Graft-versus-host Disease Mortality Research Articles

Post-transplant Cyclophosphamide Versus Thymoglobulin in HLA-Mismatched Unrelated Donor Transplant for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Limited information is available on the efficacy of post-transplantation cyclophosphamide (PTcy) or thymoglobulin for graft-versus-host disease (GVHD) prophylaxis in mismatched unrelated donor (MMUD) transplants. We retrospectively compared outcomes of 76 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who underwent 7/8 HLA-MMUD transplantation and received either PTcy (50 mg/kg on day 3 and 4) or thymoglobulin (total dose 4.5 mg/kg) for GVHD prophylaxis. In addition, tacrolimus and mycophenolate were used in both groups. Propensity score-based multivariable analyses (PSCA) were performed to adjust confounding effects of patient characteristics between both groups. Between January 2006 and June 2019, 25 patients received PTcy, and 51 received thymoglobulin. Median age of the population was 57 years, 78% of patients had AML, most common graft source was peripheral blood (96%), and 46% received myeloablative conditioning regimens. Median time to neutrophil (15 versus 11 days, P < .001) and platelet engraftment (21 versus 15 days, P=.002) was prolonged in the PTcy group. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (12% versus 19.6%, P=.38), whereas chronic GVHD at 1 year was lower with PTcy compared to thymoglobulin (16% versus 49%, P=.006). Using PSCA, no difference in survival, relapse, relapse-free survival, and GVHD-free relapse-free survival was seen between groups. However, thymoglobulin was associated with higher incidence of acute (hazard ratio [HR]=2.63, P=.01) and chronic GVHD (HR=4.43, P=.03), and non-relapse mortality (HR 3.38, P=.04) compared to PTcy. Our study demonstrated that PTcy resulted in significantly lower rates of acute and chronic GVHD and non-relapse mortality compared to thymoglobulin in 7/8 HLA-MMUD transplants for AML and MDS.

Chronic graft-versus-host disease: focusing on the B cells

Graft-versus-host disease (GVHD) has posed many challenges in allogeneic HSCT. Thanks to the development of immunomodulating approaches, the mortality of acute GVHD (aGVHD) is drastically decreased. Nevertheless, chronic GVHD (cGVHD) is became the leading causes of death in patients who survived of aGVHD. Various studies have demonstrated the essential role of B cells in the development of cGVHD. B cells are directly involved in allogeneic reactions through a variety of mechanisms such as alloantibody production, triggering complement system, promoting antibody-dependent cellular cytotoxicity (ADCC), and cross-presentation of immune complexes. It has been known that the pathways involved in the B-cell homeostasis and survival, such as BAFF, BCR, and Notch2 signaling pathways are abnormal in cGVHD. Post-HSCT lymphopenia triggers the continuous release of BAFF, leading to abnormalities in B cell homeostasis, and increasing the survival of alloreactive/autoreactive B cells, leading to production of allo/auto-antibodies. On the other hand, reduction of regulatory B cells following HSCT, causes loss of T cell peripheral tolerance, leading to cGVHD incidence. Therefore, B cells deserve special consideration in allogeneic HSCT, and targeting alloreactive B cells might be a promising approach in cGVHD management. In this article, we discussed the role of B cells in pathophysiology of cGVHD. Keywords: Chronic graft-versus-host disease, Hematopoietic stem cell transplantation, B cell, BAFF

Natural killer cell alloreactivity in HLA-haploidentical hematopoietic transplantation: a study on behalf of the CTIWP of the EBMT.

Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched ("haploidentical") hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9-3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3-1.2), p = 0.14, interaction p < 0.001). This effect was the consequence of reduced incidences of acute and chronic GvHD and non-relapse mortality.

