Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL‐class fusion

Moorman, Anthony V.; Schwab, Claire; Winterman, Emily; Hancock, Jerry; Castleton, Anna; Cummins, Michelle; Gibson, Brenda; Goulden, Nick; Kearns, Pamela; James, Beki; Kirkwood, Amy A.; Lancaster, Donna; Madi, Mabrouk S.; McMillan, Andrew; Jayashree, Muralidharan; Norton, Alice; O’Marcaigh, Aengus; Patrick, Katharine; Bhatnagar, Neha; Qureshi, Amrana; Richardson, Deborah; Stokley, Simone; Taylor, G. W.; Delft, Frederik W. van; Moppett, John; Harrison, Christine J.; Samarasinghe, Sujith; Vora, Ajay

doi:10.1111/bjh.17093

Cited by 31 publications

(33 citation statements)

References 16 publications

(71 reference statements)

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“…Interestingly, their 5-year EFS and 5-year OS did not differ significantly compared with the no-TKI group [9]. However, the non-randomized UKALL2011 trial demonstrated a reduced risk of relapse for ABL-class fusion patients with MRD ≥ 1% treated with adjuvant TKI, without a significantly increased risk of severe toxicity [95]. Due to the diversity and small number of Ph-like patients, it was hard to plan a randomized clinical trial on the basis of developing treatment standards.…”

Section: Treatment Of Ph-likementioning

confidence: 90%

Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

Kaczmarska

Śliwa

Zawitkowska

et al. 2021

IJMS

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Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in their first remission (CR1). Over the last few years, the treatment of childhood ALL has significantly improved due to standardized research protocols. Hematopoietic stem cell transplantation (HSCT) has been the gold standard therapy in ALL Ph+ patients, but recently first-generation tyrosine kinase inhibitor (TKI)-imatinib became a major milestone in increasing overall survival. Genomic analyses give the opportunity for the investigation of new fusions or mutations, which can be used to establish effective targeted therapies. Alterations of the IKZF1 gene are present in a large proportion of pediatric and adult ALL Ph+ cases. IKZF1 deletions are present in ~15% of patients without BCR-ABL1 rearrangements. In BCR-ABL1-negative cases, IKZF1 deletions have been shown to have an independent prognostic impact, carrying a three-fold increased risk of treatment failure. The prognostic significance of IKZF1 gene aberrations in pediatric ALL Ph+ is still under investigation. More research should focus on targeted therapies and immunotherapy, which is not associated with serious toxicity in the same way as classic chemotherapy, and on the improvement of patient outcomes. In this review, we provide a molecular analysis of childhood ALL with t(9;22)(q34;q11.2), including the Ph-like subtype, and of treatment strategies.

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Section: Treatment Of Ph-likementioning

confidence: 90%

Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

Kaczmarska

Śliwa

Zawitkowska

et al. 2021

IJMS

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“…Interestingly, another imatinib sensitive ABL1 fusion, the EML1-ABL1, has been reported in a single case of T-ALL with a cryptic t(9;14)(q34;q32) [93]. Moreover, it has been recently reported that ABL2, PDGFRA, and PDGFRB, other ABL-class tyrosin-kinases are also recurrently involved in T-ALL, and that they all predict sensitivity towards TKi [94].…”

Section: The Abl1/src-family Kinases and The Rationale For The Use Of Tyrosine-kinase Inhibitorsmentioning

confidence: 99%

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

Bardelli

Arniani

Pierini

et al. 2021

Genes

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T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.

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“…Among 21 slow responders with an ABL-class fusion treated on UKALL2011, 13 were identified prospectively and treated with imatinib. The four-year relapse/refractory rate for the TKI group was 0% compared to 62.5% for the control group, with event-free survival rates of 83.9% vs. 37.5%, respectively [ 78 ]. Superior outcome was also observed in ABL-class fusion patients treated with TKI (imatinib or dasatinib) compared to chemotherapy alone on the AIEOP-BFM or FRALLE/GRAALL protocols [ 79 , 80 ].…”

Section: Treatment Strategies For Ph-like Allmentioning

confidence: 99%

Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia

Iacobucci

Roberts

2021

Genes

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Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to BCR-ABL1-positive ALL, Ph-like ALL is characterized by IKZF1 or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL.

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Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL‐class fusion

Cited by 31 publications

References 16 publications

Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia

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