What does the evidence suggest thus far about the potential role of JAK/STAT inhibitors in the prevention and treatment of B-ALL?

Dr Tasian: There are substantial preclinical data and emerging clinical data regarding the activity of JAK/STAT inhibition in treatment of Philadelphia chromosome-like (Ph-like) ALL driven by CRLF2JAK2, or EPOR rearrangements.3-6 Additional preclinical studies have also suggested therapeutic potential of JAK/STAT inhibition in some types of T-ALL.7

Dr Maloney: B-ALL is characterized by well-described sentinel chromosome abnormalities that are often important markers for prognosis and treatment outcome. More recently described genomic lesions were found by a gene expression profile that mimicked that of patients with Ph+ leukemia, but these patients did not have the Philadelphia chromosome abnormality and thus were labeled as Ph-like.


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Within this group are patients with abnormalities in the JAK/STAT pathway, and one-half of these cases are characterized by high expression of CRLF2 and translocations involving CRLF2.8,9 Point mutations in JAK1 and JAK2 as well as in JAK2 fusion proteins or truncating rearrangements have been tested in vitro against JAK2 inhibitors with some response.10

What next steps are needed to move this line of investigation forward, and how close do you think we are to realizing this strategy for use in humans? 

Dr Tasian: Clinical trials are actively investigating the therapeutic potential of JAK inhibitors in combination with chemotherapy for pediatric, adolescent, and young adult patients with newly diagnosed CRLF2-rearranged and other JAK pathway-mutant Ph-like ALL.11,12 These trials in ALL are based upon the extensive characterization of the genetic landscape of Ph-like ALL, the success and FDA approval of JAK inhibitors for adults with myeloproliferative neoplasms, and pediatric-specific safety data of JAK inhibition in children with relapsed/refractory cancers through a phase 1 clinical trial.13,14 

Dr Maloney: With the important basic science work to describe these lesions, continued clinical trials, like those currently underway, are important to define how to use JAK/STAT inhibition in the treatment of ALL with abnormalities in this pathway. If this strategy is successful, additional targeted agents against this pathway may be needed. 

What are some of the key challenges that need to be addressed in order to progress in this area? 

Dr Tasian: Preclinical data from our group and others suggest that CRLF2-rearranged Ph-like ALL is not fully JAK pathway-addicted and that combinatorial targeted inhibitor approaches may be necessary for complete disease eradication.15-17 Understanding the tolerability and potential efficacy of multi-TKI therapies — or combination of JAK inhibitors with immunotherapies — for patients with Ph-like ALL has not yet been investigated in clinical trials.

Conversely, preclinical and emerging clinical data suggest that JAK2-rearranged and EPOR-rearranged Ph-like ALL are quite JAK oncogene-addicted and appear exquisitely sensitive to JAK/STAT inhibition.18 Understanding this potential heterogeneity amongst Ph-like ALL genetic subtypes remains a major knowledge gap and requires further investigation.

Dr Maloney: Continued research in both basic science and clinical trials will be needed to further understand the molecular pathways in the JAK/STAT pathway. There is always potential that new lesions and rearrangements may be described, for which a more specific inhibitor in the JAK/STAT pathway can be developed. Ongoing clinical trials with additional JAK/STAT inhibitors may be needed to define the best agent for inhibition and to continue to improve the outcome of B-ALL with these alterations. 

References

  1. Casado-García A, Isidro-Hernández M, Oak N, et al. Transient inhibition of the JAK/STAT pathway prevents B-ALL development in genetically predisposed mice. Cancer Res. 2022;82(6):1098-1109. doi:10.1158/0008-5472.CAN-21-3386
  2. Martin-Lorenzo A, Hauer J, Vicente-Duenas C, et al. Infection exposure is a causal factor in B-cell precursor acute lymphoblastic leukemia as a result of Pax5-inherited susceptibility. Cancer Discov. 2015;5:1328-1343. doi:10.1158/2159-8290.CD-15-0892
  3. Tasian SK, Doral MY, Borowitz MJ, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833-842. doi:10.1182/blood-2011-12-389932
  4. Maude SL, Tasian SK, Vincent T, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510-3518. doi:10.1182/blood-2012-03-415448
  5. Schwartzman O, Savino AM, Gombert M, et al. Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome. Proc Natl Acad Sci U S A. 2017;114(20):E4030-E4039. doi:10.1073/pnas.1702489114
  6. Tasian SK, Loh ML, Hunger SP. Philadelphia chromosome-like acute lymphoblastic leukemia. Blood. 2017;130(19):2064-2072. doi:10.1182/blood-2017-06-743252
  7. Maude SL, Dolai S, Delgado-Martin C, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125(11):1759-1767. doi:10.1182/blood-2014-06-580480
  8. Pui CH, Roberts KG, Yang JJ, Mullighan CG. Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2017;17(8):464-470. doi:10.1016/j.clml.2017.03.299
  9. Vainchenker W, Leroy E, Gilles L, Marty C, Plo I, Constantinescu SN. JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders. F1000Res. 2018;7:82. doi:10.12688/f1000research.13167.1
  10. Downes CE, McClure BJ, McDougal DP, et al. JAK2 alterations in acute lymphoblastic leukemia: molecular insights for superior precision medicine strategies. Front Cell Dev Biol. 2022;10:942053. doi:10.3389/fcell.2022.942053
  11. ClinicalTrials.gov. A phase 2 study of ruxolitinib with chemotherapy in children with acute lymphoblastic leukemia. Accessed September 24, 2022.
  12. ClinicalTrials.gov. Ruxolitinib and chemotherapy in adolescents and young adults with Ph-like acute lymphoblastic leukemia. Accessed September 24, 2022.
  13. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 201;371(11):1005-1015. doi:10.1056/NEJMoa1403088
  14. Loh ML, Tasian SK, Rabin KR, et al. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a Children’s Oncology Group phase 1 consortium study (ADVL1011). Pediatr Blood Cancer. 2015;62(10):1717-1724. doi:10.1002/pbc.25575
  15. Tasian SK, Teachey DT, Li Y, et al. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2017;129(2):177-187. doi:10.1182/blood-2016-05-707653
  16. Savino AM, Sarno J, Trentin L, et al. The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL. Leukemia. 2017;31(11):2365-2375. doi:10.1038/leu.2017.93
  17. Hurtz C, Wertheim GB, Loftus JP, et al. Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL. J Clin Invest. 2020;130(7):3637-3653. doi:10.1172/JCI134424
  18. Ding YY, Kim H, Madden K, et al. Network analysis reveals synergistic genetic dependencies for rational combination therapy in Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Cancer Res. 2021;27(18):5109-5122. doi:10.1158/1078-0432.CCR-21-0553