Strong humoral response after Covid-19 vaccination correlates with the common HLA allele A*03:01 and protection from breakthrough infection.

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.

MYC rearrangements in HIV-associated large B-cell lymphomas: EUROMYC, a European retrospective study.

ABSTRACT: Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse.

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Mother Donors Improve Outcomes after HLA Haploidentical Transplantation: A Study by the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation.

Transplacental trafficking of maternal and fetal cells during pregnancy establishes long-term reciprocal microchimerism in both mother and child. Consequently, the maternal immune system may become sensitized to paternal histocompatibility antigens. It has been hypothesized that mother's "exposure" to paternal HLA haplotype antigens during pregnancy may affect the outcome of hematopoietic stem cell transplantation (HSCT) when the mother serves as a donor for the child. In T cell-depleted HLA haploidentical HSCT, maternal donors have been associated with improved transplantation outcomes. The present retrospective multicenter study, conducted on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society of Blood and Marrow Transplantation, involved 409 patients (102 pediatric and 307 adult) with acute leukemia who underwent HLA-haploidentical HSCT. The goal of the study was to evaluate the role of maternal donors in a large cohort of haploidentical transplantation recipients. Transplantation from maternal donors was associated with a lower relapse incidence in T cell-depleted HSCTs (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.16 to 3.92; P = .018) as well as in a limited series of unmanipulated in vivo T cell-depleted HSCTs (HR, 4.15; 95% CI, 0.94 to 18.35; P = .06), along with better graft-versus-host disease/relapse-free survival (GRFS) in T cell-depleted HSCT (HR, 1.67; 95% CI, 1.02 to 2.73; P = .04). These results indicate that the mother is the preferred donor to provide better GRFS in T cell-depleted HLA-haploidentical HSCT for acute leukemia.

Correlation analysis between virtual and Complement-Dependent-Cytotoxicity crossmatch in a monocenter retrospective series of 118 allografted patients.

PURPOSE OF THE STUDY: The detection of patients' anti-HLA antibodies before allogeneic hematopoietic stem cell transplantation (HSCT) may affect post-transplant outcome, due to a potential detrimental impact on engraftment or toxicity-related issues. Crossmatch (XM) techniques provide support to physicians during the pre-transplant phase but the role of Complement-Dependent Cytotoxicity XM (CDC-XM) is not well-defined when performed routinely and in parallel with the virtual XM. PATIENTS AND METHODS: We report here our experience with both virtual and CDC-XM tests on n = 118 patients undergoing search for a donor other than HLA-identical sibling from July 2013 to June 2018 at our Institution. When anti-HLA antibodies (Abs) were present, they were classified as donor-specific Abs (DSA) or non-DSA. RESULTS: On the n = 118 patients, n = 35 (29.7 %) had a positive virtual XM test (of which one of more DSA were found in n = 8; 6.8 %) and n = 5 had a positive CDC-XM test. These latter, positive for HLA class II only, were interpreted as false-positive results due to prior administration of anti-CD20 to the patients, all affected by lymphoma; none of them had a positive virtual XM for anti-HLA Abs of class II. Importantly, all these patients successfully engrafted, further supporting the lack of significant impact of CDC-XM positive results in this series. CONCLUSIONS: According to our data on more than a hundred patients, routinely performed CDC-XM does not seem to add significant information with respect to virtual XM. We cannot exclude the usefulness of CDC-XM in specific situations, although a positive CDC-XM result was an unfrequent event.

Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial.

The aim of the present study was to evaluate the circulating T regulatory cells (Tregs) in patients undergoing extracorporeal photopheresis (ECP) for the prevention of chronic graft-versus-host disease (GvHD) and to search for any correlation between Tregs counts and chronic GvHD occurrence. Among n = 12 patients with complete longitudinal data, the median cumulative values of absolute peripheral Tregs counts were 21.64 and 63.49 cells/µL for patients who developed chronic GvHD and those who did not develop it, respectively (p = 0.05). The analysis of the median absolute counts of peripheral HLA-DR + Tregs provided similar results, showing that 20% (1 out of 5) and 100% (7 out of 7) of patients with HLA-DR + Tregs values of > 5 cells/µL were in the GvHD and non-GvHD groups, respectively (p = 0.01). In conclusion, the present results support the involvement of Tregs in the prevention of chronic GvHD in patients receiving ECP and suggest Tregs count as a potential biomarker of ECP effectiveness. Future strategies are needed to enhance Tregs expansion and/or activity in conjunction with ECP for an effective chronic GvHD prevention.

Clinical and prognostic role of interim 18F-FDG PET/CT in elderly Hodgkin lymphoma: a dual-center experience.

