Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy.

Armstrong strain lymphocytic choriomeningitis virus infection after accidental laboratory exposure.

BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) is a human pathogen naturally present in wild rodents. In addition, LCMV is routinely used in immunology research as a model of viral infection in mice. The Armstrong common laboratory strain and the Clone-13 variant induce acute and chronic infections in mice, respectively. The frequent use of this virus in laboratory settings is associated with a risk of human infection for laboratory personnel. In contrast to LCMV Clone-13, few human laboratory infections with LCMV Armstrong have been reported, leading to a poor understanding of symptoms related to infection with this specific LCMV strain. CASE PRESENTATION: A researcher accidentally infected herself percutaneously with LCMV Armstrong. Symptoms including headaches, dizziness, eye pain and nausea appeared seven days post-exposure and lasted ten days. LCMV-IgM antibodies were detected at 28 days post-infection and IgG seroconversion was observed later. Complete recovery was confirmed three months post exposure. CONCLUSIONS: Research involving live viruses comes with the risk of infection for research personnel. This case is the first reported accidental human infection with LCMV Armstrong. The symptoms differed from reported infections with LCMV Clone-13, by the absence of fever and vomiting, and presence of leg numbness. This report will therefore help clinicians and public health authorities to recognize the symptoms associated with LCMV Armstrong infections and to offer appropriate counselling to individuals who accidentally expose themselves.

CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naïve CD4+ T cells. Further, we describe a relationship between CD5 levels on naïve human CD4+ T cells and binding affinity to foreign peptide, in addition to a predominance of CD5hi T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5lo and CD5hi naïve human CD4+ T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naïve CD4+ T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies.

Evaluation of the Impact of Autologous Hematopoietic Stem Cell Transplantation on the Quality of Life of Older Patients with Lymphoma.

High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) improves survival in patients with chemosensitive non-Hodgkin lymphoma (NHL). Determination of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) has contributed to improve patient selection while allowing for prediction of nonrelapse mortality. We previously demonstrated the efficacy and safety of AHSCT in a cohort of older patients with chemosensitive NHL. Quality of life following AHSCT still has not been widely evaluated. The goal of this study was to assess the long-term quality of life of elderly patients surviving AHSCT. This single-center, Research and Ethics Committee-approved study investigated QoL in survivors of AHSCT for the treatment of NHL in a cohort of older patients. Inclusion criteria were defined as patients age ≥60 years who underwent AHSCT for NHL between January 1, 2008, and January 1, 2015, at our center. Fifty-nine patients from the original cohort of 90 survived at a median of 50 months post-AHSCT. Forty-seven (79.7%) of those patients agreed to complete the QoL assessment questionnaires after the transplantation and are included in this report. All patients provided signed informed consent. We used the EQ-5D instrument to assess mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire to assess physical, social/family, emotional, and functional well-being and BMT-specific concerns. With both tools, a higher score indicates better QoL. Fifteen percent of patients were in relapse at the time of the QoL assessment. In the EQ-5D, few patients (9%) reported severe impairment, which requires significant negative effects in 4 or 5 domains. Lower Karnofsky Performance Status (KPS) score at the time of transplantation was negatively correlated with mobility (P= .001), self-care (P= .001), and usual activities (P= .007) dysfunction. Anxiety was significant for patients in relapsed after transplantation (P= .002). FACT-BMT questionnaire results demonstrated that physical, social, and emotional well-being were all well preserved after the transplantation, whereas functional well-being was more variable among patients. Relapse was associated with impaired functional well-being (P= .007) and lower total FACT-BMT score (P= .014). Other comparators, including the conditioning regimen, sex, age subgroups (<65 or ≥65 years), HCT-CI score, and disease status at transplantation, did not impact any of these outcomes. This study demonstrates that physical, social, and functional well-being are preserved in older patients following AHSCT. Low KPS score before AHSCT is a predictor of disability at distance from AHSCT. Relapse following AHSCT remains the most significant impediment to maintaining a good QoL. Innovative interventions to improve performance status before transplantation and measures to prevent relapse thereafter should be investigated to improve survival and QoL.

