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Additional genomic lesions in adult Ph+ ALL
ing patients into high- and low-risk categories are urgently needed to further optimize treatment. Moreover, another unsolved issue is whether all eligible patients should undergo HSCT,7,17 a procedure still associated with short- and long-term side effects, as well as treatment-related mortality. This is particularly important for patients who obtain a CMR.
To address these issues we sought to identify additional genomic lesions with prognostic significance in adult Ph+ ALL using high density Cytoscan arrays. We found that adult Ph+ ALL patients carried an average of 7.8 aberra- tions each, with deletions outnumbering gains, in line with other ALL subsets.22,30,38,39 Macro-aberrations were identified in 48% of cases and micro-aberrations in the majority of patients: among the latter, the most frequent was ΔIKZF1, which was detected in 84% of cases. ΔIKZF1 has been regarded as a poor prognostic marker in both childhood and adult ALL.34,36,39-41 This finding was not, however, confirmed in our cohort: in fact, the presence of ΔIKZF1 alone was not associated with a worse DFS. A fur- ther evaluation of the various IKZF1 isoforms showed that only the dominant-negative genotype was deleteri- ous for outcome. In addition, patients with ΔIKZF1+CDKN2A and/or PAX5, accounting for almost half the ΔIKZF1 cases, experienced a significantly inferior DFS (P=0.005) and overall survival (P=0.02), in line with previous reports on ALL in general.28,29,36,39,42,43 ΔIKZF1+CDKN2A and/or PAX5 also had a prognostic impact in multivariate analysis; survival analysis was car- ried out merging all cases enrolled in the different trials together in order to gain statistical significance.
Recently, studies have been focused on the presence of additional karyotypic aberrations in Ph+ ALL.44-48 These studies have highlighted that a high percentage of Ph+ ALL cases (60-80%) harbor additional chromosomal abnormal- ities, with the most frequent aberrations involving chro- mosomes 7, 9, and 14. Patients with additional abnormali- ties, particularly loss of 9/9p and/or CDKN2A, have a worse outcome. These results point to the importance of screening for other molecular markers, and not only IKZF1, in agreement with our findings on ΔIKZF1+CDKN2A and/or PAX5. At variance from these reports, our study also identified novel lesions that had a favorable impact on
outcome. Among these, it is worth mentioning ΔMEF2C, which occurred in 18.1% of patients and was of two sizes, a long deletion, encompassing introns 1-2 and exon 2, and a second, smaller one, involving only exon 2. MEF2C is a transcription factor involved in B-cell survival and prolifer- ation whose overexpression is associated with an unfavor- able prognosis in T-ALL and acute myeloid leukemia.49-52 In our study, the presence of ΔMEF2C-long was associated with achievement of a CMR (P=0.05) and with a signifi- cantly better DFS compared to the remaining cases (P=0.031) also in a multivariate model; as for IKZF1 dele- tions, survival analysis was performed merging the whole cohort because of the sample sizes. ΔMEF2C-long was widely distributed among cases, with no association with white blood cell count, age, type of fusion protein or addi- tional deletions. To our knowledge, this is the first report that correlates ΔMEF2C-long with prognosis in Ph+ ALL: Martinelli et al.40 and Mullighan et al.22,41 described ΔMEF2C in Ph+ ALL, but did not demonstrate a correlation with outcome. Finally, ΔKRAS was associated with a higher rate of CMR achievement upon induction (P=0.01), but not with a better DFS.
In conclusion, we show that additional genetic lesions can be found at presentation in adult Ph+ ALL patients and that these lesions have prognostic significance, with the IKZF1 dominant-negative isoform and ΔIKZF1+CDKN2A and/or PAX5 negatively affecting out- come, and ΔMEF2C and ΔKRAS being instead associated with a more favorable prognosis. Screening for these genetic lesions should, therefore, be performed at the time of diagnosis for a more refined prognostic stratifica- tion, and for a more personalized and tailored manage- ment of Ph+ ALL patients.
Acknowledgments
The authors thank Associazione Italiana per la Ricerca sul Cancro (AIRC), Special Program Molecular Clinical Oncology-Extension program, 5 x 1000 (10007), Milan (Italy) for funding RF; Finanziamento per l’avvio alla ricerca 2015 (Sapienza University of Rome) for funding MM; Finanziamento Medi Progetti Universitari 2015 for funding SC (Sapienza University of Rome); and Fondazione Le Molinette Onlus, Turin (Italy).
References
1. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85- 109.
2. Chiaretti S, Vitale A, Cazzaniga G, et al. Clinico-biological features of 5202 patients with acute lymphoblastic leukemia enrolled in the Italian AIEOP and GIMEMA proto- cols and stratified in age cohorts. Haematologica. 2013;98(11):1702-1710.
3. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults Philadelphia chromosome-positive acute lymphoblastic leukemia-results of the prospective multi- center LALA-94 trial. Blood. 2002;100(7): 2357-2366.
4. Gleissner B, Gökbuget N, Bartram CR, et al. Leading prognostic relevance of the BCR- ABL translocation in adult acute B-lineage
lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood. 2002;99(5):1536- 1543.
5. Pullarkat V, Slovak ML, Kopecky KJ, et al. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008;111(5):2563-2572.
6. Hunault M, Harousseau JL, Delain M, et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004;104(10):3028-3037.
7. Patel JN, Druhan LJ. Genetic effects on hematopoietic stem cell transplant progno- sis and outcomes, more than just histocom- patibility. Biol Blood Marrow Transplant. 2017;23(8):1227-1228.
8. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome- positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109(4):1408-1413.
9. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B proto- col. Blood. 2007;109(9):3676-3678.
10. Chiaretti S, Vitale A, Vignetti M, et al. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia. Final results of the GIMEMA LAL 0904 study. Haematologica. 2016;101(12):1544-1552.
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