Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management

The role of the p63 transcription factor in Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL), the most frequent leukemia in Western world, is characterized by a remarkably variable clinical course, likely as a reflection of the underlying biological heterogeneity. The latter is shaped by different cellular mechanisms and factors contributing to disease pathogenesis. Recent evidence has highlighted that the TA-isoform of the p63 transcription factor (TAp63) affects CLL cells viability and likely contributes to clinical aggressiveness, albeit in a hitherto elusive way. In CLL, TAp63 expression, is modulated by both immune signaling and epigenetic modifications. In activated normal B cells, the TAp63 transcription factor activates the BCL2 gene, participating in the NF-κB/TAp63/BCL2 anti-apoptotic pathway. On these grounds, here, we sought to further understand and define the role of TAp63 in the pathophysiology of CLL and also to explore molecular links between TAp63 and BCL2 in CLL cells.First, we performed TAp63 mRNA expression analysis in distinct subgoups of patients and found that elevated TAp63 expression levels are linked with adverse prognostic features and clinical outcomes, including shorter time-to-first treatment and overall survival. Moreover, we analyzed TAp63 mRNA expression in longitudinal samples of CLL cases treated with either chemoimmunotherapy or signaling inhibitors to report that TAp63 is overexpressed in relapse/refractory disease. Next, we explored molecular links between TAp63 and BCL2 in CLL cells and documented a strong correlation at both the protein and the mRNA levels, alluding to the potential prosurvival role of TAp63 in the following settings: a) both stimulated and unstimulated primary CLL cells; and, b) primary CLL cells after TAp63 downregulation by RNA interference. This finding was further supported by inducible downregulation of TAp63 expression in the MEC1 CLL cell line using CRISPR, which resulted in downregulation of BCL2 expression. In order to elucidate the transcriptional network of TΑp63, we performed ChIP-sequencing and identified high-confidence TAp63 binding regions in genes implicated in disease pathogenesis that regulate cellular processes necessary for cell survival. Furthermore, we examined whether BCL2 might constitute a transcriptional target of TAp63 and reported a significant binding profile of TAp63 in the BCL2 gene locus, across a genomic region previously characterized as a super-enhancer in CLL. Finally, we found that up-regulated TAp63 expression levels render CLL cells less responsive to apoptosis induction with the BCL2 inhibitor, venetoclax. Collectively, TAp63 emerges as a positive modulator of BCL2, hence contributing to the anti-apoptotic phenotype that underlies clinical aggressiveness and treatment resistance in CLL.