De novo accelerated phase of chronic myeloid leukemia should be recognized even in the era of tyrosine kinase inhibitors.

Overall survival of patients classified according to the European LeukemiaNet 2020 classification. Chronic phase (CP), accelerated phase (AP), blast crisis (BC), low risk (LR), intermediate risk (IR), high risk (HR).

COVID-19 in patients with chronic lymphocytic leukemia: a multicenter analysis by the Czech CLL study group.

Patients with chronic lymphocytic leukemia (CLL) have a high risk of poor outcomes related to coronavirus disease 2019 (COVID-19). This multicenter cohort study evaluated the impact of COVID-19 infection on the population of CLL patients in the Czech Republic. Between March 2020 and May 2021, 341 patients (237 males) with CLL and COVID-19 disease were identified. The median age was 69 years (range 38-91). Out of the 214 (63%) patients with the history of therapy for CLL, 97 (45%) were receiving CLL-directed treatment at diagnosis of COVID-19: 29% Bruton tyrosine kinase inhibitor (BTKi), 16% chemoimmunotherapy (CIT), 11% Bcl-2 inhibitor, and 4% phosphoinositide 3-kinase inhibitor. Regarding the severity of COVID-19, 60% pts required admission to the hospital, 21% pts were admitted to the intensive care unit (ICU), and 12% received invasive mechanical ventilation. The overall case fatality rate was 28%. Major comorbidities, age over 72, male gender, CLL treatment in history, CLL-directed treatment at COVID-19 diagnosis were associated with increased risk of death. Of note, concurrent therapy with BTKi compared to CIT was not associated with better outcome of COVID-19.

Deep Molecular Response Achieved with Chemotherapy, Dasatinib and Interferon α in Patients with Lymphoid Blast Crisis of Chronic Myeloid Leukaemia.

The treatment outcome in patients with chronic myeloid leukaemia (CML) in blast crisis (BC) is unsatisfactory despite the use of allogeneic stem cell transplantation (ASCT). Moreover, in some patients ASCT is contraindicated, with limited treatment options. We report the case series of two patients with lymphoid BC CML in whom ASCT was not approachable. The first patient developed BC two months after diagnosis in association with dic(7;9)(p11.2;p11.2) and T315I mutation. Blast crisis with central nervous system leukemic involvement and K611N mutation of the SETD2 gene developed abruptly in the second patient five years after ceasing treatment with nilotinib in major molecular response (MMR) at the patient's request. Both underwent one course of chemotherapy in combination with rituximab and imatinib, followed by dasatinib and interferon α (INFα) treatment in the first and dasatinib alone in the second case. Deep molecular response (DMR; MR 4.0) was achieved within a short time in both cases. It is probable that DMR was caused by a specific immune response to CML cells, described in both agents. The challenging medical condition that prompted these case series, and the subsequent results, suggest a re-visit to the use of a combination of well-known drugs as an area for further investigation.

Antiphospholipid antibody-mediated NK cell cytotoxicity.

Antiphospholipid syndrome (APS) is an autoimmune thrombophilia that is characterised by thrombosis and obstetric complications in the presence of antiphospholipid antibodies (aPL). Pregnancy complications remain a challenging problem for patients with APS, especially during the first trimester. Although natural killer (NK) cells constitute up to 70% of decidual lymphocytes during the first trimester, their contribution to early pregnancy loss in APS is largely unknown. We aimed to analyse whether aPL are able to recruit antibody-dependent cellular cytotoxicity (ADCC) of NK cells, with special emphasis on the differences in the effects of aPL containing anti-ß2GPI domain 1 (anti-ß2GPI-D1) antibodies (aPL+/D1+) and those that do not (aPL+/D1-). Our findings revealed a differential distribution of NK subsets in the presence of different aPL. Namely, aPL+/D1- IgGs increased CD56dim/CD16dim cells, while aPL+/D1 + IgGs increased the number of CD56bright/CD16dim cells. ADCC NK cell cytotoxicity was found to be higher in the presence of aPL+/D1- IgGs, as defined by an increased target cell death, degranulation and increased expression of CD11b, CD69 and NKG2D. Overall, our evidence showed that aPL are able to recruit ADCC, suggesting NK cells as candidate cells for APS-related obstetric complications.

