COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study.

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic.

It is feasible and safe to stop specialized follow-up of asymptomatic lower risk chronic lymphocytic leukemia.

Approximately half of patients with chronic lymphocytic leukemia (CLL) will never require treatment, still they are recommended life-long specialized follow-up (sFU). To prioritize health care resources, local hospital management implemented ending sFU in asymptomatic patients with CLL international prognostic index (CLL-IPI) and CLL without need of treatment (CLL-WONT) low to intermediate risk, who were covered by universal health care. To evaluate the feasibility and safety of ending sFU, we investigated 3-year clinical outcomes among 112 patients selected by clinical assessment to end sFU as compared with 88 patients continuing sFU. Patients who ended sFU were older but otherwise lower risk compared with patients continuing sFU. Overall survival (OS) was similar in patients ending and continuing sFU (3-year OS 87% and 80%, respectively; P=0.16). Hospital visits per patient-year were lower (median 0.7 vs 4.3, P<0.0001) and time to first infection was longer (P=0.035) in patients ending sFU as compared with those who continued sFU: this included fewer COVID infections (8 [7%] vs 17 [18%]; P=0.029) and shorter in-hospital antimicrobial treatment (median 4 vs 12 days, respectively; P=0.026). Finally, one in six patients got re-referred including 4 patients meeting iwCLL criteria for need of treatment. This also resulted in a lower 3-year first treatment rate for patients ending sFU compared with patients continuing sFU (4% vs 23%, respectively; P<0.0001). In conclusion, it is feasible and safe to end sFU for patients with CLL who have low to intermediate risk CLL-IPI and CLL-WONT scores upon thorough clinical evaluation prior to ending specialized follow-up.

Improved Innate Immune Function in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Therapy in Clinical Trials.

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) have increased risk of severe infections. Although adaptive immune dysfunction is well described, clinical tools for identifying patients at risk are lacking, warranting investigation of additional immune components. In contrast to chemotherapy, targeted agents could spare or even improve innate immune function. Therefore, we investigated innate immune phenotypes and function in patients with CLL before and during targeted treatment. EXPERIMENTAL DESIGN: Baseline and consecutive blood samples were collected from patients with CLL treated with acalabrutinib (n = 17) or ibrutinib+venetoclax (n = 18) in clinical trials. Innate immune function was assessed by TruCulture, a whole-blood ligand-stimulation assay quantifying cytokine release in response to standardized stimuli. Innate immune phenotypes were characterized by flow cytometry. As a proxy for infections, we mapped antimicrobial use before and during treatment. RESULTS: At baseline, patients with CLL displayed impaired stimulated cytokine responses to the endotoxin lipopolysaccharide (LPS) along with deactivated monocytes, enrichment of myeloid-derived suppressor cells and metamyelocytes, and elevated (unstimulated) proinflammatory cytokines. Two/three cycles of acalabrutinib or ibrutinib normalized LPS-stimulated responses, in parallel with decreased duration of infections. Innate immune profiles and elevated proinflammatory cytokines further normalized during longer-term acalabrutinib or ibrutinib+venetoclax, paralleled by decreased infection frequency. CONCLUSIONS: Innate immune impairment and infection susceptibility in patients with CLL were restored in parallel during targeted therapy. Thus, targeted treatment may reduce the risk of infections in CLL, as currently under investigation in the PreVent-ACaLL phase 2 trial of acalabrutinib+venetoclax for high-risk CLL (NCT03868722).

Treatment effect modifiers in hospitalised patients with COVID-19 receiving remdesivir and dexamethasone.

BACKGROUND: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. METHODS: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. RESULTS: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37-0.57) and 0.47 (95% confidence interval, 0.39-0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. CONCLUSIONS: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

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.

Erratum: Author Correction: Early stimulated immune responses predict clinical disease severity in hospitalized COVID-19 patients.

[This corrects the article DOI: 10.1038/s43856-022-00178-5.].

Early stimulated immune responses predict clinical disease severity in hospitalized COVID-19 patients.

Background: The immune pathogenesis underlying the diverse clinical course of COVID-19 is poorly understood. Currently, there is an unmet need in daily clinical practice for early biomarkers and improved risk stratification tools to help identify and monitor COVID-19 patients at risk of severe disease. Methods: We performed longitudinal assessment of stimulated immune responses in 30 patients hospitalized with COVID-19. We used the TruCulture whole-blood ligand-stimulation assay applying standardized stimuli to activate distinct immune pathways, allowing quantification of cytokine responses. We further characterized immune cell subsets by flow cytometry and used this deep immunophenotyping data to map the course of clinical disease within and between patients. Results: Here we demonstrate impairments in innate immune response pathways at time of COVID-19 hospitalization that are associated with the development of severe disease. We show that these impairments are transient in those discharged from hospital, as illustrated by functional and cellular immune reconstitution. Specifically, we identify lower levels of LPS-stimulated IL-1ß, and R848-stimulated IL-12 and IL-17A, at hospital admission to be significantly associated with increasing COVID-19 disease severity during hospitalization. Furthermore, we propose a stimulated immune response signature for predicting risk of developing severe or critical COVID-19 disease at time of hospitalization, to validate in larger cohorts. Conclusions: We identify early impairments in innate immune responses that are associated with subsequent COVID-19 disease severity. Our findings provide basis for early identification of patients at risk of severe disease which may have significant implications for the early management of patients hospitalized with COVID-19.

Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial.

BACKGROUND: Targeted time-limited treatment options are needed for patients with relapsed or refractory chronic lymphocytic leukaemia. The aim of this study was to investigate the efficacy of minimal residual disease (MRD)-guided, time-limited ibrutinib plus venetoclax treatment in this patient group. METHODS: HOVON141/VISION was an open-label, randomised, phase 2 trial conducted in 47 hospitals in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden. Eligible participants were aged 18 years or older with previously treated chronic lymphocytic leukaemia with or without TP53 aberrations; had not been exposed to Bruton tyrosine-kinase inhibitors or BCL2 inhibitors; had a creatinine clearance rate of 30 mL/min or more; and required treatment according to International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. Participants with undetectable MRD (<10-4; less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes) in peripheral blood and bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (weekly ramp-up 20 mg, 50 mg, 100 mg, 200 mg, up to 400 mg once daily) were randomly assigned (1:2) to ibrutinib maintenance or treatment cessation. Patients who were MRD positive continued to receive ibrutinib monotherapy. Patients who became MRD (>10-2) during observation reinitiated treatment with ibrutinib plus venetoclax. The primary endpoint was progression-free survival at 12 months after random assignment in the treatment cessation group. Progression-free survival was analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety assessment. The study is registered at ClinicalTrials.gov, NCT03226301, and is active but not recruiting. FINDINGS: Between July 12, 2017, and Jan 21, 2019, 230 patients were enrolled, 225 of whom were eligible. 188 (84%) of 225 completed treatment with ibrutinib plus venetoclax and were tested for MRD at cycle 15. After cycle 15, 78 (35%) patients had undetectable MRD and 72 (32%) were randomly assigned to a treatment group (24 to ibrutinib maintenance and 48 to treatment cessation). The remaining 153 patients were not randomly assigned and continued with ibrutinib monotherapy. Median follow-up of 208 patients still alive and not lost to follow-up at data cutoff on June 22, 2021, was 34·4 months (IQR 30·6-37·9). Progression-free survival after 12 months in the treatment cessation group was 98% (95% CI 89-100). Infections (in 130 [58%] of 225 patients), neutropenia (in 91 [40%] patients), and gastrointestinal adverse events (in 53 [24%] patients) were the most frequently reported; no new safety signals were detected. Serious adverse events were reported in 46 (40%) of 116 patients who were not randomly assigned and who continued ibrutinib maintenance after cycle 15, eight (33%) of 24 patients in the ibrutinib maintenance group, and four (8%) of 48 patients in the treatment cessation group. One patient who was not randomly assigned had a fatal adverse event (bleeding) deemed possibly related to ibrutinib. INTERPRETATION: These data point to a favourable benefit-risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukaemia, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population. FUNDING: AbbVie and Janssen.

Pre-diagnostic trajectories of lymphocytosis predict time to treatment and death in patients with chronic lymphocytic leukemia.

Background: The dynamics of pre-diagnostic lymphocytosis in patients with ensuing chronic lymphocytic leukemia (CLL) need to be explored as a better understanding of disease progression may improve treatment options and even lead to disease avoidance approaches. Our aim was to investigate the development of lymphocytosis prior to diagnosis in a population-based cohort of patients with CLL and to assess the prognostic information in these pre-diagnostic measurements. Methods: All patients diagnosed with CLL in the Greater Copenhagen area between 2008 and 2016 were included in the study. Pre-diagnostic blood test results were obtained from the Copenhagen Primary Care Laboratory Database encompassing all blood tests requested by Copenhagen general practitioners. Using pre-diagnostic measurements, we developed a model to assess the prognosis following diagnosis. Our model accounts for known prognostic factors and corresponds to lymphocyte dynamics after diagnosis. Results: We explore trajectories of lymphocytosis, associated with known recurrent mutations. We show that the pre-diagnostic trajectories are an independent predictor of time to treatment. The implementation of pre-diagnostic lymphocytosis slope groups improved the model predictions (compared to CLL-IPI alone) for treatment throughout the period. The model can manage the heterogeneous data that are to be expected from the real-world setting and adds further prognostic information. Conclusions: Our findings further knowledge of the development of CLL and may eventually make prophylactic measures possible.

Patients with CLL have a lower risk of death from COVID-19 in the Omicron era.

Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. Infection with the Omicron variant has been described as a milder disease course in the general population. However, the outcome for immunocompromised patients has not previously been reported. In a cohort of patients with CLL tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at hospital test sites in the time periods before and after dominance of the Omicron variant, rates of hospitalizations and intensive care unit admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the Omicron sublineage BA.2 variant. However, for a larger population-based cohort of patients with CLL (including the hospital cohort), 30-day mortality was 2%. Thus, patients with CLL with close hospital contacts and, in particular, those >70 years of age with 1 or more comorbidities should be considered for closer monitoring and preemptive antiviral therapy upon a positive SARS-CoV-2 test.

Prediction of clinical outcome in CLL based on recurrent gene mutations, CLL-IPI variables, and (para)clinical data.

A highly variable clinical course, immune dysfunction, and a complex genetic blueprint pose challenges for treatment decisions and the management of risk of infection in patients with chronic lymphocytic leukemia (CLL). In recent years, the use of machine learning (ML) technologies has made it possible to attempt to untangle such heterogeneous disease entities. In this study, using 3 classes of variables (international prognostic index for CLL [CLL-IPI] variables, baseline [para]clinical data, and data on recurrent gene mutations), we built ML predictive models to identify the individual risk of 4 clinical outcomes: death, treatment, infection, and the combined outcome of treatment or infection. Using the predictive models, we assessed to what extent the different classes of variables are predictive of the 4 different outcomes, within both a short-term 2-year outlook and a long-term 5-year outlook after CLL diagnosis. By adding the baseline (para)clinical data to CLL-IPI variables, predictive performance was improved, whereas no further improvement was observed when including the data on recurrent genetic mutations. We discovered 2 main clusters of variables predictive of treatment and infection. Further emphasizing the high mortality resulting from infection in CLL, we found a close similarity between variables predictive of infection in the short-term outlook and those predictive of death in the long-term outlook. We conclude that at the time of CLL diagnosis, routine (para)clinical data are more predictive of patient outcome than recurrent mutations. Future studies on modeling genetics and clinical outcome should always consider the inclusion of several (para)clinical data to improve performance.

Identifying patients with chronic lymphocytic leukemia without need of treatment: End of endless watch and wait?

INTRODUCTION: Early-stage chronic lymphocytic leukemia (CLL) challenges specialized management and follow-up. METHODS: We developed and validated a prognostic index to identify newly diagnosed patients without need of treatment (CLL-WONT) by a training/validation approach using data on 4708 patients. Composite scores derived from weighted hazards by multivariable analysis defined CLL-WONT risk groups. RESULTS: Age (>65 years: 1 point), Binet stage (B: 2 points), lactate dehydrogenase (LDH) (>205 U/L: 1 point), absolute lymphocyte count (15-30 × 109 /L: 1 point; >30 × 109 /L; 2 points), ß2-microglobulin (>4 mg/L: 1 point), IGHV mutation status (unmutated: 1 point), and 11q or 17p deletion (1 point) were independently associated with shorter time to first treatment (TTFT). Low-risk patients demonstrated 5-year TTFT of 2% by internal validation, but 7-19% by external validation. Including all patients with complete scores, the 5-year TTFT was 10% for the 756 (39%) CLL-WONT low-risk patients, and the 704 (37%) patients who were both CLL-WONT and CLL-IPI low risk demonstrated even lower 5-year TTFT (8%). CONCLUSION: We have adopted the CLL-WONT at an institution covering 1 800 000 individuals to allow patients with both low-risk CLL-WONT and CLL-IPI to be managed by primary healthcare providers, thereby prioritizing specialized hematology services for patients in dire need.

Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study.

BACKGROUND: There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. METHODS: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). RESULTS: The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38-.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29-.46). CONCLUSIONS: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.

Clinical Outcomes in Patients with Multi-Hit TP53 Chronic Lymphocytic Leukemia Treated with Ibrutinib.

PURPOSE: TP53 aberration (TP53 mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each TP53 aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) TP53 aberrations remains unclear, particularly in the context of targeted agents. PATIENTS AND METHODS: We performed deep sequencing of TP53 using baseline samples collected from 51 TP53 aberrant patients treated with ibrutinib in a phase II study (NCT01500733). RESULTS: We identified TP53 mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit TP53, respectively. The multi-hit TP53 subgroup was enriched with younger patients who had prior treatments and unmutated immunoglobulin heavy-chain variable region gene status. We observed significantly shorter overall survival, progression-free survival (PFS), and time-to-progression (TTP) in patients with multi-hit TP53 compared with those with single-hit TP53. Clinical outcomes were similar in patient subgroups stratified by 2 or >2 TP53 aberrations. In multivariable analyses, multi-hit TP53 CLL was independently associated with inferior PFS and TTP. In sensitivity analyses, excluding mutations below 1% VAF demonstrated similar outcome. Results were validated in an independent population-based cohort of 112 patients with CLL treated with ibrutinib. CONCLUSIONS: In this study, single-hit TP53 defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit TP53 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit TP53 CLL.See related commentary by Bomben et al., p. 4462.