Resistance to Bruton's tyrosine kinase (BTK) and BCL2 inhibitors, such as ibrutinib (Ibru) and venetoclax (Ven), remains a major therapeutic challenge in Mantle Cell Lymphoma (MCL), which limits treatment options. The receptor tyrosine kinase ROR1, aberrantly expressed in MCL and other malignancies but largely absent in normal adult tissues, has been implicated in tumour cell proliferation, survival, and migration. This study aimed to elucidate mechanisms underlying Ibru and Ven resistance in MCL and to investigate the therapeutic potential of targeting ROR1 using the small molecule inhibitor KAN571C in Ibru and/or Ven resistant MCL cell lines. Ibru-, Ven-, and Double (Ibru+Ven)-resistant models were generated from the JEKO-1, Granta-519, and Z138 MCL cell lines. The cytotoxic effects of Ibru, Ven, and KAN571C were assessed in both naïve and drug-resistant models using MTT assays. Western blotting was employed to analyse downstream signalling alterations following exposure to KAN571C. KAN571C induced potent cytotoxicity in both naïve and drug-resistant models, preferentially in venetoclax- and ibrutinib/venetoclax-resistant cells. Mechanistically, KAN571C dephosphorylated ROR1 at tyrosine kinase (TK) and proline-rich domains (PRD), suppressed downstream PI3K/AKT and β-catenin signalling, and activated caspase-dependent apoptosis. Notably, long-term exposure (2 weeks) failed to establish KAN571C-resistant cell lines. Our findings identify ROR1 as a convergent mediator of resistance in MCL and highlight KAN571C as a potential therapeutic strategy to overcome treatment refractoriness.

ABSTRACT:Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N = 301; n = 132, treatment-naive [TN]; n = 169, relapsed/refractory [R/R]), data from SEQUOIA (phase 3; TN; zanubrutinib; NCT03336333), ALPINE (phase 3; R/R; zanubrutinib vs ibrutinib; NCT03734016), and AU-003 (NCT02343120) (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n = 127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n = 75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among patients treated with zanubrutinib and 38.5% among those treated with ibrutinib, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n = 24; median follow-up, 69.6 months), 10 of 24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% confidence interval [CI], 95.2-98.8), and in ALPINE was 89.3% (95% CI, 80.1-95.3) with zanubrutinib vs 76.0% (95% CI, 64.7-85.1) with ibrutinib. Responses deepened over time in both TN and R/R populations. The most frequent nonhematologic treatment-emergent adverse events occurring in >20% of patients treated with zanubrutinib with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea, and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and R/R settings.

Cell membranes undergo biophysical remodeling as an adaptation to the surroundings and to perform specific biological functions. However, the extent and relevance of such changes in human immune cells remain unknown, largely because of the lack of single-cell and multidimensional methodologies. Here we apply a cytometry-based method to fill this gap by combining biophysical profiling with simultaneous analysis of immune cell markers. This platform reveals notable cell-type-dependent plasma membrane order heterogeneity in immune cells. By sorting immune cells according to their membrane order and performing transcriptome and spatial surface proteome analyses together with functional tests, we show that plasma membrane order can be used to identify subsets of immune cells with distinct phenotypes and functional behaviors. Our findings demonstrate a broad heterogeneity of plasma membrane order in immune cells that will provide a more precise definition of immune cell states on the basis of their biophysical properties in health and disease. Cells undergo membrane remodeling in response to the environment to perform specific functions. Now, a cytometry-based method with immune cell biomarker analysis captures variations in plasma membrane order with respect to immune cell type, phenotype and functional behavior under different health and disease states.

