Background In patients with hematologic malignancies, COVID-19 vaccine effectiveness is unknown and determinants of severe COVID-19 lack granularity.Methods To identify determinants of SARS-CoV-2 infection outcome we conducted a population-based, nationwide cohort study, including all adult Dutch residents who tested positive for SARS-CoV-2 between 1 June 2020, and 31 March 2022. Individuals were classified as having a (history of) hematologic malignancy, solid malignancy, or no malignancies. Primary outcome was severe COVID-19, defined as COVID-19-related hospitalization or death following first SARS-CoV-2 infection.Results Among 4 649 341 included individuals, those with hematologic malignancies were at highest risk of severe COVID-19. Vaccine effectiveness against severe COVID-19 in patients with hematologic malignancies was up to 74% (95% CI, 60% to 83%), depending on the SARS-CoV-2 variant period, the number of received vaccinations, and the time interval since vaccination. Risk of severe COVID-19 was highest for patients with recently diagnosed hematologic malignancies and declined over time, except for patients with chronic hematologic malignancies. Risk of severe COVID-19 tended to be higher in patients on tumor-specific treatment such as CD38 and CD20 antibodies, proteasome inhibitors, and protein kinase inhibitors.Conclusions COVID-19 vaccination lowered the risk of severe COVID-19 in SARS-CoV-2-infected patients with hematologic malignancies, although these patients remained at elevated risk compared with others. Determinants of severe COVID-19 included type of malignancy, time interval between malignancy diagnosis and SARS-CoV-2 infection, and treatment. These data can guide healthcare professionals in designing additional prevention and therapeutic strategies against respiratory virus infections for patients with hematologic malignancies.

IntroductionAnti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) are both used as in-vivo lymphodepleting treatment in allogeneic hematopoietic stem cell transplantation (HSCT), particularly in the matched unrelated donor (MUD) setting.MethodsIn this retrospective study, we compared the incidences of infections and viral reactivations and evaluated immune cell reconstitution in the first-year post-transplant between ATG- and PTCy-based conditioning regimens in nonmyeloablative MUD transplantations. Infection incidence was evaluated for the periods 0-100 vs. 101-365 days post-transplant. ResultsA total of 185 patients (ATG=95, PTCy=90), transplanted between 2014 and 2021, were included. In the first 100 days after transplantation, the cumulative incidence of bacterial infections was higher in the PTCy group (ATG 17% vs. PTCy 32%, p=0.01) while CMV reactivations were more frequent in the ATG group (36% vs. 16%, p<0.001). Beyond 100-days post-transplant, incidence of bacterial infections was higher in the ATG group (18% vs. 1%, p<0.001). Fungal infection incidence was similar in both groups/periods. The 1-year densities of viral infections (3.54 vs. 1.89, p<0.01) and CMV reactivations (2.21 vs. 0.68, p<0.01) were higher in the ATG compared to the PTCy group. After 1-year, circulating CD4+ T-cell counts were significantly lower in the ATG than in the PTCy group (p<0.001). DiscussionIn conclusion, this study shows that overall PTCy is associated with better immune reconstitution and reduced rate of viral infections/CMV reactivations compared to ATG-based conditioning. Together with our previous findings of a lower risk of acute GvHD following PTCy compared to ATG-based conditioning, these data may favor PTCy over ATG as GvHD prophylaxis.

In 2024, the EBMT activity survey surpassed one million HCTs reported since 1990, a major milestone in cellular therapy. That year, 47,204 HCTs (21,023 allogeneic, 26,181 autologous) were reported in 43,791 patients across 688 centres in 53 countries. Compared to 2023, HCT activity decreased (-1.1% overall, -3.9% autologous), while allogeneic increased ( + 2.6%) to the highest annual activity to date. CAR-T therapy reached 6,082 patients ( + 24.5% vs 2023), surpassing 20,000 since 2018. Main indications for allo-HCT were myeloid (62%), lymphoid malignancies (~24%), and non-malignant disorders (~17%). For auto-HCT were plasma cell disorders (59%), lymphomas (22%), and solid tumours (~6%). Unrelated donors (56%) increased ( + 5%), while HLA-identical siblings (25%) and haploidentical (19%) remained stable. Cord blood use continued decreasing (-6.2%). Paediatric HCT activity decreased slightly (-1.7%; -1.9% allogeneic, -1.1% autologous). CAR-T therapy expanded (lymphomas remaining the leading indication (70%), followed by multiple myeloma (18%,) and ALL (8%). Autoimmune diseases indications increased by 67%). Overall, transplant and CAR-T activity steadily increased, with pandemic-related declines mitigated by safety measures, reflecting systems resilience and variable country contributions. From 2025, the EBMT survey will capture adult and paediatric activity separately, establishing a comprehensive database to monitor trends, inform practice, define clinical needs and assess equitable access.

