Autoimmune cytopenias (AIC) affect 5-9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs - ibrutinib, idelalisib and venetoclax - have a prominent role in the treatment of CLL, but their impact on CLL-associated AIC is largely unknown. In this study, we evaluated the characteristics and outcome of pre-existing AIC, and described the incidence, quality and management of treatment-emergent AIC during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of pre-existing AIC was reported in 104/815 patients (13%). Interestingly, 80% of patients whose AIC was not resolved at the time of targeted drug start experienced an improvement or a resolution during therapy. Treatment-emergent AIC occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib and in 7% during venetoclax, with an estimated incidence rate of 5, 6 and 69 episodes per 1000 patients per year of exposure in the three treatment groups, respectively. The vast majority of patients who developed treatment-emergent AIC carried unfavorable biological features such as an unmutated IGHV, and a del(17p) and/or TP53 mutation. Notably, despite AIC, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib and venetoclax appears to have a beneficial impact on CLL-associated AIC, inducing an improvement or even a resolution of pre-existing AIC in most cases and eliciting treatment-emergent AIC in a negligible portion of patients.

Undetectable MRD (uMRD) is achievable in patients with CLL with the BCL2-inhibitor venetoclax alone or combined with the BTK-inhibitor ibrutinib. This phase 2 multicenter MRD-driven study was designed to discontinue treatment upon reaching uMRD4(<10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary endpoint of the study was proportion of uMRD4 with venetoclax+/-ibrutinib. Secondary endpoints were ORR, PR, CR, PFS, DOR, OS, and safety of venetoclax+/-ibrutinib. Patients with uMRD4 at Cycle12Day1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle24Day28/uMRD4/progression/toxicity. After Cycle24Day28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53-aberrations; 79% unmutated IGHV) started venetoclax. ORR with venetoclax was 36/38(95%) (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle12Day1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range 3-10) of combined treatment, 16/19 (84%) achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median PFS was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, 1 dropped-out). 7/32 patients (22%) remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent G3-4 adverse event, no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33/38 patients (87%) with venetoclax monotherapy or combined with ibrutinib., delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. Clinical trial number: NCT04754035

Summary Little is known of the course of COVID‐19 and the antibody response to infection or vaccination in patients with hairy‐cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti‐leukaemic treatment, developed COVID‐19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection ( n = 11 cases) and postvaccination ( n = 28) seroconversion consistently developed, except after recent anti‐CD20 or venetoclax therapy, correlating with perivaccine B‐cell count. Vaccination appeared to protect from severe COVID‐19 in 11 patients with breakthrough infection.

Objectives The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the clinical history of patients with chronic lymphocytic leukemia (CLL) in both naïve and relapsed/refractory settings. “Accelerated” chronic lymphocytic leukemia (a-CLL) is a relatively rare form of CLL representing less than 1 % of all CLL cases. a-CLL patients usually have a more aggressive course and a reduced overall survival was reported with conventional chemo-immunotherapy approaches. Methods The role of Bruton Tyrosine Kinase-inhibitor, ibrutinib, in a-CLL is well established with encouraging preliminary results. Results We report a case of a-CLL-treated first-line with second-generation BTKi, acalabrutinib with a prompt clinical response. As known, it is the first literature report on acalabrutinib in a-CLL highlighting the role of second-generation BTKi also in this high-risk setting. Conclusions Target therapies (Bruton Kinase inhibitors and Bcl2 inhibitors) have improved the therapeutic landscape of CLL. The availability of therapeutic targets requires greater diagnostic accuracy to choose the most appropriate therapy for each patient.