Ibrutinib in mantle cell lymphoma: a real-world retrospective multi-center analysis of 77 patients treated in the Czech Republic.

Ibrutinib revolutionized therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Real-world data on the outcome of unselected patients are still limited. We analyzed 77 R/R MCL patients receiving ibrutinib with at least one prior systemic anti-lymphoma therapy. After a median follow-up of 14.0 months, 56 patients relapsed/progressed, and 45 died. The overall response rate was 66%, with 31% of complete metabolic remissions on PET/CT. The median progression-free and overall survival (OS) rates were 10.3 and 23.1 months, respectively. The median OS from ibrutinib failure was 3.7 months. High proliferation rate by Ki67 (≥ 30%) and two or more previous therapy lines both negatively correlated with outcome (HR = 2.2, p = 0.04, and HR = 2.06, p = 0.08, respectively). Female gender borderline correlated with better outcome (HR = 0.53, p = 0.08). In multivariate analysis, Ki67 and response to ibrutinib both correlated with OS (p < 0.05). Importantly, ibrutinib appeared to better control nodal and extranodal lymphoma than bone marrow (BM) involvement. From 20 patients with detectable BM infiltration (before ibrutinib initiation) achieving complete (n = 13) or partial (n = 7) metabolic remission, none achieved remission in BM. We confirmed good efficacy of ibrutinib in unselected heavily pre-treated MCL patients. Our findings support the use of a combination of ibrutinib and rituximab in patients with BM involvement.

Cellular senescence marker p16INK4a and NFKB1 gene polymorphisms in lower gastro-intestinal acute graft versus host disease.

BACKGROUND: Lower gastrointestinal (GI) graft versus host disease (GVHD) represents a severe complication in allogeneic hematopoietic stem cell transplant (HSCT) recipients with high rates of transplant-related mortality. Deregulated innate immunity reactions are the features of its pathogenesis. Cellular senescence has been considered a program of the innate immunity. We focused on lower GI GVHD from the perspective of cellular senescence. OBJECTIVE: We analyzed the impact of p16INK4a expression, a hallmark of cellular senescence, in intestinal biopsies of patients with lower GI GVHD symptoms and NFKB1 gene polymorphisms (rs3774937 C/T and rs3774959 A/G) on HSCT outcome. STUDY DESIGN: Fifty-two single-center patients who presented with symptoms of lower GI GVHD were analyzed in a retrospective manner. Two SNPs located in the NFKB1 gene regions (rs3774937 C/T and rs3774959 A/G) were genotyped from the peripheral blood samples collected before the start of the conditioning. All patients underwent proctosigmoidoscopy with biopsy of the mucosa. The expression of p16INK4a was analyzed in normal intestinal crypts and stroma. RESULTS: Fifty-two patients (50% male) received HSCT for hematological diseases (acute leukemias in 67%) and developed lower GI symptoms. Patients with p16INK4a expression in the intestinal stroma were in lower risk of developing histological grade 3-4 aGVHD (RR 0.18 [95% CI 0.05-0.65]; p = 0.009). The multivariate linear regression confirmed the independent effect of p16INK4a expression on time of the lower GI aGVHD symptoms onset (Coef. 38.9 [95% CI 12.7-65.1]; p = 0.005). The NFKB1 rs3774937 CC and TT/TC genotype were present in 40 and 80% of patients with p16INK4a expression, respectively (p = 0.04). The rs3774959 AA and GG/AG genotype were present among 43 and 82% of patients with p16INK4a expression, respectively (p = 0.02). Expression of p16INK4a was associated with no clinical variable but NFKB1 genotype. CONCLUSIONS: Our results address possible new mechanisms that may lead to better understanding of HSCT-related immune complications. Cellular senescence may bring novel approaches in GVHD diagnostics and therapy.

