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Prognostic Markers in Ph-Negative Adult Acute Lymphoblastic Leukemia: Genetics and Minimal Residual Disease

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Prognostic Markers in Ph-Negative Adult Acute Lymphoblastic Leukemia: Genetics and Minimal Residual Disease Acute lymphoblastic leukemia Prognostic markers in Ph-negative adult acute lymphoblastic leukemia: genetics and minimal residual disease H. Dombret ABSTRACT The outcome of adult patients with acute lymphoblastic leukemia (ALL) has significantly improved Hopital Saint-Louis, Paris, during the last decade due to pediatric-inspired treatment intensification. In parallel, the discovery of France numerous new genetic subsets has confirmed the great ALL heterogeneity, with potential prognostic implications in children as well as in adults with the disease. This includes, for instance, IKZF1 gene Correspondence: abnormalities and BCR-ABL1 -like definition in B-cell precursor ALL or NOTCH pathway activation in Hervé Dombret T-cell ALL. Finally, the evaluation of the quality of early response to therapy through assessment of the E-mail: [email protected] level of minimal residual disease (MRD) has been progressively implemented in adult ALL trials. In this new promising context, there is a need for a prospective re-evaluation of the individual risk, in order to design the next generation of ALL treatment that will likely include more stratifications based on Hematology Education: targetable features and risk of ALL recurrence. In this process, genetic studies and MRD monitoring the education program for the appear to represent interesting complementary tools. annual congress of the European Learning goals Hematology Association At the conclusion of this activity, participants should be able to: 2014;8:7-14 - describe currently identified genetics events that significantly modulate the risk in adult ALL; - summarize current available MRD data in adult ALL; - discuss treatment options/stratifications in the light of these parameters. Introduction cally defined subsets to current therapy, leading to better risk classifications and treatment opti - The genetics of acute lymphoblastic mizations. In ALL, some frequent new recurrent leukemia (ALL), as in other tumors, is now bet - alterations, not listed in the WHO classification, ter known as an increasing number of genetic have been reported to be associated with poten - changes are being discovered through the use of tial strong prognostic value, including focal array-based approaches and next generation deletions of the IKZF1 gene coding for the tran - sequencing technologies. This new genetic land - scription factor IKAROS in BCP-ALL or scape allows clinicians to better understand the NOTCH pathway gene mutations in T-ALL. pathogenesis pathways at work in acute lym - These alterations might play an important role in phoblastic leukemia and in disease subsets. This defining new risk subgroups. However, ALL new knowledge may herald the development of risk subgroups have still not been standardized. treatments designed to target recurrent genetic In childhood ALL; the National Cancer Institute events, including those present across different (NCI) risk classification is based on age and 2 cancers. In ALL, the current WHO classification white blood cell count (WBC) only. Most already discriminates some genetic subsets, but groups, including adult ALL groups, are also only based on standard cytogenetic analysis using other factors, like immunophenotype, cen - (Table 1). 1 Some subsets are very rare, like ALL tral nervous system (CNS) involvement or not, carrying the t(5;14)(q31;q32) translocation, cytogenetics, DNA index, and early response to some are essentially observed in adults, while therapy, leading to a long list of prognostic fac - others are much more frequent in children. In tors that would have to be considered in order 3 addition, no specific subsets are defined for T- for a standardized risk model to be built. lineage ALL (T-ALL). This classification should Philadelphia chromosome (Ph)-positive ALL be up-dated in the very near future. Actually, carrying the t(9;22)(q34;q11.2) translocation, standard and next generation sequencing tech - which is diagnosed in approximately 25% of niques have recently identified numerous new adult but only in 2% of pediatric cases, is now recurrent gene alterations in both B-cell precur - considered a distinct disease entity due to its sor (BCP)- and T-ALL. Independently, some sensitivity to specific treatments including tyro - variations in gene expression levels or specific sine kinase inhibitors (TKIs). gene expression profiles (GEPs) have also been Early response to therapy may be assessed described, contributing to a more comprehen - by the sensitivity of the disease to corticos - sive characterization of ALL genetics. teroids, evaluated by peripheral blood (PB) blast The description of a more complete genetic counts after a 1-week pre-phase, and/or early landscape for a given cancer also allows a bone marrow (BM) blast clearance, evaluated refined analysis of the susceptibility of geneti - on a BM aspirate usually performed after two Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 7| 19 th Congress of the European Hematology Association additional weeks of induction chemotherapy. However, early standard treatment, like ALL with high hyperdiploidy or response is now preferentially assessed by level of minimal ALL carrying the ETV6-RUNX1 gene fusion, are very residual disease (MRD) at time of achieving complete remis - common in children while more rarely observed in sion (CR) after the first induction course or later on during adults. 