High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment

Heatley, Sue L.; Sadras, Teresa; Kok, Chung Hoow; Nievergall, Eva; Quek, Kelly; Dang, Phuong; McClure, Barbara J.; Venn, Nicola C.; Moore, Sarah; Suttle, Jeffrey C.; Law, Tamara; Ng, Anthea; Muskovic, Walter; Norris, Murray D.; Révész, Tamás; Osborn, Michael; Moore, Andrew S.; Suppiah, Ram; Fraser, Chris; Alvaro, Frank; Hughes, Timothy P.; Mullighan, Charles G.; Marshall, Glenn M.; Pozza, Luciano Dalla; Yeung, David T.; Sutton, Rosemary; White, Deborah L.

doi:10.3324/haematol.2016.162925

Cited by 52 publications

(81 citation statements)

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“…Several of these alterations are targeted by TKIs, suggesting a potential role for tailored treatment (Roberts et al , , ). Furthermore, all authors confirmed an association with poor outcome, while the relationship with minimal residual disease (MRD) is still debated (Roberts et al , ; Heatley et al , ).…”

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confidence: 99%

Rapid identification of BCR/ABL1‐like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time‐polymerase chain reaction: clinical, prognostic and therapeutic implications

et al. 2018

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BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases. By screening 142 B-lineage ALL patients with the "BCR/ABL1-like predictor", we identified 28/142 BCR/ABL1-like patients (19·7%). Overall, BCR/ABL1-like cases were enriched in JAK/STAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P = 0·001), thus corroborating the validity of the prediction. Clinically, the BCR/ABL1-like cases identified by the BCR/ABL1-like predictor achieved a lower rate of complete remission (P = 0·014) and a worse event-free survival (P = 0·0009) compared to non-BCR/ABL1-like ALL. Consistently, primary cells from BCR/ABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCR/ABL1-like ALL cases at diagnosis.

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confidence: 99%

Rapid identification of BCR/ABL1‐like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time‐polymerase chain reaction: clinical, prognostic and therapeutic implications

et al. 2018

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“…2). 9,12,16,[19][20][21][22][23] With regard to the first approach, the quantification of transcripts was performed either by low-density array (LDA) or quantitative real-time polymerase chain reaction (Q-RT-PCR), and the majority of them refer to the method developed by Harvey et al, 19 who developed a 15-gene LDA classifier. The latter method and its scoring system later were used by Roberts et al 8 It is interesting to note that BCR/ABL1like ALL cases harboring tyrosine kinase (TK) rearrangements display higher scores.…”

Section: Screening Methodsmentioning

confidence: 99%

“…Subsequently, Roberts et al studied a broad cohort of pediatric patients with ALL who were enrolled in MRD‐driven protocols and highlighted that pediatric patients with BCR/ABL1 –like ALL, although demonstrating higher MRD levels at the end of induction, had a survival similar to that of patients with non– BCR/ABL1 ‐like ALL when treated with intensive therapies that included transplantation procedures. In contrast, Heatley et al, who analyzed patients enrolled in the Australian and New Zealand Children’s Haematology/Oncology Group (ANZCHOG) ALL8 clinical trial, which was based on MRD evaluation for risk stratification, demonstrated that despite a risk‐adjusted treatment approach, a high rate of disease recurrence was recorded among children who were retrospectively identified as having Ph–like ALL.…”

Section: Introductionmentioning

confidence: 99%

BCR/ABL1–like acute lymphoblastic leukemia: How to diagnose and treat?

Chiaretti

Messina

Foà

2018

Cancer

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BCR/ABL1–like acute lymphoblastic leukemia (ALL) accounts for 15% to 30% of B‐lineage ALL, with a peak of incidence occurring in adolescence. This subgroup of patients is characterized by a peculiar transcriptional profile that resembles that of true BCR/ABL1–positive cases, and have a heterogeneous genetic background and a poor outcome. Next‐generation sequencing studies have demonstrated that the majority of patients carry rearrangements of tyrosine kinases or cytokine receptors and mutations of janus kinase (JAK)/signal transducer and activator of transcription (STAT), thus opening the way to the possible use of targeted therapeutic approaches. However, several issues remain unresolved at both the diagnostic and therapeutic level, such as the definition of a standardized method to identify BCR/ABL1–like ALL and the design of ad hoc clinical trials examining tyrosine kinase inhibitors or other tailored treatments. These aspects are discussed in this review.

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“…Multiple studies have identified poor outcomes for patients with Ph-like B-ALL across all age groups. Ph-like B-ALL is associated with a higher risk of induction failure, measurable residual disease (MRD) positivity [24], higher relapse rates (as high as 70% at 3 years), and lower overall survival [4,9,10,[12][13][14]16,22,[25][26][27][28][29][30][31]. In the initial description of Ph-like B-ALL in pediatric patients reported by investigators from St. Jude's Children's Research Hospital, deletion or mutation of IKZF1 was associated with poor outcomes.…”

Section: Clinical Features and Outcomesmentioning

confidence: 99%

“…While some studies indicate that MRD-directed therapy can improve outcomes in these patients [10,24], other studies demonstrate otherwise [2,24,25,33]. Data from a limited number of patients derived from the HOVON study group clinical trials indicate that allogeneic stem cell transplant (ASCT) in the first complete remission may improve outcomes in Ph-like B-ALL.…”

Section: Clinical Features and Outcomesmentioning

confidence: 99%

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

Shiraz

Payne

Muffly

2020

IJMS

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Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.

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High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment

Cited by 52 publications

References 14 publications

Rapid identification of BCR/ABL1‐like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time‐polymerase chain reaction: clinical, prognostic and therapeutic implications

Rapid identification of BCR/ABL1‐like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time‐polymerase chain reaction: clinical, prognostic and therapeutic implications

BCR/ABL1–like acute lymphoblastic leukemia: How to diagnose and treat?

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

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