Single UM171-expanded cord blood transplant can cure severe idiopathic aplastic anemia in absence of suitable donors.

Haplo-identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenitor cells leading to prolonged cytopenias and a high risk of infections. CB stem cell expansion may theoretically solve these pitfalls but has not been used previously in non-malignant diseases, likely due to fear of graft rejection and lack of availability of expanded CBs outside clinical trials. We report the first case of an adult patient with severe aplastic anemia who was successfully transplanted with a UM171-expanded CB graft. After a conditioning of rabbit antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, a UM171 expanded graft of 3.29 × 106 CD34 + cells/kg (a 51-fold increase) was infused. Full donor chimerism was observed on day + 14, with neutrophil and platelet engraftment on days + 23 and + 27. There was no severe infection or graft-vs-host disease. UM171-expanded grafts offer a valuable option for patients with aplastic anemia in need of transplantation but have no suitable donor.

Newly diagnosed multiple myeloma patients treated with tandem auto-allogeneic stem cell transplant have better overall survival with similar outcomes at time of relapse compared to patients who received autologous transplant only.

BACKGROUND: Long-term survival in patients progressing after tandem autologous-allogeneic stem cell transplant (SCT) has been reported, suggesting a persistent graft-vs-myeloma (GvM) effect even after post-transplant progression. METHODS: In order to confirm this observation, we updated the results of our previously published cohort of 92 newly diagnosed myeloma patients who received tandem transplant and compared them with 81 contemporary patients who received autologous transplant only. RESULTS: With a median follow-up of 13.1 and 10.2 years, respectively, median overall survival (OS) in the tandem group has not been reached, compared with 6.1 years after auto-SCT (P ≤ .001). Disease progression occurred less frequently after tandem transplant, with an estimated 10-year cumulative incidence of 49% vs 76% (P ≤ .001). Cumulative incidence of extensive chronic graft-vs-host disease (cGVHD) was high at 83%, with modest benefits on OS (60% vs 49%, P = .550) but sharp improvement of progression-free survival (PFS; 55% vs 10%, P = .002) at 10 years associated with development of cGVHD. After first progression, median OS was 5.8 years in tandem and 5.2 years in the auto-group (P = .062); median PFS was also similar. CONCLUSION: Despite confirmation of better outcomes after upfront tandem transplant, our data do not support persistence of a strong, clinically significant graft-vs-myeloma effect after first progression, emphasizing the need to better characterize the GvM effect.

Double-Negative T Cell Levels Correlate with Chronic Graft-versus-Host Disease Severity.

Chronic graft-versus-host disease (cGVHD) is a major complication, affecting 50% to 80% of long-term survivors of allogeneic hematopoietic stem cell transplantation. Current cGVHD therapies are neither specific nor curative, and patients are typically maintained for several months to years under immunosuppressive regimens that are associated with important side effects and increased susceptibility to life-threatening infections. As a result, continued investigation into the pathology of the disease and the search for novel diagnostic and therapeutic strategies to treat cGVHD remains a high priority. We report that the cellular dynamics of various immune cell subsets are related to cGVHD onset and severity in a cohort of allogeneic hematopoietic stem cell transplantation recipients. We document a decrease in the proportion of CD45RO+ CD4-CD8- (double-negative [DN]) T cells at the onset of cGVHD, a time at which serum levels of B cell activating factor and B cells are increased. We also find that DN T cell levels are correlated with cGVHD severity. Our present findings are in line with the view that activated DN T cells exhibit their immunoregulatory potential by eliminating B cells in vivo. Taken together, these findings suggest that maintaining elevated DN T cell numbers before the onset of cGVHD may prevent pathological B cell responses.

Allodepleted T-cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft-versus-host disease (GVHD) in the absence of GVHD prophylaxis.

Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104 -5 × 106  CD3+  cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3-2 × 106  CD3+  cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T-cell therapeutics.