Hodgkin lymphoma (HL) has a bimodal age distribution curve, with a second peak in people aged more than 60 years. Interim PET/CT (iPET/CT) is highly predictive for PFS and OS in young HL, but it has not been sufficiently studied in the elderly. In this retrospective dual-center study, 82 patients with HL and aged 65 or more who performed iPET/CT were included. At iPET/CT, 60 patients had a complete metabolic response, 18 partial responses, and 4 progressions of disease. Baseline PET/CT metabolic features were not significantly correlated with the metabolic response at interim. In patients with interim complete metabolic response, PFS and OS were significantly longer than in patients without complete response(p < 0.001 and p = 0.004). Patients with negative iPET had 2-year PFS and OS rates of 57 and 88% compared with 24 and 58% in patients with positive iPET (p < 0.001). iPET/CT results demonstrated to be independent prognostic factors for PFS and OS.

Safety and efficacy of netupitant/palonosetron and dexamethasone in classical Hodgkin's lymphoma patients with inadequate chemotherapy-induced nausea and vomiting prophylaxis with palonosetron and dexamethasone: a single-center real-life experience.

We analyzed safety of NEPA (netupitant/palonosetron) and dexamethasone (NEPA+DEX) for the management of chemotherapy-induced nausea and vomiting (CINV) in classical Hodgkin's lymphoma patients that experienced CINV with a prophylaxis with palonosetron (PALO + DEX). In a retrospective, monocentric, noncomparative study, we analyzed adverse events and CINV grading in patients who switched from PALO + DEX to NEPA + DEX. Among 32 patients treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) during the study period, 47% did not properly control CINV with PALO + DEX and were shifted to NEPA + DEX. Among these, 53.3% properly controlled CINV is for all the remaining chemotherapy cycles. We did not observe an increase of adverse events after switching to NEPA. In our study, NEPA did not show drug-drug interaction with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy agents and NEPA administration was well tolerated with mild and transient adverse events.

Prognostic Impact of Immunohistochemical p53 Expression in Bone Marrow Biopsy in Higher Risk MDS: a Pilot Study.

BACKGROUND AND OBJECTIVES: Mutations of the TP53 gene have an unfavorable prognosis in Myelodysplastic Syndromes (MDS). The product of the TP53 gene is the p53 protein. Most of the TP53 mutations entail the accumulation of the protein in the nucleus of tumor cells. The immunohistochemical (IHC) staining for p53 can be a surrogate suggesting a mutational status and, if overexpressed, seems to be of prognostic value by itself. The best prognostic cut-off value of overexpression is controversial. The aim of this pilot study is to investigate the correct value from a homogenous group of patients with higher IPSS-R risk MDS. METHODS: In sixty consecutive patients diagnosed with MDS and categorized as "intermediate," "high" and "very high" IPSS-risk, the bone marrow biopsies performed at diagnosis were retrospectively re-examined for IHC p53 expression. The result of p53 expression was subsequently related to survival. RESULTS: A worse overall survival was observed both in patients whose IHC p53 expression was ≥5% and ≥ 10% compared to patients with a p53 expression below 5% (p= 0.0063) or 10% (p=0.0038) respectively. CONCLUSIONS: The ICH p53 expression in bone marrow biopsy in higher risk MDS was confirmed to have prognostic value. These results indicate more than 10% expression as the best cut off value.

Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation.

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.

Beneficial role of CD8+ T-cell reconstitution after HLA-haploidentical stem cell transplantation for high-risk acute leukaemias: results from a clinico-biological EBMT registry study mostly in the T-cell-depleted setting.

HLA-haploidentical haematopoietic stem cell transplantation (haplo-HSCT) is increasingly offered to patients with high-risk acute leukaemia. Unfortunately, haplo-HSCT is followed by a delayed immunoreconstitution. The aim of this EBMT registry study was to explore the clinical impact of lymphocyte subset counts after haplo-HSCT. We considered 144 leukaemic patients transplanted in the period 2001-2012. Pre-transplantation clinical variables and differential immune-cell counts (CD3, CD4, CD8 T cells, NK and B cells) measured before day 100 were evaluated for their capacity to predict overall survival, relapse mortality or non-relapse mortality (NRM). Negative prognostic factors for overall survival were advanced disease state at transplantation, host age and CMV seropositivity. Higher CD3, CD4 and CD8 counts were associated with a better overall survival and a lower NRM. Strikingly, when tested in multivariable analysis, higher CD3 and CD8 counts were still significantly associated with a lower NRM. These results indicate that an accelerated T-cell reconstitution correlates with less transplantation mortality, likely due to the protective role of T cells against viral infections. This observation suggests that CD8+ T-cell counts should be investigated as surrogate biomarkers of outcome in prospective haplo-HSCT trials.

Adjuvant role of SeptiFast to improve the diagnosis of sepsis in a large cohort of hematological patients.

