HIGH INCIDENCE OF PHILADELPHIA CHROMOSOME-LIKE ACUTE LYMPHOBLASTIC LEUKEMIA (PH-LIKE ALL) IN OLDER ADULTS WITH B-ALL
(Abstract release date: 05/19/16)
EHA Library. Perl A. 06/10/16; 133153; P165
Disclosure(s): AEP has served as a consultant to Novartis, Daiichi Sankyo, Astellas US Pharma, Actinium Pharmaceuticals, Arog Pharmaceuticals, Asana Biosciences, and Seattle Genetics.
Dr. Alexander Perl
Contributions
Contributions
Abstract
Abstract: P165
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Tyrosine kinase inhibitor (TKI) treatment of patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) improves response and survival in younger adults and has allowed de-escalation of conventional chemotherapy, particularly in older patients. Similar therapeutic approaches may also benefit patients with the Philadelphia chromosome-like (Ph-like) B-ALL subtype recently described in children and adolescents/young adults (AYA), as these leukemias are driven by activating mutations in kinase-associated signaling pathways. The frequency of adult Ph-like B-ALL is largely unknown, however.
Aims
We analyzed diagnostic B-ALL specimens from adult patients (range 18-88 years) by a validated, highly sensitive 15-gene low-density gene expression array (LDA) to determine the frequency of Ph-like ALL.
Methods
We analyzed 90 cryopreserved B-ALL samples from the institutional tissue banks at the University of Pennsylvania and University of Michigan by LDA to identify specimens with a kinase-active gene expression profile, as previously reported (Harvey, et al. Blood 2013, 123(21):826a). All samples were tested by reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL1 fusion. LDA signature-positive specimens without detected BCR-ABL1 transcript (Ph-like ALL) were categorized as CRLF2 (cytokine receptor-like factor 2)-overexpressing or non-overexpressing using LDA quantification of expression levels. CRLF2-overexpressing specimens were subsequently assessed for IGH-CRLF2 and P2RY8-CRLF2 rearrangements and JAK1 and JAK2 mutations via FISH, PCR, or RT-PCR with Sanger sequencing.
Results
By RT-PCR, 37.8% (34/90) of ALL specimens were BCR-ABL1+. Additionally, we identified a 20.0% (18/90) incidence of Ph-like ALL with a median age at diagnosis of 43 years (range 19-64). 77.8% (14/18) of the Ph-like ALL specimens harbored CRLF2 rearrangements, including 7 patients with concomitant JAK2 mutations. Using multiplexed RT-PCR, the 4 non-CRLF2-overexpressing Ph-like specimens were then evaluated for 39 published Ph-like kinase fusions; no recurrent gene fusions were identified. Correlative biology studies confirmed activation of JAK/STAT and/or ABL pathway signaling in primary Ph-like ALL specimens, as well as therapeutic efficacy of JAK or ABL kinase inhibition in adult Ph-like ALL patient-derived xenograft models.
Conclusion
We identified a Ph-like gene expression signature in 20% of adults with B-ALL. Importantly, we also demonstrate for the first time that the majority of adult B-ALL is associated with activated kinase signaling. Unlike pediatric/AYA Ph-like ALL, in which kinase fusions occur frequently, CRLF2 rearrangement is the predominant genetic lesion in adult Ph-like ALL. We propose that adult ALL diagnostic testing algorithms include flow cytometric assessment of surface CRLF2 (thymic stromal lymphopoietin receptor) expression, a surrogate marker for CRLF2 rearrangement, with subsequent genetic confirmation. Finally, we demonstrate a substantial population of patients ≥40 years of age with non-Ph+ B-ALL who may also benefit from TKI therapies. The efficacy of such treatments should be evaluated via appropriate clinical trials, as clinical translation of our findings will potentially transform therapeutic approaches for adults with Ph-like ALL.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): ALL, Elderly, Gene expression profile, Signal transduction
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Tyrosine kinase inhibitor (TKI) treatment of patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) improves response and survival in younger adults and has allowed de-escalation of conventional chemotherapy, particularly in older patients. Similar therapeutic approaches may also benefit patients with the Philadelphia chromosome-like (Ph-like) B-ALL subtype recently described in children and adolescents/young adults (AYA), as these leukemias are driven by activating mutations in kinase-associated signaling pathways. The frequency of adult Ph-like B-ALL is largely unknown, however.
Aims
We analyzed diagnostic B-ALL specimens from adult patients (range 18-88 years) by a validated, highly sensitive 15-gene low-density gene expression array (LDA) to determine the frequency of Ph-like ALL.
