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Summary: This prospective study evaluated seroconversion rates in response to BNT162b2 (Pfizer‐BioNTech) COVID‐19 vaccine booster in 44 B‐cell non‐Hodgkin lymphoma (B‐NHL) patients who failed to respond to two prior doses [42 previously exposed to anti‐CD20 monoclonal antibodies (moAbs) including 13 under maintenance treatment]. Seroconversion was obtained in 29.5% of the patients. Longer time from last anti‐CD20 moAb (>6 months) and diagnosis of aggressive lymphoma compared to other, incurable B‐NHLs were associated with increased seroconversion rates (47.8% vs.10.5%, p = 0.019 and 50% vs. 17.9%, p = 0.025 respectively). Thus, seronegative patients with B‐NHL that completed anti‐CD20 therapy more than 6 months prior to the booster have greater chances to achieve seroconversion. [ABSTRACT FROM AUTHOR]

In an attempt to elucidate the pathogenic role of a CD4+ cytotoxic T-cell clone NT4.2 isolated from the bone marrow of a patient with cyclosporine-dependent aplastic anaemia, we characterized the T-cell clone as well as its cytotoxicity against an autologous Epstein-Barr (EB) virus-transformed B-lymphoblastoid cell line (LCL). NT4.2 expressed BV21+ BJ2.7+ with a complementarity-determining region (CDR) 3 motif of SQGQGEVEQY which was homologous to that of a T-cell clone isolated from a patient with connective tissue disease. NT4.2 started to lyse LCL cells within 2 h and exerted maximal cytotoxicity within 3 h of incubation. The cytotoxicity required the presence of divalent cations and was not associated with DNA fragmentation of the target cells. Anti-CD59 monoclonal antibodies (MoAb) blocked the cytotoxicity to the same degree as anti-CD3, HLA-DR or CD2 mAb. Flow cytometric analysis of the peripheral blood of this patient during remission after cyclosporine therapy revealed 1.7% of granulocytes to be deficient in CD59. These findings indicate that NT4.2 exerts its cytotoxicity through a perforin-mediated pathway, not a Fas/Fas ligand-dependent pathway, and that haemopoietic stem cells lacking CD59 may evade cytotoxic T lymphocytes, leading to the in vivo expansion of a paroxysmal nocturnal haemoglobinuria clone. [ABSTRACT FROM AUTHOR]

Immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs) and anti‐CD38 monoclonal antibodies (MoAbs) are the pillars of modern multiple myeloma (MM) therapy. The prognosis of patients with MM that became refractory to these three classes (triple‐class refractory [TCR]) is historically poor. Observational studies indicate an overall response rate of ~30% and overall survival inferior to 1 year with existing therapies. While no randomised trial has been completed in this setting, several agents exploring new mechanisms of action showed activity in TCR MM in single‐arm trials, including anti‐B‐cell maturation antigen (BCMA) chimeric antigen receptor T cells, anti‐BCMA antibody‐drug conjugates and exportin 1 (XPO1) inhibitors. Among agents in development, anti‐BCMA bispecific T‐cell engagers (TCE), and non‐BCMA TCEs demonstrated activity in most patients. Additionally, specific agents may exhibit unique activity in biologically defined patient subsets, as exemplified by venetoclax in t(11;14) MM. The main open questions in TCR MM are preferred sequence of existing therapies, the utility of sequential use of agents with similar mechanism of action, but different immunotherapy target and the relative efficacy of the different anti‐BCMA platforms. Here, we summarise the existing literature and provide general guidance on selecting therapy for this challenging and heterogenous group of patients. [ABSTRACT FROM AUTHOR]

To gain further insight into ART 4 ( DO) gene alleles ( DO * A, DO * JO 1, DO * A-WL , DO * DOYA , DO * B , DO * B-WL , DO * B-SH -Q149K, DO*B-(WL)-I175N, DO*HY1, DO*HY2, DO*DOMR) and evaluate the impact of synonymous nucleotide polymorphisms on protein expression and mRNA accumulation of DO*A-HA, DO*A-SH and DO*B-SH alleles, human erythroleukaemic K562 cells were transducted with variant DO-lentiviral particles and analysed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Monoclonal antibody (MoAb) detection of DO*A-HA and DO*JO1 transductants was lower than DO*A transductants, while detection of DO*A-SH, DO*A-WL and DO*DOYA transductants was higher. Variant DO*B alleles, i.e. DO*B-SH, DO*B-WL, DO*HY1, DO*HY2 and DO*DOMR, showed reduced MoAb binding. The unexpected modifications of protein expression of the DO*A-HA, DO*A-SH and DO*B-SH alleles that differ from the DO*A or DO*B alleles by a single synonymous polymorphism were abolished by reversion, thus implying involvement of these polymorphisms. Depending on the Leu208 codon used, detection level ranged from 1 to 4·14. In the variant alleles resulting from single synonymous polymorphism, mRNA accumulation correlated roughly with MoAbs detection levels, suggesting post-transcriptional regulation. Other than a few reports involving aberrant splicing, the experiments described herein provide the first evidence that synonymous nucleotide polymorphisms can influence Dombrock blood group expression. Such polymorphisms should be taken into account for molecular screening and potential impact on transfusion. [ABSTRACT FROM AUTHOR]