13,14 Conversely, apart from a peculiar high inci - early consolidation phases. This assessment can be made by dence in infants, t(v;11q23) translocations associated with several techniques, including patient-specific Ig/TCR quan - MLL gene rearrangement appear to be more frequent in titative PCR (RQ-PCR), flow cytometry (FCM), and more adults. Similarly, focal deletions of the IKZF1 gene could recently next generation Ig/TCR sequencing (NGS). Again, be more frequently observed in adults, even when not con - the best technique to be used and which time points will be sidering Ph-positive ALL that display IKZF1 deletion in the most informative are two major practical issues that have up to 80% of the cases. Positive deregulation of the still not been clearly settled. Nonetheless, MRD levels have cytokine receptor gene CRLF2 expression may arise from been demonstrated to be highly powerful prognostic factors cryptic translocations involving the IGH locus in 14q32 or in adult as in pediatric ALL. from cryptic interstitial pseudo-autosomal deletions In this complex and constantly changing setting, some involving the P2RY8 locus. Rare activating mutations of principal questions remain. 1) Among ALL-related factors, the CRLF2 gene have also been observed. Deregulation of which are the most clinically relevant prognostic factors to CRLF2 has been observed with a particular high incidence date, especially when patients are receiving the current in Down syndrome associated ALL. 15 Other copy number intensified pediatric-inspired therapy? In other words, do anomalies, or sequence or deletion mutations have been newly refined genetic subsets better predict risks than old observed with a higher incidence at relapse, such as TP53 factors like WBC or immunophenotype? 2) Does MRD and CREBBP alterations. 11 Among Ph-negative ALLs, a supersede ALL-related prognostic factors including base- so-called BCR-ABL1 -like subset has been recently identi - 4 line and genetic characteristics? 3) Has MRD the same fied on the basis of a GEP similar to that of Ph-positive prognostic value in each ALL genetic subset? 4) Which fac - ALL. This subset displays a high incidence of IKZF1 dele - tor(s) best predict benefit from stem cell transplantation tion and approximately half of BCR-ABL1- like ALL cases (SCT) effect? In other words, which factor(s) should be used have CRLF2 rearrangements and JAK1/2 mutations. 16-20 In to define patients who will most likely benefit from allo - addition, whole genome sequencing has revealed other geneic SCT in first CR? Answering these questions remains cytokine receptor and kinase activating mutations in these a difficult task, as risk assessment likely depends on the type patients, including ABL1 , PDGFRB, IL7R and EPOR of ALL treatment given to the patients, not to mention that mutations. adult ALL is a rare disease and subsets even more so, making In T-ALL, chromosomal abnormalities frequently it difficult to use a classical test/validation cohort approach. involve the genes coding for T-cell receptor (TCR) alpha/delta chain at 14q11.2, beta chain at 7q34 or gamma Genetic subsets in adult ALL chain at 7p14. Partner genes generally code for a transcrip - tion factor, like TAL1 , LMO1/2 , TLX1 , TLX3 , or HOXA (Table 2). More recently, novel genomic alterations have The genetic landscape of ALL been identified by microarrays and sequencing, including a high incidence of mutations in the genes coding for Several groups have performed large cytogenetic and NOTCH1 or its regulator FBXW7, leading to NOTCH genomic analysis of BCP-ALL and T-ALL, based on stan - pathway activation. Overall, NOTCH1/FBXW7 mutations dard karyotype, fluorescence in situ hybridization (FISH), are found in up to 70% of T-ALL cases. Inactivating dele - DNA index, polymerase chain reaction (PCR), multiplex tions or nonsense mutations of the PTEN gene are found ligation-dependent probe amplification (MLPA) and in approximately 20% of the cases, while frequent inacti - microarrays, and then completed by next generation vating mutation of the X-linked PHF6 gene have been sequencing. Results (more frequently obtained in pediatric recently reported. 21 Of interest, NOTCH1 pathway activa - than in adult ALL) have been detailed in some recent tion and PTEN downregulation have both been demon - reviews. 5-12 The most frequent cytogenetic anomalies and strated to be associated with MYC activation 22,23 making gene mutations/deletions identified in Ph-negative BCP- MYC an important player in T-ALL. Rare t(8;14) chromo - ALL are summarized in Table 2. Some cytogenetic sub - somal translocations may also directly increase c-MYC groups that are associated with a favorable outcome after expression. 24 Finally, early T-cell precursors (ETP) ALLs Table 1.
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