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The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear.Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of a constitutively-active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicates that deregulated action of the mitotic active form of MUS81 in S-phase leads to the cleavage of stalled replication forks before their reversal, bypassing fork deprotection, and engaging a Polθ-dependent DSBs repair.Collectively, our findings describe a novel mechanism leading to PARPi resistance that involves unscheduled MUS81-dependent cleavage of intact, unreversed replication forks. Since this cleavage occurs mimicking the phosphorylated status of S87 of MUS81, our data suggest that hyperphosphorylation of this residue in S-phase might represent a novel biomarker to identify resistance to PARPi.

Autoimmune cytopenias (AICs) have been reported as a common complication in chronic lymphocytic leukemia (CLL) with autoimmune hemolytic anemia (AIHA), accounting for most cases. According to iwCLL guidelines, AICs poorly responsive to corticosteroids are considered indication for CLL-directed treatment. Chemo-immunotherapy has classically been employed, with variable results, and little data are available on novel agents, the current backbone of CLL therapy. The use of idelalisib in the setting of AICs is controversial and recent recommendations suggest avoiding idelalisib in this setting. Ibrutinib, through ITK-driven Th1 polarization of cell-mediated immune response, is known to produce an immunological rebalancing in CLL, which stands as a fascinating rationale for its use to treat autoimmunity. Although treatment-emergent AIHA has rarely been reported, ibrutinib has shown rapid and durable responses when used to treat AIHA arising in CLL. There is poor evidence regarding the role of BCL-2 inhibitors in CLL-associated AICs and the use of venetoclax in such cases is debated. Furthermore, their frequent use in combination with anti-CD20 agents might represent a confounding factor in evaluating their efficacy. In conclusions, because of their ability to mitigate an immunological dysregulation that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice when treatment of autoimmune cytopenias is required.

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%, NOI, 3.3%, OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p &lt, 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.

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Background The provision of effective and tolerable therapy in elderly and unfit patients is a clear priority in CLL. The BCL2 inhibitor venetoclax has shown remarkable efficacy in relapsed/refractory population and recently, in unfit untreated patients receiving a fixed duration schedule combined with obinutuzumab. Large retrospective real word experiences confirmed the efficacy and survival outcomes previously seen in trials. Although toxicity analysis including rates of tumor lysis syndrome (TLS), dose interruptions and discontinuations have been assessed in a recent cohort (Eyre et al. BJH 2020), the question of whether age and fitness may affect efficacy and survival on venetoclax treatment is still open. Methods This is a multicenter retrospective analysis evaluating 158 patiens in 14 Italian centers treated with venetoclax from February 2017 to May 2020. For each patient we analyzed the impact of age (6), major CIRS comorbidity (at least one organ with a CIRS score ≥3, CIRS3+), ECOG-PS (0-1 versus >1) and CCI ( The survival functions for the time-to-event variables were estimated by Kaplan-Meier method and the related strata compared using the log-rank test. Multivariate analyses were performed too using the Cox regression. Results Patients characteristics are shown in table 1. Median time of observation for the whole population was 11.9 months (2.1 - 40.2). Median months of venetoclax treatment were 9.4 (range 2.1 - 40.2). Overall, 111 (70.3%) patients are continuing with therapy. A total of 42 (26.6%) patients permanently discontinued venetoclax: 7 (4.4%) due to toxicity; 25 (15.8%) due to progressive disease and/or Richter Transformation; 16 (10.1%) for other reasons. Among 158 patients, 41 (25.9%) discontinued treatment for ≥7 days with a median of 8 days/patient interruption. At least one dose reduction episode occurred in 36 patients (22.8%) and in 21 (13.3%) venetoclax was permanently administered at a lower dosage. Concomitant medications were reported in 134 (84.8%) patients, 75 of whom took ≥4 drugs in addition to venetoclax. In 32 cases (20.3%) venetoclax was administered concomitantly with CYP3A4 inhibitors/inducers. Patients age did not influence tox-DTD and PDR as well as patients outcomes in terms of EFS PFS and OS. In the elderly CIRS > 6 significantly influenced PDR (p 0.012) but not tox-DTD. In younger patients CIRS >6 did not show effect on treatment management; CIRS3+ instead, led to higher rate of tox-DTD (p 0.044). Progression free survival, EFS and OS were not affected by CIRS3+ and CIRS>6 even when patients were stratified according to age. Patients with an ECOG >1 experienced more tox-DTD (P 0.003) and a significantly shorter PFS (p 1 was independently associated with shortened PFS. While baseline neutropenia and concomitant treatment with CYP3A4 inhibitors/inducers led to a significant PDR, the presence of a compromised renal function did not influence patients management. Conclusions To our knowledge this is the first analysis assessing whether age, ECOG-PS and comorbidities retain a predictive value with venetoclax and if number and types of concomitant medications may interfere on treatment outcome. Age, CIRS and CIRS3+ did not affect patients management and outcomes; however, ECOG was the only significant factor related to fitness independently influencing outcome at the multivariate analysis. Disclosures Coscia: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding. Ciolli:Abbvie: Research Funding; Janssen: Honoraria. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Reda:Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses. Mauro:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Consultancy; Shire-Takeda: Membership on an entity's Board of Directors or advisory committees. Murru:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale:Janssen: Honoraria. Montillo:Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria; Astra Zeneca: Honoraria; Janssen: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding. Tedeschi:Janssen: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau.