Detection of CALM-AF10 Fusion Transcript Does Not Predict A Poor Prognosis in Children with T-Lineage Acute Lymphoblastic Leukemia Treated with AIEOP ALL 2000 Protocol and Subsequent Modified 2000 Study (R-2006).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1578-1578 ◽  
Author(s):  
Luca Lo Nigro ◽  
Elena Mirabile ◽  
Manuela Tumino ◽  
Cinzia Caserta ◽  
Giovanni Cazzaniga ◽  
...  
Keyword(s):  
High Risk ◽  
Poor Prognosis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Prognostic Impact ◽  
Intensive Chemotherapy ◽  
Hematopoietic Stem ◽  
Chemotherapy Strategy ◽  
The Impact

Abstract Abstract 1578 Poster Board I-604 Background T-ALL accounts for about 15% of pediatric ALL and still represents a clinical challenge, because more than 20% of children experience a recurrent disease which has a dismal prognosis. Characterization of molecular alterations with prognostic impact may be useful for an early identification of patients at high risk of failure in whom more intensive treatments, including hematopoietic stem cell transplantation (HSCT) may be considered. CALM-AF10 results from a recurring t(10;11)(p13;q14-21) chromosomal translocation and is the most frequent fusion transcript in both adult and pediatric patients with T-ALL. Its presence has been associated with a poor prognosis (Asnafi V et al. Blood 2003; van Grotel M et al Haematologica 2006). The aim of the present study was i) to define the incidence of CALM-AF10 among homogeneously treated children with T-ALL and ii) to evaluate the outcome of these patients. Materials and Methods We studied 201 patients with T-ALL, diagnosed and enrolled between 9/2000 and 12/2007 in the ALL-2000 protocol and the subsequent modified 2000 study (ALL-R-2006) of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) which consist of an intensive chemotherapy strategy based on BFM-ALL schedules. Patients were mainly stratified according to prednisone response evaluation (good response: blast count at day 8 less than 1000/mmc) and detection of minimal residual disease (MRD) performed at day 33 (Timepoint 1) and at day 78 (Timepoint 2). When both TPs were negative children were considered to be at Standard Risk (SR); patients with TP1 and/or TP2 positive and TP2 '10-3 were considered to be at Intermediate Risk (MR); children with TP2 positive ≥10-3 belong to the high risk (HR) group. Patients with prednisone poor response and MRD-HR were considered eligible for HSCT from a sibling donor in first complete remission. Event free survival (EFS) and overall survival (OS) estimates with 95% CIs were calculated through the Kaplan-Meier method and differences compared with the log-rank test. RT-PCR reactions for detection of CALM-AF10 were performed as previously reported (Asnafi V et al Blood 2003) Results Ten patients resulted not eligible and were excluded from analysis. Among the 191 evaluable children with T-ALL, 14 (7,3%) were positive for CALM-AF10. Twelve (85%) of these patients were males. Median age was 8 years (range 2 – 13). Immunophenotyping showed thymic/intermediate features in 6 cases, mature in 5, early in 1, biclonal in 1 and unknown in 1, respectively. Eight cases showed a poor prednisone (PDN) response. Based on a randomized study performed in induction in the frame of the ALL-2000 protocol on the efficacy of PDN vs dexametasone (DXM) 8 children were treated with PDN and 3 with DXM The remaining 3 cases, belonging to the ALL R-2006 protocol, were treated with DXM (n=2) and PDN (n=1). MRD-based stratification allowed the allocation of 3, 8 and 3 patients in the SR, MR and HR, respectively. Four cases relapsed (3 in the central nervous system and 1 in the bone marrow). EFS at 5 years of the 14 CALM-AF10 positive T-ALL children versus the 177 who were negative was 70.1% vs 63.9%, respectively (p-value log-rank=0.61). Small numbers did not allow to fully evaluate the impact of different variables such as initial steroid treatment (PDN vs DXM) or the MRD-based risk-group assignment Conclusions This study performed in a vast cohort of children with T-ALL shows that CALM-AF10 is found in about 7% of children with T-ALL and that does not predict a poor outcome when an intensive chemotherapy strategy is employed. Disclosures No relevant conflicts of interest to declare.