BACKGROUND: Following solid organ or hematopoietic cell transplantation, refractory opportunistic viral reactivations are a significant cause of morbidity and mortality but can effectively be controlled by virus-specific T-cell transfer. Among effective and safe strategies is the use of "third-party" (neither from the transplant donor nor recipient) virus-specific T cells that can be manufactured from healthy donors and used as "off-the-shelf" therapies. Leukoreduction system chambers (LRSCs), recovered after routine plateletpheresis, were evaluated as a potential source of peripheral blood mononuclear cells (PBMCs) for the manufacturing of clinical-scale virus-specific T cell. STUDY DESIGN AND METHODS: PBMCs from the same donors obtained either from LRSCs or peripheral blood were compared, focusing on T-cell function and phenotype as well as the potential to generate cytomegalovirus (CMV)-specific T-cell lines from both CMV seropositive and seronegative donors. RESULTS: PBMCs from both sources were comparable except for a transient downregulation of CD62L expression on freshly extracted PBMCs from LRSCs. Both nonspecific stimulation using anti-CD3/CD28 antibodies and CMV peptides revealed that LRSCs or blood T cells were equivalent in terms of expansion, differentiation, and function. Moreover, PBMCs from LRSCs can be used to generate autologous monocyte-derived dendritic cells to prime and expand CMV-specific T cells from seronegative donors. CONCLUSION: LRSCs are a reliable source of PBMCs for the generation of virus-specific T cells for immunotherapy. These findings have implications for the development of third-party therapeutic T-cell products from well-characterized blood product donors.

VEGF Requires the Receptor NRP-1 To Inhibit Lipopolysaccharide-Dependent Dendritic Cell Maturation.

To stimulate a productive T cell response, dendritic cells (DC) must undergo maturation characterized by heightened cell surface expression of MHC and costimulatory molecules as well as cytokine production. Conversely, the inhibition of DC maturation is a central mechanism of immune tolerance. The control of the DC maturation process relies on the integration of several cellular stimulatory or inhibitory signals. The soluble factors and their receptors controlling this central aspect of DC biology are incompletely characterized. We show that murine bone marrow-derived DC (BMDC) maturation induced by LPS, as opposed to polyinosinic:polycytidylic acid or cytosine-phosphate-guanine, is robustly inhibited by vascular endothelial growth factor (VEGF), a previously identified immunosuppressive cytokine. Using BMDC from wild type and conditional knockout mice, we show that neuropilin-1 (NRP-1), a known receptor of VEGF, is necessary to suppress LPS-dependent BMDC maturation. The absence of NRP-1 had no ostensible effects on the biology of BMDC in the absence of VEGF. However, NRP-1-deficient BMDC remained completely insensitive to the VEGF-dependent inhibition of BMDC maturation in culture. In the presence of VEGF, NRP-1 directly interacted with the LPS receptor TLR4 and suppressed downstream signaling through ERK and NF-κß, resulting in a sharp inhibition of MHC class II and costimulatory molecules (CD40, CD86) expression as well as proinflammatory cytokine production. Consequently, we identify NRP-1 as a target to optimize DC maturation within environments that are rich in VEGF, such as tumors.

Defining novel parameters for the optimal priming and expansion of minor histocompatibility antigen-specific T cells in culture.

