High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults

Kathryn G. Roberts, Zhaohui Gu, Debbie Payne-Turner, Kelly McCastlain, Richard C. Harvey, I. Ming Chen, Deqing Pei, Ilaria Iacobucci, Marcus Valentine, Stanley B. Pounds, Lei Shi, Yongjin Li, Jinghui Zhang, Cheng Cheng, Alessandro Rambaldi, Manuela Tosi, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Jacob M. RoweSelina Luger, Mark R Litzow, Martin S. Tallman, Peter H. Wiernik, Ravi Bhatia, Ibrahim Aldoss, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Stephen Kornblau, Hagop M. Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L. Willman, Charles G. Mullighan

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.

Original languageEnglish (US)
Pages (from-to)394-401
Number of pages8
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume35
Issue number4
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Fingerprint

Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Phosphotransferases
Protein-Tyrosine Kinases
Disease-Free Survival
Mutation
Cytokine Receptors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. / Roberts, Kathryn G.; Gu, Zhaohui; Payne-Turner, Debbie; McCastlain, Kelly; Harvey, Richard C.; Chen, I. Ming; Pei, Deqing; Iacobucci, Ilaria; Valentine, Marcus; Pounds, Stanley B.; Shi, Lei; Li, Yongjin; Zhang, Jinghui; Cheng, Cheng; Rambaldi, Alessandro; Tosi, Manuela; Spinelli, Orietta; Radich, Jerald P.; Minden, Mark D.; Rowe, Jacob M.; Luger, Selina; Litzow, Mark R; Tallman, Martin S.; Wiernik, Peter H.; Bhatia, Ravi; Aldoss, Ibrahim; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.; Stock, Wendy; Kornblau, Stephen; Kantarjian, Hagop M.; Konopleva, Marina; Paietta, Elisabeth; Willman, Cheryl L.; Mullighan, Charles G.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 35, No. 4, 01.02.2017, p. 394-401.

