Risk Factors For Graft-versus-host Disease Research Articles

Risk factors for graft-versus-host-disease after donor lymphocyte infusion following T-cell depleted allogeneic stem cell transplantation.

Unmodified donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation (alloSCT) can boost the beneficial Graft-versus-Leukemia (GvL) effect but may also induce severe Graft-versus-Host-Disease (GvHD). To improve the balance between GvL and GvHD, it is crucial to identify factors that influence the alloreactivity of DLI. We investigated the effects of the presence of patient-derived antigen-presenting cells at time of DLI as estimated by the bone marrow (BM) chimerism status, lymphopenia as measured by the absolute lymphocyte count (ALC) at time of DLI, and the presence of a viral infection (de novo or reactivation) close to DLI on the risk of GvHD after DLI. The cohort consisted of patients with acute leukemia or myelodysplastic syndrome who prophylactically or pre-emptively received DLI as standard care after alemtuzumab-based alloSCT. In patients at high risk for relapse, DLI was administered at 3 months after alloSCT (n=88) with a dose of 0.3x106 or 0.15x106 T cells/kg in case of a related or unrelated donor, respectively. All other patients (n=76) received 3x106 or 1.5x106 T cells/kg, respectively, at 6 months after alloSCT. For both DLIs, patients with reduced-intensity conditioning and an unrelated donor had the highest risk of GvHD. For DLI given at three months, viral infection within 1 week before and 2 weeks after DLI was an additional significant risk factor (hazard ratio (HR) 3.66 compared to no viral infection) for GvHD. At six months after alloSCT, viral infections were rare and not associated with GvHD. In contrast, mixed BM chimerism (HR 3.63 for ≥5% mixed chimerism compared to full donor) was an important risk factor for GvHD after DLI given at six months after alloSCT. ALC of <1000x106/l showed a trend for association with GvHD after this DLI (HR 2.05 compared to ≥1000x106/l, 95% confidence interval 0.94-4.45). Furthermore, the data suggested that the presence of a viral infection close to the DLI at three months or ≥5% mixed chimerism at time of the DLI at six months correlated with the severity of GvHD, thereby increasing their negative impact on the current GvHD-relapse-free survival. These data demonstrate that the risk factors for GvHD after DLI depend on the setting of the DLI.

A Complex Relationship between Clostridium Difficile Infection and Graft Versus Hoste Disease: Fundeni Clinical Institute Experience

Introduction: Clostridium difficile infection (CDI) is a common complication in patients who have undergone hematopoietic stem cell transplantation (HSCT) due to prolonged hospitalization, prolonged neutropenia, use of broad-spectrum antibiotics, mucosal damage, changes in gut microbiota and compromised immunity. The incidence of CDI in patients undergoing allogeneic HSCT varies between 12 and 34% in the literature and has gradually increased in recent years in Europe North America due to the NAP1 strain. In the patient who has experienced allogeneic HSCT, diagnostic testing for CDI should include both nucleic acid amplification test (NAAT) and enzyme immunoassays (EIA) for toxins A and B, because detection of toxins A and B tests have a sensitivity of 75-80%. 5 In HSCT patients, CDI appears to be strongly associated with graft versus host disease (GVHD), gut GVHD and/or severe GVHD, but this has not been universally demonstrated. The aim: For this reason, we wanted to see whether patients who developed a CDI between day 0 and day 100 were at higher risk for gut GVHD or for severe GVHD. Results: Between January 2017 and August 2022, we performed 290 of allogeneic hematopoietic stem cell transplant procedures, in the Fundeni Clinical Institute. 50/290 developed CDI within the first 100 days after HSCT and before the diagnosis of intestinal GVHD, and 240/290 did not develop CDI. 16/50 (32%) of those with CDI developed acute GVHD, respectively 402/240 (43%) of those without CDI. From these 13/16, respectively 50/102 hade gut involvement. Of the 118 patients with acute GVHD, 13/16 in the group with CDI, respectively 30/102 in the group without CDI were assigned to severe acute GVDH (grade III and IV). Mortality due to gut GVHD in the group with CDI was 46%, respectively 14% in the group without CDI. In conclusion: CDI is not a risk factor for GVHD, but gut damage is usually associated. CDI infection is associated with severe forms of GVHD, and the implication of the digestive tract in these patients increases mortality. Also, often in the patient with digestive GVHD, CDI can coexist, making them difficult to treat.