BACKGROUND: Adoptive transfer of minor histocompatibility antigen (MiHA)-specific T cells is a promising therapy for patients with hematological cancers. However, the efficacy of the transferred cells is hampered by the acquisition of terminal effector differentiation and exhaustion features during expansion in vitro thus preventing their function and persistence in vivo. Yet, the factors that induce T-cell differentiation and functional impairment in culture remain poorly defined and are likely to vary depending on the method used for expansion. METHODS: Using the clinically relevant HLA-A0201-restricted MiHA HA-1 as well as reagents and procedures that are readily transferable to a clinical environment, we designed a novel culture protocol and defined how exhaustion features appeared in function of time. The optimal time points for the expansion of "fit" MiHA-specific T cells were delineated using phenotypic and functional assessments including KLRG-1 and PD-1 surface markers as well as Ki67 staining and cytokine secretion assays. RESULTS: Following a priming phase, an enrichment step and a rapid expansion stage, our method generates MiHA-specific T-cell lines. Evidence of phenotypic and functional dysfunction appear in function of culture duration, but display different characteristics following the extension of the priming or rapid expansion phases. While repeated antigen exposure during the priming phase induced the decline of the antigen-specific population and the expression of PD-1 and KLRG-1 on antigen-specific CD8+ T cells, the prolongation of an antigen-free expansion phase induced proliferation arrest and the relative loss of antigen-specific cells without impairing polyfunctional cytokine secretion or inducing PD-1 and KLRG-1 expression. A similar pattern was also observed after stimulating a virus-specific memory repertoire, except for the more rapid acquisition of exhaustion features upon repeated antigen exposure. CONCLUSION: Our results offer novel insights on the impact of culture duration on the acquisition of T-cell exhaustion features. Using a new clinical-compliant protocol, we define critical parameters to monitor in order to optimally differentiate and expand MiHA-specific T cells in culture prior to adoptive transfer.

Early exposure to interleukin-21 limits rapidly generated anti-Epstein-Barr virus T-cell line differentiation.

BACKGROUND AIMS: The adoptive transfer of ex vivo-expanded Epstein-Barr virus (EBV)-specific T-cell lines is an attractive strategy to treat EBV-related neoplasms. Current evidence suggests that for adoptive immunotherapy in general, clinical responses are superior if the transferred cells have not reached a late or terminal effector differentiation phenotype before infusion. The cytokine interleukin (IL)-21 has shown great promise at limiting late T-cell differentiation in vitro, but this remains to be demonstrated in anti-viral T-cell lines. METHODS: We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation. RESULTS: We generated clinical-scale EBV-restricted T-cell line expansion with balanced T-cell subset ratios. The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells. Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation. CONCLUSIONS: Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy.

Abstracts of the Cell Therapy Transplant Canada 2023 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May-2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as "Award Recipient" within the relevant category. We congratulate all the presenters on their research and contributions to the field.

SMAD3 prevents graft-versus-host disease by restraining Th1 differentiation and granulocyte-mediated tissue damage.

Gene expression profiling of human donor T cells before allogeneic hematopoietic cell transplantation revealed that expression of selected genes correlated with the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3, a core component of the transforming growth factor-ß signaling pathway, whose expression levels vary more than a 6-fold range in humans. The putative role of SMAD3 in the establishment of graft-host tolerance remained elusive. We report that SMAD3-KO mice present ostensibly normal lymphoid and myeloid cell subsets. However, the lack of SMAD3 dramatically increased the frequency and severity of GVHD after allogeneic hematopoietic cell transplantation into major histocompatibility complex-identical recipients. Lethal GVHD induced by SMAD3-KO donors affected mainly the intestine and resulted from massive tissue infiltration by T-bet(+) CD4 T cells and granulocytes that caused tissue damage by in situ release of Th1 cytokines and oxidative-nitrosative mediators, respectively. Our report reveals the nonredundant roles of SMAD3 in the development of tolerance to the host. Furthermore, our data support the concept that SMAD3 levels in donor cells dictate the risk of GVHD and that SMAD3 agonists would be attractive for prevention of GVHD.

Immature and mature bone marrow-derived dendritic cells exhibit distinct intracellular mechanical properties.

Dendritic cells (DCs) patrol the organism at an immature stage to detect the presence of pathogens. Once activated, these mature DCs reach the lymph nodes to activate antigen-specific T lymphocytes and thus initiate an adaptative immune response to control the pathogen. The migration of both immature and mature DCs is a key process for their optimal function. DC migration requires transit through narrow constrictions that is allowed by their high local and global deformation capabilities. In addition to cytoplasmic changes, the nucleus mechanical properties also have a major impact for cellular migration and motility. Yet, nucleus intracellular mobility of dendritic cells or its variation upon maturation have not been investigated. Our study defines the biophysical phenotypic variations of dendritic cells upon maturation using interferometric deformability cytometry. This method characterizes different cellular mechanical properties, such as elongation and nucleus offset, by assessing the refractive index spatial distribution of shear-induced deformed cells. By using these parameters, our data suggest that in vitro bone marrow derived dendritic cell (BMDC) maturation induces cell stiffening and reduces nucleus mobility, allowing to distinguish immature and mature dendritic cells. Overall, our method provides insights on intracellular mechanical properties of two dendritic cell states.