Methods
We analyzed 90 cryopreserved B-ALL samples from the institutional tissue banks at the University of Pennsylvania and University of Michigan by LDA to identify specimens with a kinase-active gene expression profile, as previously reported (Harvey, et al. Blood 2013, 123(21):826a). All samples were tested by reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL1 fusion. LDA signature-positive specimens without detected BCR-ABL1 transcript (Ph-like ALL) were categorized as CRLF2 (cytokine receptor-like factor 2)-overexpressing or non-overexpressing using LDA quantification of expression levels. CRLF2-overexpressing specimens were subsequently assessed for IGH-CRLF2 and P2RY8-CRLF2 rearrangements and JAK1 and JAK2 mutations via FISH, PCR, or RT-PCR with Sanger sequencing.
Results
By RT-PCR, 37.8% (34/90) of ALL specimens were BCR-ABL1+. Additionally, we identified a 20.0% (18/90) incidence of Ph-like ALL with a median age at diagnosis of 43 years (range 19-64). 77.8% (14/18) of the Ph-like ALL specimens harbored CRLF2 rearrangements, including 7 patients with concomitant JAK2 mutations. Using multiplexed RT-PCR, the 4 non-CRLF2-overexpressing Ph-like specimens were then evaluated for 39 published Ph-like kinase fusions; no recurrent gene fusions were identified. Correlative biology studies confirmed activation of JAK/STAT and/or ABL pathway signaling in primary Ph-like ALL specimens, as well as therapeutic efficacy of JAK or ABL kinase inhibition in adult Ph-like ALL patient-derived xenograft models.
Conclusion
We identified a Ph-like gene expression signature in 20% of adults with B-ALL. Importantly, we also demonstrate for the first time that the majority of adult B-ALL is associated with activated kinase signaling. Unlike pediatric/AYA Ph-like ALL, in which kinase fusions occur frequently, CRLF2 rearrangement is the predominant genetic lesion in adult Ph-like ALL. We propose that adult ALL diagnostic testing algorithms include flow cytometric assessment of surface CRLF2 (thymic stromal lymphopoietin receptor) expression, a surrogate marker for CRLF2 rearrangement, with subsequent genetic confirmation. Finally, we demonstrate a substantial population of patients ≥40 years of age with non-Ph+ B-ALL who may also benefit from TKI therapies. The efficacy of such treatments should be evaluated via appropriate clinical trials, as clinical translation of our findings will potentially transform therapeutic approaches for adults with Ph-like ALL.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): ALL, Elderly, Gene expression profile, Signal transduction
Abstract: P165
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Tyrosine kinase inhibitor (TKI) treatment of patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) improves response and survival in younger adults and has allowed de-escalation of conventional chemotherapy, particularly in older patients. Similar therapeutic approaches may also benefit patients with the Philadelphia chromosome-like (Ph-like) B-ALL subtype recently described in children and adolescents/young adults (AYA), as these leukemias are driven by activating mutations in kinase-associated signaling pathways. The frequency of adult Ph-like B-ALL is largely unknown, however.
Aims
We analyzed diagnostic B-ALL specimens from adult patients (range 18-88 years) by a validated, highly sensitive 15-gene low-density gene expression array (LDA) to determine the frequency of Ph-like ALL.
Methods
We analyzed 90 cryopreserved B-ALL samples from the institutional tissue banks at the University of Pennsylvania and University of Michigan by LDA to identify specimens with a kinase-active gene expression profile, as previously reported (Harvey, et al. Blood 2013, 123(21):826a). All samples were tested by reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL1 fusion. LDA signature-positive specimens without detected BCR-ABL1 transcript (Ph-like ALL) were categorized as CRLF2 (cytokine receptor-like factor 2)-overexpressing or non-overexpressing using LDA quantification of expression levels. CRLF2-overexpressing specimens were subsequently assessed for IGH-CRLF2 and P2RY8-CRLF2 rearrangements and JAK1 and JAK2 mutations via FISH, PCR, or RT-PCR with Sanger sequencing.
Results
By RT-PCR, 37.8% (34/90) of ALL specimens were BCR-ABL1+. Additionally, we identified a 20.0% (18/90) incidence of Ph-like ALL with a median age at diagnosis of 43 years (range 19-64). 77.8% (14/18) of the Ph-like ALL specimens harbored CRLF2 rearrangements, including 7 patients with concomitant JAK2 mutations. Using multiplexed RT-PCR, the 4 non-CRLF2-overexpressing Ph-like specimens were then evaluated for 39 published Ph-like kinase fusions; no recurrent gene fusions were identified. Correlative biology studies confirmed activation of JAK/STAT and/or ABL pathway signaling in primary Ph-like ALL specimens, as well as therapeutic efficacy of JAK or ABL kinase inhibition in adult Ph-like ALL patient-derived xenograft models.