Allogeneic Hematopoietic Stem Cell Transplant Outcomes in Adults with Inherited Myeloid Malignancies

Recognition of hereditary hematopoietic malignancies (HHMs) has accelerated in recent years, with deleterious germline variants in more than 20 genes recognized as drivers of myeloid malignancies. Individuals with HHMs generally receive similar treatment plans as those with de novo disease. Hematopoietic stem cell transplantation (HSCT) is often employed as a curative approach for myeloid malignancies, and in those with germline pathogenic (P)/likely pathogenic (LP) predisposition variants, there is a preference for use of related donors who lack the familial variant. However, there are limited data on the outcomes of patients with HHMs who are treated in this manner. In this study, we used comprehensive clinical and genomic data to investigate the allogeneic transplant-related outcomes in the largest international myeloid HHM cohort reported to date. We performed a retrospective analysis of all patients with myeloid malignancies who underwent germline predisposition testing at The University of Chicago (UofC) or the Central Adelaide Health Network between 2010 and 2021; or were known to have deleterious germline DDX41 variants from the University of Pennsylvania and Moffitt Cancer Center. We studied 472 patients, of whom 28% (80/289) in the UofC cohort and 20% (35/175) in the Adelaide cohort had a deleterious germline variant causative of HHMs. In the UofC cohort, P/LP CHEK2 variants were the most common, whereas P/LP DDX41 variants were most common in the Adelaide cohort (Fig. 1). A total of 161 patients (34% of the entire cohort) underwent allogeneic HSCT for their myeloid neoplasm (Table 1). There were no differences in the distribution of diagnoses, donor types, disease status at the time of HSCT (remission vs active disease), conditioning regimens, or conditioning intensity. All donor cells were mobilized from peripheral blood. Almost all donors lacked the deleterious germline causative variant, with one donor sharing a deleterious familial DDX41 variant with the relative/HSCT recipient. The median time to engraftment was similar between those who had vs lacked germline HHM variants. Patients with P/LP germline DDX41 variants had higher rates of severe (stage 3-4) acute graft versus host disease (GVHD) when compared to patients with P/LP CHEK2, those with other germline variants, or those without P/LP germline variants (38% vs 0, 12%, and 9%, respectively; p=0.002). Notably, severe gastrointestinal GVHD was seen in a third of patients with P/LP germline DDX41 variants as opposed to <10% incidence in other groups (p<0.001, Table 1). Similarly, 33% of patients with P/LP germline DDX41 variants experienced moderate to severe chronic GVHD, whereas this incidence was 29% for patients with P/LP germline CHEK2 variants, 4% for patients with other P/LP germline variants, and 10% for patients without a P/LP inherited variant (p=0.008). Patients with P/LP germline DDX41 variants who received post-HSCT cyclophosphamide had lower rates of severe acute GVHD compared to those who received other forms of GVHD prophylaxis (0% vs 53%, p=0.03). To adjust for the effects of known GVHD risk factors, we performed a multivariable logistic regression analysis. Germline DDX41 status remained an independent predictor of both acute GVHD (OR: 4.76, range 1.27-17.9; p=0.01) and chronic GVHD (OR: 3.39, range 1.09-10.5; p=0.03). Importantly, post-HSCT cyclophosphamide use was associated with a reduced risk of acute GHVD when adjusted for other variables (OR: 0.10, range 0.01-0.71; p=0.008). Our data establish severe GVHD as a clinically relevant post-transplant phenomenon in germline DDX41-associated HHMs and suggest that donor-derived wild-type T-cells may become activated by a pro-inflammatory milieu conferred by P/LP germline DDX41 variants. Moreover, our observations suggest that post-HSCT cyclophosphamide is an effective strategy for GVHD prevention in these individuals. Broader confirmation of our results in other heterogeneous patient cohorts will serve to expand the spectrum of known pathogenic variants implicated in HHMs and support the development of targeted interventions for those with deleterious germline HHM alleles. Finally, these results argue for germline genetic testing in patients prior to allogeneic HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ATG-F Versus ATG-T for Graft Versus Host Disease Prevention in Allogeneic Stem Cell Transplantation: A Retrospective Comparative Study