Infectious complications of induction treatment for acute myeloid leukaemia using the "7 + 3" protocol without antibiotic prophylaxis - 15 years of experience of one clinical site.

BACKGROUND: Infectious complications during induction chemotherapy of acute myeloid leukaemia are very common. Prophylactic use of antibiotics however is an ongoing challenge in this situation due to bacterial multi-drug resistance. The aim of this study was to provide a comprehensive overview of the incidence of infectious complications in patients with AML undergoing induction therapy using the "7+3" protocol without routine antibiotic prophylaxis at one clinical site providing specialised haematological care in the Czech Republic, over a period of 15 years. The study also evaluates the aetiological spectrum of causative agents and the development of antibiotic resistance in the context of the use of the various classes of antibiotics. The analysis includes evaluation of the importance of risk factors for infectious complications and their impact on treatment of the underlying disease. The data are compared with published figures for similar cohorts of patients. PATIENTS AND METHODS: This study presents a retrospective analysis of infectious complications in 242 patients with acute myeloid leukaemia undergoing the first cycle of induction therapy without routine antibiotic prophylaxis in one clinical site in Czech Republic during years 2006-2020. RESULTS: A total of 363 febrile episodes (FE) were recorded. At least 1 FE during the induction was detected in 229 (94.6%) patients. Clinically defined infection was the cause in 96 (26.4%) FEs and blood stream infection in 69 (19.0%) FEs. Both complications occurred simultaneously in 29 (8.0%) FEs. 169 (46.6%) FEs were evaluated as fever of unknown origin (FUO). The achievement of complete remission had a significant effect on the duration of the FE (6 vs. 9 days, P=0.0005) and on the overall survival duration (79.3 vs. 6.5 months, P<0.0001). Patients diagnosed with infection or FUO at diagnosis were significantly more likely to suffer from colonisation by multi-drug resistant bacterial strains at discharge (29.2% vs. 16.3%, P=0.022). This group of patients used antibiotic therapy for a significantly longer time (35 vs. 23 days, P<0.0001). Infection was a contributing cause of death in 18 (7.4%) patients. Mortality was significantly related to the failure to achieve complete remission (P<0.0001). CONCLUSION: Infectious mortality during induction treatment without routine antibiotic prophylaxis was comparable to the published cohorts with prophylaxis. Regular microbiology surveillance with adequate initial antibiotic treatment can compensate routine antibiotic prophylaxis with slower development of antibiotic resistance.

Breakthrough COVID-19 in Vaccinated Patients with Haematologic Malignancies-The First Single-Centre Experience from the Czech Republic.

Vaccination is an important tool in the fight against the COVID-19 pandemic in patients with haematologic malignancies. The paper provides an analysis of the course of breakthrough SARS-CoV-2 infection in a group of vaccinated patients with haematological malignancy and a comparison with a historical cohort of 96 non-vaccinated patients with haematologic malignancies and bone marrow failure syndromes (two patients) in the treatment of COVID-19. A severe or critical course of COVID-19 was significantly less frequent in the group of vaccinated patients (10.2% vs. 31.4%, p = 0.003). The need for hospitalisation due to COVID-19 was significantly lower in vaccinated patients (27.1% vs. 72.6%, p < 0.0001) and the duration of hospitalisation was significantly shorter (10 vs. 14 days, p = 0.045). Vaccinated patients were insignificantly less likely to require oxygen therapy during infection. COVID-19 mortality was significantly higher in non-vaccinated patients (15.6% vs. 5.1%, p = 0.047). The paper demonstrated a significant positive effect of vaccination against COVID-19 on a less severe clinical course of infection, lower need for hospitalisation and mortality. However, the results need to be evaluated even in the context of new antivirals and monoclonal antibodies against SARS-CoV-2 or virus mutations with different biological behaviour.

Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers.