Poor Prognosis for IKZF1 Intra-Gene Deletions in Pediatric Ph− B-Cell Precursor Acute Lymphoblastic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3518-3518 ◽  
Author(s):  
Chiara Palmi ◽  
Daniela Silvestri ◽  
Giulia Longinotti ◽  
Elena Vendramini ◽  
Valentino Conter ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Poor Prognosis ◽  
Gene Deletion ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Rt Pcr ◽  
Full Cohort ◽  
Pcr Multiplex

Abstract Abstract 3518 Introduction. In the AIEOP-BFM ALL 2000 study, the MRD-based risk groups stratification allowed to achieve more than 80% cure rate. However, relapse is still the most frequent adverse event, occurring mainly in the largest subgroup of non-high risk (HR) patients. This emphasizes the need for new prognostic markers for upfront identification of patients with a high risk of relapse. Recently, new genomic abnormalities of the CRLF2 and Ikaros (IKZF1) genes have been reported in the subset of BCP-ALL patients without known chromosomal aberrations. We recently analyzed the poor prognostic impact of P2RY8-CRLF2 fusion in a representative cohort of 464 non-DS Ph- BCP-ALL patients enrolled in Italy into AIEOP-BFM ALL2000 study from February 2003 to July 2005. Aim. In order to estimate the incidence and prognostic value of IKZF1 deletions, alone or in combination with CRLF2 alterations, we initiated the screening of the full cohort of patients. A pilot test of a subset of 154 non-DS, Ph-, BCP-ALL patients treated in Italy according to the AIEOP-BFM ALL 2000 protocol from February 2003 to June 2004 has been completed so far. Methods. Ig/TcR PCR-MRD and RT-PCR screening for known chromosomal translocation were routinely performed; P2RY8-CRLF2 fusion was detected by RT-PCR. Multiplex Ligation-dependent Probe Amplification (MLPA) (Salsa MLPA P335-A3 ALL-IKZF1 kit; MRC-Holland, Amsterdam, NL) was performed to identify IKZF1 deletions together with deletions in additional B-cell development genes. Patients positive for IKZF1 deletions were further analyzed by Salsa MLPA P202-A1 IKZF1 kit to confirm and better define the extension of the IKZF1 gene deletion. Results. IKZF1 deletions were detected in 22/154 cases (14.3%), in keeping with incidence data reported in the literature. In 9 cases (5.8%) the deletion was intra-genic, involving only some exons of the IKZF1 gene, while in 13 cases (8.4%) the deletion was encompassing the whole IKZF1 gene. Three out of 16 patients (18.8%) carried both IKZF1 and CRLF2 deletions. Overall, the 5-year Cumulative Incidence of Relapse (median follow-up: 5.8 years) was 23±9% for patients carrying IKZF1 deletions and 12.2±2.9% for patients who did not (p=0.22). Interestingly, out of 13 cases with complete deletion of IKZF1, only one case (1/13, 7.7%) relapsed, vs 4/9 cases (44.4%) positive for IKZF1 intra-gene deletion. Conclusions. IKZF1 intra-gene deletion, but not whole gene deletion, showed a tendency to be associated with poor prognosis in childhood BCP-ALL treated according to the AIEOP-BFM ALL 2000 protocol. Whether these results will be confirmed at the completeness of this study, the assessment of IKZF1 status might serve as a new stratification marker. It will be of particular interest to verify whether different IKZF1 deletions within non-HR patients by MRD will have a prognostic impact. Disclosures: No relevant conflicts of interest to declare.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Intensification of Chemotherapeutic Regimens and Hematopoietic Stem Cell Transplantation Are Responsible for Improved Overall Survival in Adult Acute Lymphoblastic Leukemia in a Single Center Over the Last Forty Years

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4227-4227
Author(s):  
Estrella Carrillo ◽  
Nancy Rodriguez ◽  
Juan Francisco Dominguez ◽  
Jose Gonzalez ◽  
Jose Francisco Falantes ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Overall Survival ◽  
Nervous System ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Central Nervous System Involvement ◽  
Male Gender ◽  
Hematopoietic Stem ◽  
System Involvement ◽  
The Impact

