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G. Del Poeta et al.
Moreover, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response upon ibrutinib treatment, suggesting the retention of CD49d-expressing cells in tissue sites via activated VLA-4 .7
Consistently with the high frequency of pre-treated patients in our cohort (154 of 180), the OS values at 2 and 4 years (84% and 71% respectively), were similar to those reported for the phase III RESONATE study in patients with previously treated CLL/SLL.37
We have recently reported that NOTCH1 M identify a subgroup of patients with CLL with worse prognosis in the setting of a rituximab-based induction and consolidation treatment.38 Here, we described a negative prognostic impact of NOTCH1 M also in the ibrutinib setting. Our findings differ from those resulting from the extended fol- low up from the RESONATE study of relapsed/refractory CLL, where the presence of NOTCH1 M did not negatively affect the efficacy of ibrutinib on disease progression out- comes.37 This difference can be explained by the very low cut-off (>1%) chosen for NOTCH1 M in our study, although for the validation of these findings additional independent cohorts are needed.
The here reported capacity of BAX/BCL-2 index to iden- tify patients with a different response to ibrutinib could be of interest in the light of the treatments protocols associat- ing B-cell receptor inhibitors and BH3 mimetics such as venetoclax.39
Moreover, the additive negative prognostic value of NOTCH1 M and low BAX/BCL-2 ratio described by us, fur- ther support the rationale to improve the efficacy of ibruti- nib by using the BCL-2 inhibitor venetoclax in patients with NOTCH1 mutated CLL.10 Interestingly, an additive prog- nostic impact of the combination of BAX/BCL-2 and NOTCH1 M in the setting of chemo-immunotherapy was also reported by us.10
Several independent cohorts of patients confirmed the adverse clinical outcome of NOTCH1 M with CLL in uni- variate analysis,20-23,40 although conflicting results are report- ed about its independent prognostic effect. In particular, NOTCH1 M did not retain independent significance as a predictor of time-to-first treatment in one of the largest series of patients with CLL,41 while in another study it emerged as an independent predictor of shorter survival, along with TP53 abnormalities.42 Here NOTCH1 M were confirmed to be an independent prognostic factor together with previous lines of therapy and TP53 both with respect to PFS and OS. The apparent higher prognostic impact of NOTCH1 M compared to TP53 mutation, as emerged in our multivariable analysis, may be explained by the greater number of TP53 mutated cases treated first line with ibruti- nib, hence with a better prognosis than NOTCH1 M cases that were more frequently treated with ibrutinib in second or further lines of therapy.
The current use of B-cell receptor and BCL-2 inhibitors led to high-rate improvement of outcome in CLL. However, several issues remain, resulting in resistance/progression thus limiting the eradication of the tumour. The growing evidence for a critical role of the NOTCH1 pathway in CLL makes this cancer gene a target to design tailored treat- ments for this peculiar subset through specific NOTCH1- targeted therapies. In this context, γ-secretase inhibitors are the most extensively explored anti-NOTCH1 molecules and their combination with fludarabine demonstrated anti- tumour effects in primary CLL with NOTCH1 M.43 Noteworthy, a humanized antibody targeting NOTCH1 (clinicaltrials gov. Identifier: OMP-52M51) entered phase I trial in relapsed/refractory lymphoid malignancies.44 However, to date, the future treatment of CLL with NOTCH1 M relies on the association of small molecule inhibitors targeting both the BCR pathway and the anti- apoptotic BCL-2 protein.
Disclosures
No conflicts of interest to disclose.
Contributions
GDP and VG designed the study, interpreted data, performed statistical analysis, wrote the manuscript and gave final approval of the manuscript; AB and AZ contributed to study design and data interpretation and to write the manuscript; LL, AC and MIDP contributed to interpret the data and to write the manu- script; AZ, FMR and GDP obtained flow cytometric data; FMR performed FISH cytogenetic analysis; VG, FP and RB investigat- ed IGHV, NOTCH1 and TP53 mutations; FB, SA, GG, AV contributed to study design and data interpretation; II, MP, PdF, MC recruited the patients and collected clinical data.
Acknowledgments
This study was supported in part by Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST), Programmi di Ricerca di Interesse Nazionale; Ministero della Salute (Ricerca Finalizzata Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS], Rome, Italy; Associazione Italiana Ricerca Cancro (AIRC), Investigator Grant IG-21687 (to V.G.); Progetto Ricerca Finalizzata PE 2016-02362756, Ministero della Salute, Rome, Italy (to V.G.); Progetto Ricerca Finalizzata RF-2018-12365790 (to A.Z.); Fondazione Cariplo (grant 2012-0689); Associazione Italiana contro le Leucemie, Linfomi e Mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; Fondazione per la Vita di Pordenone, Italy; Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia (“Linfonet” Project), Trieste, Italy; “5x1000 Intramural Program”, Centro di Riferimento Oncologico, Aviano, Italy.
The authors thank the members of their Departments of Hematology clinical staff for their invaluable support to this CLL clinical research program.
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