Febrile neutropenia and sepsis are common and life-threatening complications in hematological diseases. This study was performed retrospectively in 514 patients treated for febrile neutropenia at our institute, to investigate the clinical usefulness of a molecular tool, LightCycler® SeptiFast test (SF), to promptly recognize pathogens causing sepsis in hematological patients. We collected 1837 blood samples of 514 consecutive hematological patients. The time of processing is short. Overall, 757 microorganisms in 663 episodes were detected by molecular test and standard blood cultures (BC): 73.6% Gram-positive bacteria, 23.9% Gram-negative bacteria, and 2.5% fungal species. This large analysis demonstrated a significant episode-to episode agreement (71.9%) between the two methods, higher in negative samples (89.14%), and a specificity of 75.89%. Clinical variables that gave a statistically significant contribution to their concordance were absolute neutrophil count, ongoing antimicrobial therapy, timing of test execution, and organ localization of infection. The large analysis highlights the potential of molecular-based assays directly performed on blood samples, especially if implementing the detection of antibiotic resistance genes, which was lacking in the used study.

Human Herpesvirus 6 Infection Following Haploidentical Transplantation: Immune Recovery and Outcome.

Human herpesvirus 6 (HHV-6) is increasingly recognized as a potentially life-threatening pathogen in allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively evaluated 54 adult patients who developed positivity to HHV-6 after alloSCT. The median time from alloSCT to HHV-6 reactivation was 34 days. HHV-6 was present in plasma samples from 31 patients, in bone marrow (BM) of 9 patients, in bronchoalveolar lavage fluid and liver or gut biopsy specimens from 33 patients, and in cerebrospinal fluid of 7 patients. Twenty-nine patients developed acute graft-versus-host disease (GVHD), mainly grade III-IV, and 15 had concomitant cytomegalovirus reactivation. The median absolute CD3+ lymphocyte count was 207 cells/µL. We reported the following clinical manifestations: fever in 43 patients, skin rash in 22, hepatitis in 19, diarrhea in 24, encephalitis in 10, BM suppression in 18, and delayed engraftment in 11. Antiviral pharmacologic treatment was administered to 37 patients; nonetheless, the mortality rate was relatively high in this population (overall survival [OS] at 1 year, 38% ± 7%). A better OS was significantly associated with a CD3+ cell count ≥200/µL at the time of HHV-6 reactivation (P = .0002). OS was also positively affected by the absence of acute GVHD grade III-IV (P = .03) and by complete disease remission (P = .03), but was not significantly influenced by steroid administration, time after alloSCT, type of antiviral prophylaxis, plasma viral load, or organ involvement. Although HHV-6 detection typically occurred early after alloSCT, better T cell immune reconstitution seems to have the potential to improve clinical outcomes. Our findings provide new insight into the interplay between HHV-6 and the transplanted immune system.

INSULIN-LIKE GROWTH FACTOR-1 AND ANEMIA IN OLDER SUBJECTS: THE INCHIANTI STUDY.

OBJECTIVE: Recent studies indicate a role for the age-related decline of anabolic hormones, especially testosterone, in the onset of "anemia of aging." Some of testosterone's erythropoietic activities are mediated by insulin-like growth factor (IGF)-1, which also seems to have independent erythropoietic effects. However, the associations among IGF-1, anemia, and hemoglobin (Hb) have not been adequately investigated in older populations. METHODS: We used data from a representative sample of 953 subjects ≥65 years who participated in the InCHIANTI (Invecchiare in Chianti) Study and were not on growth hormone (GH) or erythropoietin therapy and were not diagnosed with hematologic malignancies or other cancers. Anemia was defined according to the World Health Organization (WHO) criteria by Hb level ≤13 g/dL in males and ≤12 g/dL in females. Backward multiple regression analyses including age, IGF binding protein (IGFBP)-3, testosterone, comorbidities, inflammatory markers, and anemia-related measures were used to address the relationship between IGF-1 and Hb and between IGF-1 and anemia in both sexes. RESULTS: We found that 46/410 (11.2%) males and 71/543 (13.0%) females were defined as anemic. After adjustment for age, anemic males (100 ± 54 vs. 130 ± 56, P<.001) and females (89.1 ± 48 vs. 110 ± 52, P = .001) exhibited lower IGF-1 levels than their nonanemic counterparts. IGF-1 levels were independently and negatively associated with anemia in males (ß ± SE = -0.0005 ± 0.0002, P = .04) but not in females (ß ± SE = -0.0002 ± 0.0002, P = .40). In both males (ß ± SE = 0.002 ± 0.001, P = .03) and females (ß ± SE = 0.002 ± 0.0009, P = .03), IGF-1 levels were independently and positively associated with Hb levels. CONCLUSION: In older males but not in females, IGF-1 levels are negatively associated with anemia. IGF-1 levels are independent and positive determinants of Hb concentration in both sexes.

Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells.

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/µL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.