Abstract Abstract 4227 Background Acute lymphoblastic leukemia (ALL) of adults is an infrequent and heterogeneous disease according to presentation pattern, prognosis and treatment. It is widely assumed that age above 30 years, leukocytosis >25 ×109/L, central nervous system involvement and specific cytogenetic disorders such as t(9;22) or MLL rearrangement entail bad prognosis. There are controversial studies on the impact of intensification chemotherapy and hematopoietic stem cell transplantation (HSCT) on survival of these high-risk groups. Aims To identify biological, clinical and prognostic characteristics in adult ALL patients diagnosed and followed in a single center throughout 40 years as long as the impact on clinical outcome of different consecutive therapeutic approaches, including HSCT, in different periods. Patients and methods Throughout 1970 to 2011, 230 patients were prospectively registered and retrospectively analyzed. Most patients accomplishing pre-determined criteria received treatment according to PETHEMA or locally developed therapeutic protocols (including HSCT in relapse high-risk patients, since 1978). Critical variables at diagnosis such as age, gender, phenotype (from 1978), cytogenetic (from 1999), white blood cells count (WBC) and central nervous system involvement, were analyzed. Response to induction chemotherapy, relapse rate (RR) and 5 year overall survival (OS) were analyzed in the whole cohort and separately by decade when treatment protocols were different. The clinical impact of HSCT was analyzed on a subgroup of patients homogeneously treated since 1994. Statistical analysis was performed by mean of Chi-square and Kaplan Meier tests, as appropriate. Outcome Table 1 summarizes the presentation pattern and its prognostic value. At diagnosis features such male gender, age above 30 years, central nervous system involvement, leukocytosis >10×109/L, MLL rearrangement, t(9:22) and complex karyotype entailed a worse prognosis. For the whole cohort the 5 years OS was 30%. CR was achieved in 73% and the RR was 38%. 5 years OS has improved by decades: 11% in the 70s, 24% in the 80s, 30% in the 90s, and 41% in XXI century (p<0,01). Patients selected for intensive chemotherapeutic protocols achieved a similar CR rate in each decade (nearly 80%) while the RR decreased through the years (70s: 68%, 80s: 44%, 90: 42%, 00–11: 25%; p<0,01). Patients treated with chemotherapy plus HSCT achieved in 5 years (from 1994) an OS of 69% in comparison with the 30% obtained in those patients who only received chemotherapy (p<0,01). Conclusion Male gender, age above 30, WBC >10×10e9/L, t(9;22), MLL-rearrangement, complex karyotype and CNS involvement conferred poor prognosis in adult ALL. Intensification of chemotherapeutic regimens produced a progressive decrease in relapse rate, leading to an improvement in overall survival over the years. HSCT seems to partially overcome the poor prognosis related to high risk factors. Disclosures: Perez-Simón: Janssen-Cilag: Patents & Royalties.

Effects of G-CSF On Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2564-2564
Author(s):  
Jordan Basnett ◽  
Adam Cisterne ◽  
Kenneth F Bradstock ◽  
Linda J Bendall
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Microarray Analysis ◽  
Environmental Changes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Extracellular Matrix Components ◽  
The Impact

Abstract Abstract 2564 G-CSF is commonly used to treat chemotherapy-induced neutropenia and for the mobilization of hematopoietic stem cells for transplantation in patients with leukemia. Administration of G-CSF has profound effects on the bone marrow microenvironment including the cleavage of molecules required for the maintenance of lymphopoiesis, including CXCL12 and VLA-4. We have recently reported that G-CSF results in the dramatic suppression of B-lymphopoiesis. This, together with previous reports by ourselves, and others, showing that disruption of CXCL12 or VLA-4 slow the progression of B-lineage ALL lead us to consider that G-CSF may similarly antagonize the progression of ALL. To explore this possibility, we examined the impact of G-CSF administration on six human ALL xenografts using a NOD/SCID mouse model. Mice were engrafted without radiation and G-CSF commenced when 1% of the bone marrow consisted of ALL cells. G-CSF was administered twice daily for 10 days, at which time all animals were culled and leukemia assessed in the blood, bone marrow and spleens. Surprisingly G-CSF was found to increase disease progression in two of xenografts investigated (1345 and 0398, referred to as G-CSF responsive xenografts hereafter), while the remainder demonstrated a small reduction in leukemia, with one showing a statistical significant decrease. No evidence for a direct mitogenic effect of G-CSF could be demonstrated in any of the xenografts using exogenous G-CSF in vitro cultures in the presence or absence of human or murine stromal support. Consistent with these findings, and previous reports, little to no G-CSF receptor was detected by flow cytometry or microarray analysis of xenografts. Microarray analysis of the xenografts revealed significant differences in gene expression between the G-CSF responsive xenografts and the remainder of the samples. A total of 83 genes were expressed at a higher level and 127 genes at a lower level in the G-CSF responsive xenografts. The more highly expressed genes included cell cycle regulators (eg cyclin A1), adhesion molecules (eg ALCAM), extracellular matrix components and surface receptors. Perhaps the most interesting was the exclusive expression of the acetylcholine receptor (cholinergic receptor, nicotinic, beta 4, nAChRb4) in the G-CSF responsive cases. Analysis of a large public dataset of childhood ALL samples revealed significantly higher expression of this gene in ALL samples with rearranged MLL (p<0.03). However, small numbers of cases in all ALL subgroups had greater than an 2 fold higher expression compared to normal B cell progenitors. The role of nAChR in the response of ALL cells to micro-environmental changes induced by G-CSF remains to be determined, however, nAChR has known roles in cell proliferation and inhibition of apoptosis. Furthermore G-CSF is known to induce acetylcholine production in other tissues. In summary, G-CSF inhibited leukemia progression in the majority of patient xenografts, however, in a subset of samples G-CSF accelerated disease progression. Clinically, G-CSF administration to ALL patients has not been associated with any major adverse outcomes. However our data suggest that a small subset of patients may experience accelerated disease. Identification of features associated with adverse responses to G-CSF will permit the identification of patients for whom G-CSF may present a risk for increased disease progression. Disclosures: No relevant conflicts of interest to declare.

