OUTCOME OF 100 TP53-DISRUPTED CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED FRONT-LINE WITH IBRUTINIB. A REAL-LIFE CAMPUS CLL STUDY.

Background: Disruption of the TP53 gene, including 17p13 deletion (17p-) and/or TP53 gene mutation (TP53m), is a negative prognostic bio- marker in chronic lymphocytic leukemia (CLL) associated with genome complexity, early relapse and shorter survival after chemo-immunother- apy. Although the first-in class BTK inhibitor ibrutinib has proven to be highly active in CLL with unfavorable features, data on treatment-naive (TN) patients with TP53 abnormalities derive from almost 90 patients included in 5 clinical trials. Aims: The aim of this study is to describe the efficacy and discontinu- ation rate of ibrutinib in TN CLL patients with TP53 disruption in the real-life setting. Methods: Medical charts of CLL patients followed in 14 centers belonging to the Italian Campus CLL network were retrospectively reviewed to identify CLL with 17p- (cut-off 10%) and/or TP53m treated front-line with ibrutinib. The primary endpoint was the rate of discontinuation. Secondary endpoints were progression-free sur- vival (PFS), time-to-next treatment (TTNT), overall survival (OS). Survival after ibrutinib discontinuation was also assessed. CLL diag- nosis and response assessment were carried out according to the iwCLL 2018 guidelines. Adverse events were classified according to the CTCAE v5.0 grading. Statistical analyses were performed with Prism 7. Results: One hundred TN CLL patients were recruited in this study. Fifty-one patients were male, the median age at the start of ibrutinib was 71 years (range 37-87), including 35 octogenarians, the median CIRS was 4 (range 0-13), 42 had a creatinine clearance <60ml/min. According to Rai’s classification, 27 were in stage III and 18 in stage IV. □2-micro- globulin was increased in 28 patients. Seventy-seven patients were IGHV unmutated, 33 displayed only 17p-, 22 only TP53m and 45 both 17p- and TP53m. The overall response rate was 84%, including 10% of complete remis- sions (confirmed by bone marrow biopsy). After a median follow-up of 24 months, 13 patients relapsed, 10 required further therapy, 2 devel- oped a Richter syndrome (RS) transformation and 8 died (4 infections, 1 melanoma, 1 RS, 1 sudden death). The median PFS, TTNT and OS have not been not reached. The 12, 24 and 36-month PFS was 91%, 82% and 75%, respectively. The 12, 24 and 36-month TTNT was 94%, 89% and 82%. The 12, 24 and 36-month OS was 96%, 92% and 87% (Fig. 1A). We observed that PFS was shorter in patients older than 75 years (2-yy PFS 69% vs 89%, p=0.04) and who did not respond (85% vs 66%, p=0.03). Twenty-eight patients discontinued treatment, 20 due to adverse events (8 infections, 5 atrial fibrillations, 4 others and 3 deaths), 6 due to CLL progressions and 2 RS. After 12 and 24 months of treatment, the cumulative incidence of discontinuation for the whole cohort was 18% and 32%. In particular, it was 17% and 26% due to adverse events, 1% and 5% due to CLL relapse, 1% and 3% for RS (Fig. 1B). Patients who discontinued ibrutinib due to adverse events had a shorter PFS and OS (both p<0.0001). After a median obser- vation of 14 months after ibrutinib discontinuation, the estimated median PFS and TTNT were 11 and 20 months, respectively (Fig. 1C). Overall, 22 infective events (9 grade □3), 8 atrial fibrillations, 8 minors but no major occurred. Summary/Conclusion: We report the largest real-life study of ibrutinib in TN CLL patients with TP53 abnormalities, confirming the efficacy of ibrutinib in this subset of patients. Although ibrutinib discontinuation is not uncommon, only a few patients needed fur- ther treatment. Patients who stopped ibrutinib due to adverse had a shorter survival.