Background: Graft versus host disease (GVHD) is one of the major complications in allogeneic stem cell transplantation, leading to excessive post-transplant morbidity and mortality. Anti-Thymocyte Globulin (ATG) is a widely used anti GVHD prophylaxis adjunct, in addition to a calcineurin inhibitor and either methotrexate or mycophenolate mofetil. Among available ATG sera are antithymocyte globulin (ATG-T) (Sanofi Genzyme, Cambridge MA), derived from rabbit vaccination with human thymocytes, and the anti-T-lymphocyte globulin (ATG-F) (Neovii, Rapperswil, Switzerland, ATG Fresenius®), derived from the human Jurkat T-cell line. Data comparing the two agents, regarding transplant outcomes is still lacking. Methods: Since 2015, ATG-F (15 mg/kg) has become the preferred prophylactic agent at the Hadassah medical center. We retrospectively compared the transplant outcomes between 52 patients treated prophylactically with ATG-F (15 mg/kg) during 2015-2018 and 46 patients treated with ATG-T (10 mg/kg), during 2011-2018. Our research aims were directed towards investigating rates of engraftment, infections, GVHD, relapse, and overall survival. Results Demographic, disease and pre-transplant characteristics (median age, gender, disease status at transplantation entry, age adjusted comorbidity index) of the two groups were mostly similar. There was no significant difference in median recipient and donor age, and conditioning regimen intensity. There was a higher rate of patients transplanted for MDS and secondary AML in the ATG-F group while a higher rate of lymphoproliferative diseases in the ATG-T group (p=0.038). Comparing patients' characteristics for the available risk factors for GVHD, there was a borderline significant higher incidence of HLA mismatch in the ATG-T group compared to the ATG-F group (39.1% Vs. 21.2%; p=0.052), and a significantly higher number of patients received single agent cyclosporine in the ATG-T group (30.4% vs 3.8%, p<0.01). In terms of risk factors for infections, there was a significantly higher incidence of positive CMV-IgG in both donor and recipient in the ATG-F vs ATG-T group, 82.4% vs 60.9%, p=0.022). Analyzing transplant outcomes, the incidence of acute GVHD of any grade was significantly higher in the ATG-T group (p=0.007, Fig. 1), while the incidence of grade 3-4 acute GVHD was comparable (p=0.186). Incidence of any grade and moderate-severe chronic GVHD was comparable in both groups (p>0.05). There was no statistically significant difference in disease-free survival and overall survival rates between the groups (p>0.05). A combined analysis of moderate-severe chronic GVHD-free, relapse-free survival (GRFS) showed no difference between the groups (p=0.686, Fig. 2). Median time to absolute neutrophil count (ANC) and Platelet engraftment was 15 vs. 14 and 16 vs. 17 days in the ATG-T and ATG-F group, respectively. There was no difference in the incidence of bacteremia or CMV reactivation between the two groups (p=0.79; p=0.704, respectively). Conclusion Our retrospective study shows that ATG-F was non-inferior to ATG-T regarding engraftment rate, incidence of grade 3-4 acute GVHD and moderate-severe chronic GVHD, disease free survival and overall survival. The higher incidence of acute GVHD of any grade detected in the ATG-T group might reflect the higher rate of HLA mismatch and combination with single agent cyclosporine prophylaxis. Study limitations include its retrospective nature and changes in transplant care over the study years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune tolerance induced by hematopoietic stem cell infusion after HLA identical sibling kidney transplantation.

After the first attempt to induce operational tolerance, it has taken decades to implement it in clinical practice. Recipients with Human leukocyte antigen (HLA) identical sibling donors were enrolled. Hematopoietic stem cells (HSCs) infusion was done after HLA identical sibling kidney transplantation (KTx). Three cases included were followed up for over 8 years. The perioperative conditioning protocol included anti-CD20, rabbit anti-thymocyte globulin (ATG), total lymphoid irradiation (TLI), and cyclophosphamide. Infusion of CD3+ cells and CD34+ cells was conducted. The withdrawal of immunosuppression was determined by mixed lymphocyte reaction (MLR) and graft biopsy. Case 1 and Case 2 showed persistent chimerism, while chimerism was not detected in Case 3. All three recipients showed a low-level response to donor-specific stimulation. Case 1 and Case 3 met the withdrawal rules at 16 and 32 months after transplantation, respectively. Graft function was stable, and no rejection signs were observed in routine biopsies until 94 and 61 months after transplantation. Case 2 was diagnosed with graft-versus-host disease (GVHD) 9 months after transplantation and recovered after an enhanced immunosuppression therapy. Steroids were withdrawn after 1 year, and 0.5 mg tacrolimus twice a day is currently the only immunosuppression at 8 years and 8 months. In conclusion, our clinical experience indicated the efficacy of non-myeloablative conditioning protocol for tolerance induction in HLA identical patients. Complete chimerism might be a risk factor for GVHD.

