In several countries, most whole blood units donated by healthy volunteers are separated into their components (mainly red blood cells, plasma, and platelets). However, despite its importance, the production of blood components has been studied only marginally in the literature dealing with the blood supply chain (BSC).In fact, no scheduling approach has been developed specifically to address this production in detail. In this study, we provide a description of the BSC production phase from a scheduling perspective by considering the European system in particular. We also consider the specific features of this production system in light of the broad classes of chemical processing and disassembly systems, relying on the idea that a whole blood unit is broken down, or processed, into specific components. We review the literature on management and scheduling systems in these contexts to identify insights or methodologies that could inform future research in formulating a scheduling problem for blood component production. Finally, on the basis of these analyses, we suggest future research directions for improving the management of the BSC production phase.

The well-known side effects of long-term immunosuppressive treatment after solid organ transplantation (SOT) represent a substantial burden of morbidity and lead to increased mortality of transplanted patients with respect to the general population. Operational tolerance through donor hematopoietic chimerism in SOT recipients has been reported to be possible, with long-term success even in the presence oftransient or mixed chimerism1-4. Favorable results have been mainly obtained in human leukocyte antigen (HLA)-identical or haploidentical transplants5,6 whereas mixed chimerism is rarely sustained in HLA-disparate settings, as is the case of most SOT from either living or deceased donors. Although feasible, combined bone marrow and SOT from the same HLA-disparate donor is associated with high risks of graft-versus-host disease and mortality that are not acceptable for patients who are candidates for SOT. In addition, the optimal timing and the technical issues of harvesting hematopoietic stem cells (HSC) from deceased organ donors are still to be defined7,8, while considering the complexity of the sequence of multi-organ procurement in the operating room. Despite being a "third-party" from an immunological point ofview, banked cord blood units (CBU), currently available for use in allogeneic hematopoietic stem cell transplantation (HSCT), may represent an interesting source of HSC for the purpose of immune tolerance after SOT, whenever a permissive HLA match exists between the CBU, the deceased organ donor and the final recipient. To provide some potential basis for future immune tolerance protocols, we describe the actual HLA match between a sample of deceased multi-organ donors in Italy and all the CBU banked in the Italian Cord Blood Network (ITCBN).

Among the complications occurring after allogeneic hematopoietic stem cell transplantation (HSCT), infection by human Cytomegalovirus (CMV) represents one of the most relevant in terms of morbidity/mortality and specific management is required by either monitoring viral load and administer anti-CMV therapies. Due to the physiological role of the Human Leucocyte Antigen (HLA) system in presenting foreign antigens to the adaptive immune system to enhance viral clearance, we measured here the HLA antigen load for two immunodominant CMV peptides and correlate with transplant outcome in 238 consecutive adult patients undergoing haploidentical HSCT at a single center. Interestingly, a higher class I antigen load (i.e. above the median) for protein IE1 correlated with an inferior absolute incidence of CMV infection; moreover, a statistically significant correlation with lower non-relapse mortality and higher overall survival was observed (HR: 0.32, 0.12-0.84, p = 0.02; 0.34 (0.17-0.69, p = 0.003; respectively), with a protective effect in patients with high antigen load values. Despite additional research is needed, our exploratory data support the role of the HLA polymorphism on CMV infection and survival after HSCT. The introduction of CMV antigen load as a new potential predictive factor might contribute to further define the post-transplant risk on an individualised basis.

The presence of donor-specific anti-HLA antibodies (DSAs) in patients who are candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a recognized risk factor for delayed engraftment and mortality. In the absence of an alternative donor, patient desensitization is indicated to reduce or eliminate DSAs; however, harmonization among transplant centers remains insufficient and reduction of DSAs is sometimes unsuccessful. Here, we present the feasibility and results of our recent monocenter experience on nine immunized HLA class I DSA+ patients undergoing pre-transplant desensitization using HLA-specific platelet transfusion, as a means of antibody adsorption through platelets expressing the same HLA specificities targeted by DSAs. All allo-HSCTs were from HLA-mismatched donors, both unrelated or related haploidentical. The approach appeared safe for donors and patients and potentially useful in mitigating the detrimental impact of class I DSAs, with successful engraftment observed in two of four patients with MFI > 10,000 and in all patients with MFI <10,000. Until harmonized and more risk-adapted desensitization strategies become available, sharing inter-center experiences between clinical and transfusion units will likely improve the management of hyperimmunized patients and enhance the availability of emerging desensitizing strategies.