ABSTRACT:Patients with sickle cell disease (SCD) are at increased risk of COVID-19-related mortality compared with healthy individuals, even after vaccination. To what extent impaired vaccine-induced immunity contributes to this risk is unknown. We prospectively investigated vaccine immunogenicity in 31 patients with SCD who received COVID-19 mRNA vaccines. All patients used hydroxyurea. We quantified humoral and cellular immune responses 4 weeks after the second and third vaccinations and compared the results with those of age-, sex-, and vaccine-matched healthy individuals. Irrespective of higher naïve and lower memory B-cell subsets, serum neutralizing spike glycoprotein 1 immunoglobulin G antibody concentrations and frequencies of spike-specific memory B cells were similar to those in healthy individuals at each time point. Frequencies of CD4+ and CD8+ T cells in patients with SCD were also comparable with controls; however, type 1 cytokine production by spike-specific T cells was reduced. Reduced cytokine production and lower antibody production correlated with higher serum fetal hemoglobin levels, suggesting an association with hydroxyurea use. Although a third vaccination improved neutralizing antibody and memory B-cell responses, T helper 1 cytokine production tended to remain lower in patients than in controls. Our data point toward delayed or reduced vaccine-induced immunity, in line with previous reports, which may contribute to the increased risk of COVID-19-related mortality reported in these patients. This trial was registered at www.ccmo.nl as NL-OMON51241.

The development of acute graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is facilitated by damage-associated molecular patterns (DAMPs) released upon tissue damage due to the conditioning regimen. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme responsible for the breakdown of the DAMP cell-free heme. HO-1 plays a protective role in diseases characterized by systemic inflammation such as sepsis, but its role in the development of acute GvHD remains unclear. Here, we characterized the expression of HO-1 in a small cohort of allo-HSCT recipients with and without acute GvHD. We found HO-1 protein levels in plasma to be elevated in patients just before their acute GvHD diagnosis compared with baseline. Furthermore, HO-1 mRNA expression was increased in patients with acute GvHD at 1 and 3 months after allogeneic HSCT compared with patients without acute GvHD. Finally, induction of HO-1 in a humanized mouse model for acute GvHD led to lower disease scores and a reduction in weight loss. Overall, our data indicate that HO-1 expression is increased in patients with acute GvHD and that HO-1 induction might be able to provide protection against the disease, warranting further research into HO-1 as a target for clinical application.

Unmanipulated donor lymphocyte infusions (DLI) are crucial for enhancing the graft versus tumor (GVT) effect in post-transplant settings. Practices regarding DLI use vary widely among centers, encompassing differences in indications, prerequisites, and application methods. To explore current DLI policies, we developed a comprehensive survey that garnered responses from 165 EBMT centers across 43 countries. Notably, 97% of respondents reported using DLI in their practices. Indications for DLI included preemptive use for minimal residual disease (MRD) positivity in 86.9% of centers and mixed chimerism in 73.1%; therapeutic use for hematological relapse in 73.1%; and prophylactic use for high-risk disease in 43.8%. Active graft-versus-host disease (GVHD) and active infections were deemed absolute contraindications by 85.6% and 57.5% of centers, respectively. 35% of centers did not consider a prior history of acute (a)GVHD as an exclusion criterion. The majority (71.9%) requested immunosuppression withdrawal before DLI. Most centers (71.3%) collected DLI post-transplant, with 78.1% utilizing unstimulated apheresis. The cell doses applied at the first DLI varied significantly, depending on indication, timing, and donor type. This survey provides the largest overview of current DLI practices, highlighting the need for high-quality data to assess the risks and benefits of different approaches.

