Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia

Tran, Thai Hoa; Harris, Marian H.; Nguyen, Jonathan V.; Blonquist, Traci M.; Stevenson, Kristen E.; Stonerock, Eileen; Asselin, Barbara L.; Athale, Uma H.; Clavell, Luis A.; Cole, Peter D.; Kelly, Kara M.; Laverdière, Caroline; Leclerc, Jean‐Marie; Michon, Bruno; Schorin, Marshall A.; Welch, Jennifer; Reshmi, Shalini C.; Neuberg, Donna; Sallan, Stephen E.; Loh, Mignon L.; Silverman, Lewis B.

doi:10.1182/bloodadvances.2017014704

Cited by 40 publications

(28 citation statements)

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“…11 In one recent study, 15% of BCR-ABL1elike B-ALL cases harbored either an ABL-class fusion or an activating kinase fusion of the JAK-STAT pathway. 12 Of these cases, approximately 70% had a cooccurring IKZF1 deletion, which is an independent unfavorable prognostic factor. 12 Accordingly, we identified a concomitant heterozygous deletion of IKZF1 in our patient harboring the ZBTB20-JAK2 fusion, and several ongoing prospective studies are examining the impact of the addition of TKI to high-risk combination chemotherapy regimens in this patient population.…”

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confidence: 99%

“…12 Of these cases, approximately 70% had a cooccurring IKZF1 deletion, which is an independent unfavorable prognostic factor. 12 Accordingly, we identified a concomitant heterozygous deletion of IKZF1 in our patient harboring the ZBTB20-JAK2 fusion, and several ongoing prospective studies are examining the impact of the addition of TKI to high-risk combination chemotherapy regimens in this patient population. Although our patient's current status is unknown, the cytogenetic abnormalities discussed herein would render a poor prognostic outlook and high risk for relapse for this patient.…”

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confidence: 99%

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Identification of a Novel ZBTB20-JAK2 Fusion by Mate-Pair Sequencing in a Young Adult With B-Lymphoblastic Leukemia/Lymphoma

Peterson

Blackburn

Webley

et al. 2019

Mayo Clinic Proceedings

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involvement, and all had improvement in their symptoms. Other patients who had cutaneous and neurological involvement also had symptomatic improvements. The treatment was tolerated well, with only one patient discontinuing therapy because of headache. The performance status improved in 75% of patients, and the median survival for the cohort was 24 months. It is likely that etanercept had an effect on AL amyloidosis, but appropriate response assessment using free light chains and cardiac biomarkers was not available. To our knowledge, this is the first report of a patient with AL amyloidosis and symptoms related to GI involvement responding to therapy with adalimumab. Tumor necrosis factor a could play a role in the pathophysiology of AL amyloidosis. In our patient, diarrhea and severe abdominal pain improved dramatically after receiving a total dose of 80 mg of adalimumab subcutaneously. The effectiveness of this agent could be investigated further in phase I/II trials in patients with refractory AL amyloidosis.

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Identification of a Novel ZBTB20-JAK2 Fusion by Mate-Pair Sequencing in a Young Adult With B-Lymphoblastic Leukemia/Lymphoma

Peterson

Blackburn

Webley

et al. 2019

Mayo Clinic Proceedings

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“…The decision to transplant this patient was clear in our opinion because of the presence of other high-risk genetics indicating allogeneic HCT in CR1. This could also be applied to other high-risk features, such as IKZF1 deletion [25], which is frequently encountered in Ph-like ALL cases.…”

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confidence: 99%

Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

Aldoss

Kamal

Forman

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T Philadelphia chromosomeÀlike (Ph-like) acute lymphoblastic leukemia (ALL) is a subset of high-risk B cell ALLs. A large proportion of Ph-like ALL cases carry activating kinase mutations that could potentially allow them to be targeted by tyrosine kinase inhibitors. Ph-like ALL is not an uncommon entity, especially among adults, with a frequency exceeding 20%, including in older patients (>60 years old) with ALL. Ph-like ALL is associated with inferior outcomes across all ages, and studies have consistently shown a higher incidence of persistent postinduction minimal residual disease in patients carrying Ph-like ALL compared with other subgroups of ALL, and this translates into inferior leukemia-related outcomes. The inferior outcome of conventional chemotherapy for Ph-like ALL in adults raises the fundamental question of whether all adults with Ph-like ALL require an allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) regardless of other presenting features and treatment response parameters. Here we present and discuss several scenarios in which adults with Ph-like ALL underwent or were considered for HCT in CR1 for various reasons. Although the decision to proceed with HCT was clear and indisputable in some of these situations, in others we struggled with the decision to transplant in CR1 because of the lack of published data regarding the efficacy of allogeneic HCT as consolidation for Ph-like ALL. We emphasize the urgent need for developing well-designed studies to address this important question.

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“…10,16 It is worth mentioning that to our knowledge all the studies to date have documented that a variable percentage of cases lack kinase-activating lesions, thus causing uncertainty on the fact that these cases are "true" BCR/ ABL1-like ALL; it is interesting to note that the patients without kinase rearrangements indeed have a better prognosis compared with patients harboring these rearrangements, thus again reinforcing the suspicion regarding their correct classification. 42,43 The various mechanisms underlying the BCR/ ABL1-like ALL signatures and their distribution in different age cohorts are shown in Figures 3 and 4…”

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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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Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia

Abstract: Key Points Fifteen percent of NCI high-risk, Ph-negative, B-ALL patients harbored a kinase-activating fusion, and often associated with IKZF1 deletion. IKZF1 deletion represents an independent prognostic factor of poor outcomes, regardless of fusion-positivity.

Cited by 40 publications

References 11 publications

Identification of a Novel ZBTB20-JAK2 Fusion by Mate-Pair Sequencing in a Young Adult With B-Lymphoblastic Leukemia/Lymphoma

Identification of a Novel ZBTB20-JAK2 Fusion by Mate-Pair Sequencing in a Young Adult With B-Lymphoblastic Leukemia/Lymphoma

Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

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

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