Gut microbiome, metabolites, and tissue metabolism in graft-versus-host disease

Immune reactions promote not only graft-versus-tumor events but also graft-versus-host disease (GVHD) characterized by the activation of T-cells and antigen-presenting cells. Recent studies have unveiled the effects of microbial flora on GVHD and brought the mechanism other than immune cells. The role of tissue-intrinsic factors contributes to target-tissue resilience, repair, and regeneration and mitigates the severity of GVHD without altering alloreactive immune cells. Antibiotics, specific bacteria, and low microbiota diversity are identified as risk factors for GVHD and mortality. The current focus has shifted to target-tissue homeostasis in GVHD. Most of the gut microbiota symbiotically colonize the gut, and this homeostasis is finely tuned in the gastrointestinal tract, which has a relatively hypoxic environment dominated by anaerobic organisms. Therefore, intestinal epithelial cells (IECs) are uniquely adapted to this hypoxic environment, and cells programmed by "physiological hypoxia" tonally regulate barrier function with commensal bacteria. Metabolic changes in IECs post allo-HCT can affect the gut environment, leading to dysbiosis. This review focuses on the role of metabolism in IECs with microbiota and microbial metabolites in the GVHD setting to promote tissue tolerance.

Risk Factors for Graft-Versus-Host Disease and Survival in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Single-Center Experience.

Graft-versus-host disease is still one of the most important complications after hematopoietic stem cell transplantation. The risk factors remain unclear, with effects of graft-versus-host disease on survival varying among different centers. We aimed to determine risk factors that may affect development of graft-versus-host disease and the corresponding patient survival rates at a single pediatric hematopoietic stem cell transplant unit. Our study included 104 of 118 pediatric patients who underwent allogeneic hematopoietic stem cell transplant at our institute between 2005 and 2018. Patient characteristics, clinical information, pretransplant and posttransplant factors, and laboratory parameters were obtained from the database. Acute graft-versus-host disease was seen in 19 pediatric patients. Chronic graft-versus-host disease, which was seen in 13 of our pediatric study patients, occurred more often in those with peripheral blood stem cell than in those with bone marrow transplant (odds ratio of 9.969; 95% CI, 1.040-95.547; P = .046). Female donor-to-male recipient transplant was significantly associated with incidence of chronic graft-versus-host disease (odds ratio of 8.51; 95% CI, 1.323-54.843; P = .024). Later neutrophil engraftment was associated with incidence of acute graft-versus-host disease (odds ratio of 1.107; 95% CI, 1.012-1.212; P = .02). Although there are some known risk factors for graft-versus-host disease in adult patients, little is known about risk factors in children. In our comprehensive study in pediatric patients, we found that peripheral blood stem cell transplant, female-tomale transplant, and later neutrophil engraftment were associated with incidence of graft-versus-host disease. Although peripheral blood as a source of stem cells and female-to-male transplant are known risk factors, later neutrophil engraftment was a new finding as a possible risk factor for acute graft-versushost disease. This finding requires further verification in future prospective studies.

Pre-transplant hepatic steatosis (fatty liver) is associated with chronic graft-vs-host disease but not mortality.

Allogeneic-HCT (allo-HCT), while potentially curative, can result in significant complications including graft versus host disease (GVHD). Prior studies suggest that metabolic syndrome may be one risk factor for GVHD. We hypothesized that hepatic steatosis on pre-HCT computed tomography (CT) scans may be a marker for development of GVHD and poor outcomes in allo-HCT. In this retrospective study, we reviewed the pre-HCT CT scans and transplant outcome data of patients who underwent allo-HCT at Duke University Medical Center from 2009 to 2017. The presence of steatosis was confirmed using CT attenuation measurements. We then assessed the association between pre-HCT hepatic steatosis and HCT-related outcomes including GVHD. 80 patients who had pre-HCT CT scans were included in the study. Pre-transplant hepatic steatosis was associated with the development of chronic GVHD (OR 4.2, p = 0.02), but was not associated with acute GVHD (OR 1.3, p = 0.7), non-relapse mortality (p = 0.81) or overall survival (p = 0.74). Based on this single center retrospective study, pre-transplant hepatic steatosis is associated with development of chronic GVHD. Further, prospective study with other imaging modalities including non-contrasted CT scans is needed to determine if this association is reproducible.

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM=79, MA-PB=183, RIC-BM=192, RIC-PB=192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P=.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P=.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P=.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT.Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.

Periodontal disease might be a risk factor for graft versus host disease. A systematic review.

The aim of this systematic review was to determine a potential association between periodontal disease and graft versus host disease (GVHD). PubMed, Scopus and Web of Science databases were searched to identify all relevant articles. The eligibility criteria were prospective, retrospective, cross-sectional, cohort, case-control studies and interventional studies that assessed periodontal parameters in GVHD adults' patients. Seven studies, published between 2000 and 2018, were eligible. The aggravation of periodontal tissues is due to inadequate oral hygiene, dental plaque, decays, gum recession, retained roots, tooth loss, periodontally infected teeth. Several studies have indicated that periodontitis treatment performed before transplantation showed the reduction of gingival inflammation and maintenance of periodontal health. Periodontitis might be a risk factor for GVHD. However, due to the limited number of studies included in the review and their heterogeneity, more data are needed to sustain the correlation between periodontitis and GVHD.

