however, this tech - nique requires preparation of clonotype-specific primers for each individual S536 which is laborious and time-consuming. We developed the LymphoSIGHT™ platform, a high-throughput sequencing method, which universally amplifies DIFFERENT MINIMAL RESIDUAL DISEASE (MRD) LEVELS PREDICT antigen-receptor gene segments and can identify all leukemia-specific POST-TRANSPLANTATION OUTCOME IN MRD+ ACUTE LYMPHOBLAS - sequences at diagnosis, allowing monitoring of disease progression and clon - TIC LEUKEMIA (ALL) al evolution during therapy (Faham et al , Blood 2012). 1,* 2 2 3 2 2 R Bassan , O Spinelli , E Oldani , T Intermesoli , M Tosi , B Peruta , Aims: In this study, we compared the sequencing and ASO-PCR methods for E Borlenghi 4, E Pogliani 5, E Bona 6, V Cassibba 7, A Scattolin 1, C Romano 8, F measuring MRD in follow-up samples and analyzed the extent of clonal evo - Ciceri 9, A Cortelezzi 10 , G Gianfaldoni 11 , D Mattei 12 , E Audisio 13 , A Rambaldi 2 lution present in diagnostic and follow-up samples from 37 ALL patients.
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