Germline pathogenic ATM (ataxia-telangiectasia mutated) variants are associated with the risk of multiple cancers; however, genetic testing reveals a large number of ATM variants of uncertain significance (VUS). Here, we studied germline ATM variants occurring in a real-world cohort of 336 patients with chronic lymphocytic leukaemia (CLL) and public cancer whole-exome/genome-sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). We found that two-thirds of rare germline ATM variants are pathogenic (18%-50%) or VUS-predicted pathogenic (50%-82%), depending on cancer type and reaching a prevalence of up to 8%, and one-third are VUS-predicted benign. Patients with both pathogenic and VUS-predicted pathogenic variants, all heterozygous, mostly missense, are more predisposed to biallelic ATM inactivation by acquiring deletion (del)11q than patients without these variants, similar to patients with somatic ATM variants. A functional assay of ATM activity in primary CLL cells proved that VUS-predicted pathogenic ATM variants partially reduce ATM activity and concurrent del(11q) leads to complete loss of ATM activity. The rare germline variants were associated with reduced progression-free survival in CLL on novel agents, comparable to somatic ATM or TP53 disruptions. Our results highlight the need to determine the pathogenicity of VUS in clinically relevant genes such as ATM.

Towards a Better Characterisation of Leukemic Cells in Chronic Lymphocytic Leukaemia: Cell-Size Heterogeneity Reflects Their Activation Status and Migratory Abilities.

Chronic lymphocytic leukaemia (CLL) is a genetically, morphologically and phenotypically heterogeneous chronic disease with clinical variability between patients. Whether the significant heterogeneity of cell size within the CLL population contributes to the heterogeneous features of this disease has not been investigated. The present study aimed to characterise the phenotypic and functional properties of two subpopulations of typical CLL cells that differ in cell size: small (s-CLL) and large (l-CLL) CLL cells delineated by forward scatter cytometry. The s-CLL cells were characterised by the CD5lowCXCR4hi phenotype, while the l-CLL cells were characterised by the CD5hiCXCR4dim phenotype and indicated a higher expression of CXCR3, CD20, CD38 and HLA-DR. The l-CLL cells displayed higher migration activity towards CXCL12, a tendency towards a higher proliferation rate and an increased capacity to produce IgM in the presence of CpG compared with s-CLL cells. When stimulated with CpG and CXCL12, l-CLL cells were characterised by a higher polarisation phenotype and motility than s-CLL cells. Our study revealed that the differences in CLL cell size reflected their activation status, polarisation and migratory abilities. Our data provide evidence of the importance of cell-size heterogeneity within a CLL pool and the dynamics of cell-size changes for disease pathogenesis, thus deserving further investigation.

Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities.

Extramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). EMM is frequently associated with high-risk cytogenetics, but their complex genomic architecture is largely unexplored. We used whole-genome optical mapping (Saphyr, Bionano Genomics) to analyse the genomic architecture of CD138+ cells isolated from bone-marrow aspirates from an unselected cohort of newly diagnosed patients with EMM (n = 4) and intramedullary MM (n = 7). Large intrachromosomal rearrangements (> 5 Mbp) within chromosome 1 were detected in all EMM samples. These rearrangements, predominantly deletions with/without inversions, encompassed hundreds of genes and led to changes in the gene copy number on large regions of chromosome 1. Compared with intramedullary MM, EMM was characterised by more deletions (size range of 500 bp-50 kbp) and fewer interchromosomal translocations, and two EMM samples had copy number loss in the 17p13 region. Widespread genomic heterogeneity and novel aberrations in the high-risk IGH/IGK/IGL, 8q24 and 13q14 regions were detected in individual patients but were not specific to EMM/MM. Our pilot study revealed an association of chromosome 1 abnormalities in bone marrow myeloma cells with extramedullary progression. Optical mapping showed the potential for refining the complex genomic architecture in MM and its phenotypes.

