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Ph-like ALL
achieve remission with intensive therapy but despite that are anticipated to experience a poorer survival mainly due disease relapse.108 The Ph-like signature was reported in 24% of ALL patients over the age of 6522 but no prospec- tive studies have included these patients, considering their genetic profile. Given that in most patients of advanced age, prolonged intensive chemotherapy followed by allo- geneic SCT is not feasible, all such patients should be con- sidered at high risk of relapse, regardless of their gene expression profile. The most promising approach thus far, which provided a considerable long-term survival in Ph- negative ALL patients older than 60 years, was reported by Kantarjian et al.109 In their protocol, researchers from MD Anderson Cancer Center replaced a significant por- tion of chemotherapy with inotuzumab ozogamicin, hence creating a less toxic first-line regimen.109 With a median follow-up of 29 months, the 2-year progression- free survival rate of 52 patients with a median age of 68 years was 59%. Blinatumomab can also be safely added to such a protocol.110 We consider such a modified induction an acceptable approach for all Ph-negative ALL patients of advanced age. As previously discussed, the addition of tar- geted agents is rational only if BCR/ABL-activating genetic aberrations are identified and thus, for patients treated on such protocols molecular evaluation can be limited to BCR/ABL-activating lesions only. Outside of clinical trials, the patient in question should be treated with a less toxic regimen. Assuming that such regimen will not result in MRD eradication, blinatumomab should be added as early
as possible, and inclusion of inotuzumab ozogamicin should be encouraged, if its off-label use is possible.
Summary
Patients with the Ph-like gene expression pattern are at a high risk of relapse and theoretically could be offered treatment considering specific genetics of their disease. However, given that this group of patients is heteroge- neous, it is unlikely that prospective studies will be con- ducted for each specific mutation to identify optimal treat- ment protocols. Moreover, no consensus exists regarding the preferred approach to be used for the diagnosis of Ph- like ALL and management of a specific patient. Under these circumstances, the following three principles should guide the management of these patients. Screening for the Ph-like pattern should be adopted in routine practice in all patients. Patients should be informed that current screen- ing methods may miss rare gene mutations that could be subject to off-label use of available targeted therapies (e.g., crizotinib); nevertheless, the effect of targeted therapy on such rare leukemic mutations has not been reported. If the ABL-activating aberration is identified, adding TKI to ther- apy is advised. All patients with identified kinase-activat- ing aberrations should be defined as high risk; hence, intensification of chemotherapy, treatment with kinase targeting agents and/or antibody-derived novel agents may be considered.
References
1. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classifi- cation study. Lancet Oncol. 2009;10(2):125- 134.
2. Boer JM, Koenders JE, van der Holt B, et al. Expression profiling of adult acute lym- phoblastic leukemia identifies a BCR-ABL1- like subgroup characterized by high non- response and relapse rates. Haematologica. 2015;100(7):e261-264.
3. MullighanCG,SuX,ZhangJ,etal.Deletion of IKZF1 and prognosis in acute lym- phoblastic leukemia. N Engl J Med. 2009;360(5):470-480.
4. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph- like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015.
5. Russell LJ, Capasso M, Vater I, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid trans- formation in B-cell precursor acute lym- phoblastic leukemia. Blood. 2009;114(13): 2688-2698.
6. YodaA,YodaY,ChiarettiS,etal.Functional screening identifies CRLF2 in precursor B- cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2010;107(1):252-257.
7. Chiaretti S, Brugnoletti F, Messina M, et al. CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell pre- cursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities. Leuk Res. 2016;41:36-42.
8. Tsai AG, Yoda A, Weinstock DM, Lieber
MR. t(X;14)(p22;q32)/t(Y;14)(p11;q32)
CRLF2-IGH translocations from human B- lineage ALLs involve CpG-type breaks at CRLF2, but CRLF2/P2RY8 intrachromoso- mal deletions do not. Blood. 2010;116(11): 1993-1994.
9. Vesely C, Frech C, Eckert C, et al. Genomic and transcriptional landscape of P2RY8- CRLF2-positive childhood acute lym- phoblastic leukemia. Leukemia. 2017;31(7): 1491-1501.
10. Morak M, Attarbaschi A, Fischer S, et al. Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL. Blood. 2012;120(26):5134-5142.
11. Palmi C, Vendramini E, Silvestri D, et al. Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. Leukemia. 2012;26(10):2245-2253.
12. Ensor HM, Schwab C, Russell LJ, et al. Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood. 2011;117(7):2129-2136.
13. Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572- 581.
14. Herold T, Schneider S, Metzeler KH, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, per- sistence of minimal residual disease and poor prognosis. Haematologica. 2017;102 (1):130-138.
15. Reshmi SC, Harvey RC, Roberts KG, et al.
Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Blood. 2017;129(25):3352- 3361.
16. Konoplev S, Lu X, Konopleva M, et al. CRLF2-positive B-cell acute lymphoblastic leukemia in adult patients: a single-institu- tion experience. Am J Clin Pathol. 2017;147 (4):357-363.
17. van der Veer A, Waanders E, Pieters R, et al. Independent prognostic value of BCR-ABL1- like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B- cell precursor ALL. Blood. 2013;122(15): 2622-2629.
18. Heatley SL, Sadras T, Kok CH, et al. High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment. Haematologica. 2017;102(12):e490-e493.
19. Ge Z, Gu Y, Zhao G, et al. High CRLF2 expression associates with IKZF1 dysfunc- tion in adult acute lymphoblastic leukemia without CRLF2 rearrangement. Oncotarget. 2016;7(31):49722-49732.
20. Boer JM, Steeghs EM, Marchante JR, et al. Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget. 2017;8(3):4618-4628.
21. Jaso JM, Yin CC, Lu VW, et al. B acute lym- phoblastic leukemia with t(14;19) (q32;p13.1) involving IGH/EPOR: a clinically aggressive subset of disease. Mod Pathol. 2014;27(3):382-389.
22. Roberts KG, Gu Z, Payne-Turner D, et al. High frequency and poor outcome of Philadelphia chromosome-like acute lym- phoblastic leukemia in adults. J Clin Oncol. 2017;35(4):394-401.
23. Iacobucci I, Li Y, Roberts KG, et al.
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