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Final results of the GIMEMA LAL1509 for Ph+ ALL
ment in the study, including 16 who had already achieved a CR or CRi.
In the pre-TKI era, allo-SCT in first remission was con- sidered the standard of care for all eligible patients. After the introduction of TKI, the use of allo-SCT in first CHR has been questioned.19,34-38 Although our study was not powered to define its role, allo-SCT did not seem to have an impact on survival. This might be due to the small sam- ple size of patients who performed the procedure and may also be influenced by protocol violations, which rep- resent a major limit of the study: indeed, five patients in CMR after dasatinib induction underwent allo-SCT. Finally, allo-SCT was aggravated by mortality in five patients. In the report by Ravandi et al.27 only a small pro- portion of patients underwent allo-SCT in first remission without any improvement in survival. A recent report from Chang and colleagues36 also reported no benefit in OS and DFS at 3 years between transplanted and non- transplanted patients in a retrospective study (76% vs. 71.3%, P=0.56; 70.5% vs. 80.1%, P=0.94, respectively) in Ph+ ALL patients treated with dasatinib plus chemothera- py followed or not by allo-SCT. In contrast, in the report by the US Intergroup study, the landmark analysis at 175 days showed a significant advantage in both OS and relapse-free survival (P=0.038 and P=0.0037, respectively) in transplanted patients.33 In our cohort of transplanted patients, for patients relapsed after allo-SCT, all of them were MRD-positive before the procedure. This finding is in line with a recent publication by Candoni and col- leagues in which the 5-year CIR was higher in Ph+ ALL patients that were MRD+ prior to the allograft.37
With regard to the specific biologic features investigated, we observed, during induction, a significantly better clear- ance of the BCR-ABL1 transcript in p190 patients as opposed to p210 patients; interestingly, this, however, did not translate into an improved DFS and OS, thus suggesting that the kinetics of MRD clearance is different between the p190 and p210 cases. Further investigations are ongoing on this specific issue. Similarly, DFS was not statically better for patients achieving CMR after induction, mostly because of the small sample size and also indicating that patients who failed to achieve CMR can be rescued by an effective post-induction treatment.
At variance, patients with IKZF1 deletions plus CDKN2A/B and/or PAX5 deletions had a significantly worse DFS and OS, all relapsing within 24 months: this finding held true also in cases that achieved CMR. Also, the IKZF1-plus signature was the only prognostic factor to have an impact on DFS and OS in both univariate and multivari- ate analyses. Therefore, screening for these genetic lesions
should be performed in all Ph+ ALL patients at the time of diagnosis for a more refined prognostic stratification, and to further optimize treatment.23,26,31
Taken together, the results of this study document that durable remissions and long-term survival can be achieved with a total therapy strategy based on a chemotherapy-free induction, with an OS rate of 56.3% at a median follow-up of 57.4 months. Even in the TKI era, allo-SCT still remains an effective treatment for eligible adult patients; further efforts need to be made to identify which patients may be spared the procedure and its related toxicity, through the design of trials with a larger sample size that allow patients’ stratification according to their molecular features. Whether the use of more powerful BCR-ABL1 inhibitors such as ponatinib, may improve OS in Ph+ ALL remains to be deter- mined.38,39 The cardiovascular toxicity of ponatinib may counteract the potential benefit of this drug in patients with serious comorbidities. Finally, the upfront integration of TKI with immunoconjugates or BiTE antibodies - such as blina- tumomab - appears capable of inducing a high percentage of molecular response in adult Ph+ ALL patients and could eventually lead to higher rates of long-term responses.31
Disclosures
RF has served on advisory boards and at speaker bureaus of Janssen, AbbVie, Novartis, Amgen, Incyte, Pfizer and Servier; SC has served on advisory boards of Amgen, Pfizer, Incyte and Shire; the other authors declare no conflicts of interest.
Contributions
SC provided samples and clinical data, analyzed data and wrote the manuscript; MA analyzed data and wrote the manu- script; AV provided clinical data; LE and MM performed experi- ments; AP performed statistical analyses; PF contributed to protocol management; FDR, LS, FF, CC, GM, FR, FF, NC, CB, AT, SS, NDR, AM and GB provided clinical data; MV contributed to pro- tocol management; RF designed the research and the trial, and crit- ically revised the manuscript.
Acknowledgements
The authors wish to thank Sanofi and Bristol Myers Squibb, which provided clofarabine and dasatinib, respectively, free of charge.
Funding
The authors wish to thank the Associazione Italiana per la Ricerca sul Cancro (AIRC) 5x1000, Special Program Metastases (21198), Milan (Italy) to RF; Finanziamento Medi Progetti Universitari 2015 to SC (Sapienza University of Rome) and PRIN 2017 (2017PPS2X4_002) to SC.
References
1. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85- 109.
2. Mancini M, Scappaticci D, Cimino G, et al. A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Blood. 2005;105(9):3434-3441.
3.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
protocols and stratified in age cohorts.
Haematologica. 2013;98(11):1702-1710.
4. Burmeister T, Schwartz S, Bartram CR, et al. Patients’ age and BCR–ABL frequency in adult B- precursor ALL: a retrospective analysis from the GMALL study group.
Blood. 2008;112(3):918-919.
5. Yanada M, Takeuchi J, Sugiura I, et al. High
complete remission rate and promising out- come by combination of imatinib and chemotherapy for newly diagnosed BCR- ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006;24(3):460-466.
6.Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541.
7. 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 with- out additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B proto- col. Blood. 2007;109(9):3676-3678.
8. Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as
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