Characterizing Rare Variants in Drug Metabolism Genes in Refractory Pediatric High-Risk Pre-B ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 879-879
Author(s):  
Andrew Hughes ◽  
Joseph Giacalone ◽  
Todd E Druley
Keyword(s):  
Genetic Variation ◽  
High Risk ◽  
Metabolic Pathways ◽  
Rare Variants ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Patient Specific ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem ◽  
Pooled Sequencing

Abstract Abstract 879 Introduction: We are working to understand how rare genetic variation can influence incidence and outcomes of pediatric high-risk leukemia. Despite improvements in standard-risk outcomes, children with high-risk precursor-B acute lymphoblastic leukemia (HR-ALL) have not enjoyed similar success. Recent studies demonstrate that there are critical metabolic pathways involved in the transition from normal precursor-B (pre-B) cells to leukemic cells as well as involved in proper therapeutic response (Mullighan, Nature 2007; Kang, Blood 2011). The Rare Variant Hypothesis predicts that a population of affected individuals would harbor a diverse collection of functionally significant variants in the genes involved in these pathways. Thus, the manner in which these critical genes or pathways become disrupted may be quite variable, but the outcome is very similar. Therefore, we hypothesize that rare variants in critical metabolic pathways influence the incidence and outcome of pediatric HR-ALL. We established Children's Oncology Group (COG) protocol AALL10B2 to study this question from existing patient DNA samples. Methods: Using our pooled sequencing strategy (Druley, Nat Methods 2009) and novel computational analysis software, SPLINTER (Vallania, Genome Res 2010), we have sequenced 54 candidate genes associated with pediatric leukemia in three pools of genomic DNA. One pool from 96 germline DNA samples from patients enrolled on COG HR-ALL protocol P9906, a second pool from 96 matched P9906 leukemia DNA samples, and a third from 93 ethnically matched unaffected pediatric controls. We called an average of 3,987 variants per pool (range 3822–4209) and validated variants by individual custom genotyping. The correlation between aggregated individual minor allele frequencies and pooled sequencing variant calling was excellent for all three pools (R2 range = 0.90–0.93). Results: By directly mapping the variants from the three pools, we identified gene regions with variation in the patients, but not controls. We found two genes with regions of excess patient-specific germline genetic variation, cytochromes 1A1 and 3A5 (CYP1A1 and CYP3A5). The CYP3A isozymes are involved in the activation of epipodophyllotoxins, anthracyclines and cyclophosphamide along with the clearance of vincristine and glucocorticoids, and common variants in these genes have previously been correlated with an increased incidence of pediatric ALL (Joseph, Pediatr Blood Cancer 2004; Aydin-Sayitoglu, Am J Hematol 2006; Borst, Eur J Haematol 2011). A heat map of genome-wide expression array results for our patient population (our 96 pilot patients from the P9906 trial and an additional 250 enrolled in the AALL0232 trial) against the 54 genes in our survey identified a previously unappreciated subpopulation (of ∼10% of patients) that trended toward inferior relapse-free survival and demonstrated significant overexpression of 14 genes: (in alphabetical order): ATM, CDKN1A, CYP1A1, CYP3A5, IKZF1, MDM2, MLL, MTHFR, NAT2, NQO1, PAX5, PTPN11, TCF3, TPMT. These patients did not possess other high-risk chromosomal translocations. Validation in 250 matched germline and HR-ALL DNA samples from participants in the COG AALL0232 study is underway, along with functional characterization and validation of the identified variants. Conclusions: We have identified a potential new genomic signature for a subset of HR-ALL patients who appear predisposed to poor therapeutic outcomes. Our preliminary results support the hypothesis that pediatric HR-ALL incidence and outcomes are influenced by a pre-existing profile of germline genetic variation, which is reasonable given the fact that it is exceptionally mathematically unlikely that these children would acquire the entire cadre of deleterious genetic variants required for malignant transformation solely through somatic mutation. Such results are “clinically-actionable” now. Children demonstrating functionally significant variants in these genes or similar patterns of gene expression could be immediately referred for hematopoietic stem cell transplantation in first remission rather than being exposed to years of highly toxic chemotherapy that is unlikely to be successful anyway. Meanwhile, in vitro functional studies will facilitate the discovery of alternate therapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