Background Immunocompromised individuals were identified early in the pandemic as being at increased risk of severe COVID-19 and have demonstrated variable immune responses to SARS-CoV-2 vaccination. Although coordinated vaccination programmes are now well established, their long-term effects on sustained immunity in the present patient populations remain insufficiently understood. Methods The prospective SARS-CoV-2 mRNA vaccine trial COVAXID was conducted in a well-characterised, real-world cohort of 539 immunocompromised and healthy individuals across 21 subgroups, organised into six main categories. At the 36-month time point, 218 participants remained. Participants provided blood samples for assessment of binding antibody titres and pseudo-neutralisation activity against ancestral SARS-CoV-2 and 21 variants, including Omicron sub-lineages. T cell responses were evaluated in a defined subset of participants. Immunogenicity outcomes were analysed over a three-year period in relation to SARS-CoV-2 vaccination, SARS-CoV-2 infection, and immunoglobulin replacement therapy (IGRT). Findings Between years two and three, antibody titres and neutralisation capacity showed a consistent pattern of maintenance or increase across most study groups and subgroups. These increases were driven by cumulative exposure to vaccine booster doses, SARS-CoV-2 infection, and, in some cases, passive immunisation through IGRT. CD4+ and CD8+ T cell responses were detected across all study groups. Early immune responses were primarily vaccine-driven, whereas later immune profiles reflected substantial contributions from natural infection and anti-SARS-CoV-2 antibodies in IGRT products. Interpretation The findings support continued, tailored vaccination strategies for elderly and immunocompromised individuals. Integrating immune monitoring with infection history and adjunctive therapies may help refine booster policies, optimise protection, and strengthen future vaccination programmes for high-risk populations. Funding The present studies were supported by the European Research Council, Karolinska Institutet, Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and the Swedish Research Council.

BACKGROUND:Venetoclax-rituximab (VR) following covalent Bruton tyrosine kinase (BTK) inhibitor therapy is the fixed-duration standard of care for patients with chronic lymphocytic leukaemia (including small lymphocytic lymphoma). Pirtobrutinib, a non-covalent BTK inhibitor, is approved for use after treatment with a covalent BTK inhibitor as a continuous therapy option. We aimed to evaluate the addition of pirtobrutinib to VR as a fixed-duration regimen in patients with relapsed or refractory chronic lymphocytic leukaemia. METHODS:This open-label, multicentre, randomised, controlled, phase 3 trial was conducted at 152 sites (comprising community hospitals and academic centres) across 22 countries. Eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic lymphocytic leukaemia (including small lymphocytic lymphoma), and had previously been treated with at least one line of therapy that could include a covalent BTK inhibitor. Patients who had previously received a non-covalent BTK inhibitor, venetoclax, or another BCL2 inhibitor were not eligible. Enrolled patients were randomly assigned (1:1) using an interactive web-based randomisation system, stratified by del(17p) status and previous exposure to covalent BTK inhibitors, and assigned to receive either pirtobrutinib plus VR (PVR) or VR. Both groups received oral venetoclax (25 cycles) and intravenous rituximab (six cycles); the PVR group also received oral pirtobrutinib for 28 cycles, with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax initiation. For this prespecified interim analysis, the primary endpoint was progression-free survival in the intention-to-treat population, assessed by a masked independent review committee (IRC) as per 2018 International Workshop on Chronic Lymphocytic Leukemia guidelines. Safety analyses were conducted in the safety population, defined as all randomly assigned patients who took at least one dose of any study treatment. All analyses were based on a data cutoff date of Feb 2, 2026. The trial is registered at ClinicalTrials.gov, NCT04965493, and is ongoing but no longer recruiting. FINDINGS:Between Oct 13, 2021, and Oct 28, 2024, 784 patients were screened, of whom 639 were randomly assigned: 321 to the PVR group and 318 to the VR group. The median age of patients was 68·0 years (IQR 60·0-74·0), of whom 439 (69%) were male and 200 (31%) were female. The median number of previous therapies was 2 (IQR 1-3); 510 (80%) of 639 patients had previous exposure to covalent BTK inhibitors, of whom 362 (71%) discontinued their most recent drug of this class owing to progressive disease. At a median follow-up of 27·3 months (IQR 19·5-38·7), PVR showed a significant improvement in IRC-assessed progression-free survival compared with VR (hazard ratio 0·547 [95% CI 0·400-0·748]; p=0·0001). The median 24-month progression-free survival rate was 87% (95% CI 82·3-90·4) in the PVR group versus 72% (65·7-77·0) in the VR group, and the median progression-free survival was not reached (IQR 31·7-not estimable) in the PVR group versus 39·7 months (21·5-50·0) in the VR group. This benefit was consistent across prespecified subgroups, including patients with previous exposure to covalent BTK inhibitors. The most frequent treatment-emergent adverse event of any grade in both groups was diarrhoea, reported in 106 (34%) of 316 patients in the PVR group and 110 (35%) of 311 patients in the VR group. The frequency of treatment-emergent adverse events of grade 3 or higher was similar in both groups (249 [79%] of 316 patients in the PVR group vs 227 [73%] of 311 patients in the VR group); the rate of tumour lysis syndrome of grade 3 or higher was lower in the PVR group (1%; three of 316) than in the VR group (4%; 12 of 311). Rates of atrial fibrillation or flutter of any grade were low (11 [3%] of 316 patients in the PVR group vs eight [3%] of 311 patients in the VR group). Rates of treatment discontinuation owing to treatment-emergent adverse events deemed as related to any of the study drugs were similar: 5% (17 of 316 patients) in the PVR group versus 5% (16 of 311 patients) in the VR group. There were five treatment-related deaths: one in the PVR group and four in the VR group. INTERPRETATION:In patients with previously treated chronic lymphocytic leukaemia, PVR showed significant improvement in progression-free survival compared with VR, with consistent results in patients who had previously received covalent BTK inhibitors and no new safety signals. To our knowledge, these results represent the first randomised phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory chronic lymphocytic leukaemia, supporting PVR as a potential new standard of care. FUNDING:Eli Lilly and Company.

