scholarly journals Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yin-Chen Hsu ◽  
Chih-Hsiang Yu ◽  
Yan-Ming Chen ◽  
Kathryn G. Roberts ◽  
Yu-Ling Ni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukaemia ◽  
B Cell ◽  
Lymphoblastic Leukaemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Genetic Alterations ◽  
Childhood All ◽  
Free Survival ◽  
Polymerase Chain

AbstractPhiladelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.

Acute Lymphoblastic Leukaemia Has a Poor Outcome in Children with Down Syndrome Due to Infective Death in Remission (Results of UK MRC ALL 97 Trial).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 873-873 ◽  
Author(s):  
Josu de la Fuente ◽  
Sue Richards ◽  
David K. Webb ◽  
Ian M. Hann ◽  
Christopher D. Mitchell ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
High Rate ◽  
Childhood All ◽  
Free Survival ◽  
Children With Down Syndrome ◽  
Medical Research Council Trial ◽  
The Uk

Abstract Acute lymphoblastic leukaemia (ALL) has a poorer outcome in children with Down syndrome (DS) which has been attributed in the past to a higher incidence of infective death in remission and late relapses. We report on the outcome of children with DS enrolled on the UK Medical Research Council trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Thirty seven children had DS (2%), of whom three were treated on the high risk protocol (HR1). Thirty-three (89%) achieved complete remission at the end of induction, 3 died during induction (8%), and one died later without remission. The median follow up was 4.9 years (2.4–7.8). The 5-year event free survival (EFS: 48.0%, SD 8.9) was not an improvement on the previous MRC UKALL XI trial (57.9%, SD 8.0, p=0.2) and was significantly worse than for children without DS (p<0.00005). At the time of follow up, 46% of the children had died (n=17). Five patients suffered relapse, and the relapse rate was not significantly different from those without DS. One patient known to have cardiac disease died during maintenance due to arrhythmia and 8 died of infection, resulting in a significantly higher rate of death in remission (28%) than in children without DS (3%, p<0.00005). Infective deaths were associated with intensification therapy, except in one child who died during interim maintenance. It was possible to isolate a microorganism in 50% of the cases (two cases of Pseudomonas, one Staphylococcus aureus, one Staphylococcus epidermidis and yeast) plus Rhinovirus was found in a nasopharyngeal aspirate of a fifth case with clinical evidence of bacterial sepsis. For the randomised comparisons (prednisolone versus dexamethasone n=30, mercaptopurine versus thioguanine n=23), results within the DS patients were not significantly different from those in all patients, with benefit for dexamethasone. The increase in remission deaths with DS was greater with prednisolone, and with mercaptopurine (p for interaction = 0.0002, <0.00005, respectively). The revision of the trial in 1999 which adopted the template of CCG 1952 which improved EFS, did so for DS patients also, with no change in the DS remission death rate. In conclusion, children with DS may benefit from increased treatment intensity but still have an unacceptably high rate of infective death in remission.

The Genomic Landscape of Relapsed B-Cell Acute Lymphoblastic Leukaemia (B-ALL) in Adolescents and Adults

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3769-3769
Author(s):  
Vikki Rand ◽  
Stephen Johnstone ◽  
Rachel E Crossland ◽  
Sarah Wilkinson ◽  
Andrew G Hall
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
B Cell ◽  
Disease Progression ◽  
Lymphoblastic Leukaemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Childhood All ◽  
Genomic Landscape ◽  
Backtracking Analysis