I TableGeometric mean concentrations of anti-SARS-CoV-2 IgG and response rates according to seven different cohorts of haematological malignancy patients compared to a control cohort at 5 and 12 weeks after BNT162b2 vaccination. Keywords: severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); BNT162b2; haematological cancers EN severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) BNT162b2 haematological cancers 362 367 6 01/17/22 20220115 NES 220115 To date, studies on anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine efficacy in blood cancers show that different responses may be observed according to the haematological malignancy diagnosis, stage of disease and ongoing treatment. Single dose of BNT162b2 mRNA vaccine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces neutralising antibody and polyfunctional T-cell responses in patients with chronic myeloid leukaemia. Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. [Extracted from the article]

Finally, other potential treatment options to reduce relapse/progression post alloSCT include post-transplantation cyclophosphamide (ptCy). Keywords: myeloma therapy; stem cell transplantation; cytogenetics EN myeloma therapy stem cell transplantation cytogenetics 244 248 5 12/27/21 20220101 NES 220101 Treatment of patients with relapsed multiple myeloma (MM) after autologous stem cell transplantation (autoSCT) remains challenging. Consequently, a future goal in MM therapy is to combine modern treatment concepts and alloSCT in suitable patients to reduce disease burden and enhance disease control in patients with relapsed high-risk MM. Details on re-induction treatment and response rates prior to alloSCT, engraftment and post alloSCT response rates, maintenance therapy, donor lymphocyte infusions (DLI) and relapse therapies are shown in Table I. The median age at alloSCT was 50 (range 34-64) years. [Extracted from the article]

Human thrombopoietin (TPO) is a haemopoietic growth factor that is essential for the growth and development of megakaryocytes. However, c-Mpl, the TPO receptor, has been detected in human leukaemic cell lines with a myelomonocytic phenotype. These results raise the possibility that dendritic cells (DC), a putative myeloid lineage cell, may also express c-Mpl and respond to TPO. In haemopoietic stem cell transplantation, DC could induce graft-versus-host disease by its strong antigen-presenting capacity. In this study we have examined the effect of TPO on differentiation and the antigen-presenting capacity of DC. To differentiate DC, cord blood CD34+ cells were cultured in the presence of a cytokine cocktail either in serum-free medium or RPMI1640 containing 10% fetal bovine serum. Flow cytometric analysis and immunocytochemical staining demonstrated that c-Mpl was expressed on DC. Furthermore, the expression of c-Mpl mRNA was detected in DC by RNase protection assay. However, when TPO was added to the culture system there were no significant changes in the differentiation and mixed leucocyte-stimulating capacity of DC. These findings suggest that TPO may be administered following cord blood transplantation without significant augmentation of antigen presentation mediated by DC. [ABSTRACT FROM AUTHOR]

Stuart F. Schlossman, an immunologist and hematologist, passed away at the age of 88 from pancreatic cancer. He made significant contributions to the field of immunology, particularly in the study of T lymphocytes and leukocyte differentiation antigens. Schlossman's research led to the development of monoclonal antibodies and the characterization of the human T-cell receptor. His work also had implications for understanding diseases such as multiple sclerosis, renal graft rejection, and infectious mononucleosis. Schlossman mentored many researchers and his contributions continue to impact the field of hematology. [Extracted from the article]

Summary: Blinatumomab and inotuzumab ozogamycin represent promising alternatives to conventional chemotherapy in acute lymphoblastic leukaemia (ALL). We analysed data from 29 children with ALL treated under compassionate use with blinatumomab, inotuzumab or both. The complete remission (CR) rate in a heavily pretreated population with overt relapse was 47·6%. At earlier stages (first/second CR), both antibodies represented a useful tool to reduce minimal residual disease, and/or avoid further toxic chemotherapy until stem cell transplantation. Six patients developed grade 3 reversible non‐haematological toxicity. The 12‐month overall survival and event‐free survival rates were 50·8 ± 26·4% and 38·9 ± 25·3% with blinatumomab, 45·8 ± 26% and 27·5 ± 25% with inotuzumab. [ABSTRACT FROM AUTHOR]