IntroductionChronic lymphocytic leukemia (CLL) has proven difficult to treat with chimeric antigen receptor (CAR) T cell therapy. CLL cells can negatively alter T cell fitness and induce a pseudohypoxic state. We hypothesized that production of CAR T cells under restricted oxygen conditions resembling physiological oxygen levels that can be encountered in tissues (i.e. 2% O2) could promote outgrowth of hypoxia-tolerant CAR T cells.MethodsWe performed in vitro phenotypic and functional assessments of CD19-directed CAR T cells produced in either 21% (NorCAR) or 2% (HypCAR) O2 derived from healthy donors (HDs) or patients with CLL. ResultsProduction of HD-derived CAR T cells in 2% O2 promoted the enrichment of a naïve-like subset. HypCAR and NorCAR cells were functionally distinct; CD4+ HypCAR cells produced more IL-2 and tumor necrosis factor than CD4+ NorCAR cells. Production in 2% O2 was not detrimental to viability or proliferation upon cognate antigen-stimulation and led to increased activation. After chronic stimulation in hypoxia, HypCAR-product remained enriched in naïve-like cells, and demonstrated cytotoxic and cytokine production capacity. In CAR T cells derived from patients with CLL, NorCAR and HypCAR subsets were functionally and phenotypically comparable, but displayed different mitochondrial metabolism. DiscussionWe demonstrated that production in 2% O2 is not detrimental, confers subtle but lasting functional and phenotypic changes in CAR T cells warranting further research on the impact of hypoxic production on CAR T cell functionality in hypoxic tumor microenvironments.