Retinoic acid–responsive CD8 effector T cells are selectively increased in IL-23–rich tissue in gastrointestinal GVHD

AbstractGastrointestinal (GI) graft-versus-host disease (GVHD) is a major barrier in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The metabolite retinoic acid (RA) potentiates GI-GVHD in mice via alloreactive T cells expressing the RA receptor-α (RARα), but the role of RA-responsive cells in human GI-GVHD remains undefined. Therefore, we used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T cells in tissues and blood of patients who had received allo-HSCT and to characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after exposure to RA. RARαhi mononuclear cells were increased in GI-GVHD tissue, contained more cellular RA-binding proteins, localized with tissue damage, and correlated with GVHD severity and mortality. By using a targeted candidate protein approach, we predicted the phenotype of RA-responsive T cells in the context of increased microenvironmental interleukin-23 (IL-23). Sequential immunostaining confirmed the presence of a population of RARαhi CD8 T cells with the predicted phenotype that coexpressed the effector T-cell transcription factor T-bet and the IL-23–specific receptor (IL-23R). These cells were increased in GI- but not skin-GVHD tissues and were also selectively expanded in the blood of patients with GI-GVHD. Finally, functional approaches demonstrated that RA predominantly increased alloreactive GI-tropic RARαhi CD8 effector T cells, including cells with the phenotype identified in vivo. IL-23–rich conditions potentiated this effect by selectively increasing β7 integrin expression on CD8 effector T cells and reducing CD4 T cells with a regulatory cell phenotype. In summary, we have identified a population of RA-responsive effector T cells with a distinctive phenotype that is selectively expanded in human GI-GVHD and that represents a potential new therapeutic target.

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function.

Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING signaling in host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Host hematopoietic antigen-presenting cells (APCs) play key roles in donor T-cell priming during GVHD initiation. However, how STING regulates host hematopoietic APCs after allo-HCT remains unknown. We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs. STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT. Using bone marrow chimeras, we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c+ cells played a dominant role in suppressing allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation, and function of APCs, including macrophages and dendritic cells. Consistently, constitutive activation of STING attenuated the survival, activation, and function of APCs isolated from STING V154M knock-in mice. STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression, and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrated that systemic administration of a STING agonist (bis-(3'-5')-cyclic dimeric guanosine monophosphate) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.

Allogeneic hematopoietic cell transplantation using fludarabine plus myeloablative busulfan and melphalan confers promising survival in high-risk hematopoietic neoplasms: a single-center retrospective analysis

ABSTRACT Objectives Optimal selection of pretransplant conditioning is crucially vital for improving survival and quality-of-life of patients who receive allogeneic hematopoietic cell transplantation (allo-HCT), particularly in those with high-risk diseases. In this study, we evaluated the efficacy and safety of recently-developed reduced-toxicity myeloablative regimen that combines fludarabine, intravenous busulfan, and melphalan (FBM). Methods We conducted a single-center retrospective analysis of 39 patients (23 with myeloid neoplasms and 16 with lymphoid neoplasms), with a median age of 50 (range, 17–68) years, who underwent their first allo-HCT using the FBM regimen. Graft types were bone marrow in 11, peripheral blood in 11, and cord blood in 17 patients. Cyclosporine- or tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was administered. The primary end point of the study was the overall survival rate at 2-year after transplantation. Results After a median follow-up of 910 days for the surviving patients, 2-year overall survival was 62% for the entire cohort; 73% in the low-to-intermediate-risk group and 44% in the high-to-very high-risk group classified by the refined CIBMTR Disease Risk Index. Cumulative incidences of engraftment, grade II-IV acute GVHD, chronic GVHD, relapse, and non-relapse mortality were 95%, 56%, 56%, 31%, and 17%, respectively. Conclusion These results suggest that our FBM regimen can be applied to allo-HCT using various graft types and yields acceptable outcomes with relatively low non-relapse mortality in both myeloid and lymphoid neoplasms. Also, we observed a promising survival in the group of patients with high-risk diseases, warranting more accumulation of patients and longer follow-up.

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes.

PurposeAllogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS).MethodsWe report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months–21 years).ResultsWith a median follow-up of 26 months (range 7 months–9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III–IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%.ConclusionThis alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS.Trial registrationClinicalTrials.gov Identifier: NCT04232085

Associations of Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation with Number of Predicted Class II Restricted mHA

Background: Leukemia relapse after allogeneic hematopoietic cell transplantation (alloHCT) has been associated with loss of heterozygosity of class II HLA, suggesting that T cells targeting leukemia via class II interactions may be critical for graft-vs-leukemia (GvL) effects and protection from relapse (Zeiser &amp; Vago, 2019). Therefore, we aimed to determine whether the number of predicted class-II restricted minor histocompatibility antigens (mHAs) in alloHCT recipients associates with clinical outcome. Specifically, we investigated: (1) if the number of mHAs expressed on leukemia and bone marrow cells (GvL mHAs) is correlated with incidence of leukemia relapse, and/or (2) if mHAs expressed on acute graft versus host disease (GvHD) target organs (GvH mHAs) correlated with incidence of GvHD. We expected increased GvL mHAs to be associated with increased survival, and increased GvH mHAs to be associated with increased incidence of GvHD. Methods: The study population was derived from donor-recipient alloHCT pairs (DRPs) treated for Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), and Myelodysplastic Syndrome (MDS) from the CIBMTR and previously analyzed in DISCOVeRY-BMT. To predict HLA class II restricted mHAs in alloHCT recipients, we translated nonsynonymous single nucleotide variants present in each recipient, but absent in their respective donor, into all possible peptides 15-24 amino acids long. We used netMHCIIpan to score these peptides and select those most likely to be presented (Reynisson et al., 2020). Predicted mHAs highly expressed in skin, hepatobiliary, and bowel tissues were classified as GvH mHAs, and those highly expressed highly in, testis, and bone marrow were classified as GvL mHAs. The impact of mHA on disease related mortality (DRM), leukemia free survival (LFS), disease relapse and death due to GVHD were assessed with competing risk models. We next determined whether knowledge of the number of GvL and GvH mHAs improves the ability of models to predict clinical outcome. We fit optimal logistic regression models (elastic net regularization with Monte Carlo cross validation) to predict GvHD mortality and relapse mortality at 1 year after alloHCT using: (1) clinical data only, and (2) both clinical data and number of GvH/GvL mHAs. Lastly, using the same regularization and cross-validation procedures as above, we determined which variables contributed most to the Cox regression models of overall survival. Results: The number of GvL-restricted and GvH-restricted class-II mHAs were significantly correlated (Figure 1). Patients who died of disease before 1 year after alloHCT had significantly fewer GvL mHAs when controlling for covariates (HR=.89, 95% CI .89, .99, P= 0.04) (Figure 2). There was no association between GvL mHAs and LFS or relapse. Surprisingly, death due to GvHD by 1 year after alloHCT was lower for recipients with more GvL mHAs (HR=.88, 95% CI= .76, 1.01 , P=.08) (Figure 3), however, because GvH and GvL mHAs are highly correlated, we believe this reflects better overall survival associated with increased GvL mHAs. Neither the predictive models that included the number of GvH/GvL mHAs nor the Cox regression models fitted with GvL mHA numbers performed better than models trained on clinical data alone (Figure 4). Conclusions: GvL mHAs were inversely associated with DRM at 1-year post-alloHCT as expected. Contrary to our hypothesis, the number of GvH mHAs was inversely associated with GvHD mortality at 1 year. This may reflect better overall survival associated with increased GvL mHAs, as GvH and GvL mHAs are highly correlated. The potential association between class-II mHAs and DRM warrant further investigation and validation. If validated, this supports the development of class-II mHA targeted immunotherapies. Disclosures Pasquini: Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Armistead:GeneCentric: Consultancy; Cell Microsystems: Patents &amp; Royalties: Patent application U.S. 16/347,104 "Automated collection of a specified number of cells". Vincent:GeneCentric Therapeutics: Consultancy.