Research output: Contribution to journalArticle

Roberts, KG, Gu, Z, Payne-Turner, D, McCastlain, K, Harvey, RC, Chen, IM, Pei, D, Iacobucci, I, Valentine, M, Pounds, SB, Shi, L, Li, Y, Zhang, J, Cheng, C, Rambaldi, A, Tosi, M, Spinelli, O, Radich, JP, Minden, MD, Rowe, JM, Luger, S, Litzow, MR, Tallman, MS, Wiernik, PH, Bhatia, R, Aldoss, I, Kohlschmidt, J, Mrózek, K, Marcucci, G, Bloomfield, CD, Stock, W, Kornblau, S, Kantarjian, HM, Konopleva, M, Paietta, E, Willman, CL & Mullighan, CG 2017, 'High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 35, no. 4, pp. 394-401. https://doi.org/10.1200/JCO.2016.69.0073
Roberts, Kathryn G. ; Gu, Zhaohui ; Payne-Turner, Debbie ; McCastlain, Kelly ; Harvey, Richard C. ; Chen, I. Ming ; Pei, Deqing ; Iacobucci, Ilaria ; Valentine, Marcus ; Pounds, Stanley B. ; Shi, Lei ; Li, Yongjin ; Zhang, Jinghui ; Cheng, Cheng ; Rambaldi, Alessandro ; Tosi, Manuela ; Spinelli, Orietta ; Radich, Jerald P. ; Minden, Mark D. ; Rowe, Jacob M. ; Luger, Selina ; Litzow, Mark R ; Tallman, Martin S. ; Wiernik, Peter H. ; Bhatia, Ravi ; Aldoss, Ibrahim ; Kohlschmidt, Jessica ; Mrózek, Krzysztof ; Marcucci, Guido ; Bloomfield, Clara D. ; Stock, Wendy ; Kornblau, Stephen ; Kantarjian, Hagop M. ; Konopleva, Marina ; Paietta, Elisabeth ; Willman, Cheryl L. ; Mullighan, Charles G. / High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017 ; Vol. 35, No. 4. pp. 394-401.
@article{8d3d0ef54d8746ed8ac8a386661d788b,
title = "High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults",
abstract = "Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20{\%} of adults with ALL, including 27.9{\%} of young adults (age 21 to 39 years), 20.4{\%} of adults (age 40 to 59 years), and 24.0{\%} of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5{\%} [95{\%} CI, 14.9{\%} to 29.3{\%}; n = 155] v 49.3{\%} [95{\%} CI, 42.8{\%} to 56.2{\%}; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88{\%} of patients with Ph-like ALL, including CRLF2 rearrangements (51{\%}), ABL class fusions (9.8{\%}), JAK2 or EPOR rearrangements (12.4{\%}), other JAK-STAT sequence mutations (7.2{\%}), other kinase alterations (4.1{\%}), and Ras pathway mutations (3.6{\%}). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.",
author = "Roberts, {Kathryn G.} and Zhaohui Gu and Debbie Payne-Turner and Kelly McCastlain and Harvey, {Richard C.} and Chen, {I. Ming} and Deqing Pei and Ilaria Iacobucci and Marcus Valentine and Pounds, {Stanley B.} and Lei Shi and Yongjin Li and Jinghui Zhang and Cheng Cheng and Alessandro Rambaldi and Manuela Tosi and Orietta Spinelli and Radich, {Jerald P.} and Minden, {Mark D.} and Rowe, {Jacob M.} and Selina Luger and Litzow, {Mark R} and Tallman, {Martin S.} and Wiernik, {Peter H.} and Ravi Bhatia and Ibrahim Aldoss and Jessica Kohlschmidt and Krzysztof Mr{\'o}zek and Guido Marcucci and Bloomfield, {Clara D.} and Wendy Stock and Stephen Kornblau and Kantarjian, {Hagop M.} and Marina Konopleva and Elisabeth Paietta and Willman, {Cheryl L.} and Mullighan, {Charles G.}",
year = "2017",
month = "2",
day = "1",
doi = "10.1200/JCO.2016.69.0073",
language = "English (US)",
volume = "35",
pages = "394--401",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "4",

}

TY - JOUR

T1 - High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults

AU - Roberts, Kathryn G.

AU - Gu, Zhaohui

AU - Payne-Turner, Debbie

AU - McCastlain, Kelly

AU - Harvey, Richard C.

AU - Chen, I. Ming

AU - Pei, Deqing

AU - Iacobucci, Ilaria

AU - Valentine, Marcus

AU - Pounds, Stanley B.

AU - Shi, Lei

AU - Li, Yongjin

AU - Zhang, Jinghui

AU - Cheng, Cheng

AU - Rambaldi, Alessandro

AU - Tosi, Manuela

AU - Spinelli, Orietta

AU - Radich, Jerald P.

AU - Minden, Mark D.

AU - Rowe, Jacob M.

AU - Luger, Selina

AU - Litzow, Mark R

AU - Tallman, Martin S.

AU - Wiernik, Peter H.

AU - Bhatia, Ravi

AU - Aldoss, Ibrahim

AU - Kohlschmidt, Jessica

AU - Mrózek, Krzysztof

AU - Marcucci, Guido

AU - Bloomfield, Clara D.

AU - Stock, Wendy

AU - Kornblau, Stephen

AU - Kantarjian, Hagop M.

AU - Konopleva, Marina

AU - Paietta, Elisabeth

AU - Willman, Cheryl L.

AU - Mullighan, Charles G.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.

AB - Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.

UR - http://www.scopus.com/inward/record.url?scp=85016717027&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016717027&partnerID=8YFLogxK

U2 - 10.1200/JCO.2016.69.0073

DO - 10.1200/JCO.2016.69.0073

M3 - Article

C2 - 27870571

AN - SCOPUS:85016717027

VL - 35

SP - 394

EP - 401

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 4

ER -