Conclusion
We identified a Ph-like gene expression signature in 20% of adults with B-ALL. Importantly, we also demonstrate for the first time that the majority of adult B-ALL is associated with activated kinase signaling. Unlike pediatric/AYA Ph-like ALL, in which kinase fusions occur frequently, CRLF2 rearrangement is the predominant genetic lesion in adult Ph-like ALL. We propose that adult ALL diagnostic testing algorithms include flow cytometric assessment of surface CRLF2 (thymic stromal lymphopoietin receptor) expression, a surrogate marker for CRLF2 rearrangement, with subsequent genetic confirmation. Finally, we demonstrate a substantial population of patients ≥40 years of age with non-Ph+ B-ALL who may also benefit from TKI therapies. The efficacy of such treatments should be evaluated via appropriate clinical trials, as clinical translation of our findings will potentially transform therapeutic approaches for adults with Ph-like ALL.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): ALL, Elderly, Gene expression profile, Signal transduction
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Tyrosine kinase inhibitor (TKI) treatment of patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) improves response and survival in younger adults and has allowed de-escalation of conventional chemotherapy, particularly in older patients. Similar therapeutic approaches may also benefit patients with the Philadelphia chromosome-like (Ph-like) B-ALL subtype recently described in children and adolescents/young adults (AYA), as these leukemias are driven by activating mutations in kinase-associated signaling pathways. The frequency of adult Ph-like B-ALL is largely unknown, however.
Aims
We analyzed diagnostic B-ALL specimens from adult patients (range 18-88 years) by a validated, highly sensitive 15-gene low-density gene expression array (LDA) to determine the frequency of Ph-like ALL.
Methods
We analyzed 90 cryopreserved B-ALL samples from the institutional tissue banks at the University of Pennsylvania and University of Michigan by LDA to identify specimens with a kinase-active gene expression profile, as previously reported (Harvey, et al. Blood 2013, 123(21):826a). All samples were tested by reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL1 fusion. LDA signature-positive specimens without detected BCR-ABL1 transcript (Ph-like ALL) were categorized as CRLF2 (cytokine receptor-like factor 2)-overexpressing or non-overexpressing using LDA quantification of expression levels. CRLF2-overexpressing specimens were subsequently assessed for IGH-CRLF2 and P2RY8-CRLF2 rearrangements and JAK1 and JAK2 mutations via FISH, PCR, or RT-PCR with Sanger sequencing.
Results
By RT-PCR, 37.8% (34/90) of ALL specimens were BCR-ABL1+. Additionally, we identified a 20.0% (18/90) incidence of Ph-like ALL with a median age at diagnosis of 43 years (range 19-64). 77.8% (14/18) of the Ph-like ALL specimens harbored CRLF2 rearrangements, including 7 patients with concomitant JAK2 mutations. Using multiplexed RT-PCR, the 4 non-CRLF2-overexpressing Ph-like specimens were then evaluated for 39 published Ph-like kinase fusions; no recurrent gene fusions were identified. Correlative biology studies confirmed activation of JAK/STAT and/or ABL pathway signaling in primary Ph-like ALL specimens, as well as therapeutic efficacy of JAK or ABL kinase inhibition in adult Ph-like ALL patient-derived xenograft models.
Conclusion
We identified a Ph-like gene expression signature in 20% of adults with B-ALL. Importantly, we also demonstrate for the first time that the majority of adult B-ALL is associated with activated kinase signaling. Unlike pediatric/AYA Ph-like ALL, in which kinase fusions occur frequently, CRLF2 rearrangement is the predominant genetic lesion in adult Ph-like ALL. We propose that adult ALL diagnostic testing algorithms include flow cytometric assessment of surface CRLF2 (thymic stromal lymphopoietin receptor) expression, a surrogate marker for CRLF2 rearrangement, with subsequent genetic confirmation. Finally, we demonstrate a substantial population of patients ≥40 years of age with non-Ph+ B-ALL who may also benefit from TKI therapies. The efficacy of such treatments should be evaluated via appropriate clinical trials, as clinical translation of our findings will potentially transform therapeutic approaches for adults with Ph-like ALL.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): ALL, Elderly, Gene expression profile, Signal transduction
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