Improvement in Survival of AML and MDS Patients Following Allogeneic Transplant: A Long-Term Institutional Experience

Improvement in Survival of AML and MDS Patients Following Allogeneic Transplant: A Long-Term Institutional Experience

Trend in Survival in Patients Undergoing Allogeneic Stem Cell Transplantation: An Institutional Experience

Trend in Survival in Patients Undergoing Allogeneic Stem Cell Transplantation: An Institutional Experience

Sting Negatively Regulates Allogeneic T-Cell Responses By Constraining Antigen-Presenting Cell Function

The endoplasmic-reticulum-resident protein STING (Stimulator of IFN genes) is a downstream signaling effector of cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase). STING-mediated innate immune activation plays a key role in tumor- and self-DNA elicited anti-tumor immunity and autoimmunity, respectively, yet the mechanism remains largely unclear. We utilized murine models of allogeneic hematopoietic cell transplantation (allo-HCT) to study the biology of STING in antigen-presetting cells (APCs) and T cells. STING expression in donor T cells was dispensable for their ability to induce graft-versus-host disease (GVHD), a major complication of allo-HCT in the clinic. However, when STING-deficient mice were used as recipients, more severe disease was induced after allo-HCT. Using bone marrow (BM) chimeras where STING was absent in different compartments, we found that STING-deficiency on host hematopoietic cells (Fig. A), but not on non-hematopoietic cells, was primarily responsible for exacerbating the disease. Furthermore, STING expression on host CD11c+ cells played a dominant role in the regulation of allogeneic T-cell responses (Fig. B). Mechanistically, STING deficiency resulted in increased survival, activation and function of irradiated APCs, including macrophages and dendritic cells (DCs, fig. C-D). To further determine the role of STING in APCs, we generated a STING V154M knock-in mouse model, in which V154M mutation in TMEM173 causes constitutive activation of STING. Consistently, constitutive activation of STING attenuated the survival, activation and function of APCs isolated from STING V154M knock-in mice. In addition, STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression and migration into intestinal tissues (Fig. E), resulting in accelerated/exacerbated disease. Using pharmacologic approaches, we demonstrate that systemic administration of a STING agonist (c-di-GMP) to recipient mice before transplantation significantly reduced GVHD mortality (Fig. F). In conclusion, we report an inhibitory role of STING in regulating survival and T-cell priming function of hematopoietic APCs, especially CD11c+ cells, after allo-HCT. We validate that pharmacological activation of STING may serve as a potential therapeutic strategy to constrain APCs and induce immune tolerance. Figure Disclosures No relevant conflicts of interest to declare.

BEAM-Campath Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Lymphoma: High Incidence of Long-Term Mixed Donor-Recipient Chimerism and the Response to Donor Lymphocyte Infusions

BiCNU (carmustine), etoposide, Ara-C, melphalan (BEAM) and Campath conditioning was developed to reduce the high transplant-related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy, as well as to some extent a platform for allogeneic stem cell engraftment. Significant numbers of patients appeared to have persistent recipient-derived hematopoiesis, and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM-Campath conditioned allogeneic stem cell transplantation at our center (2003 to 2017) to characterize the patterns of chimerism and patient outcomes. Chimerism was analyzed with short tandem repeat PCR. Mixed donor-recipient chimerism (MDRC) was defined as 5% to 94.9% donor. Fifty-two patients (n=30 male), with a median age of 45 years, were identified with histologic diagnoses of Hodgkin lymphoma (n=13), diffuse large B cell lymphoma (n=7), low-grade non-Hodgkin lymphoma (n=16), mantle cell lymphoma (n=10), and T cell lymphoma (n=6). Pretransplant, 93% achieved complete response (52%) or partial response (41%) with a median of 3 prior therapies (n=3 prior autologous stem cell transplantation). Donors were Matched sibling donors (MSD) (n=21), matched unrelated donors (MUD) (n=24), miss-matched unrelated donors (MMUD) (n=6), and syngeneic (n=1). Acute graft-versus host disease (GVHD) developed in 52% (81% grade I to II) and chronic GVHD (83% extensive) in 12%. MDRC of T cells (MDRCt) developed in 62% (n=32), and 29% (n=15) developed MDRC of myeloid cells (MDRCm) at a median onset of 100 days. Donor lymphocyte infusion (DLI) was given to 17 patients, with a median starting dose of 1×106/kg. The first DLI was given at a median of 225 days post-transplant (range, 99 days to 5.3 years). Of these, 9 developed acute post-DLI GVHD and 2 limited chronic GVHD. Conversion to full donor occurred in 47% MDRCt and 50% MDRCm. Multivariate analysis identified sibling donor type as associated with increased MDRCt (P=.035; hazard ratio [HR], 0.17) and reduced total nucleated cell dose with increased MDRCm (P=.021; HR, 0.76). The median follow-up was 6 years, and 2-year NRM cumulative incidence was 16% (95% confidence interval [CI], 7% to 27%). Ten-year progression and extensive GVHD-free survival was 45% (95% CI, 28% to 61%), and overall survival was 66% (95% CI, 50% to 78%). One-year landmark analysis identified no increased GVHD or relapse risk with MDRCt or MDRCm but reduced nonrelapse mortality (NRM) risk with MDRCt (P=.001). BEAM-Campath allografts for high-risk lymphoma achieve long-term disease-free survival with low rates of GVHD and transplant-related mortality. The frequent development of myeloid MDRC demonstrates that BEAM-Campath is a nonmyeloablative conditioning regimen in almost a third of patients. MDRCt is associated with reduced NRM, but neither MDRCt or MDRCm is associated with increased GVHD or relapse.

