Yair Herishanu

The impact of venetoclax‐based therapies on autoimmune cytopenias (AIC) in patients with chronic lymphocytic leukemia (CLL) is largely unknown. This study aimed to evaluate preexisting and treatment‐emergent AIC in patients with CLL treated with venetoclax, focusing on the differential impact of venetoclax monotherapy versus venetoclax‐based combinations. In this retrospective multicenter study, data from 1720 patients were collected; 23.1% received venetoclax single agent and 76.9% venetoclax combinations (mostly containing anti‐CD20 monoclonal antibodies and/or BTK inhibitors). Combination regimens were used in 97.7% of treatment‐naïve (TN) patients and 65.8% of patients with relapsed/refractory (R/R) CLL. Preexisting AIC were reported in 11.7% of patients (8.7% in TN and 13.4% in R/R, P = 0.005). CLL‐related genetic risk factors and disease outcomes did not differ in patients with and without preexisting AIC. Irrespective of treatment type, venetoclax therapy resulted in AIC resolution or improvement in 63% of patients with active or controlled AIC. Treatment‐emergent AIC occurred in 2.6% of patients (2% in TN and 2.9% in R/R, not statistically significant). AIC episodes were reported in 4.3% of patients treated with venetoclax monotherapy and in 2.1% of those treated with venetoclax‐based combinations (P = 0.02). After standard management, AIC was considered resolved or controlled in 82% of the patients, with no substantial difference between treatment groups. Venetoclax‐based therapies have a beneficial impact on the outcome of CLL‐associated preexisting AIC. Treatment‐emergent AIC is a rare and generally manageable event. Although more frequent with venetoclax monotherapy in unadjusted analysis, this association was attenuated after adjustment for baseline prognostic factors.

Background: Chronic lymphocytic leukemia (CLL) is characterized by T-cell dysfunction that limits the efficacy of immunotherapies, including CD20×CD3 bispecific antibodies. Protein tyrosine phosphatases non-receptor type 2/1 PTPN2/PTPN1 are central intracellular negative regulators of T-cell activation. Preclinical studies show that deletion or PTPN2/PTPN1 inhibition increased T-cell activation, proliferation, and antitumor activity. This study aimed to investigate the potential of PTPN2/PTPN1 inhibition in combination with the bispecific antibody mosunetuzumab as a therapeutic approach for CLL. Methods: Peripheral blood mononuclear cells (PBMCs) obtained from CLL patients were used in all experiments. The effects of PTPN2/PTPN1 inhibition in combination with mosunetuzumab, were evaluated using flow cytometry, confocal microscopy, ELISA, and Incucyte Live-Cell Analysis to assess T-cell activation, immune synapse formation and cytotoxic activity. Results: Pretreatment with the PTPN2/PTPN1 inhibitor ABBV-CLS-484 (AC484) enhanced T-cell activation following CD3/CD28 stimulation, as demonstrated by increased expression of the activation markers CD69 and CD25. Confocal microscopy revealed increased CD8+ T-cell size, enhanced granzyme B expression and release, and more robust immune synapse formation following treatment with mosunetuzumab +/-AC484. Incucyte imaging of CLL-T-cell co-cultures demonstrated enhanced T-cell proliferation, increased CLL-T-cell clustering, and a modest increase in cytotoxicity with the combination of AC484 and mosunetuzumab. Consistent with these findings, ELISA assays showed increased secretion of granzyme B and IFN-γ. Conclusion: Combining the PTPN2/PTPN1 inhibitor AC484 with mosunetuzumab enhanced T-cell activation, proliferation, granzyme B and IFN-γ secretion, and anti-CLL cytotoxicity in CLL samples, supporting further evaluation of PTPN2/PTPN1 inhibition as a strategy to enhance the efficacy of CLL immunotherapy.

Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia. We present results from ELEVATE-TN after a median follow-up of 74.5 months. Overall, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; chlorambucil-obinutuzumab, n = 177). Median age was 70 years, 63.0% had unmutated immunoglobulin heavy chain variable region gene (uIGHV), 13.6% had del(17p) and/or mutated TP53, and 17% had complex karyotype (CK; ≥3 chromosomal abnormalities). Median progression-free survival (PFS) was not reached (NR) for acalabrutinib-obinutuzumab and acalabrutinib vs 27.8 months for chlorambucil-obinutuzumab (both P < .0001); estimated 72-month overall PFS rates were 78.0%, 61.5%, and 17.2%, respectively. Acalabrutinib-obinutuzumab resulted in improved PFS vs acalabrutinib monotherapy (hazard ratio [HR], 0.58; P = .0229). Patients with uIGHV, del(17p) and/or mutated TP53, or CK had significantly improved PFS with acalabrutinib ± obinutuzumab vs chlorambucil-obinutuzumab (P < .0001, P ≤ .0009, and P < .0001 for both acalabrutinib-containing arms, respectively). Median overall survival (OS) was NR for all treatments, with significantly longer OS for acalabrutinib-obinutuzumab than chlorambucil-obinutuzumab (HR, 0.62; P = .0349). Estimated 72-month OS rates were 83.9%, 75.5%, and 74.7% for acalabrutinib-obinutuzumab, acalabrutinib, and chlorambucil-obinutuzumab, respectively. Adverse events (AEs) occurring after >4 years were mostly grade 1 to 2. Rates of AEs, serious AEs, and events of clinical interest were similar between acalabrutinib-containing arms and consistent with the known safety profiles of acalabrutinib and obinutuzumab. Efficacy and safety of acalabrutinib-containing arms were maintained, with longer PFS in both acalabrutinib arms than chlorambucil-obinutuzumab including in patients with high-risk features. This trial was registered at www.ClinicalTrials.gov as #NCT02475681.

Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high‐count monoclonal B lymphocytosis) infected by SARS‐CoV‐2, including the development of post‐COVID condition. Data from 1540 patients with CLL infected by SARS‐CoV‐2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS‐CoV‐2 variants emergence. Post‐COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4‐month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL‐directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post‐COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post‐COVID. The median time to resolution of the post‐COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS‐CoV‐2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post‐COVID conditions, warranting further investigations.

Patients with chronic lymphocytic leukaemia (CLL) infected with SARS-CoV-2 are at increased risk of severe COVID-19 and death. The outcomes of CLL patients with COVID-19 during the omicron subvariants and in particular with BA.5 are not fully elucidated. Here, we report the outcomes of 128 CLL patients diagnosed with COVID-19 from December 2021 through November 2022. The hospitalization and 30-day mortality rates were 26.6% (n = 34) and 4.7% (n = 6), respectively. Both hospitalizations and mortality were lower during the outbreaks of the BA.2 and BA.5 subvariants (17.2%, 0% vs. 15.2%, 0%, respectively) compared with the period dominated by the BA.1 subvariant (41.5%, 11.3%).

Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8–13.6] vs. 14.1 [95% CI: 10–18.1] months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5–18.2] vs. 18.4 [95% CI 14.8–22.1] months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with 2 EN sites, respectively (16.5 months [95% CI 13.4–19.6] vs. 8.7 months [95% CI 4.6–12.8], p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.