Blasts in context: the impact of the immune environment on acute myeloid leukemia prognosis and treatment.

Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development of AML, with a focus on T cells and other lymphoid cells. The types and function of different immune cells involved in the AML microenvironment as well as their putative role in the onset of disease and response to treatment are presented. We also describe how the immune context predicts the response to immunotherapy in AML and how these therapies modulate the immune status of the bone marrow. Finally, we focus on allogeneic stem cell transplantation and summarize the current understanding of the immune environment in the post-transplant bone marrow, the factors associated with immune escape and relevant strategies to prevent and treat relapse.

Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence.

Cord blood (CB) transplantation is hampered by low cell dose and high nonrelapse mortality (NRM). A phase 1-2 trial of UM171-expanded CB transplants demonstrated safety and favorable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase 1-2 trial with those after unmanipulated CB and matched-unrelated donor (MUD) transplants. Data from recipients of CB and MUD transplants were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients were directly matched for the number of previous allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index, and performance status. Primary end points included NRM, progression-free survival (PFS), overall survival (OS), and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) at 1 and 2 years after alloHCT. Overall, 137 patients from CIBMTR (67 CB, 70 MUD) and 22 with UM171-expanded CB were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared with CB controls. Compared with MUD controls, UM171 recipients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades 3-4 acute GVHD and chronic GVHD compared with MUD graft recipients. Compared with real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS. This trial was registered at www.clinicaltrials.gov as #NCT02668315.

Bortezomib Maintenance After Allogeneic Transplantation in Newly Diagnosed Myeloma Patients Results in Decreased Incidence and Severity of Chronic GVHD.

Allogeneic hematopoietic cell transplantation (HCT) has curative potential in myeloma but remains hampered by high rates of relapse and chronic graft-versus-host disease (GVHD). We hypothesized that bortezomib (BTZ) as maintenance therapy after allo HCT could not only decrease the incidence of relapse but also the incidence and severity of chronic GVHD. The primary endpoint of this study was to determine whether BTZ maintenance decreases the incidence and severity of chronic GVHD using National Institutes of Health (NIH) criteria. The secondary endpoints were to determine the immunosuppression burden, organ involvement and survival (overall survival, progression-free survival) in patients either receiving or not receiving BTZ. In this retrospective study, we compared the outcome of 46 myeloma patients who received BTZ after upfront tandem auto-allo HCT between 2008 and 2020 to 61 patients without maintenance. We explored the impact of BTZ maintenance on incidence and severity of chronic GVHD using the 2014 NIH criteria. At 2 years, incidences of overall (61.2% versus 83.6%; P = .001), and moderate/severe chronic GVHD (44.5% versus 77.0%; P = .001) were significantly lower in BTZ recipients who had less mouth (43% versus 67%; P = .018) and eyes (9% versus 41%; P = .001) involvement at initial diagnosis. We report a lower use of systemic steroids (45.1% versus 76.4%; P < .001), mycophenolate mofetil (15.5% versus 28.2%; P = .031) and tacrolimus (34.5% versus 70.6%; P < .001) in BTZ recipients. Probability of being alive and off systemic immunosuppressants at 3 years was 77% in BTZ recipients and 56% in controls (P = .046). To date, there is no difference in survival between both groups. In summary, BTZ maintenance improved incidence and severity of chronic GVHD and should be considered as a valid option in myeloma patients receiving upfront tandem auto-allo HCT.

Impact of Implementing a Bendamustine-Based Conditioning Regimen on Outcomes of Autologous Stem Cell Transplantation in Lymphoma while Novel Cellular Therapies Emerge.