Η Χρόνια Λεμφοκυτταρική Λευχαιμία (ΧΛΛ) είναι η πιο συχνή αιματολογική κακοήθεια στη Δύση. Χαρακτηρίζεται από αξιοσημείωτη κλινική ετερογένεια η οποία είναι συνυφασμένη με την ετερογένεια που παρατηρείται σε βιολογικό επίπεδο, με πολλούς διαφορετικούς κυτταρικούς μηχανισμούς να συνεισφέρουν στην ανάπτυξη και την εξέλιξη της νόσου. Πρόσφατες μελέτες έχουν αναδείξει ότι ο μεταγραφικός παράγοντας p63, και συγκεκριμένα η ισομορφή του ΤΑp63, επηρεάζει την επιβίωση των ΧΛΛ κυττάρων και κατ΄επέκταση την κλινική επιθετικότητα των ασθενών μέσω άγνωστων μηχανισμών. Η έκφραση της TAp63 στη ΧΛΛ ρυθμίζεται τόσο μέσω επιγενετικών τροποποιήσεων όσο και από ερεθίσματα του μικροπεριβάλλοντος του λευχαιμικού κλώνου. Στα φυσιολογικά ώριμα Β κύτταρα η TAp63 επάγει την πρωτεΐνη BCL2 και προάγει την επιβίωση τους συμμετέχοντας στο αντιαποπτωτικό μονοπάτι NFκB/TAp63/BCL2. Σε αυτό το πλαίσιο, στην παρούσα εργασία διερευνήθηκε σε μοριακό επίπεδο ο ρόλος της ΤΑp63 και η συσχέτιση της με την BCL2 έτσι ώστε να αναδειχθούν τα ρυθμιστικά κυκλώματα μέσω των οποίων η TAp63 επηρεάζει την επιβίωση των λευχαιμικών κυττάρων.Αρχικά πραγματοποιήθηκε μελέτη της έκφρασης του ΤΑp63 σε επίπεδο mRNA σε διαφορετικές υποομάδες ασθενών με ΧΛΛ και διαπιστώθηκε πως εκφράζεται σε υψηλότερα επίπεδα σε ασθενείς με δυσμενή προγνωστικά χαρακτηριστικά ενώ τα υψηλά επίπεδα έκφρασής της συσχετίζονται με μικρότερο χρόνο έως την πρώτη θεραπεία αλλά και μικρότερη ολική επιβίωση. Επιπλέον, ύστερα από μέτρηση της έκφρασης του TAp63 σε διαχρονικά δείγματα ασθενών με ΧΛΛ που είχαν λάβει θεραπεία, βρέθηκε πως υπερεκφράζεται σε περιπτώσεις ανθεκτικής/υποτροπιάζουσας ΧΛΛ τόσο ύστερα από ανοσοχημειοθεραπεία όσο και ύστερα από θεραπεία με αναστολείς σηματοδότησης. Αναφορικά με τη μοριακή διασύνδεση μεταξύ TAp63 και BCL2, παρατηρήθηκε ισχυρή συσχέτιση μεταξύ των επιπέδων έκφρασης των δύο σε επίπεδο mRNA και σε πρωτεϊνικό επίπεδο στις ακόλουθες συνθήκες: α) πρωτογενή κύτταρα ασθενών με ΧΛΛ που βρίσκονταν τόσο σε αδιέγερτη όσο και σε διεγερμένη κατάσταση και β) πρωτογενή κύτταρα ασθενών με ΧΛΛ μετά από καταστολή της έκφρασης του γονιδίου TAp63 με RNA παρεμβολή. Τα ευρήματα αυτά επιβεβαιώθηκαν επιπλέον και στην κυτταρική σειρά MEC1 η οποία είχε τροποποιηθεί γενετικά έτσι ώστε να υποεκφράζει τo TAp63 κατά επαγόμενο τρόπο, όπου η καταστολή του γονιδίου είχε ως αποτέλεσμα τη μείωση της έκφρασης του γονιδίου BCL2. Στη συνέχεια, με σκοπό να αποσαφηνιστεί το σύνολο των μεταγραφικών στόχων του μεταγραφικού παράγοντα TAp63 πραγματοποιήθηκε ανοσοκατακρήμνιση χρωματίνης ακολουθούμενη από αλληλούχηση νέας γενιάς τόσο σε πρωτογενή κύτταρα ασθενών με ΧΛΛ όσο και στην κυτταρική σειρά MEC1. Και στις δύο περιπτώσεις, μεταξύ των γονιδίων – στόχων αναγνωρίστηκαν γονίδια που εμπλέκονται στην παθοφυσιολογία της ΧΛΛ και ρυθμίζουν καίριες κυτταρικές διεργασίες. Σχετικά με το BCL2, ανιχνεύθηκε ισχυρή πρόσδεση της TAp63 σε περιοχή του γονιδίου που είναι χαρακτηρισμένη ως υπερ-ενισχυτής της μεταγραφής, ενισχύοντας την υπόθεση πως η ΤΑp63 λειτουργεί ως θετικός ρυθμιστής του BCL2 στα κύτταρα της ΧΛΛ. Τέλος, διερευνήθηκε η πιθανή κλινική σημασία των παραπάνω ευρημάτων μέσω ex vivo αξιολόγησης του φαρμακολογικού αναστολέα της BCL2 Venetoclax σε πρωτογενή κύτταρα ασθενών με ΧΛΛ που εξέφραζαν διαφορικά επίπεδα TAp63. Οι περιπτώσεις που εξέφραζαν υψηλά επίπεδα ΤΑp63 βρέθηκαν να εμφανίζουν μεγαλύτερη αντοχή στον αναστολέα.Συνολικά, στην παρούσα εργασία προσφέρονται ισχυρές ενδείξεις ότι ο μεταγραφικός παράγοντας ΤAp63 συμμετέχει στους μηχανισμούς που προσδίδουν κλινική επιθετικότητα και χημειοανθεκτικότητα στη ΧΛΛ, μέσω κυτταρικών μηχανισμών που εμπλέκουν τον αντι-αποπτωτικό παράγοντα ΒCL2