Individuals with chronic lymphocytic leukemia (CLL) face increased risk of severe COVID-19. This study from Sweden, a country with few mandatory restrictions at the onset of the pandemic, used 10 nationwide registers to compare risks of severe COVID-19 outcomes of PCR-verified SARS-CoV-2 infections through February 2023 in individuals with vs without CLL. From a population of 8,275,839 (6,653 CLL) individuals born 1930-2003, 2,088,163 first infections (1,289 CLL) were included. The 90-day all-cause mortality rate and adjusted relative risk (aRR [95% CI]) for individuals with CLL vs the general population was 24.8% (1.95 [1.58-2.41)) during Wild-type, 17.2% (2.38 [1.58-3.57)) during Alpha, 4.1% (0.71 [0.24-2.08]) during Delta, and 12.6% (1.49 [1.24-1.78]) during Omicron. Their mortality during Omicron was 0.6% (<65 years), 5.4% (65-74 years), and 19.7% (>75 years). Small molecule inhibitors (1.56 [1.03-2.37]) and corticosteroid usage (1.45 [1.04-2.02]) was associated with increased mortality. Next, we analyzed the all-cause mortality in the capital (Stockholm), widely affected by SARS-CoV-2 at the onset of the pandemic. Mortality in individuals with CLL increased by 55% during the first 6 months of 2020 vs 2019 and age- and sex aRR by June 30 was 1.53 [1.09-2.15] for individuals with CLL (P=.02) and 1.29 [1.25-1.33] for the general population (P<.001). Collectively, a significantly increased risk of severe COVID-19 and death was observed among individuals with CLL in Sweden, particularly at the onset of the pandemic when few national protective measures were introduced, but also after Omicron emerged, emphasizing the need for a more pro-active pandemic strategy for CLL.

Background: Covalent Bruton tyrosine kinase inhibitors (cBTKi) have dramatically changed the treatment (tx) landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), especially in the first-line setting. However, cBTKi resistance or intolerance eventually occurs. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib demonstrated safety and efficacy in the phase 1/2 BRUIN study among patients (pts) with R/R CLL/SLL, including pts previously treated with a BTKi. Pirtobrutinib is approved for treating CLL in adults in the EU after prior tx with a BTKi, and in the USA for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTKi and a BCL-2i. Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529) with more than 5 years (yrs) follow-up (f/u), focusing on efficacy and safety of pirtobrutinib in pts with CLL/SLL in the post-cBTKi setting. Methods: Pts with prior cBTKi-exposed CLL/SLL were eligible for tx with pirtobrutinib. Endpoints included overall response rate (ORR) per 2018 iwCLL criteria, ORR including partial response with lymphocytosis (PR-L), duration of response (DOR), and progression-free survival (PFS), assessed by independent review committee (IRC; presented herein) and investigator, overall survival (OS), and safety. Data cut was 27 January 2025, providing a median study f/u of 34.1 months (mos; range, 0.5-69.8). Results: Among the 282 pts with CLL/SLL who were cBTKi-exposed and treated with pirtobrutinib, of which 84.4% (238/282) received 200 mg as the starting dose, the median age was 69 yrs (range, 36-88). The median number of prior therapies was 4 (range, 1-11), with 45.4% of pts having received prior BCL2i, and 77.0% having discontinued prior cBTKi due to progressive disease (PD), 19.5% due to toxicity, and 3.5% due to other reasons/missing. High-risk features were frequent: unmutated IGHV in 85.8% (193/225), mutated TP53 in 40.4% (99/245), and del(17p) in 29.2% (59/202). The ORR was 72.3% (95% CI, 66.7-77.5). ORR including PR-L was 81.6% (95% CI, 76.5-85.9), which was consistent across subgroups including BCL2i-exposed (80.5%; 95% CI, 72.5-86.9), BCL2i-naive (82.5%; 95% CI, 75.5-88.1), unmutated IGHV (82.9%; 95% CI, 6.8-87.9), del(17p) (88.1%; 95% CI, 77.1-95.1), and prior cBTKi discontinuation due to PD (79.7%; 95% CI, 73.8, 84.9) or toxicity (87.5%; 95% CI, 76.8-94.4). The median DOR was 18.4 mos (95% CI, 14.82-20.27), with 36-mos DOR rate of 28.0% (21.6-34.7). The median PFS was 18.7 mos (95% CI, 16.6-21.8) among all pts and the 36-mos PFS rate was 25.0% (95% CI, 19.4-31.0) with 44 mos of f/u. Further, the median PFS was 22.3 mos (95% CI, 19.3-27.6) for BCL2i-naive pts, and 15.9 mos (95% CI, 13.6-17.5) for BCL2i-exposed pts; 16.6 mos (95% CI, 13.8-19.4) among those who discontinued prior cBTKi therapy due to PD, and not estimable (NE) (95% CI, 25.2-NE) in those who discontinued due to toxicity. Among all pts with CLL/SLL, with a median f/u of 46.5 mos, the median OS was NE (95% CI, 47.8-NE), with the 36-mos OS rate of 62.0% (95% CI, 55.8-67.7). Median time on pirtobrutinib was 20.0 mos (range, 0.2-69.8), and 43 (15.2%) pts were still on tx at data cutoff. The most frequent TEAEs, regardless of attribution, were fatigue (38.7%), neutropenia/neutrophil count decreased (35.8%), diarrhea (30.5%), cough (29.8%), COVID-19 (28.4%), and contusion (27.7%). The most frequent grade ≥3 TEAEs were infection (36.5%) and neutropenia/neutrophil count decreased (29.8%). Low rates of grade ≥3 TEAE of hypertension (5.3%), hemorrhage/hematoma (2.5%), and atrial fibrillation/flutter (2.1%) were observed. Grade 5 TEAEs, regardless of attribution, occurred in 35 (12.4%) pts. Overall, 11 (3.9%) pts had a TRAE leading to a dose reduction, and 9 (3.2%) pts had a TRAE leading to pirtobrutinib discontinuation. Conclusion: In heavily pretreated R/R post-cBTKi CLL/SLL pts, pirtobrutinib continues to show favorable and durable efficacy. Pirtobrutinib is well-tolerated, with low rates of hypertension, hemorrhage/hematoma, and atrial fibrillation/flutter, which can be frequently observed with cBTKi. Additionally, dose reductions/discontinuations due to pirtobrutinib TRAEs were low. No new pirtobrutinib safety signals were identified with more than 5 yrs of f/u.