COVID-19 in 96 Patients With Hematologic Disease: The First Single-center Experience From the Czech Republic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) represents an important infectious complication associated with high mortality rates in patients with hematologic diseases. There have not been published any epidemiologic studies from Czech Republic so far. PATIENTS AND METHODS: This study is the first analysis of patients with hematologic malignancies and bone marrow failure syndromes treated at single hematology center in the Czech Republic between March 1 and December 31, 2020, in whom COVID-19 infection was confirmed. RESULTS: The sample comprised 96 patients aged 26 to 84 years (median, 66.0 years). At the time of their COVID-19 diagnosis, 75 patients (78.1%) were treated for hematologic diseases. Twenty-seven patients (28.1%) in the sample had complete remission (CR) of their hematologic disease. They were nonsignificantly more likely to have asymptomatic to moderate COVID-19 infection than those who failed to achieve CR (74.1% vs. 56.5%; P = .06). A more severe course of the infection was significantly correlated with older age (P = .047). Lung involvement was also statistically significantly associated with older age (P = .045). Over the study period, a total of 15 patients died. Age greater than 60 years was significantly associated with deaths from COVID-19 (P = .036), with failure to achieve CR having a statistically nonsignificant impact on mortality (P = .22). CONCLUSION: These results confirm the prognostic significance of age for achieving treatment response of hematologic disease as well as the severity and mortality of COVID-19 in hematology patients.

Revisiting Richter transformation in the era of novel CLL agents.

Richter transformation (RT) is the development of aggressive lymphoma - most frequently diffuse large B-cell lymphoma (DLBCL) and rarely Hodgkin lymphoma (HL) - arising on the background of chronic lymphocytic leukaemia (CLL). Despite recent advances in CLL treatment, RT also develops in patients on novel agents, usually occurring as an early event. RT incidence is lower in CLL patients treated with novel agents in the front line compared to relapsed/refractory cases, with a higher incidence in patients with TP53 disruption. The genetic heterogeneity and complexity are higher in RT-DLBCL than CLL; the genetics of RT-HL are largely unknown. In addition to TP53, aberrations in CDKN2A, MYC, and NOTCH1 are common in RT-DLBCL; however, no distinct RT-specific genetic aberration is recognised yet. RT-DLBCL on ibrutinib is frequently associated with BTK and PLCG2 mutations. Here, we update on genetic analysis, diagnostics and treatment options in RT in the era of novel agents.

The role of new technologies in myeloproliferative neoplasms: Application of next-generation sequencing in myelofibrosis.

INTRODUCTION: Driver mutations in Philadelphia chromosome-negative myeloproliferative neoplasms are well known. In the past, whole-genome sequencing identified nondriver mutations in other genes, potentially contributing to evolution of malignant clones. METHODS: Next-generation sequencing was used to assess the presence of any mutations in 14 candidate genes at the point of diagnosis and the resultant impact on the clinical course of the disease. RESULTS: The study analysed 63 patients with myelofibrosis (MF). Nondriver mutations were detected in 44% of them. The most frequently affected genes were ASXL1 (27%), TET2 (11%) and SF3B1 (6%). The frequency of such mutations was highest in primary MF (59%) and lowest in the prefibrotic phase of primary MF (21%). Patients with prognostically unfavourable sequence variants in genes had significantly worse overall survival (53 vs 71 months; HR = 2.77; 95% CI 1.17-6.56; P = .017). CONCLUSION: In our study, multivariate analysis proved DIPSS to be the only significant factor to predict patient survival. DIPSS contains all of the important clinical and laboratory factors except genetic changes. Stratification of patients according to DIPSS is still beneficial although there are newer and improved scoring systems like GIPSS or MIPSS70. Assessing subclonal mutations in candidate genes during diagnosis may aid in the identification of high-risk MF patients and is therefore relevant for making a prediction for overall survival more accurate.

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukaemia using patient similarity networks.