Abstract Despite significant advancements in the treatment of paediatric B-cell acute lymphoblastic leukaemia (B-ALL), ALL remains one of the most challenging adult malignancies. Outcome of adult B-ALL is poor with only 40% 5-year event-free survival compared to >80% in children. B-ALL is characterised by the acquisition of chromosomal abnormalities and many are strong predictors of outcome. The difference in the prevalence of cytogenetic subtypes and specific genomic abnormalities observed between adult and childhood ALL suggests a difference in tumour biology that may contribute to the differences in patient outcome. Detailed analysis of the paediatric B-ALL genome have revealed a plethora of abnormalities targeting key pathways. Although specific alterations have been investigated in adult and adolescent B-ALL, studies of the genomic landscape remain scarce. In this study we set-out to define the genomic landscape of adolescent and adult relapsed B-ALL. Genomic backtracking analysis of sequential diagnostic and relapse samples revealed known and novel abnormalities that may play a role in chemoresistance and disease progression in these tumours. DNA was isolated from the diagnostic and relapse samples from 12 adolescents/adult patients (5 female and 7 male) diagnosed with B-ALL. Eight of the 12 patients had remission samples available. Known cytogenetic abnormalities were detected in 7 patients: high hyperdiploid, t(1;19), t(8;14) and t(4;11) rearrangements. Two cases were positive for the BCR-ABLfusion gene. The mean age at diagnosis was 36.8 years (range 16-59 years) of which 10 relapsed early, within 2 years of initial diagnosis. DNA for the 12 diagnostic, 12 relapse and 8 remission sample were hybridised to the Affymetrix SNP6.0 array to determine copy number abnormalities (CNAs). The mutational landscape was captured for 4 cases using the Agilent SureSelect Human All Exon V4+UTR kit and sequenced to depths of 200X. The incidences of the most prevalent abnormalities in paediatric B-ALL were determined in each adult/adolescent sample: CDKN2A/B 88% (21/24), IKZF1 20% (5/24), PAX5 8% (2/24), ETV6 0% (0/24), RB1 8% (2/24), BTG1 8% (2/24) and EBF1 17% (4/24). Deletions of CDKN2A/B were detected in all but one patient. In 9 cases the abnormality was seen at both diagnosis and relapse and one case had a de novo deletion at relapse. A further case had a sub-clone harbouring CDKN2A/B deletion at diagnosis that emerged as the dominant clone at relapse. Deletion of CDKN2A/Bhas been associated with poor overall survival and has been reported at high incidence in relapsed adult BCR-ABL1-ALL, but the association with prognosis and relapse in other subtypes has not been confirmed. Genomic backtracking analysis of the matched diagnostic and relapse samples identified, on average, 36 somatic mutations at relapse that were either not detected or were only detectable in a sub-clone at diagnosis. An average of 0.05 mutations per Mb were computationally predicted to be damaging to the function of the protein. Novel de novo mutations seen at relapse were identified in cancer-related genes: FAT4, CDCA7 and PVRL4. Sequencing at depth of >200X demonstrates the ability to detect mutations in the resistant clone which could be involved in disease progression. Mutations in the ATP-binding cassette transporter gene, ABCC9, were identified in a sub-clone at diagnosis at a variant frequency of 5% (13/268 reads) and at 43% (113/260) in the relapse sample. ABCC9is involved in drug resistance suggesting a potential role in chremoresistance in this patient. In conclusion, in-depth genomic analysis and whole-exome sequencing of matched diagnostic and relapse samples in adult/adolescent B-ALL has identified known and novel genomic abnormalities. Deletion of CDKN2A/B was prevalent in 11 of the 12 cases confirming the importance of this region in relapsed B-ALL. We have identified novel mutations in genes associated with chemoresistance and tumorigenesis: ABCC9, FAT4, CDCA7 and PVRL4. Our study provides the most comprehensive genetic portrait of adult relapsed B-ALL to date and is a significant step to defining the genetic causes of disease progression and chemoresistance. Disclosures No relevant conflicts of interest to declare.

Combining BCL-2 Inhibitors with Parthenolide to Treat Childhood Acute Lymphoblastic Leukaemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2531-2531
Author(s):  
Paraskevi Diamanti ◽  
William J Barendt ◽  
Benjamin C Ede ◽  
Charlotte V. Cox ◽  
Allison Blair
Keyword(s):  
Clinical Trials ◽  
Drug Treatment ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Conflicts Of Interest ◽  
Minimal Risk ◽  
Childhood All ◽  
Childhood Acute Lymphoblastic Leukaemia