Spontaneous Mutations of Bcor and Jak1/2 genes Lead to an Aggressive Leukemia of B-1 Progenitor B Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3573-3573
Author(s):  
Sheryl M Gough ◽  
Liat Goldberg ◽  
Marbin Pineda ◽  
Robert L Walker ◽  
Yuelin J Zhu ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Progenitor Cell ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Hot Spot ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Hematopoietic Stem

Abstract NUP98 gene fusions, generated by non-random chromosomal translocations, are associated with a wide spectrum of high risk hematologic malignancies and have been shown to alter normal hematopoietic stem and progenitor cell (HSPC) gene expression programs. A recurrent t(11;17)(p15;p13) translocation in patients with AML leads to the production of a NUP98–PHF23 (NP23) fusion gene. The consequent NP23 fusion protein retains the PHD domain, known to bind H3K4me3, and is thought to have aberrant chromatin regulation properties. We have generated a transgenic mouse model of the NUP98-PHF23 gene fusion which develops a range of hematologic malignancies, most commonly pre-T LBL and AML. However, approximately 10% of NP23 mice develop an aggressive B-1 progenitor acute lymphoblastic leukemia (pro B-1 ALL). B-1 and B-2 lymphocytes have distinct developmental pathways and are thought to represent arms of the innate and adaptive immune systems, respectively. Mature B-2 lymphocytes predominate in the peripheral circulation, and are characterized by expression of B220; whereas B-1 lymphocytes are more prevalent in the pleural and peritoneal cavities, and do not express B220. Murine B cell malignancies typically stain positive for B220, and represent transformed B-2 cells. In the present study, NP23 progenitor ALLs displayed an immunophenotype (Lin-B220- CD19+ AA4.1+) that was identical to that of the recently described B-1 progenitor cell. All B-1 progenitor ALLs exhibited clonal rearrangements of the IgH gene locus. Specifically, these rearrangements involve favored usage of 3’ VH regions, similar to observations with fetal B-1 progenitor cells, further supporting the notion that these are leukemias of B-1 progenitors. Using whole exome sequencing, we found acquired mutations in the BCL6 interacting corepressor (Bcor) gene in 5 out of 7 B-1 progenitor leukemias. The mutations were all frame shift or nonsense mutations, and were located within a 9 bp “hot spot” in Bcor exon 8. In addition, 4 of 7 cases had somatic mutations of Janus kinase 1 (Jak1) or 2 (Jak2), and 7/7 cases showed hyperphosphorylation of Stat3 or Stat5, consistent with the contention that the Jak1/2 mutations are activating mutations, and leading to a hypothesis that the NP23 pro B-1 ALLs which do not harbor Jak1/2 mutations may have acquired an unidentified mutation in the Jak-Stat pathway. Of note, Jak1/2 mutations have previously been identified in a subset of high-risk pediatric B-cell precursor ALL patients. The striking correlation between Bcor and Jak1/2 mutations, occurring specifically in a subset of NP23 leukemias, implies that these three mutations (NP23, Bcor, and Jak1/2) collaborate and provide the oncogenic setting for B-1 progenitor transformation. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4474-4474
Author(s):  
Bingqing Tang ◽  
Zhixiang Wang ◽  
Dainan Lin ◽  
Xianjun He ◽  
Zihong Cai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Validation Cohort ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Poor Outcome ◽  
Cd20 Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract 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&lt;0.01) and OS 74.6±4.5% (P&lt;0.05), respectively. CD20 expression was also associated with inferior EFS than CD20-negative group (P&lt;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&lt;0.05 ) and IKZF1 del/CD20- (P&lt;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+. Disclosures No relevant conflicts of interest to declare.