Prothrombin is now accepted as one of the target antigens recognised by antiphospholipid (aPL) antibodies. However, it is not clear whether anti-prothrombin antibodies are pathogenic in vivo and if so, the possible mechanism(s) involved. Here, we examined the pathogenic effects of the IS6 monoclonal anti-prothrombin antibody isolated from a patient with Antiphospholipid Syndrome (APS). IS6 antibody was purified from hybridoma supernatant. Its pathogenic potentials were studied in an in vivo model of induced thrombosis. The expression of tissue factor (TF) and E-selectin on human umbilical vein endothelial cells (HUVEC) was determined by cyto-enzyme-linked immunosorbent assay. Transcription of TF mRNA was determined by quantitative real time-polymerase chain reaction (RT-PCR). In vivo, the thrombus size increased significantly when treated with IS6 compared with control-treated mice (5388 ± 1035 μm2 vs. 2845 ± 1711 μm2). In vitro, IS6 induced significant expression of TF and E-selectin on HUVEC, when compared with control preparation (3·1- and 5·1-fold increase compared with the control-treated cells). RT-PCR analysis of TF mRNA transcription showed a 2·5-fold increase of IS6-treated cells over the value obtained with control-treated cells. Taken together, these data show that IS6 monoclonal anti-prothrombin antibody promotes thrombosis and this is associated with TF and E-selectin expression. [ABSTRACT FROM AUTHOR]

Summary: Autologous patient‐derived adoptive T‐cell therapies have revolutionized the management of relapsed multiple myeloma (MM). However, the current manufacturing and quality control processes result in lengthy vein‐to‐vein time, making bridging therapy necessary for most patients. Yet the decision and choice of optimal bridging therapy are complex in the heavily pretreated relapsed MM patient. In this perspective piece, the authors provide their approach and considerations while selecting an optimal bridging regimen before autologous chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Summary: To compare the clinical efficacy of porcine anti‐lymphocyte globulin (p‐ALG) and rabbit anti‐thymocyte globulin (r‐ATG) in the treatment of haematological malignancies using haploidentical haematopoietic stem cell transplantation (haplo‐HSCT), this study was conducted. The incidences of neutrophil and platelet engraftment, respectively, were 100%, 93.6% and 94.4%; 100%, 93.6% and 90.3% in p‐ALG 75 mg/kg (n = 57), p‐ALG 90 mg/kg (n = 49), and r‐ATG 7.5 mg/kg (n = 72). The median time to neutrophil engraftment and platelet engraftment were 11, 12 and 12 days (p = 0.032); 13, 14 and 13 days (p = 0.013), respectively. The incidence of grades II–IV acute graft‐versus‐host disease and cumulative incidence of chronic graft‐versus‐host disease were 16.7% versus 12.5% versus 13.3% (p = 0.817) and 14.7% versus 12.1% versus 19.5% in p‐ALG 75 mg/kg, p‐ALG 90 mg/kg and r‐ATG groups. Notably, the cytomegalovirus infection rate in the p‐ALG 75 mg/kg group was significantly lower than the other two groups. The cumulative incidence of 2‐year relapse and 2‐year overall survival rates were similar (p = 0.901, p = 0.497). The lower dose of p‐ALG (75 mg/kg) had a similar efficacy and safety profile compared with r‐ATG (7.5 mg/kg) in the setting of haplo‐HSCT. Therefore, p‐ALG (75 mg/kg) may be an appropriate alternative to r‐ATG in the conditioning regimen of haplo‐HSCT. [ABSTRACT FROM AUTHOR]

In the present study we examined the effect of immune complexes (IC) on the survival of chronic lymphocytic leukaemia (B-CLL) B cells. Our results showed that either precipitating IC (pIC), Ab-coated erythrocytes (E-IgG) or heat-aggregated IgG (aIgG) significantly inhibited spontaneous apoptosis of B-CLL cells, as well as that induced by fludarabine, chlorambucil or dexamethasone. After depletion of T lymphocytes, monocytes and NK cells, incubation with IC was no longer able to delay B-CLL cells apoptosis, suggesting that prevention of apoptosis depends on IC interaction with accessory leucocytes. The release of IFNγ by non-malignant cells upon activation with IC was responsible, to some extent, for IC effects as shown by the fact that neutralizing anti-IFNγ MoAb partially prevented their ability to inhibit B-CLL cells apoptosis. The observation that treatment with IC resulted in increased expression of HLA-DR on B-CLL cells suggests that inhibition of apoptosis is associated with cellular activation. [ABSTRACT FROM AUTHOR]