Characteristics of graft-versus-host disease occurring after alemtuzumab-containing allogeneic stem cell transplants: incidence, organ involvement, risk factors and survival.

T-cell depletion with alemtuzumab represents an effective form of graft-versus-host disease (GVHD) prophylaxis after allogeneic haematopoietic stem cell transplantation (allo-HSCT); however, little is known regarding the impact of in vivo alemtuzumab on either the incidence or clinical characteristics of acute and chronic GVHD. We therefore studied 201 consecutive adult patients who received an alemtuzumab-based, reduced-intensity conditioned (RIC) allograft. With a median follow-up of 24months, the cumulative incidence of classic acute and late acute (persistent, recurrent and late onset) GVHD grades II-IV (grades III-IV) was 34% (13%) and 20% (8%) respectively; the cumulative incidence of classic chronic GVHD and overlap syndrome were 4% and 7% respectively. A previous diagnosis of classic acute GVHD is a risk factor for chronic GVHD (hazard ratio 10·91, 95% confidence interval 2·35-50·63, P=0·0023) while late onset acute GVHD is not a risk factor for later development of chronic GVHD. Unrelated donor transplant is a risk factor for the development of classic acute GVHD but not for late onset or chronic GVHD. In conclusion, this study describes a distinctive pattern of GVHD following alemtuzumab-RIC allografts, identifies the risk factors for GVHD development and provides prognostic information of patients with GVHD.

PS1571 EVALUATION OF RISK FACTORS OF GVHD FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION FOR PATIENTS WITH B THALASSEMIA MAJOR:10 YEARS FOLLOW‐UP IN 568 PATIENTS

Background:Hematopoietic stem cell transplantation (HSCT) is considered a well‐established curative therapy for β‐thalassemia major (TM),however, graft‐versus‐host disease (GVHD) is one of the major limiting factors in successful allogeneic hematopoietic stem cell transplantation (HSCT). Numerous studies have identified risk factors for GVHD,however,the impact of HLA disparity on GVHD remains unclear.Aims:This study was to assess risk factors for the development of acute GVHD and chronic GVHD and to explore the effect of locus‐specific allele‐level mismatching on GVHD for TM patients.Methods:We retrospective identified 568 patients with TM underwent allergenic HSCT between 2008–2018,with median age of 6 (1 – 23) and follow‐up of 62(1–122) months,from HLA‐identical sibling donor (SD) (n = 204; 36%), unrelated donor (UD, n = 274; 48%),sibling Cord blood(CB,n = 48,8%)and parent donor(PDn = 42,7%). Characteristics of patients was summarized in Table 1. Correlative analysis was done between donor type, disease status at transplant, locus‐specific allele levelmatching, conditioning regimen,GVHD prophylaxis, gender matching and risk of GVHD.Results:There were no differences in patients’ gender,donor genderor conditioning regimen groups in aGVHD (P value = 0.959, 0.845 and 0.312). Conditioning regimen in non‐ATG group was significantly higher than ATG group(P = 0.000)(figue1). Serum ferritin &gt;5000ng/ml was correlated with higher aGVHD. Acute GVHD incidence for serum level&lt;3000, 3000–5000 and &gt;5000 were 10.5%, 13.6%, 17.8%, respectively (P = 0.048)l. Both aGVHD and cGVHD for Patient older than 9 years old was significantly higher than those &lt;9 years old(16.1%vs9.4%P = 0,015) and (8.5% vs.3.1%)respectively(Figue2). Acute GVHD were much higher in UD transplant recipients than in SD, CB or PD recipients (P = 0.028, 0.000 and 0.000respectively). Risks for aGVHD were higher in HLA‐mm transplantation, particularly significant in two loci mm transplant. The corresponding incidence in one locus HLA‐mm and two loci HLA‐mm transplant were 19.8% vs.10.4%, p = 0.01 and 25%vs.10. %, p = 0.029 when compared to full matched transplant (Figure3). Similarly, cGVHD risk were also higher in recipient‐donor two loci HLA‐mmtransplant compared to HLA‐matched transplants (14.8% vs.4.2%, P = 0.049). Distribution of HLA mismatched loci and correlated effects on GVHD were shown in table 2. Patients receiving HLA‐A mismatch HSCT had a significant higher risk of aGVHD grade II–IV (19.3% vs.6.5%, P = 0.003) as shown in figure4. DR+DQ mm (8/10 matched) transplant significantly correlated with increased aGVHD and cGVHD (33.3% vs.11.4%, 16.7% vs.3.9%,P = 0.006,0.019,respectively) as shown figure5..Summary/Conclusion:Our data shows that donor and recipient gender disparity did not influence the risk of acute or chronic GVHD. Addition of ATG into the transplant regimen decreases the occurrence of cGVHD after PBSCT. Patient received unrelated PBSC were associated with an increased aGVHD. High serum ferritin level is also a risk factor of aGVHD for thlassemia patients. Mismatching at HLA‐A and HLA‐DR+DQ was associated with increased risk of both aGVHD and cGVHD. Older age is an independent risk factor for GVHD. We suggest that transplantation for β thalassemia major be performed before aged 9 years and iron chelation therapy pre‐HSCT is necessary. Further studies on GVHD treatment should be highlighted.image