Chronic lymphocytic leukemia (CLL) cells depend on microenvironment niches for proliferation and survival. The adhesion of tumor cells to stromal cells in such niches triggers the activation of signaling pathways crucial for their survival, including B-cell receptor (BCR) signaling. While inhibitors of Bruton’s tyrosine kinase (BTKi) have shown efficacy in patients with CLL by disrupting these interactions, acquired resistance and toxicity remain a challenge during long-term therapy. Thus, identifying additional therapeutic modalities is important. Previously, we demonstrated that 5-lipoxygenase (5-LOX) pathway inhibitors reduced mantle cell lymphoma (MCL) cell adhesion to stromal cells, motivating us to investigate their potential in the context of CLL. We employed an ex vivo co-culture model to study CLL cell adhesion to stromal cells in the absence and presence of 5-LOX pathway inhibitors (zileuton and MK886) as well as the BTKi ibrutinib that was included for comparative purposes. Our findings demonstrated that different CLL samples adhere to stromal cells differentially. We observed a variable decrease in CLL cell adhesion to stromal cells following the inhibition of the 5-LOX pathway across a spectrum of patient samples that was distinct to the spectrum for ibrutinib. Positive and negative correlations were shown between the clinical and genetic features of the CLL samples and their level of adherence to stromal cells in both the absence and presence of the tested inhibitors. These results suggest the 5-LOX pathway as a candidate for assessment as a new therapeutic target in CLL.

BACKGROUND:It is thought that patients with inborn errors of immunity (IEI) are more susceptible to severe coronavirus disease 2019 (COVID-19) than the general population, but a quantification of this potential risk is largely missing. OBJECTIVE:We assessed the impact of COVID-19 on patients with IEI. METHODS:A nationwide cohort study was performed to estimate the relative risk (RR) for hospitalization, intensive care, and death within 30 days after a positive severe acute respiratory syndrome coronavirus 2 test result in an IEI population (n = 2392) compared to the general population (n = 8,270,705) using data from Swedish national registries. Three time periods were studied: the prevaccination period, and the Alpha/Delta and Omicron periods. Adjustment was made for demographics, income, comorbidities, and vaccination status. RESULTS:During the prevaccination period, 25.2% of the IEI population was hospitalized, compared to 17.5% and 5.2% during the Alpha/Delta and Omicron periods, respectively. For the 3 time periods, the adjusted RR [95% confidence interval] for hospitalization in the IEI population compared to the general population was 3.1 [2.1-4.2], 3.5 [2.4-4.8], and 4.3 [2.5-6.7], respectively. The respective values for intensive care after COVID-19 were 5.6 [2.6-10.8], 4.7 [1.7-10.1], and 4.7 [1.7-10.1] for the 3 periods. Five patients (0.6%) in the IEI population died within 30 days of a positive PCR test result compared to 18,773 (0.2%) in the general population during the 3 study periods. CONCLUSION:Patients with IEI had a 3 to 4 times higher risk for hospitalization and a 5 times higher risk for intensive care during COVID-19 compared to the general population.