Downregulation of mTOR and P70S6Kβ2 in Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL) Is Correlated with a Poor Prognosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2508-2508 ◽  
Author(s):  
Paola Bonaccorso ◽  
Manuela Tumino ◽  
Angela D'Ambra ◽  
Elena Mirabile ◽  
Martina Barchitta ◽  
...  
Keyword(s):  
High Risk ◽  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Treatment Plan ◽  
Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
Phosphorylated Akt

Abstract Abstract 2508 Background. T-ALL accounts for about 15% of pediatric ALL and more than 20% of children experience a recurrent disease which has a dismal prognosis. Characterization of molecular alterations with prognostic impact may be useful for an early identification of patients at high risk of failure in whom more intensive and/or better tailored treatments, including hematopoietic stem cell transplantation (HSCT) may be considered. PTEN/AKT pathway has been shown to be involved in children with T-ALL (Gutierrez A et al 2009), in glucocorticoid resistance (Beesley A et al 2009) and in NOTCH-1 mutated T-ALL resistant to gamma secretase inhibitors (Palomero T et al. 2009). In the attempt to better characterize the role of the PTEN/AKT/mTOR pathway in pediatric T-ALL, we have evaluated the expression of each protein in this pathway's cascade and investigated its association with outcome. Materials and Methods. We enrolled in our study 23 children with T-ALL consecutively diagnosed at our Center in Catania from 1997 to 2009. They were treated by three consecutive AIEOP protocols. We analyzed the mRNA expression of PTEN, using RT-PCR. We evaluate by western blot analysis, the expression of the following proteins: in total (AKT; GSK3β; CK2α; CK2β; PTEN; PDK1; P70S6Kβ2; mTOR; S6K) and phosphorylated [AKT(S473) (T308); GSK3β(S9); PTEN(S380); PDK1(S241); P70S6Kβ2(S371); mTOR(S2448); S6K(Ser235/236)/(Ser240/241)] conformation. The association of these variables with the Event Free Survival (EFS) was assessed using the χ2 test. A p value ≤0.05 was considered statistically significant. Furthermore, in order to measure the association level, the Relative Risk (RR) and the corresponding 95% Confidence Interval (95%CI) were calculated. Events were considered dead of complication (DOC), relapse and HSCT. Results. Seven out of the 23 patients presented an event: 5 relapses, 1 DOC and 1 HSCT. RT-PCR analysis of PTEN expression revealed that only one case did not show any product. Conversely, western blot analysis demonstrated that all patients showed total and phosphorylated PTEN proteins. Interestingly, we observed that total AKT protein was present in all the cases except one; the phosphorylated forms were detected as follows: AKT (T308) in 15 out of the 23 patients (65%), whereas none showed expression of AKT (S473). Surprisingly, we detected a statistically significant downregulation of total and phosphorylated mTOR and P70S6Kβ2 expression in eight, nine, ten and eleven out of 22 analyzed patients respectively. Downregulation or absent expression of both total and phosphorylated P70S6Kβ2 had a statistically significant impact on EFS showing a higher risk of events, when comparing those downregulated with those exhibiting phosphorylated (RR: 2,75; 95%CI: 1,25–6,01) and total protein (RR 3,33; 95%CI: 1,29–8,59) respectively. Moreover, downregulation of mTOR(S2448) confirmed the same pattern of higher risk of events (RR: 2,77; 95%CI: 1,08–7,07) comparing those downregulated with those exhibiting expression of phosphorylated protein. Conclusions. Our data for the first time have shown that the downregulation or absent expression of mTOR and P70S6Kβ2 is associated with a very poor outcome: 5 cases had very aggressive relapses (3 died for progressive disease); one child died during induction for complication related to aggressive disease (massive splenic hemorrhagic event) and one case underwent a matched-HLA familiar HSCT because of a high risk-MRD pattern. These preliminary findings need to be confirmed in a larger-population based study. Nevertheless our data identify new markers of aggressive and resistant disease, easily available at diagnosis, suggesting that mTOR and P70S6Kβ2, which play a crucial role as negative control in the PI3K/AKT cell signalling pathway, are needed to be evaluated in a future treatment plan design with specifically targeted drugs. Moreover, our data will be confirmed by the use of a reliable and robust method such as flow cytometry which will allow us to perform a sensitive and accurate measurement of single cell characteristics, emphasizing the intracellular signaling pathways of interest. Disclosures: No relevant conflicts of interest to declare.