PS1536 EMPIRICAL ANTIBIOTIC THERAPY FOR NEUTROPENIC FEVER AFTER ALLOGENEIC STEM CELL TRANSPLANTATION INFLUENCES GRAFT‐VERSUS‐HOST DISEASE‐RELATED MORTALITY

Background:Neutropenic fever (NF) after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is common and treated with a choice of clinically equivalent empirical antibiotics. However, treatment with antibiotics results in loss of bacterial diversity; this loss has been shown to affect graft‐versus‐host disease (GVHD)‐related outcomes. We hypothesized that the differences in the spectrum of activity of antibiotics given for NF can differently affect intestinal microbiota and modulate subsequent frequency and severity of GVHD and related outcomes.Aims:With the aim to evaluate the associations among individual antibiotic treatments and GVHD‐related mortality, we retrospectively examined 340 consecutive adult recipients of allo‐HSCT at our center.Methods:For each antibiotic, we stratified patients into two cohorts: those treated with a certain antibiotic, and those never receiving that antibiotic. We then compared the cumulative incidence of GVHD‐related mortality for the two cohorts and evaluated them for potential differences using the Gray's test. The multivariate analysis was performed using the semi‐parametric proportional hazards model of Fine and Gray.Results:Between January 2011 to December 2017, 198 male and 142 female patients underwent allo‐HSCT at a median age of 47 years (range, 18–67). Among them, most patiens (67%) were treated for myeloid malignancies, while the rest had lymphoproliferative disorders (33%). The donors were related in 120 cases (35%), unrelated in 188 patients (55%) and haploidentical in 32 patients (10%). Most of the patients (69%) received peripheral blood stem cells after a reduced‐intensity conditioning regimen (64%). Most frequently administered antibiotics given between days −7 to +28 relative to allo‐HSCT were vancomycin in 57% patients, piperacillin‐tazobactam in 47% of patients, meropenem in 44% of patients and cefepime in 37% of patients. We found that treatment of NF with piperacillin‐tazobactam and vancomycin was associated with increased GVHD‐related mortality at 5 years (17% in piperacillin‐tazobactam ‐ treated patients vs. 9% in untreated patients, p = 0.03, and 16% in vancomycin ‐ treated patients vs. 8% in untreated patients, p = 0.02). The use of vancomycin was also associated with an increased incidence of grade 2–4 clinical GVHD (18% in vancomycin ‐ treated patients vs. 11% in untreated patients, p = 0.02). On the contrary, two other antibiotics, cefepime and meropenem (usually used as second‐line treatment), were not associated with GVHD‐related mortality (p = 0.52 and p = 0.62, respectively). In the multivariate analysis, the use of vancomycin remained significantly correlated (p = 0.03) with GVHD‐related mortality, after adjusting for other GVHD risk factors (age, disease risk, source of stem cells, conditioning regimen).Image/Pictures:Summary/Conclusion:Microbiota injury in allo‐HSCT patients has been observed in several ways, including reduction in commensal anaerobes, expansion of commensal Enterococcus species and loss of overall diversity. Consistent with these reports, we demonstrate that use of antibiotics such as piperacillin‐tazobactam and vancomycin leads to increased GVHD severity. A full explanation has yet to be revealed but one possible contribution could be the rise of antibiotic‐resistant enterococci; both directly with the use of vancomycin and indirectly through the use piperacillin‐tazobactam and reduction of anaerobes. Our findings raise the question to the ideal choices of antibiotics for NF, causing a reappraisal of the manner in which antibiotics have been used in allo‐HSCT so far.