Abstract Current therapies for the treatment of childhood acute lymphoblastic leukaemia (ALL) have resulted in vastly improved survival rates of around 90% in recent years. Despite these successes, around 15% of patients die of relapse. It is possible that ALL may be maintained by subpopulations of cells, known as leukaemia stem cells (LSC), that are resistant to therapy and subsequent relapses may arise from these cells. Parthenolide (PTL), a naturally occurring sesquiterpene lactone, is an NF-κB inhibitor that kills leukaemia cells by apoptosis and/or increase of reactive oxygen species. PTL has been shown to be remarkably effective against several LSC subpopulations in vivo, with complete ablation of leukaemia. In a minority of cases, leukaemia burden was reduced following PTL treatment but not eliminated. Therefore, it may be necessary to combine PTL with other agents to improve killing of all LSC subpopulations. Another pathway of increasing interest in the treatment of leukaemias is the BCL-2 family. BCL-2 has been shown to be overexpressed in over 66% of B-ALL cases and is associated with tumourigenesis in several cancers. ABT-263 is an inhibitor of BCL-2, BCL-xL and BCL-w, it has been shown to selectively target AML LSC and is in early clinical trials in lymphoid malignancies. ABT-199 is another promising inhibitor that is currently in clinical trials for CLL. ABT-199 is specific for BCL-2 and has minimal risk for thrombocytopenia. In the present study the effects of both ABT-263 and ABT-199 alone or in combination with PTL were assessed in childhood ALL samples to determine whether toxicity to leukaemia cells could be improved in vitro and in vivo. The viability of bulk cells from 11 B cell precursor (BCP) ALL cases and 11 cord blood (CB) samples following drug treatment for 24 hours were assessed using flow cytometry by staining with Annexin V and propidium iodide. Initially, PTL was used at a range of 1 to 10μM, ABT-263 from 0.025 to 1μM and ABT-199 from 0.1 to 10μM. Only PTL and ABT-263 significantly reduced the viability of ALL cells compared to CB with IC50 values of 1.2μM and 0.125μM (P≤0.01 and P≤0.0015), respectively. In vitro drug combination studies demonstrated synergism when combining PTL with ABT-263 in a 9.5:1 ratio using the Chou Talalay model. The viability of ALL cells following combination therapy (1.2μM PTL with 0.125μM ABT-263) was reduced to 38.3±32.5%, while CB viability was unaffected (96.9±29%, P<0.0001). Using this combined dose, toxicity to ALL cells was increased by a further 35% compared to PTL alone and by 25% compared to ABT-263 alone. Even at the highest combined doses tested (9.6μM PTL: 1μM ABT-263) normal CB remained relatively unaffected with 73.3±25% surviving. The effects of these drugs alone and in combination were also assessed in LSC subpopulations in 3 of these cases. Unsorted ALL cells, CD34+/CD19+ and CD34-/CD19+ subpopulations were the most responsive with viabilities ranging from 17.6±4% to 23.9±11% using 1.2μM PTL and 0.125μM ABT-263. The CD34+/CD19- and CD34-/CD19- cells were more resistant with 70.3±40% and 73.3±15% surviving, respectively. However, since we have previously shown that the effects of in vitro drug treatment do not always accurately reflect the response in vivo, it was important to evaluate the effects of these drugs in mice with established leukaemia. NOD/LtSz-scid IL-2Rγc null (NSG) mice were inoculated with 1-1.15x106 unsorted BCP-ALL cells. Once the levels of leukaemia engraftment in murine peripheral blood reached ≥ 0.1%, mice were treated with 100mg/kg ABT-263 or ABT-199 and vehicle by oral gavage for 21 consecutive days and the levels of leukaemia burden were monitored weekly. Results to date demonstrate that leukaemia levels continued to rise in placebo-treated mice, reaching 49.2±7% by day 21, while the levels in ABT-263 and ABT-199 treated mice were significantly lower at 8.6±10% and 23.7±12%, respectively (P<0.0001). The use of ABT-263 and ABT-199 significantly improved the survival of NSG compared to untreated controls (P=0.0001). These data indicate that combining PTL with ABT-263 shows promising results in the killing of bulk and LSC populations in BCP-ALL. Ongoing in vivo studies will assess the potential of using BCL-2 inhibitors in combination with PTL compared to standard chemotherapeutics. Disclosures No relevant conflicts of interest to declare.

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