Clonal haematopoiesis as a risk factor for therapy-related myeloid neoplasms in patients with chronic lymphocytic leukaemia treated with chemo-(immuno)therapy

: Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of therapy-related myeloid neoplasms (t-MN). Using target next-generation sequencing (t-NGS) panels and digital droplet polymerase chain reactions (ddPCR), we studied the myeloid gene mutation profiles of patients with chronic lymphocytic leukaemia (CLL) who developed a t-MN after treatment with chemo-(immuno)therapy. Using NGS, we detected a total of 30 pathogenic/likely pathogenic (P/LP) variants in 10 of 13 patients with a t-MN (77%, median number of variants for patient: 2, range 0-6). The prevalence of CHIP was then backtracked in paired samples taken at CLL diagnosis in eight of these patients. Six of them carried at least one CHIP-variant at the time of t-MN (median: 2, range: 1-5), and the same variants were present in the CLL sample in five cases. CHIP variants were present in 34 of 285 patients from a population-based CLL cohort, which translates into a significantly higher prevalence of CHIP in patients with a CLL who developed a t-MN, compared to the population-based cohort (5/8, 62.5% vs. 34/285, 12%, p = 0.0001). Our data show that CHIP may be considered as a novel parameter affecting treatment algorithms in patients with CLL, and highlight the potential of using chemo-free therapies in CHIP-positive cases

Different Prognostic Impact of Recurrent Gene Mutations in IGHV-Mutated and IGHV-Unmutated Chronic Lymphocytic Leukemia: A Retrospective, Multi-Center Cohort Study By Eric, the European Research Initiative on CLL, in Harmony