Few data exist on the role of genetic factors involving the HLA system on response to Covid‐19 vaccines. Moving from suggestions of a previous study investigating the association of some HLA alleles with humoral response to BNT162b2, we here compared the HLA allele frequencies among weak (n = 111) and strong (n = 123) responders, defined as those healthcare workers with the lowest and the highest anti‐Spike antibody levels after vaccination. Individuals with clinical history of Covid‐19 or positive anti‐nucleocapside antibodies were excluded. We found the common HLA‐A*03:01 allele as an independent predictor of strong humoral response (OR = 12.46, 95% CI: 4.41–35.21, p < 0.0001), together with younger age of vaccines (p = 0.004). Correlation between antibody levels and protection from breakthrough infection has been observed, with a 2‐year cumulative incidence of 42% and 63% among strong and weak responders, respectively (p = 0.03). Due to the high frequency of HLA‐A*03:01 and the need for seasonal vaccinations against SARS‐CoV‐2 mutants, our findings provide useful information about the inter‐individual differences observed in humoral response after Covid‐19 vaccine and might support further studies on the next seasonal vaccines.

Background while the detrimental role of donor-specific anti-HLA antibodies (DSAs) is well-described in the setting of hematopoietic stem cell transplantation (HSCT), few studies focus on non donor-specific ones and with controversial results Methods we here report our monocenter experience on 64 adult patients receiving allogeneic HSCT from a HLA-mismatched donor between 2014 and 2022 who were tested for the presence of anti-HLA antibodies before transplant, focusing on fifteen patients with non donor-specific anti-HLA antibodies Results the survival of patients with non donor-specific anti-HLA antibodies was inferior with respect to patients without anti-HLA antibodies and similar to patients with DSAs. Median survival of patients with non donor-specific anti-HLA antibodies was 21 months (95% CI: 9-42) vs. 61 months (95% CI: 17-77) among the anti-HLA antibody-negative patients, with a significantly higher mortality incidence rate ratio (3.3 times-fold greater, p=0.01). No pattern of death causes was found Conclusions in this monocenter series of HLA-mismatched HSCTs, impaired survival was observed in adult patients having non donor-specific anti-HLA antibodies before transplant, similar to those with DSAs. Our findings support those antibodies as a negative predictive factor even if they are not directed against the donor, thus warranting further investigation on larger cohorts.

BACKGROUND:Induction with daratumumab-based regimens followed by autologous stem cell transplantation is the current standard for newly diagnosed multiple myeloma (NDMM) patients eligible for intensive chemotherapy. However, concerns emerged regarding potential negative effects following daratumumab-based treatment on CD34+ mobilization. We here compared CD34+ mobilization and clonogenic potential between daratumumab and non-daratumumab based therapy without upfront plerixafor administration among patients affected by NDMM. MATERIALS AND METHODS:Clinical, mobilization and clonogenic data from 41 consecutively enrolled NDMM patients were analyzed. Patients underwent collection of autologous CD34+ by apheresis at the ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, from January 2021 to March 2023. Clonogenicity analysis was performed on BFU-E and CFU-GM. RESULTS:Seventy-five percent of daratumumab-treated patients underwent >1 apheresis, compared to 24% of non-daratumumab patients (p=0.0017). Daratumumab-treated patients had significantly lower CD34+ count (mean 38 vs 79/μL, respectively; p=0.0011), with a median CD34+ harvest of 3.98×106/kg (range 1.68-9.18) vs 6.87×106/kg (range 1.63-16.85) in non-daratumumab-treated (p=0.0006). In multivariate analysis the likelihood of undergoing >1 apheresis was significantly higher in older patients (OR 1.2, 95% CI 1-1.4, Z=2.10, p=0.03) and daratumumab-treated patients (OR 15, 95% CI 2.8-129, p=0.004). Moreover, daratumumab-based induction therapy demonstrated an independent negative association with BFU-E colony formation (p=0.0148), even when accounting for patient age and CD34+ levels. DISCUSSION:Our findings underscore the impact of daratumumab-based treatment on CD34+ mobilization in a real-life, upfront plerixafor-free population of NDMM patients. Higher probability of requiring multiple apheresis occurred among daratumumab-treated patients. Interestingly, the observation that daratumumab might negatively impact BFU-E colony formation, independent of CD34+ cell count, offers novel biological perspectives. Appropriate strategies should be adopted by the Apheresis teams to mitigate these potential negative effects.

