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High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL

Leukemia volume 31, pages 981–984 (2017)Cite this article

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Treatment of patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) with tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib has improved survival in younger adults and allowed de-escalation of conventional chemotherapy, particularly in older adults.1 Similar approaches may also benefit patients with the Philadelphia chromosome-like (Ph-like) B-ALL subtype recently described in children and adolescents/young adults (AYAs).2, 3 Ph-like ALL has a ‘kinase-activated’ gene expression profile similar to Ph+ ALL, but distinguishes itself by absence of BCR-ABL1 fusion and presence of activating mutations in kinase- and cytokine receptor-associated signaling pathways.3, 4 In children and AYAs, ~50% of Ph-like ALL activates JAK/STAT and PI3K/mTOR signaling via rearrangement of cytokine receptor like factor 2 (CRLF2-R) with common co-occurrence of JAK2 or JAK1 point mutations. An additional 10–15% of Ph-like ALL harbors JAK2 or EPOR rearrangements, while another 15–20% has translocations or fusions involving ABL1, ABL2, CSF1R or PDGFRB (ABL-class lesions).3, 5 As in Ph+ ALL, deletions of IKZF1, CDKN2A/B, and other lymphoid-associated transcription factors are common.4, 6 Although Ph-like ALL comprises 20–25% of B-ALL in AYAs and is associated with high relapse rates and poor survival,2, 4 the frequency, biology, genetics and clinical features of Ph-like ALL in older populations remain incompletely defined.7

Ph+ and Ph-like ALL are rare in young children, but increase in frequency during adolescence.3 Ph+ ALL incidence rises further in adulthood, peaking at >60 years. Although younger adults can be treated with pediatric protocol-inspired chemotherapy, such intensive regimens are poorly tolerated in middle-aged and older adults.8 Robust anti-leukemia activity of JAK inhibition (for example, ruxolitinib) and SRC/ABL inhibition (for example, dasatinib) has been demonstrated in preclinical models of JAK2/EPOR-mutant and ABL/PDGFRB-mutant Ph-like ALL, respectively.3, 5, 9 Clinical testing of kinase inhibitors with chemotherapy is now ongoing for children with specific genetic subtypes of Ph-like ALL (NCT02723994 and NCT02883049). Improved delineation of the genetic drivers in adult ALL may similarly facilitate development of molecularly targeted treatment approaches for appropriate patient subsets that can minimize toxicity while retaining potent anti-leukemic efficacy.

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Acknowledgements

We acknowledge Dr Yong Li, Ms Jenna Harrison, Dr Anne Lehman and Ms Gisela N Brake-Sillá for assistance with specimen preparation, and Dr Fengqi Chang, Ms Eileen Stonerock and Ms Heather Jenkins for assistance with genetic assays. We also thank Ms Joy Cannon and Dr Marlise Luskin for assistance with clinical data acquisition and analysis. This work was supported by the NIH/NCI (K08CA184418; SKT), the Hematologic Malignancies Translational Center of Excellence of the Abramson Cancer Center and the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania (NIH/NCRR UL1RR024134; SKT, GBW, MC), the Rally Foundation for Childhood Cancer Research (SKT), and an American Cancer Society CEOs Against Cancer Pennsylvania Chapter Research Scholar Grant (RSG-16-102-01-LIB to AEP). MC is supported by a Veterans Administration Merit Award 1I01BX000918. SKT receives research funding from Gilead Sciences. SKT and MC have research collaborations with Incyte Corporation without financial support. CH received support from National Institutes of Health T32HL07439.

Author contributions

SKT designed and directed the study, performed experiments, analyzed data and wrote the manuscript. CH and GBW performed experiments, analyzed data and edited the manuscript. NGB, MSL, RA, AZ, NVF and SML contributed key reagents and analyzed data. RCH, I-MC, CLW, SCR and MML performed experiments and analyzed data. MC oversaw conduction of the study and edited the manuscript. AEP directed the study, analyzed data and wrote the manuscript. All authors approved the final version of the manuscript.

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Author notes

  1. M S Lim: Current affiliation: Division of Hematopathology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Authors and Affiliations

  1. Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    S K Tasian

  2. Division of Hematology and Oncology and Abramson Cancer Center, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    C Hurtz, R Astles, A Zebrowski, N V Frey, S M Luger, M Carroll & A E Perl

  3. Division of Hematopathology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    G B Wertheim

  4. Division of Hematopathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    N G Bailey & M S Lim

  5. Department of Pathology and Hematologic Malignancies Research Program, University of New Mexico, Albuquerque, NM, USA

    R C Harvey, I-M Chen & C L Willman

  6. Department of Laboratory Medicine, Nationwide Child,

    S C Reshmi

  7. Department of Pathology, ren’s Hospital, the Ohio State University, Columbus, OH, USA

    S C Reshmi

  8. Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    M M Li

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Correspondence to S K Tasian.

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Tasian, S., Hurtz, C., Wertheim, G. et al. High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL. Leukemia 31, 981–984 (2017). https://doi.org/10.1038/leu.2016.375

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