Abstract The mutational status of the immunoglobuin heavy variable (IGHV) genes is an undisputable strong prognostic factor that subdivides patients with chronic lymphocytic leukemia (CLL) into 2 subgroups, i.e. IGHV-unmutated CLL (U-CLL) and IGHV-mutated CLL (M-CLL). U-CLL and M-CLL have distinct landscapes of genomic aberrations as well as distinct prognosis, since U-CLL is considerably more aggressive than M-CLL. That said, there is considerable clinical heterogeneity among M-CLL patients, ranging from patients without need of treatment to patients requiring early therapeutic intervention, indicating the need to further refine prognosis in this subgroup. In recent years, it has become evident that the prognostic impact of genomic aberrations may differ depending on IGHV gene mutational status. Hence, defining genomic aberrations with prognostic impact in M-CLL patients may help identifying patients with an predicted unfavorable prognosis within this subgroup, with obvious implications for management of follow up and therapy choice. To study the clinical impact of recurrent gene mutations in relation to IGHV gene mutational status, we collected a large, multi-center cohort including 4,674 patients with CLL [median age at diagnosis, 64.5 years; male/female, n=2,962 (63%)/n=1,712 (37%); Binet stage A (n=3,369, 74%), B (n=827, 18%), and C (n=387, 8%); IGHV-mutated (M-CLL, n=2,498, 56%) and IGHV-unmutated (U-CLL, n=1,927, 44%); isolated del(13q) (n=1,868, 41%), trisomy 12 (n=571, 13%), del(11q) (n=503, 11%), and del(17p) (n=249, 5.5%); treated (n=2,745, 59%) and untreated (n=1,929, 41%)] and performed next-generation sequencing (NGS) and/or Sanger sequencing of 9 genes (BIRC3, EGR2, NFKBIE, MYD88, NOTCH1, POT1, SF3B1, TP53, and XPO1) on pre-treatment samples. Overall, pathogenic mutations in any of these genes were detected in 1720/4674 patients (36.8%, using a variant allele frequency cutoff of 5% for NGS), while the remaining patients were wildtype; 2 mutations were observed in 361 patients (7.7%) and 3 or more mutations in 58 patients (1.2%). The mutation frequency for the individual genes was: TP53 (10.4%, including TP53 mutations and/or del(17p)), NOTCH1 (10.1%, 3'UTR mutations not included), SF3B1 (9.3%), XPO1 (3.9%), POT1 (3.8%), NFKBIE (3.7%), BIRC3 (3.0%), EGR2 (2.5%) and MYD88 (2.5%; Figure 1A). Except for MYD88, gene mutations in each of the investigated genes were associated with significantly shorter time-to-first-treatment (TTFT) in univariate analysis. In multivariate analysis of Binet stage A patients (n=3,369; including all genes, IGHV gene mutational status, age at diagnosis and gender), SF3B1 (Hazard Ratio (HR) 1.79; p<0.001) , BIRC3 mutations (HR 1.50; p=0.004), XPO1 (HR 1.29; p=0.020), EGR2 (HR 1.42; p=0.021) and TP53 aberrations (HR 1.21; p=0.028), along with unmutated IGHV genes (HR 4.21; p<0.001) and male gender (HR 1.12; p=0.027) remained as independent factors for shorter TTFT. In a multivariate model focusing on M-CLL Binet stage A patients (n=2,049), SF3B1 (HR 2.72; p<0.001), NOTCH1 (HR 1.65; p=0.006), XPO1 (HR 2.21; p=0.021) and NFKBIE mutations (HR 1.74; p=0.025) were independent markers of poor TTFT (Figure 1B), while conversely in U-CLL Binet stage A cases (n=1157), SF3B1 mutations (HR 1.49; p<0.001), TP53 aberrations (HR 1.30; p=0.011), BIRC3 mutations (HR 1.49; p=0.016) and male gender (HR 1.20; p=0.012) were significant factors for shorter TTFT (Figure 1C). In summary, different spectra of genetic mutations independently predicted short TTFT in M-CLL and U-CLL, respectively, with SF3B1 mutations as the only aberration found to be significant predictor of shorter time to first treatment in both subgroups. Importantly, mutations within several genes (i.e. SF3B1, NOTCH1, XPO1 and NFKBIE) identified patients in the M-CLL subgroup with a high-risk profile; conversely, TP53 mutations did not affect TTFT in this subgroup. On these grounds, we suggest to include analysis of recurrent gene mutations to identify high-risk patients within the M-CLL subgroup. Figure 1 Figure 1. Disclosures Brieghel: AstraZeneca: Consultancy. Rossi: Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding. Scarfo: Astra Zeneca: Honoraria; Abbvie: Honoraria; Janssen: Honoraria, Other: Travel grants. Mattsson: Gilead: Research Funding. Baliakas: Janssen: Honoraria; Gilead: Honoraria, Research Funding; Abbvie: Honoraria. Martinez-Lopez: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Serna: AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Roche: Speakers Bureau. Hernández Rivas: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Smedby: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Bullinger: Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Gilead: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Hexal: Consultancy; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Menarini: Consultancy; Novartis: Consultancy, Honoraria; Amgen: Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Research Funding. Bosch: TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Terol: BMS: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Ghia: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding. Rosenquist: Roche: Honoraria; Janssen: Honoraria; Illumina: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

International audienceRecent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes ( BIRC3 , EGR2 , MYD88, NFKBIE , NOTCH1 , POT1 , SF3B1, TP53 , and XPO1 ) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53 , BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

International audienceRecent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes ( BIRC3 , EGR2 , MYD88, NFKBIE , NOTCH1 , POT1 , SF3B1, TP53 , and XPO1 ) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53 , BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management

Correction: Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

International audienc

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Abstract Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes ( BIRC3 , EGR2 , MYD88, NFKBIE , NOTCH1 , POT1 , SF3B1, TP53 , and XPO1 ) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53 , BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management