BACKGROUND The well-known polymorphism of class I human leukocyte antigen (HLA) molecules enables the presentation of a wide repertoire of peptides, including tumor-associated antigens. The HLA evolutionary divergence (HED) is a surrogate for immunopeptidome diversity and has been recently established as a novel prognostic factor for AML patients undergoing allogeneic HSCT (Pagliuca et al. Nature Communications 2023). Preclinical evidence supports the role of HED as a possible prognostic factor also in AML patients treated with venetoclax and hypometinating agents (VH), given their immunostimulating synergic action (Wang et al. PLoS One 2013; Lee et al Blood 2021). On these premises, we started a multicentric pilot study to investigate the possible role of HED as a predictor of outcome in AML patients treated with VH. METHODS From February 2021 to April 2024 we prospectively and retrospectively enrolled consecutive AML patients with de novo or secondary AML (sAML) treated with first-line VH. Exclusion criteria were refractory/relapsed AML, having received an AML therapy different from VH (excluding hydroxyurea), or unavailability of post-treatment disease assessment by bone marrow reevaluation. The primary endpoint was the complete remission (CR) rate, while overall survival (OS) was set as secondary endpoint. Here we present the data from the first 15 patients analyzed. HED was calculated according to published literature (Chowell et al. Nat Med 2019; Pierini et al. Mol Biol and Evol 2018) and values were expressed as median for locus A, B and C and mean for the class I taken together. Patients with greater than the median HED for locus A, B and C and greater than the mean for class I were compared against those with lower than the median HED for locus A, B and C and lower than the mean for class I. RESULTS Median age at diagnosis was 74 years (range 61-85), 10/15 patients (67%) were males. Eight patients (53%) had de novo AML and 7 (47%) sAML. According to ELN 2022 classification, one patient was classified as favourable risk, 10 as intermediate risk, and 4 as adverse risk. Patients received a median of 5 (range 1-30) cycles of VH. Median follow-up was 9.2 months (interquartile range: 5-25). Overall, one-year OS and PFS were respectively 67% and 58%. At the last follow-up, 7/15 patients (47%) were alive; disease-related death occurred in 4 out of 8 patients. Sex and age were comparable between the groups; patients with lower HED had a trend toward higher platelet count at diagnosis (p 0.09). 2022 ELN risk was intermediate in 6/7 and low in 1/7 patients with high HED vs high in 4/7 high and intermediate in 3/7 patients with low HED; 6/7 patients whit high HED had a primary AML as compared to 2/7 in low HED. Interestingly, while class I HED did not correlate with the CR rate, patients with a HED-B value higher than median showed superior CR rate (7/8 vs 3/7), though not statistically significant due to the low samples size. Of note, class I HED and HED-B significantly impacted on OS, since patients with class I HED and HED-B above the medians showed longer median OS (24 vs 9 months for both factors, p=0.052 and p=0.02 respectively). CONCLUSIONS To our knowledge, this is the first study reporting the role of HLA polymorphism, throughout the analysis of HED, in the setting of VH-treated AML patients. According to our preliminary results, class I HED and HED-B may be prognostically significant in terms of OS. A larger number of patients will be analyzed in this ongoing study to verify these findings. If confirmed, HED may be integrated with the existing predictive test at diagnosis to orient therapeutic decision for elderly and/or unfit AML patients in the expanding landscape of low intensity treatments.

Indoleamine 2,3 dioxygenase 1 (IDO1), a leader tryptophan-degrading enzyme, represents a recognized immune checkpoint molecule. In neoplasia, IDO1 is often highly expressed in dendritic cells infiltrating the tumor and/or in tumor cells themselves, particularly in human melanoma. In dendritic cells, IDO1 does not merely metabolize tryptophan into kynurenine but, after phosphorylation of critical tyrosine residues in the non-catalytic small domain, it triggers a signaling pathway prolonging its immunoregulatory effects by a feed-forward mechanism. We here investigated whether the non-enzymatic function of IDO1 could also play a role in tumor cells by using B16-F10 mouse melanoma cells transfected with either the wild-type Ido1 gene (Ido1WT) or a mutated variant lacking the catalytic, but not signaling activity (Ido1H350A). As compared to the Ido1WT-transfected counterpart (B16WT), B16-F10 cells expressing Ido1H350A (B16H350A) were characterized by an in vitro accelerated growth mediated by increased Ras and Erk activities. Faster growth and malignant progression of B16H350A cells, also detectable in vivo, were found to be accompanied by a reduction in tumor-infiltrating CD8+ T cells and an increase in Foxp3+ regulatory T cells. Our data, therefore, suggest that the IDO1 signaling function can also occur in tumor cells and that alternative therapeutic approach strategies should be undertaken to effectively tackle this important immune checkpoint molecule.

Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of skin-involved T-cell non-Hodgkin lymphoma which Mycosis Fungoides and Sezary Syndrome are the most common variants. Despite considerable progress in distinguishing the pathophysiology, the treatment options are still limited for advanced-stage disease. Recent approval of novel agents such as vorinostat, brentuximab vedotin and mogamulizumab paved a way. Allogeneic hematopoietic stem cell transplantation has been shown to be a feasible option in selected advanced-stage CTCL patients. Chimeric antigen receptor (CAR) T cells have been promising for the treatment of B-cell tumors and have been approved for second-line treatment in non-Hodgkin's lymphoma. Although several obstacles still need to be addressed, CAR T cell treatment for CTCLs seems not far off. This review discusses new discoveries in pathophysiology, the state of cellular therapies in current practice, challenges for cellular treatment in advanced CTCL, and how to overcome these challenges.