Prognostic Value of Rare IKZF1 deletions in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia: An International Collaborative Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 368-368 ◽  
Author(s):  
Judith M. Boer ◽  
Arian van der Veer ◽  
Dimitris Rizopoulos ◽  
Marta Fiocco ◽  
Edwin Sonneveld ◽  
...  
Keyword(s):  
High Risk ◽  
Poor Prognosis ◽  
Prognostic Value ◽  
Rare Variants ◽  
Lymphoblastic Leukemia ◽  
Matched Pair ◽  
Prognostic Impact ◽  
Wild Type ◽  
Cell Precursor ◽  
Exon 2

Abstract BACKGROUND Deletions in IKZF1 are found in approximately 15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of the most common IKZF1 deletions affecting exons 4-7 (DEL 4-7) and exons 1-8 (DEL 1-8), but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multi-centre study we analyzed the prognostic value of these rare variants. METHODS Multiplex ligation-dependent probe amplification (MLPA) assays were performed on genomic DNA from patients’ bone marrow aspirates at diagnosis by the national study groups. Each IKZF1-deleted case was matched to three wild-type controls based on cytogenetic subtype, treatment protocol, stratification arm, white blood cell count and age at diagnosis. Known high-risk factors age <1 year (infants), BCR-ABL1-positive, and MLL-rearranged cases were excluded. We compared the cumulative incidence of relapse with death as competing event (CIR) between cases and their controls using Gray’s test. Matched pair Cox regression was used for event-free survival (EFS) analysis, and the hazard ratio (HR) with 95% confidence interval (CI) was reported. RESULTS We included 134 BCP-ALL cases with a rare IKZF1 deletion and 402 matched controls. Of these cases, 26 (19%) had a deletion in exon 2 to 3 (DEL 2-3), 32 (24%) in exon 2 to 7 (DEL 2-7), 15 (11%) in exon 2 to 8 (DEL 2-8), 27 (20%) in exon 4 to 8 (DEL 4-8), and 34 (25%) belonged to the remaining group (DEL-Other). All rare IKZF1 deletion variants together had a higher 5-year CIR compared with the matched wild-type controls (40% vs. 22%, p<0.001), and a lower matched pair EFS (HR 1.8, 95% CI: 1.4-2.3; p<0.001). Analysis of cases and matched controls within their own risk group (56 standard risk, 33 intermediate risk and 45 high risk cases), showed an unfavorable effect for rare IKZF1 deletions in all stratification groups. Rare IKZF1 deletions were found in all BCP-ALL subtypes. The frequency of ETV6-RUNX1-positive (12 cases, 9%), high-hyperdiploid (21 cases, 16%), and unclassified BCP-ALL (13 cases, 10%) was relatively low among rare IKZF1-deleted cases. Most cases were found in the B-other group (88 cases, 66%). These B-other cases had a higher 5-year CIR compared with wild-type controls (47% vs. 27%, p<0·001), which translated into a lower EFS (HR 1·8, 95% CI: 1·3-2·4, p=<0·001). CIR and EFS analysis of high-hyperdiploid cases revealed a weak trend for an adverse outcome associated with rare IKZF1 deletions (5-year CIR 29% vs. 18%, p=0·1 and HR 2·4, 95% CI: 0·8-6·7, p=0·1). No prognostic impact was seen for rare IKZF1 deletions in ETV6-RUNX1-positive BCP-ALL Separate analyses per IKZF1 deletion type showed a higher 5-year CIR for DEL 2-7 (38% vs. 18%, p=0.05), for DEL 2-8 (60% vs. 31%, p=0.02), and for DEL-Other cases (45% vs. 24%, p=0.04). Matched pair analysis of EFS revealed a poor prognosis for DEL 2-7 (HR 2·0, p=0·03), DEL 2-8 (HR 2·2, p=0·002), and DEL-Other (HR 2·2, p<0·001). The CIR and EFS of DEL 2-3 cases displayed a trend for unfavorable outcome (5-year CIR 28% vs. 17%, p=0.06; HR 1.8, p=0.1) but not for DEL 4-8 (34% vs. 26%, p>0.1; HR 1.0, p>0.1). The prognosis of each rare variant, including DEL 2-3 and DEL 4-8, was equal or worse compared with the most frequently observed and unfavorable prognostic DEL 4-7 and DEL 1-8 variants. CONCLUSIONS All types of rare IKZF1 deletions, with the possible exception of DEL 4-8 cases, had a significantly increased risk of relapse and poorer EFS compared with their matched wild-type controls. The prognosis of DEL 4-8 cases was as poor as those of the other rare variants and that of the known high-risk variants DEL 4-7 and DEL 1-8. We therefore conclude that all variants of IKZF1 deletions are equivalent in terms of their prognostic impact. Disclosures No relevant conflicts of interest to declare.