The tissue microenvironment in chronic lymphocytic leukaemia (CLL) plays a key role in the pathogenesis of CLL, but the complex blood microenvironment in CLL has not yet been fully characterised. Therefore, immunophenotyping of circulating immune cells in 244 CLL patients and 52 healthy controls was performed using flow cytometry and analysed by multivariate Patient Similarity Networks (PSNs). Our study revealed high inter-individual heterogeneity in the distribution and activation of bystander immune cells in CLL, depending on the bulk of the CLL cells. High CLL counts were associated with low activation on circulating monocytes and T cells and vice versa. The highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. PSNs revealed a low activation of immune cells in CLL progression, irrespective of IgHV status, Binet stage and TP53 disruption. Patients with high intermediate monocytes (> 5.4%) with low activation were 2.5 times more likely (95% confidence interval 1.421-4.403, P = 0.002) to had shorter time-to-treatment than those with low monocyte counts. Our study demonstrated the association between the activation of circulating immune cells and the bulk of CLL cells. The highest activation of bystander immune cells was detected in patients with slow disease course and in those treated with novel agents. The subset of intermediate monocytes showed predictive value for time-to-treatment in CLL.

High CXCR3 on Leukemic Cells Distinguishes IgHV mut from IgHV unmut in Chronic Lymphocytic Leukemia: Evidence from CD5high and CD5low Clones.

Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5high and CD5low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5high and CD5low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n = 60) subgrouped according to the IgHV mutational status (IgHV mut, n = 24; IgHV unmut, n = 36). CD5high subpopulation showed a high percentage of CXCR3 (P < 0.001), CCR10 (P = 0.001), and CD62L (P = 0.031) and high levels of CXCR5 (P = 0.005), CCR7 (P = 0.013) compared to CD5low cells expressing high CXCR4 (P < 0.001). Comparing IgHV mut and IgHV unmut patients, high levels of CXCR3 on CD5high and CD5low subpopulations were detected in the IgHV mut patients, with better discrimination in CD5low subpopulation. Levels of CXCR3 on CD5low subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5high and CD5low neoplastic cells in IgHV mut with a better prognosis compared to IgHV unmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.

Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents.

Inhibitors of B-cell receptor signaling, ibrutinib and idelalisib, and BCL-2 antagonist, venetoclax, have become the mainstay of treatment for chronic lymphocytic leukemia (CLL). Despite significant efficacy in most CLL patients, some patients develop resistance to these agents and progress on these drugs. We provide a state-of-the-art overview of the acquired resistance to novel agents. In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No distinct unifying resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax. In most cases, patients who have progressed on ibrutinib and venetoclax experience resistance-associated mutations, often present at low allelic frequencies. Resistance-associated mutations tend to occur between the second and fourth years of treatment and may already be detected several months before clinical relapse. We also discuss the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.

17ß-Estradiol Promotes Proinflammatory and Procoagulatory Phenotype of Innate Immune Cells in the Presence of Antiphospholipid Antibodies.

Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia and recurrent spontaneous miscarriages associated with extended persistence of antiphospholipid antibodies (aPL). How circulating aPL and high-17ß-estradiol (E2) environment contribute to the pregnancy complications in APS is poorly defined. Therefore, we aimed to analyse whether E2 could be responsible for the immune cell hyperactivation in aPL- positive (lupus anticoagulant, anti-cardiolipin, anti-ß2-glycoprotein) in women. For this, peripheral blood mononuclear cells (PBMCs) from 14 aPL- positive and 13 aPL- negative women were cultured in the presence or absence of E2, LPS or E2+LPS and cell immunophenotype and cytokine release were analysed. In the aPL+ group, E2 presence markedly increased the percentage of NK cells positive for CD69 (p < 0.05), monocytes positive for tissue factor (TF, CD142) (p < 0.05), and B cells expressing PD-L1 (p < 0.05), as well as the elevated production of IL-1ß comparing to aPL- women (p < 0.01). Regardless of aPL positivity, E2 augmented the procoagulatory response elicited by LPS in monocytes. Our findings show the ability of E2 to promote proinflammatory and procoagulatory phenotype of innate immune cells in individuals with aPL positivity. Our data highlights the significant impact of female hormones on the activation of immune cells in the presence of aPL.