BackgroundRelapsed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) are associated with a poor prognosis. It is unknown which re-induction therapy provides the highest chance of durable remission. Commonly used therapies are high dose cytarabine (HiDAC) and triple therapy consisting of fludarabine, cytarabine, and idarubicin combined with granulocyte colony-stimulating factor (FLAG-IDA).MethodsTwo patient cohorts with relapsed AML or HR-MDS treated with HiDAC or FLAG-IDA between October 2015 and December 2021 in two academic hospitals in the Netherlands were retrospectively analyzed.ResultsPatients were treated with either HiDAC (n=22) or FLAG-IDA (n=25). Rates of CR (71% vs. 74%, P=0.85), 1-year OS (47% vs. 51%, P=0.99) and EFS (38% vs. 35%, P=0.71) were comparable between HiDAC and FLAG-IDA. Durations of neutropenia (median 24 days (IQR 20-26) vs. 30 days (IQR 22-39), P=0.014) and thrombocytopenia (22 days (IQR 17-26) vs. 36 days (IQR 26-53)) were significantly shorter in the HiDAC group than in the FLAG-IDA group.ConclusionWhile remission rates and survival outcomes were similar, FLAG-IDA was associated with longer periods of myelosuppression and transfusion dependency compared to HiDAC in these two cohorts. HiDAC can be considered as a salvage chemotherapyfor relapsed AML/HR-MDS based on our study.

In 2023, 47,731 HCT (20,485 (42.9%) allogeneic and 27,246 (57.1%) autologous) in 43,902 patients were reported by 696 European centers. 6042 patients received advanced cellular therapies, 4888 of which were CAR-T. Compared to the previous year there was an increase in CAR-T (+52.5%), in allogeneic HCT (+7.8%) but none in autologous HCT (+0.4%). Main indications for allogeneic HCT were myeloid (11,748; 60.7%), lymphoid malignancies (4,850; 25.0%), and non-malignant disorders (2558; 13.2%). Use of allogeneic HCT increased for AML (+12.1%) and for NHL (+11.0%), particularly in T-NHL (+25.6%). Main indications for autologous HCT were lymphomas (7890; 32.2%), PCD (14,271; 58.2%), and solid tumors (1608; 6.6%) with recovering numbers for autoimmune diseases. In patients with allogeneic HCT, the use of sibling donors increased by +1.0%, haploidentical donors by +11.7%, and unrelated donors by +11.1%. Cord blood HCT decreased again by -5.4%. Pediatric HCT activity increased slightly (5455; +0.1%) with differences between allogeneic (4111; -0.5%) and autologous HCT (1344: +1.7%). Use of CAR-T increased to a cumulative total of 13,927 patients including patients treated for autoimmune diseases. Overall, numbers show a complete recovery from the pandemic dip with increased cellular therapy at the expense of autologous HCT. Allogeneic HCT activity focuses on myeloid malignancies.

Background The immunological determinants of delayed viral clearance and intrahost viral evolution that drive the development of new pathogenic virus strains in immunocompromised individuals are unknown. Therefore, we longitudinally studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune responses in relation to viral clearance and evolution in immunocompromised individuals. Methods Among Omicron-infected immunocompromised individuals, we determined SARS-CoV-2-specific T- and B-cell responses, anti-spike immunoglobulin G (IgG) and IgG3 titers, neutralization titers, and monoclonal antibody (mAb) resistance-associated mutations. The 28-day post-enrollment nasopharyngeal specimen defined early (reverse-transcription polymerase chain reaction [RT-PCR] negative <= 28 days) or late (RT-PCR positive >28 days) viral clearance. Results Of 30 patients included (median age, 61.9 [interquartile range, 47.4-72.3] years; 50% females), 20 (66.7%) received mAb therapy. Thirteen (43.3%) demonstrated early and 17 (56.7%) late viral clearance. Patients with early viral clearance and patients without resistance-associated mutations had significantly higher baseline interferon-gamma release, and patients with early viral clearance had a higher frequency of SARS-CoV-2-specific B cells at baseline. In non-mAb-treated patients, day 7 IgG and neutralization titers were significantly higher in those with early versus late viral clearance. Conclusions An early robust adaptive immune response is vital for efficient viral clearance and associated with less emergence of mAb resistance-associated mutations in Omicron-infected immunocompromised patients. This emphasizes the importance of early SARS-CoV-2-specific T- and B-cell responses and thereby provides a rationale for development of novel therapeutic approaches.