Risk Factors for Graft-Versus-Host Disease (GVHD) in Haploidentical Hematopoietic Cell Transplantation (HCT) Using Post-Transplant Cyclophosphamide (PTCy)

Haploidentical hematopoietic cell transplantation (haploHCT) has been increasing since the advent of post-transplant cyclophosphamide (PTCy). Using the CIBMTR database, we determined risk factors for acute (a) and chronic (c) graft-versus-host disease (GVHD) after haploHCT.Patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on conditioning intensity (myeloablative [MAC] or reduced intensity [RIC]) and graft source (bone marrow [BM] or peripheral blood [PB]).646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192) for analysis. The incidence of grade 2-4 aGVHD at 6 months was highest in MAC-PB (44%), followed by RIC-PB (36%), MAC-BM (36%), and RIC-BM (30%) (p=0.002). The same pattern was found for cGVHD at 2 years: 44%, 35%, 27%, and 25%, respectively (p<0.001) (Figure). In multivariable analysis (Table), RIC-BM had less grade 3-4 aGVHD compared to MAC-BM (HR 0.31, p=0.006) and less cGVHD compared to MAC-PB (HR 0.47, p=0.001). No conditioning-graft source group was significant for grade 2-4 aGVHD or overall survival. To better determine the significance of graft source, a subset analysis of MAC and RIC was performed, showing a trend for increased cGVHD with PB compared to BM in MAC (HR 1.81, p=0.05) and RIC (HR 1.72, p=0.02), however this analysis was not powered to detect differences at 0.01 significance (48% and 56% respectively). Older donor age (>50 vs. <29) was associated with grade 3-4 aGVHD (HR 3.89, p<0.001).Conditioning intensity, graft source, and donor age are risk factors for GVHD after PTCy-based haploHCT. Consistent with published data, our results indicate that the risk of cGVHD is higher after PB and PTCy does not negate this risk. These results support the use of BM as graft source in PTCy-based haploHCT. Haploidentical hematopoietic cell transplantation (haploHCT) has been increasing since the advent of post-transplant cyclophosphamide (PTCy). Using the CIBMTR database, we determined risk factors for acute (a) and chronic (c) graft-versus-host disease (GVHD) after haploHCT. Patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on conditioning intensity (myeloablative [MAC] or reduced intensity [RIC]) and graft source (bone marrow [BM] or peripheral blood [PB]). 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192) for analysis. The incidence of grade 2-4 aGVHD at 6 months was highest in MAC-PB (44%), followed by RIC-PB (36%), MAC-BM (36%), and RIC-BM (30%) (p=0.002). The same pattern was found for cGVHD at 2 years: 44%, 35%, 27%, and 25%, respectively (p<0.001) (Figure). In multivariable analysis (Table), RIC-BM had less grade 3-4 aGVHD compared to MAC-BM (HR 0.31, p=0.006) and less cGVHD compared to MAC-PB (HR 0.47, p=0.001). No conditioning-graft source group was significant for grade 2-4 aGVHD or overall survival. To better determine the significance of graft source, a subset analysis of MAC and RIC was performed, showing a trend for increased cGVHD with PB compared to BM in MAC (HR 1.81, p=0.05) and RIC (HR 1.72, p=0.02), however this analysis was not powered to detect differences at 0.01 significance (48% and 56% respectively). Older donor age (>50 vs. <29) was associated with grade 3-4 aGVHD (HR 3.89, p<0.001). Conditioning intensity, graft source, and donor age are risk factors for GVHD after PTCy-based haploHCT. Consistent with published data, our results indicate that the risk of cGVHD is higher after PB and PTCy does not negate this risk. These results support the use of BM as graft source in PTCy-based haploHCT. Figure 1 and Table 1.Table 1 Open table in a new tab

Donor Lymphocyte Infusions for Relapsed Hematological Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation: Single Center Experience