With the advent of new cellular and targeted therapies, treatment options for relapsed and refractory (r/R) lymphomas have multiplied, and the optimal approach offering the best outcomes remains a matter of passionate debate. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is still considered a treatment option for patients with chemosensitive lymphoma when cure is the expected goal. The myeloablative conditioning regimen preceding the stem cell infusion is considered the effective component of this approach. Carmustine (BCNU)-based preparative regimens, such as BEAM and BEAC, are considered the standard of care and have shown efficacy and low nonrelapse mortality (NRM). Comparative studies between conditioning regimens have failed to identify a better option. After a BCNU drug shortage in Canada followed by a steep increase in price, we elected to substitute BCNU for bendamustine (benda) in the preparative regimen. The purpose of this substitution was to improve response while preserving safety and controlling costs. From May 2015 to May 2018, a total of 131 consecutive lymphoma patients received benda-EAM conditioning. These patients were compared with 96 consecutive patients who received BCNU-based conditioning from January 2012 to May 2015. Apart from conditioning, supportive care measures were the same in the 2 groups. Patients receiving benda were older (55.7 years versus 51.1 years; P = .002). The development of grade ≥3 mucositis was more frequent with benda conditioning (39.5% versus 7.8%; P < .001) leading to a greater requirement for parenteral nutrition (48.9% versus 21.9%; P < .001). A transient creatinine increase >1.5 times the upper limit of normal (15.3% versus 4.2%; P < .008) and intensive care unit admission (6.9% versus 1.1%; P < .029) were more frequent with benda; however, there were no between-group differences in cardiac, pulmonary, or liver toxicity and NRM. With a median follow-up of 48 months for the benda group and 60 months for the BCNU group, benda was associated with significantly better progression-free survival (71% versus 61%; P = .040; hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0 to 2.7) and overall survival (86% vs 71%; P = .0066; HR, 2.6; 95% CI, 1.3 to 5.4) compared with BCNU-based conditioning regimens. While novel therapies emerge, our study demonstrates that benda-EAM is safe and effective and should be considered a valid alternative to BCNU conditioning to improve outcomes of patients with chemosensitive r/R lymphomas undergoing ASCT.

Immunogenicity, Safety, and Breakthrough Severe Acute Respiratory Syndrome Coronavirus 2 Infections After Coronavirus Disease 2019 Vaccination in Organ Transplant Recipients: A Prospective Multicenter Canadian Study.

Background: Solid organ transplant (SOT) recipients are at risk for severe coronavirus disease 2019 (COVID-19), despite vaccination. Our study aimed to elucidate COVID-19 vaccine immunogenicity and evaluate adverse events such as hospitalization, rejection, and breakthrough infection in a SOT cohort. Methods: We performed a prospective, observational study on 539 adult SOT recipients (age ≥18 years old) recruited from 7 Canadian transplant centers. Demographics including transplant characteristics, vaccine types, and immunosuppression and events such as hospitalization, infection, and rejection were recorded. Follow ups occurred every 4-6 weeks postvaccination and at 6 and 12 months from first dose. Serum was processed from whole blood to measure anti-receptor binding domain (RBD) antibodies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to assess immunogenicity. Results: The COVID-19 vaccines were found to be safe in SOT recipients with low rates of rejection requiring therapy (0.7%). Immunogenicity improved after the third vaccine dose, yet 21% developed no anti-RBD response. Factors such as older age, lung transplantation, chronic kidney disease, and shorter duration from transplant were associated with decreased immunogenicity. Patients with at least 3 doses were protected from hospitalization when experiencing breakthrough infections. Significantly increased anti-RBD levels were observed in patients who received 3 doses and had breakthrough infection. Conclusions: Three or four doses of COVID-19 vaccines were safe, increased immunogenicity, and protected against severe disease requiring hospitalization. Infection paired with multiple vaccinations significantly increased anti-RBD response. However, SOT populations should continue to practice infection prevention measures, and they should be prioritized for SARS-CoV-2 pre-exposure prophylactics and early therapeutics.