A real life use of ruxolitinib in patients with acute and chronic graft versus host disease refractory to corticosteroid treatment in Latin American patients.

IntroductionGraft-versus-host disease (GVHD) is a serious complication in allogeneic transplantation. The first-line treatment is high doses of corticosteroids. In the absence of response to corticosteroids, several immunosuppressive drugs can be used, but they entail an elevated risk of severe infections. Added to this, there are patients who do not improve on any immunosuppressive treatment, with subsequent deteriorated quality of life and high mortality. Ruxolitinib has been shown to induce responses in refractory patients. In this study we have presented our real-life experience.MethodsA retrospective analysis was performed on patients with severe GVHD refractory to corticosteroids. Demographic, previous treatment, response and mortality data were collected.ResultsSince 2014, seventeen patients with GVHD were treated with ruxolitinib due to refractoriness to corticosteroids and immunosuppressants and a few to extracorporeal photopheresis, 8 with acute GVHD (1 pulmonary, 4 cutaneous grade IV and 3 digestive grade IV) and 9 with chronic GHVD (5 cutaneous sclerodermiform, 2 pulmonary and 1 multisystemic). The overall response to ruxolitinib treatment for acute GVHD was 80%, 40% with partial response and 40% with complete remission. Global response in chronic GVHD was 79%. The GVHD mortality was only seen in acute disease and was 40%. Causes of mortality in those patients were severe viral pneumonia, post-transplantation hemophagocytic syndrome and meningeal GVHD refractory to ruxolitinib.ConclusionsIn our series, the use of ruxolitinib as a rescue strategy in acute or chronic GVHD was satisfactory. Ruxolitinib treatment in patients with a very poor prognosis showed encouraging results. However, the GVHD mortality remains high in refractory patients, showing that better therapeutic strategies are needed.

Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n=491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n=723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.03 to 1.54) and acute GVHD mortality (HR, 1.63; 95% CI, 1.08 to 2.46), but not chronic GVHD diagnosis (HR, 1.04; 95% CI: .84 to 1.28) or chronic GVHD mortality (HR, .88; 95% CI, .53 to 1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected.

Tissue mast cell counts may be associated with decreased severity of gastrointestinal acute GVHD and nonrelapse mortality

AbstractThe functions of mast cells in human graft-versus-host disease (GVHD) are unknown. We studied 56 patients who had an allogeneic hematopoietic cell transplantation (alloHCT) with a biopsy for diagnosis of gastrointestinal tract (GIT) GVHD before any treatment (including steroids): 35 with GIT GVHD, 21 HCT recipients whose biopsies did not confirm GVHD, and 9 with a new diagnosis of inflammatory bowel disease (IBD) as a comparison. The median number of mast cells (mean of CD117+ cells, counted in 3 selected spots under 40× magnification) was similar between patients with GVHD (59 cells) and those without GVHD (60 cells). However, the median number of mast cells was significantly associated with maximum clinical stage of GIT GVHD; the lowest counts of mast cells were observed in the highest clinical stage of GIT GVHD (stage 1, 80; stage 2, 69; stage 3, 54; stage 4, 26; P = .01). Moreover, every decrease by 10 mast cells was associated with increased nonrelapse mortality through 1 year (hazard ratio, 0.77; 95% confidence interval, 0.59-1.00; P = .05). AlloHCT recipients all had significantly fewer mast cells, even those without GVHD compared with those with IBD (median, 59 vs 119; P < .01). The median number of GIT mast cells was also significantly lower in patients who received myeloablative conditioning (61.5 cells) than in those who received reduced intensity conditioning (78 cells) in the entire study population (P = .02). We conclude that GIT mast cells are depleted in all alloHCT patients, more prominently in those receiving myeloablative conditioning and those with severe GIT GVHD. Our novel findings warrant further investigation into the biological effects of mast cells in GIT GVHD.