AbstractPatients with chronic lymphocytic leukemia (CLL) were at high risk early in the COVID-19 pandemic. The Omicron SARS-CoV-2 variant is considered less aggressive, but a significant fatality rate was recently reported from CLL register studies. Here we report on Omicron hybrid immunity in CLL after vaccinations against SARS-CoV-2 followed by disease. Post-infection systemic and mucosal immunity against SARS-CoV-2 were analyzed in patients with CLL (n = 38) during the Omicron BA.1/BA.2 time-period. Most patients (30/38, 79%) had received 3 to 4 vaccine doses, yet median anti-Spike antibody titers were 0 U/mL (range 0–6,528) at the onset of infection. Significantly elevated serum antibody levels were observed post-infection (p = 0.0027 vs baseline) to a median of 3,145 U/mL (range 0->25 000) which correlated with inhibition of Spike-ACE2 binding. Low convalescent IgA responses were noted in both saliva and serum in patients with ongoing BTKi/BCL-2i therapy compared with early-stage untreated patients (p = 0.010; p = 0.051). Post-Omicron CD4 + and CD8 + T cell responses were observed at levels similar to those of healthy donors. Forty-seven percent of the patients required hospitalization but there was only one possibly related death. Broad immunity was observed in patients with CLL following Omicron infection. Impaired mucosal immunity during BTKi therapy requires further studies.

BACKGROUND:Data on the outcomes of COVID-19 in people living with HIV (PLHIV), specifically in relation to vaccination status, are lacking during the Omicron era. METHODS:This nationwide registry-based study included all resident in Sweden ≥18 years with a positive SARS-CoV-2 PCR test during January 2021-February 2023. We estimated adjusted odds ratios (adjOR) for COVID-19 hospitalisation and severe COVID-19 (ICU admission and 90-day mortality), categorised by SARS-CoV-2 vaccination status (0-1, 2, and ≥3 doses), and HIV-status. Analyses were then categorised by time periods of pre-Omicron, Omicron during public testing, and Omicron after public testing. RESULTS:1348 PLHIV and 1 669 389 people without HIV (PWoH) were included. PLHIV were older, more migrant (65 vs. 22%) and male (59 vs. 46%). Of PLHIV, 96% were on antiretroviral treatment and 94% virally suppressed. AdjORs of COVID-19 hospitalisation were similar irrespective of HIV-status, controlled for demographics, calendar month of infection, comorbidities, and income. PLHIV were more likely to be hospitalised than PWoH during Omicron and public testing (adjOR 2.3, 95% CI 1.1-4.2), but not after public testing. The odds of severe COVID-19 were three times higher in PLHIV compared to PWoH vaccinated with 2 doses (adjOR 3.2, 95% CI 1.3-6.9), but not when vaccinated with ≥3 doses (adjOR 0.7, 95% CI 0.2-1.6). Migrant and low nadir CD4+ T-cells were associated with higher odds of hospitalisation in unvaccinated PLHIV. CONCLUSIONS:This nationwide study, including mostly well-treated PLHIV, highlights the importance of vaccination with booster dose/s for effective protection against severe COVID-19 in PLHIV.KEY POINTPeople living with HIV compared to people without HIV did not have higher odds of COVID-19 hospitalisation irrespective of SARS-CoV-2 vaccination status (0-1 dose, 2 doses, ≥3 doses) when adjusting for known risk factors including comorbidities and socioeconomic status.