Factor VIII (FVIII) inhibitor alloantibodies react with combinations of the A2, C2 and A3-C1 domains of the FVIII molecule. Some inhibitors block binding of FVIII to both von Willebrand factor (VWF) and phospholipid, and recognize a C2 domain epitope which overlaps both binding sites. In order to determine the essential binding regions for alloantibodies inhibitory for FVIII activity, we have performed inhibitor neutralization assays and competitive inhibition assays using 10 overlapping synthetic peptides spanning the carboxy-terminal region of the C2 domain (residues 2288–2332). We found one peptide (2315–2330, L9) which neutralized the anti-FVIII activity of four out of five different C2 alloantibodies by 50%, 39%, 47% and 57%, respectively. Neutralization of these alloantibodies by recombinant C2 domain (residues 2173–2332) was 68%, 50%, 59%, 86% and >95%, respectively. The inhibitor which was not neutralized by L9 peptide and reacted by immunoblotting with peptide 2218–2307, did not prevent binding of FVIII to VWF and only partially inhibited binding of FVIII to phosphatidylserine. Mutants of the L9 peptide were prepared in which each residue from 2315–2330 was sequentially substituted by glycine. Inhibitor neutralization experiments using these peptides demonstrated that Arg2320 and Cys2326 or Glu2327 are important for the effect of L9 peptide, since their substitution by glycine reduced its neutralizing effect by 60% to >90%, suggesting that they are crucial for formation of the one of the C2 inhibitor epitopes. [ABSTRACT FROM AUTHOR]

Neutrophils from 13 children who received G-CSF for the collection of peripheral blood progenitors while they were in haematological steady state were studied at various times after G-CSF injection for FcγR expression (FcγRI or CD 64, FcγRII or CD32, and FcγRIII or CD16) and for their ability to exert antibody-dependent cell cytotoxicity (ADCC) through FcγRI. Changes in IFNγ, IL8, IL10, MCP1 and TNFα mRNA levels in peripheral blood cells were also studied 4 h and 24 h after the first G-CSF injection. FcγRI expression increased strongly after 24 h and then remained at the same level throughout treatment. In contrast, FcγRIII expression sharply decreased at day 1 and diminished even further thereafter. No change in FcγRII was observed. ADCC exerted by neutrophils through FcγRI started to increase after 24 h with the peak level at day 5. Cytokine mRNA analyses indicated a reproducible and strong increase of IL8 mRNA (11/13 children) after 24 h, whereas the changes in the mRNA levels of the other cytokines tested were more heterogenous (IFNγ: three; IL10: six; MCP1: five; TNFα: four, of the 13 children). Therefore this study opens the way to an optimized therapeutic schedule for the combined use of G-CSF and monoclonal antibodies in adjuvant immuno-intervention. [ABSTRACT FROM AUTHOR]

We recently established a human granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent cell line (HML) from colony-constituent cells grown by peripheral blood cells of a patient with acute megakaryoblastic leukaemia. The HML cells possessed megakaryocytic features, as determined by cytochemical, electron microscopic and flow cytometric analysis. In the present study we examined the effects of retinoic acid (RA) on the development of HML cells. All-trans-RA, 13-cis-RA and 9-cis-RA at 10-8 mol/l to 10-5 mol/l inhibited the GM-CSF-dependent cell growth. Some of the RA-treated cells contained prominent azurophilic granules and were positive for peroxidase. They also reacted with Biebrich scarlet, Luxol fast blue and a monoclonal antibody against eosinophil peroxidase. In addition, exposure to RA increased the frequency and the intensity of major basic protein-positive cells. However, eosinophil-derived neurotoxin and eosinophil cationic protein were not detected or were only detected at a low level in the lysates of the HML cells treated with RA. Although IL-5 alone could not stimulate cell growth, the addition of IL-5 to the cultures containing stem cell factor + all-trans-RA was required for the expression of the eosinophilic phenotype. These results suggest that the HML cell line is a megakaryoblastic cell line with the potential to differentiate into the eosinophilic lineage. HML cells may be a useful model for elucidating the eosinophilic differentiation programme. [ABSTRACT FROM AUTHOR]