Abstract Background Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) requiring urgent treatment. Standardization of its diagnosis and optimal management is challenging. This study aimed to evaluate the role of centralized, rapid testing of ADAMTS13 in patients experiencing acute TMAs requiring plasma-exchange (PEX) and to estimate the incidence of TTP in a large Italian Region. Methods We perfomed a cohort study in the frame of the project “Set-up of a Lombardy network for the study and treatment of patients undergoing apheresis”, including 11 transfusion centers in the Region. Consecutive patients referred from 2014 to 2016 with acute TMAs requiring PEX were enrolled. Centralized ADAMTS13 activity testing was performed at the Milan Hemophilia and Thrombosis Center within 24 h. Results Forty-three TMA patients (44 events) were enrolled, of whom 35 (81%) had severe ADAMTS13 deficiency. Patients with severe ADAMTS13 deficiency were younger, mainly women, with a higher prevalence of autoimmune disorders and a lower prevalence of cancer. Clinical and laboratory characteristics of patients with and without severe ADAMTS13 deficiency largely overlapped, with a lower platelet count being the only baseline marker that significantly differed between the two patient groups (ADAMTS13 activity < 10% vs ≥ 10%: median difference of -27 × 109/l, 95% CI − 37 to − 3). PEX treatment was initiated in all patients, but soon discontinued in cases without severe ADAMTS13 deficiency. In this group, the mortality rate was higher and no episode exacerbations or relapses within 6 months occured. The estimated average annual incidence of acute acquired TTP events was 1.17 [0.78–1.55] per million people. Conclusions Severe ADAMTS13 deficiency distinguished two groups of patients with largely overlapping clinical features but different treatment and disease course. This study provides a feasible model implemented in a large Italian region for the practical clinical approach to TMAs and underlines the importance of urgent ADAMTS13 activity testing for an accurate differential diagnosis and therapeutic approach.

Introduction: Soon after the onset of the SARS-CoV-2 pandemic, viral screening by nasopharyngeal swab became mandatory for allogeneic hematopoietic stem cell (HSC) donor eligibility. Methods: We described our monocenter experience with allogeneic HSC donors from February 1 to the October 31, 2020 to verify whether the introduction of SARS-CoV-2 screening altered the donor eligibility and/or entailed a prolongation of the evaluation process. Results: A total of 21 allogeneic HSC donors were screened during the above-mentioned period upon request by the local transplant physicians or by the Italian Bone Marrow Donor Registry; among the HSC donors (n = 17) who completed the eligibility process and further received the nasopharyngeal swab, all but one were negative for the presence of SARSCoV-2. The positive donor remained asymptomatic for the whole duration of the infection, which lasted six weeks. However, he was temporarily excluded from donation. The median duration of the evaluation process was not significantly different, compared to the same period of 2019 (p-value = 0.11). Conclusion: The mandatory SARS-CoV-2 screening in allogeneic HSC donors allowed for the detection of 6% positivity in this monocenter series over a 9-month period. Despite the inconvenience of this unexpected non-eligibility, the exclusion of a SARS-CoV-2 positive donor represented an important safety measure for the donor, with respect to a new and still partially unknown virus. The screening did not alter the length of the donor evaluation and thus, did not cause a delay in the eligibility process. (C) 2021 Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Espana, S.L.U.

The polymorphism of the HLA system has been extensively studied in COVID-19 infection, however there are no data about the role of HLA on vaccine response. We report here the HLA-A, -B, -C, and DRB1 allelic frequencies of n = 111 individuals after BNT162b2 mRNA vaccine, selected on the basis of lower antibody levels (<5% percentile) after the second dose among a total of n = 2569 vaccinees, and compare them with the frequencies of a reference population. We found that differences in the frequencies of the alleles HLA-A*03:01, A*33:03, B*58:01 and at least one haplotype (HLA-A*24:02 similar to C*07:01 similar to B*18:01 similar to DRB1*11:04) are associated with a weaker antibody response after vaccination, together with the age of vaccinees. Our results might suggest a role played by some HLA alleles or haplotypes in antibody production after the BNT162b2 mRNA vaccine, giving insights into the tracking of potentially susceptible individuals across populations. Further studies are needed to better define our exploratory findings and dissect the role of HLA polymorphism on response to anti-COVID-19 vaccines.