As in younger patients, allogeneic stem cell transplantation (alloHSCT) offers the best chance for durable remission in older patients (≥60 years) with acute myeloid leukemia (AML). However, defining ...the best treatment strategy (and in particular, whether or not to proceed to alloHSCT) for elderly patients with AML remains a difficult decision for the hematologist, since potential toxicity of conditioning regimens, risks of graft-versus-host disease, impaired immune reconstitution and the need for prolonged immunosuppression may be of major concern in these vulnerable patients with complex needs. Hopefully, significant progress has been made over the past decade in alloHSCT for elderly patients and current evidence suggests that chronological age per se (between 60 and 75) is not a reliable predictor of outcome after alloHSCT. Here, we review the current state of alloHSCT in elderly patients with AML and also discuss the different approaches currently being investigated to improve both accessibility to as well as success of alloHSCT in these patients.
Background Severe combined immunodeficiency can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as recombination-activating gene 1 (RAG1) , RAG2 , ...or DNA cross-link repair 1C (DCLRE1C). Defective DNA recombination causes a developmental block in T and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give rise to a partial loss of T cells in a spectrum including leaky severe combined immunodeficiency (LS) and Omenn syndrome (OS). These patients not only experience life-threatening infections because of immunodeficiency but also experience inflammatory/autoimmune conditions caused by the presence of autoreactive T cells. Objective We sought to develop a preclinical model that fully recapitulates the symptoms of patients with LS/OS, including a model for testing therapeutic intervention. Methods We generated a novel mutant mouse (Dclre1c leaky ) that develops a LS phenotype. Mice were monitored for diseases, and immune phenotype and immune function were evaluated by using flow cytometry, ELISA, and histology. Results Dclre1c leaky mice present with a complete blockade of B-cell differentiation, with a leaky block in T-cell differentiation resulting in an oligoclonal T-cell receptor repertoire and enhanced cytokine secretion. Dclre1c leaky mice also had inflammatory symptoms, including wasting, dermatitis, colitis, hypereosinophilia, and high IgE levels. Development of a preclinical murine model for LS allowed testing of potential treatment, with administration of cytotoxic T-lymphocyte-associated protein 4-Ig reducing disease symptoms and immunologic disturbance, resulting in increased survival. Conclusion These data suggest that cytotoxic T-lymphocyte-associated protein 4-Ig should be evaluated as a potential treatment of inflammatory symptoms in patients with LS and those with OS.
We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell ...transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy.
We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130).
Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003).
New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.
Graft-versus-host disease (GVHD) remains a serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). While post-transplant administration of cyclophosphamide (PTCy) is ...increasingly used as GVHD prophylaxis, its precise mechanisms of action and its impact on graft-versus-leukemia effects have remained debated. Here, we studied the mechanisms of xenogeneic GVHD (xGVHD) prevention by PTCy in different humanized mouse models. We observed that PTCy attenuated xGVHD. Using flow cytometry and single-cell RNA-sequencing, we demonstrated that PTCy depleted proliferative CD8+ and conventional CD4+ T cells but also proliferative regulatory T cells (Treg). Further, T-cell receptor β variable region sequencing (TCRVB) analyses demonstrated that highly xenoreactive T-cell clones were depleted by PTCy. Although Treg frequencies were significantly higher in PTCy-treated than in control mice on day 21, xGVHD attenuation by PTCy was not abrogated by Treg depletion. Finally, we observed that PTCy did not abrogate graft-versus-leukemia effects.
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•Post-transplant cyclophosphamide prevents GVHD by depleting alloreactive T-cells•Post-transplant cyclophosphamide depletes proliferative regulatory T cells•Post-transplant cyclophosphamide does not abrogate graft-versus-leukemia effects
Medicine; Molecular biology; Immunology
Allogeneic hematopoietic stem cell transplantation is increasingly used as treatment for patients with life-threatening blood diseases. Its curative potential is largely based on immune-mediated ...graft-versus-leukemia effects caused by donor T cells contained in the graft. Unfortunately, donor T cells are also the cause of graft-versus-host disease. The vast majority of human leukocyte antigen-matched allogeneic hematopoietic stem cell transplants are nowadays carried out with peripheral blood stem cells as the stem cell source. In comparison with bone marrows, peripheral blood stem cells contain more hematopoietic stem/progenitor cells but also one log more T cells. Consequently, the use of peripheral blood stem cells instead of bone marrow has been associated with faster hematologic recovery and a lower risk of relapse in patients with advanced disease, but also with a higher incidence of chronic graft-versus-host disease. These observations have been the basis for several studies aimed at assessing the impact of immunoregulation with anti-thymocyte globulin on transplantation outcomes in patients given human leukocyte antigen-matched peripheral blood stem cells from related or unrelated donors. After a brief introduction on anti-thymocyte globulin, this article reviews recent studies assessing the impact of anti-thymocyte globulin on transplantation outcomes in patients given peripheral blood stem cells from human leukocyte antigen-matched related or unrelated donors as well as in recipients of grafts from human leukocyte antigen haploidentical donors.
We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given ...hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor–mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression.
Factors affecting response to SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients remain to be elucidated.
Forty allo-HCT recipients were included in a ...study of immunization with BNT162b2 mRNA vaccine at days 0 and 21. Binding antibodies (Ab) to SARS-CoV-2 receptor binding domain (RBD) were assessed at days 0, 21, 28, and 49 while neutralizing Ab against SARS-CoV-2 wild type (NT50) were assessed at days 0 and 49. Results observed in allo-HCT patients were compared to those obtained in 40 healthy adults naive of SARS-CoV-2 infection. Flow cytometry analysis of peripheral blood cells was performed before vaccination to identify potential predictors of Ab responses.
Three patients had detectable anti-RBD Ab before vaccination. Among the 37 SARS-CoV-2 naive patients, 20 (54%) and 32 (86%) patients had detectable anti-RBD Ab 21 days and 49 days postvaccination. Comparing anti-RBD Ab levels in allo-HCT recipients and healthy adults, we observed significantly lower anti-RBD Ab levels in allo-HCT recipients at days 21, 28 and 49. Further, 49% of allo-HCT patients versus 88% of healthy adults had detectable NT50 Ab at day 49 while allo-HCT recipients had significantly lower NT50 Ab titers than healthy adults (P = 0.0004). Ongoing moderate/severe chronic GVHD (P < 0.01) as well as rituximab administration in the year prior to vaccination (P < 0.05) correlated with low anti-RBD and NT50 Ab titers at 49 days after the first vaccination in multivariate analyses. Compared to healthy adults, allo-HCT patients without chronic GVHD or rituximab therapy had comparable anti-RBD Ab levels and NT50 Ab titers at day 49. Flow cytometry analyses before vaccination indicated that Ab responses in allo-HCT patients were strongly correlated with the number of memory B cells and of naive CD4
T cells (r > 0.5, P < 0.01) and more weakly with the number of follicular helper T cells (r = 0.4, P = 0.01).
Chronic GVHD and rituximab administration in allo-HCT recipients are associated with reduced Ab responses to BNT162b2 vaccination. Immunological markers could help identify allo-HCT patients at risk of poor Ab response to mRNA vaccination.
The study was registered at clinicaltrialsregister.eu on 11 March 2021 (EudractCT # 2021-000673-83).
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