We looked at treatment rates and center density across countries for patients treated in 2022; 46,143 HCTs (19,011 (41.2%) allogeneic, 27,132 (58.8%) autologous) reported by 689 centers. 4329 patients received advanced cellular therapies, 3205 were CAR-T. We found considerable differences in utilization of autologous, allogeneic HCT and more so for CAR-T. Differences in procedure type and for allogeneic HCT in donor use and disease indication are highlighted. For instance, countries with the highest use of unrelated donors per 10 million inhabitants were Germany (297) and the Netherlands (230), for identical sibling HCT it was Israel (148) and Lebanon (113), for haploidentical it was Israel (94) and Italy (94) and for cord blood it was the Netherlands (24) and the United Kingdom (15). We looked at HCT use for specific indications in allogeneic HCT (AML CR1, MDS, MPN and BMF). We correlated treatment rates with GNI and with demographic age structure and show correlations in HCT and CAR-T use and center density, highest in Italy for allogeneic and autologous HCT and in Switzerland for CAR-T. Resource restricted countries tend to concentrate HCT use in a limited number of centers. These data are useful for comparisons across countries.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

Since the early description of three patients with relapsed leukaemia after allogeneic haematopoietic cell transplantation (HCT) who obtained complete remission after donor lymphocyte infusions (DLIs), the added value of this procedure to induce or maintain graft-versus-leukaemia immunity has been undisputed. For more than 30 years, DLIs have become common practice as prophylactic, pre-emptive, or therapeutic immunotherapy. However, as with many aspects of allogeneic HCT, centres have developed their own routines and practices, and many questions related to the optimal applications and toxicity, or to the immunobiology of DLI induced tumour-immunity, remain. As a part of the Practice Harmonization and Guidelines Committee and the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation effort, a panel of experts with clinical and translational knowledge in transplantation immunology and cellular therapy met during a 2-day workshop in September, 2023, in Lille, France, and developed a set of consensus-based recommendations for the application of unmanipulated DLI after allogeneic HCT for haematological malignancies. Given the absence of prospective data in the majority of publications, these recommendations are mostly based on retrospective studies and expert consensus.

Background aimsThe success of allogeneic hematopoietic cell transplantation (HCT) as therapy for hematologic conditions is negatively impacted by the occurrence of graft-versus-host disease (GVHD). Tissue damage, caused, for example, by chemotherapy and radiotherapy, is a key factor in GVHD pathogenesis. Innate lymphoid cells (ILCs) are important mediators of tissue repair and homeostasis. The presence of ILCs before, and enhanced ILC reconstitution after, allogeneic HCT is associated with a reduced risk to develop mucositis and GVHD. However, ILC reconstitution after allogeneic HCT is slow and often incomplete. A way to replenish the pool of ILC relies on the differentiation of hematopoietic progenitor cells (HPCs) into ILC.MethodsWe developed an ex vivo stromal cell–containing culture system to study the capacity of HPCs to differentiate into all mature helper ILC subsets.ResultsILC development depended on the source of HPCs. ILCs developed at high frequencies from umbilical cord blood– and fetal liver–derived HPC and at low frequencies when HPCs were obtained from allogeneic or autologous adult HCT grafts or healthy adult bone marrow. Although all helper ILC subsets could be generated from adult HPC sources, development of tissue protective ILC2 and NKp44+ ILC3 was notoriously difficult.ConclusionsOur data suggest that slow ILC recovery after allogeneic HCT may be related to an intrinsic incapability of adult HPC to develop into ILC.

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (6 World Health Organization regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT numbers increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA-identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/10 million population was observed for autologous HCT (correlation coefficient [r]=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation was detected from related donors (r=0.48 for HLA-identical sibling; r=0.45 for other). The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

In 2022, 46,143 HCT (19,011 (41.2%) allogeneic and 27,132 (58.8%) autologous) in 41,854 patients were reported by 689 European centers. 4329 patients received advanced cellular therapies, 3205 of which were CAR-T. An additional 2854 patients received DLI. Changes compared to the previous year were an increase in CAR-T treatments (+27%) and decrease in allogeneic (−4.0%) and autologous HCT (−1.7%). Main indications for allogeneic HCT were myeloid malignancies (10,433; 58.4%), lymphoid malignancies (4,674; 26.2%) and non-malignant disorders (2572; 14.4%). Main indications for autologous HCT were lymphomas (7897; 32.9%), PCD (13,694; 57.1%) and solid tumors (1593; 6.6%). In allogeneic HCT, use of sibling donors decreased by −7.7%, haploidentical donors by −6.3% and unrelated donors by −0.9%. Overall cord blood HCT decreased by −16.0%. Use of allogeneic, and to a lesser degree autologous HCT, decreased for lymphoid malignancies likely reflecting availability of new treatment modalities, including small molecules, bispecific antibodies, and CAR-T cells. Pediatric HCT activity remains stable (+0.3%) with differences between allogeneic and autologous HCT. Use of CAR-T continues to increase and reached a cumulative total of 9039 patients treated with wide differences across European countries. After many years of continuous growth, increase in application of HCT seems to have slowed down.

