Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies

Uçkun, Fatih M.; Nachman, James B.; Sather, Harland N.; Sensel, Martha G.; Kraft, Peter; Steinherz, Peter G.; Lange, Beverly; Hutchinson, Raymond J.; Reaman, Gregory H.; Gaynon, Paul S.; Heerema, Nyla A.

doi:10.1002/(sici)1097-0142(19981101)83:9<2030::aid-cncr21>3.3.co;2-h

Cited by 21 publications

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“…The risks of slow response might to some extent be overcome by increased therapy intensity; in the CCG experience with HR-ALL and slow early response as evaluated on the day 7 bone marrow, the outcome was improved by augmented post-induction chemotherapy [33]. Certain cytogenetic changes have been established with very poor outcome: the Philadelphia translocation t(9;22) [38,39], the t(4;11) or MLL-gene rearrangement [40,41], as well as hypodiploidy [42,43]. Our patients with t(9;22) benefited from stem cell transplantation in 1CR (9-year EFS 55% vs. 17% for chemotherapy, P ¼ 0.02) although these groups were small (19 SCT vs. 6 chemo).…”

Section: Discussionmentioning

confidence: 89%

Outcome of children with high‐risk acute lymphoblastic leukemia (HR‐ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation

Saarinen‐Pihkala

Gustafsson

Carlsen

et al. 2003

Pediatric Blood & Cancer

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Section: Discussionmentioning

confidence: 89%

Outcome of children with high‐risk acute lymphoblastic leukemia (HR‐ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation

Saarinen‐Pihkala

Gustafsson

Carlsen

et al. 2003

Pediatric Blood & Cancer

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“…The recent demonstration that TERF2 inhibits ATM at telomeric ends (Karlseder et al, 2004) also suggests that it acts, at least in part, independently of telomerase (Ancelin et al, 2002). Children with a BCR-ABL positive or RUNX1 amplified ALL do poorly on current treatment protocols (Uckun et al, 1998;Robinson et al, 2003). It may be possible to therapeutically exploit the overexpression of TERF2 in this subset of childhood ALL.…”

Section: Discussionmentioning

confidence: 99%

Prospective gene expression analysis accurately subtypes acute leukaemia in children and establishes a commonality between hyperdiploidy and t(12;21) in acute lymphoblastic leukaemia

et al. 2005

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Summary We have prospectively analysed and correlated the gene expression profiles of children presenting with acute leukaemia to the Royal London and Great Ormond Street Hospitals with morphological diagnosis, immunophenotype and karyotype. Total RNA extracted from freshly sorted blast cells was obtained from 84 lymphoblastic [acute lymphoblastic leukaemia (ALL)], 20 myeloid [acute myeloid leukaemia (AML)] and three unclassified acute leukaemias and hybridised to the high density Affymetrix U133A oligonucleotide array. Analysis of variance and significance analysis of microarrays was used to identify discriminatory genes. A novel 50‐gene set accurately identified all patients with ALL and AML and predicted for a diagnosis of AML in three patients with unclassified acute leukaemia. A unique gene set was derived for each of eight subtypes of acute leukaemia within our data set. A common profile for children with ALL with an ETV6–RUNX1 fusion, amplification or deletion of ETV6, amplification of RUNX1 or hyperdiploidy with an additional chromosome 21 was identified. This suggests that these rearrangements share a commonality in biological pathways that maintains the leukaemic state. The gene TERF2 was most highly expressed in this group of patients. Our analyses demonstrate that not only is microarray analysis the single most effective tool for the diagnosis of acute leukaemias of childhood but it has the ability to identify unique biological pathways. To further evaluate its prognostic value it needs to be incorporated into the routine diagnostic analysis for large‐scale clinical trials in childhood acute leukaemias.

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“…Because of the high rates of relapse and rapid development of drug resistance in patients with Ph+ ALL, only approximately 10% of patients experience long‐term benefits from standard combination chemotherapy alone (Dombret et al , 2002; Gleissner et al , 2002; Kantarjian et al , 2004). The frequency of the Ph chromosome increases with increasing age, from approximately 3% in children and adolescents, to 22% among adult patients aged 21–50 years, and 44% in patients aged more than 50 years, making it the most common cytogenetic abnormality in adult ALL (Secker‐Walker et al , 1991; Uckun et al , 1998).…”

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confidence: 99%

Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome‐positive acute lymphoblastic leukaemia

2009

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SummaryAcute lymphoblastic leukaemia (ALL) is a heterogeneous disease that is often associated with several chromosomal and molecular abnormalities. Patients who have the Philadelphia (Ph) chromosome and associated BCR-ABL1 oncogene have a particularly poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only known curative treatment for Ph+ ALL and facilitating allo-HSCT in eligible patients is a key treatment goal. However, many patients relapse after allo-HSCT, particularly those with measurable residual disease prior to transplantation, and a significant percentage of patients are ineligible for allo-HSCT, particularly older patients. Hence, many patients require additional/alternative therapies to prolong survival. Studies are ongoing to determine the most effective first-line drug regimens for patients who subsequently undergo allo-HSCT and ineligible patients. Tyrosine kinase inhibitors targeted to Bcr-Abl are important novel therapies for Ph+ ALL. Although imatinib administered in combination with chemotherapy is established as the current first-line strategy, relapse is common, even among allo-HSCT recipients. Emerging data indicate that more potent multi-targeted kinase inhibitors (including dasatinib, nilotinib, and bosutinib) have promising efficacy in the first-or second-line setting. Here, the evidence base for existing drug treatments for Ph+ ALL is discussed and emerging therapeutic strategies are explored.

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Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies

Cited by 21 publications

References 0 publications

Outcome of children with high‐risk acute lymphoblastic leukemia (HR‐ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation

Outcome of children with high‐risk acute lymphoblastic leukemia (HR‐ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation

Prospective gene expression analysis accurately subtypes acute leukaemia in children and establishes a commonality between hyperdiploidy and t(12;21) in acute lymphoblastic leukaemia

Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome‐positive acute lymphoblastic leukaemia

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