Introduction Due to disease- and treatment-related immune defects, patients with chronic lymphocytic leukemia (CLL) have an increased risk of severe disease and death from COVID-19, as well as impaired responses to SARS-CoV-2 vaccination. Thus, we performed a retrospective nationwide analysis on the risk of severe disease and death in individuals with CLL compared to matched controls without CLL in Sweden during the first 3 years of the COVID-19 pandemic in Sweden, using multiple national and population-based registers. The impact of vaccination status and specific CLL directed therapies on outcome, during different phases of the pandemic was also studied. Methods We conducted a nationwide cohort study considering all SARS-CoV-2 infection episodes (>90 days between positive PCR tests) from individuals born 1930-2003, residing in Sweden from 1 February 2020 to 31 March 2023. Data from multiple nationwide registers with high coverage (including, but not limited to, the Total Population Register, the National Cause of Death Register, the National Vaccination Register and the INCA CLL register) were used. An infection episode was classified as exposed to CLL when a CLL diagnosis was registered any time before and up until 90 days after the positive PCR test. Each exposed episode was matched to an unexposed episode using a combination of exact and propensity score-based matching without replacement. Exact matching included age category, sex, born in Sweden, residential region, infection episode number, calendar month of positive PCR test, and SARS-CoV-2 variant. Propensity score matching included calendar week, age, and more detailed information on region of birth and residential region. Primary outcome was 90-day all-cause mortality, and secondary outcomes were 90-day COVID-19 mortality, COVID-19 hospital admission and ICU admission. Standardized mean difference (SMD) was used to assess balance before and after matching. Risk ratios (RRs) adjusted for matching factors as well as income quartile, education level, COVID-19 vaccination status, and comorbidities (based on prescription drug use) were calculated using modified Poisson regression with confidence intervals (CIs) derived from a sandwich variance estimator. Results From a population of 8,275,839 individuals (6,653 with CLL, 8,269,186 without CLL), 2,088,163 first infection episodes (1,289 CLL, 2,086,874 no CLL) and 140,041 subsequent infection episodes (83 CLL, 139,958 no CLL) were identified. From these, 1,369 episodes from individuals with CLL were matched to the same number of controls. The matching removed substantial differences observed in age, sex, region of birth, and SARS-CoV-2 variant. After matching, SMD values >0.1 were only observed for education level, immunosuppressive drug use, and COVID-19 vaccination status. The 90-day all-cause mortality was 15% (n=199) in individuals with CLL and 8% (n=113) in controls, of which 63% (n=126) and 47% (n=53) had a COVID-19 diagnosis as main cause of death. The adjusted RR (95% CI) was 1.71 (1.38-2.11) for CLL compared with controls. The 90-day all-cause mortality rate in CLL was 25% (64/258) for Wild-type, 12% (23/194) for Alpha/Delta, and 12% (112/916) for Omicron. The adjusted RRs (95% CIs) for Wild-type, Alpha/Delta, and Omicron were 1.79 (1.26-2.54), 2.17 (1.08-4.33), and 1.59 (1.19-2.12). The adjusted RR (95% CI) was 1.64 (1.21-2.24) for unvaccinated, 1.57 (1.17-2.10) for >2 doses, 1.59 (1.16-2.18) for >3 doses, and 1.97 (1.21-3.20) for >4 doses. The adjusted RR (95% CI) was 2.41 (1.79-3.24) when restricting analyses to 90-day COVID-19 mortality. Risks were also significantly increased for COVID-19 hospital admission and ICU admission. When including all 2,228,204 episodes, the adjusted RR (95% CI) was 1.68 (1.48-1.90), similar to the matched cohort analysis. Conclusions SARS-CoV-2 infected individuals with CLL had a 2.4 times higher 90-day all-cause mortality, COVID-19 hospital and ICU admission compared with matched controls. This increased risk remained throughout different SARS-CoV-2 variant periods, reinforcing the importance of sustained efforts to protect this frail patient population from infection also during the endemic phase of COVID-19. However, the consistent RR of death compared to controls through different vaccination statuses indicates a benefit in protection from death in individuals with CLL similar to that seen in controls.

What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back.