Rationale Sickle cell disease (SCD) is recognized as a chronic inflammatory condition. Impaired vaccination responses, frequent alloimmunization, a high prevalence of autoimmune diseases and an increased risk of graft rejection following hematopoietic stem cell transplantation indicate altered adaptive immune responses. Therefore, elucidating the phenotype of peripheral blood mononuclear cells (PBMC) in SCD is essential for improving insight and future patient management. Aim To evaluate the characteristics of adaptive immune cells involved in chronic inflammation and related pathophysiology in SCD patients, we investigated the differences in PBMC subsets between SCD patients and ethnicity- and age-matched healthy controls (HCs). Methods PBMCs from HbSS/HbSβ0 patients (≥ 12 years) in steady state and HCs were analyzed using a 5x14-color flow cytometry panel for in-depth characterization of B, T, T-helper (Th), T follicular-helper (Tfh), natural killer (NK) cells, monocytes and dendritic cells (DCs). Measurements were standardized using rainbow calibration beads on a Symphony flow cytometer. Cell populations were identified manually and computationally by conventional gating (FlowJo) and unsupervised clustering (FlowSOM), respectively. Statistics included Benjamini-Hochberg correction of false discovery rate. Results The study included 46 patients (37% female, 94% HbSS, 78% on hydroxyurea): 26 adults (median age 25 years, range 18 - 57) and 20 adolescents (16 years, 12 - 18). Among 18 HCs (33% HbAS), 12 were adults (30 years, 22 - 42) and 6 were adolescents (16.5 years, 13 - 18). Subgroup analysis revealed no differences in proportions of immune cell subsets between age groups or hydroxyurea use. Gated analysis of B cells (CD45+CD14-CD19+) showed major differences between patients and HCs: patients had higher naive transitional B cells (IgD+CD27-, p <0.001) and lower proportions of unswitched memory (IgD+CD27+, p <0.001), switched memory (IgD-CD27+, p <0.001), and double negative memory (IgD-CD27-, p= 0.003) B cells. Patients also had fewer activated naive/activated memory (CD24-CD38-, p= 0.029) B cells within total B cells. Computational analysis confirmed these results with 11 of 18 FlowSOM metaclusters showing significant differences between patients and HCs: one metacluster, representing naive transitional B cells and containing 68% of total B cells, was enriched in patients (p= 0.004) but with a lower mean fluorescence intensity (MFI) of CD21 (p= 0.007). Several metaclusters containing memory B cell subsets were less abundant in patients. Gated analysis of T cells (CD45+CD14-CD3+) revealed no differences in CD4+ or CD8+ cells, regulatory (CD4+CD25+CD127-FoxP3+), naive (CCR7+CD45RA+), effector (CCR7-CD45RA+), central memory (CCR7+CD45RA-), effector memory (CCR7-CD45RA-) T cells, or Th subsets. However, patients had more γδ+ T cells (p <0.001) and less αβ+ T cells (p <0.001) compared to HCs. Computational analysis showed that MCs containing CD4-CD8- double negative (DN) T cells were significantly enriched in patients compared to HCs (p= 0.008), which was confirmed by manual gating of DN T cells. SCD patients had fewer conventional CD11c+CD141+ cDC1s (p <0.001) and CD11c+CD1c+ cDC2s (p= 0.021), but more CD123+ plasmacytoid DCs (p= 0.024). Total NK cells were decreased, but with a higher proportion of regulatory CD56++ NK cells (p= 0.005). Patients had more classical monocytes (CD14+CD16-, p= 0.001), but fewer Slan+ and non-classical monocytes (CD14-CD16+, p <0.001). FlowSOM analysis revealed, that metaclusters containing CD56-, but Slan+ and/or CD16+ monocytes, one metacluster matching the phenotype of cDC1s, and one metacluster containing CD11c+ NK cells were significantly diminished in patients. Conclusion We present a comprehensive and unique computational immune phenotype evaluation of PBMCs in SCD patients. Our analysis reveals significant perturbations in B cell subsets, with a shift towards naive transitional and less memory B cells, likely due to SCD-related hyposplenia. SCD patients also exhibit increased DN and γδ+ T cells, common in autoimmune and chronic inflammatory conditions. Finally, we observed a decrease of cDCs, Slan+ monocytes and NK cells expressing CD11c, crucial for regulating immune responses. Further study of these PBMC subsets may reveal new insights into chronic inflammation and adaptive immune dysregulation in SCD.