scholarly journals Frequency of p190 and p210 BCR-ABL Fusions Genes in Acute Lymphoblastic Leukemia in a Long Group of Adults and Childhood

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5273-5273 ◽  
Author(s):  
Rosa Maria Arana-Trejo ◽  
Gregorio Ignacio ◽  
Raquel Amador-Sánchez ◽  
Jorge Cruz-Rico ◽  
Maria-Paula Hernández ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Age Group ◽  
Fusion Genes ◽  
Rt Pcr ◽  
Pcr Multiplex ◽  
The Impact

Abstract The Ph chromosome is a translocation (9;22)(q34;q11), that results in the constitutive activation of the BCR/ABL tyrosine kinase. The incidence of BCR/ABL in Acute Lymphoblastic Leukemia (ALL) increases with age, from less than 5% in younger children to 20-30% in older adults, with a peak incidence in patients aged 35-50 years. BCR/ABL1 has diverse breakpoints, in adult patients with Ph+ ALL the p190BCR/ABL transcript e1a2/e3a2 may be documented in 50-70%; p210BCR/ABL b2a2/b3a2 in 15-30% of patients and <1% having both breakpoint. Childhood patients with Ph+ ALL fusion genes present p190BCR/ABL transcipt e1a2/e3a2 in 90% and the remaining present other fusion transcrit or co-expression of both p190 and p210 BCR-ABL. OBJETIVE. The aim of this study was identify the occurrence of fusion genes to p190 and p210 BCR-ABL rearrangements in adult and childhood patients with ALL. METHODS. We include between 2008-2015 870 patients with ALL de novo from seven different hospitals from México, the 45% (394) were childood and the rest 55% (476) were adults. All patients were studied to RT-PCR multiplex and nested in RNA for fusion transcripts 190 and p210 BCR-ABL, at diagnosis, according to the international BIOMED-1 protocol. RESULTS. From 870 patients with ALL, the most frequent subtype FAB were L2 (87%) and second L1 (13%). The immunophenotype by B-ALL was to 80%, bilineal in 5% and the rest have not data. The overall incidence to BCR-ABL in both children and adults with ALL were to 17% [147/870]. The analysis by age group were; in 476 adults with ALL, their average age was 37 years old (range 17-84 years) and their incidence of BCR-ABL positive was 20% (95/476 cases). The distributions by type of fusion transcript were 83% p190 and 17% p210; we did not observe co-expression of transcripts to BCR-ABL. In children patients the average age was 9 years old (range 0.1-16 years), the incidence of BCR-ABL was 13.2% (52/394 cases). The distributions by type of fusion transcript to BCR-ABL were p190 78.8%; p210 13.4% and their co-expression by both isoforms 8%. CONCLUSION. The 20% frequency for BCR-ABL1 in adults with ALL is concordant with others reports published, with values from 17% to 37% with predominancy of p190 (83%). In our pediatric patients group with ALL, document a frequency of 13.2% by BCR-ABL1 positive; it is higher than other populations reporting 5-10%. The distributions of fusion transcript p190 and p210 coincides with previous prevalence estimates in other countries where p190 transcript was the most frequent. But the coexpression of both isoforms [p190/p210] were 8% it has not been reported in this age group with ALL. In conclusion, we recommend to identify the BCR-ABL transcript type in every patients with ALL at diagnosis, using a RT-PCR verified method for P190/p210 and followed the patient by mesure the impact clinical and will be adjust the treatment like o plus the cytogenetic studies. Disclosures No relevant conflicts of interest to declare.

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