The effect that β-lactam antibiotics have on progression free and overall survival in multiple myeloma patients undergoing autologous stem cell transplantation.

e20518 Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p &lt; 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p &lt; 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.

STING Negatively Regulates Allogeneic T Cell Responses by Constraining Function of Antigen Presenting Cells

Abstract Stimulator of interferon genes (STING) plays an important role in eliciting innate immune responses by sensing tumor and microbial DNA in anti-tumor and anti-infection responses, respectively. How the STING signal affects allogeneic response is not clear. To address this question, we utilized murine models of allogeneic hematopoietic stem cell transplantation (allo-HCT). By transferring donor bone marrow (BM) and T cells into allogeneic recipients, we found that significantly more severe graft-versus-host disease (GVHD) was induced in STING−/− recipients as compared to WT controls. By generating BM-chimeric mice in which STING was deficient in hematopoietic or non-hematopoietic antigen-presenting cells (APCs), we confirmed that STING on hematopoietic cells was primarily responsible for constraining host APC function. We further demonstrated that STING on host CD11c+ APCs played a predominant role in the regulation of allogenic T-cell responses. Mechanistically, we found that host CD11c+IAb+ cells deficient for STING could survive better and be activated more strongly after allo-HCT. As a consequence, STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression and migration into intestinal tissues, resulting accelerated/exacerbated GVHD after allo-HCT. Using pharmacologic approaches, we further demonstrated that systemic administration of STING agonist (c-diGMP) on recipient mice before irradiation significantly reduced GVHD mortality. In conclusion, we reveal a novel role of STING in APC activity that dictates T-cell allogenic responses, and validate STING as a potential therapeutic target for controlling GVHD after allo-HCT.

Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?

Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD); however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft-versus-host disease (GVHD). Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.

Disease risk and GVHD biomarkers can stratify patients for risk of relapse and nonrelapse mortality post hematopoietic cell transplant.

The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-vs-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and non-relapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n=1604) was divided into two cohorts: historical (2006–2015, n=702) and current (2015–2017, n=902) with similar non-relapse mortality, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16% and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.

NFKB1 gene single-nucleotide polymorphisms: implications for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) represents a significant cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). NF-kB system is a master regulator of innate immunity responses. It controls the expression of various cytokines and chemokines many of which are involved in GVHD pathogenesis. Chemo(radio) therapy administered during conditioning induces DNA damage and activates DNA damage response (DDR) signaling resulting in irreversible cell cycle arrest - cellular senescence which has been described to be associated with robust pro-inflammatory secretion mostly controlled by NF-kB. The NFKB1 gene encodes the DNA-binding subunit of the NF-kB complex. Using the candidate gene approach, we analyzed possible association of two single-nucleotide polymorphisms (SNPs) rs3774937 C/T and rs3774959 A/G of the NFKB1 gene with GVHD and transplant-related mortality (TRM) occurrence in 109 recipients allografted from HLA-identical donor. Both SNPs in recipients were found to be strongly associated with acute GVHD. Nevertheless, no significant association with chronic GVHD and TRM was found. Presented pilot results contribute to pre-clinical observations and suggest that NF-kB may be an important regulator of HSCT-related inflammatory reactions such as acute GVHD. Novel pathogenic mechanisms of GVHD may arise from perspectives of DDR and cellular senescence where NF-kB plays an essential role.