Abstract Introduction:Donor lymphocyte infusion (DLI) is one of the therapeutic options for patients with relapsed or refractory hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). DLI can augment the graft-versus-tumor (GVT) effect; however, it can sometimes induce severe graft-versus-host disease (GVHD) and infectious complications induced by bone marrow aplasia or immunosuppressive therapy. In this study, we wanted to assess the risk factors for GVHD and transplant-related mortality (TRM) as well as disease outcomes according to the reason for DLI in patients who received DLI after allo-HSCT. Patients and Methods:We retrospectively analyzed 152 patients with various hematological malignancies who received a total of 250 DLI in our center between March 1991 and July 2018 for disease relapse and at different intervals after allo-HSCT. We used our institutional database to evaluate details and characteristics of patients and DLI outcomes. The probabilities of overall survival were calculated from the day of transplantation with Kaplan-Meier analysis using SPSS (IBM SPSS Statistics 21; IBM Corp., Chicago, IL) statistical tool kit. Results:Median patient age was 34 years (range, 14-67 years); the patient cohort included 96 males (63.2%) and 36.8 female (56%). Patients evaluated in this study were adult patients with acute myeloid leukemia (n=64), chronic myeloid leukemia (n=36), multiple myeloma (n=6), non-hodgkin lymphoma (4), primary myelofibrosis (n=6), myelodisplastic syndrome (n=3), and severe aplastic anemia (n=3). One hundred thirty-six (10.5%) and sixteen (10.5%) patients had sibling (SD) and unrelated donors (UD), respectively. The stem cell source was peripheral blood stem cells (PBSC) in 116 patients (76.3%) and the other 36 patients (23.8%) received bone marrow stem cells (BMSC). Patients underwent an allo-HSCT with a MAC (n= 109) or RIC (n=43) regimens at a median of 12.5 months from diagnosis. Cyclosporine and methotrexate were used as the main graft versus host disease (GVHD) prophylaxis in our cohort. All patients received DLI for relapse or progression. Median number of DLI was 1 (range, 1-5), the median interval between transplant and first DLI was 6 months (range, 3-86 months), median number of infused CD3+cells x 106/kg of recipient body weight was 1.5x107(range, 0.5x107- 11.1x107). The median time from relapse to the first DLI was 1.9 months (range, 0.1-32.7 months). Thirty-one patients (21%) developed acute grade II to IV GVHD and 10 patients (7%) developed extensive chronic GVHD. We could not demonstrate the higher CD3+ cell dose of DLI associated with an increased risk of GVHD. Furthermore, none of our patients presented graft hypoplasia after DLI. At a median follow-up from transplantation interval of 16.3 months (range, 0.5-188.2 months), 35 patients were still alive (%60). The OS at 1 and 3 years was 63.4±0.4 and 28.2±0.4, respectively (Figure 1). The primary cause of death was relapse of the original disease in most of the patients, whereas 14 patients died of TRM (15.3%). Discussion:Various modifications of DLI have been investigated in combination with molecular-targeted agents to enhance the antitumor effect while minimizing GVHD. Therefore, further studies of larger randomized cohorts with high quality data management are required to clarify the role of DLI in relapsed hematological malignancies. Figure. Figure. Disclosures Civriz Bozdag: TAKEDA: Consultancy; MSD: Research Funding; NOVARTIS: Consultancy. Özcan:MSD: Other: travel support, Research Funding; Jazz: Other; Janssen: Other: Travel Support, Research Funding; Novartis: Research Funding; Archigen: Research Funding; Jazz: Other: Travel support; Bayer: Research Funding; Abbvie: Other: Travel payment; Celgene: Other: Travel support, Research Funding; BMS: Honoraria; Roche: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; MSD: Research Funding. Ilhan:Roche: Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau. Beksac:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A Fatal Case of Gastrointestinal Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (GVHD) is an increasingly common complication of solid organ transplant recipients. It can affect a wide range of epithelial target tissues including the gastrointestinal tract. A 40-year-old female presented to our hospital with two days of frequent high volume and watery diarrhea. Associated symptoms included nausea, vomiting, and diffuse abdominal pain. Her medical history included type I diabetes mellitus and deceased donor kidney-pancreas transplant. She was maintained on immunosuppression with azathioprine, tacrolimus, and prednisone. Her physical examination was notable for cachexia, diffuse abdominal pain, and a confluent and erythematous macular rash. Laboratory values included a white blood cell count of 0.8 x1000/uL (range 4.0-10), absolute neutrophil count 0.7x1000/uL (range 1.0-11), hemoglobin 6.9g/dL (range 12-18), platelet 109x1000/uL (range 140-440), total bilirubin 12.1mg/dL (range <1.20), direct bilirubin 9.3 (range <0.20), alkaline phosphatase 294U/L (range 30-130), and alanine aminotransferase 124U/L (range 0-34). She was started on intravenous immune gamma-globulin and broad spectrum anti-bacterial, viral and fungal agents. Computerized tomography scan of the abdomen and pelvis with IV contrast (Figure 1) showed bowel wall thickening of the colon moreso than small bowel, consistent with GVHD. She underwent a flexible sigmoidoscopy for definitive diagnosis. Pathology from colonic biopsy (Figure 2, 3) showed severe apoptosis, crypt attenuation, and paucity of inflammation without viral inclusions or neutrophils, pathologically characteristic of GVHD. She was started on high dose steroids and ruxolitinib (janus kinase inhibitor) to help control her GVHD. She had an unfortunate hospital course complicated by severe clostridium difficile colitis, enterococcus bacteremia, and eventually hypoxemic respiratory failure. She was transferred to the medical intensive care unit and transitioned to hospice care where she ultimately died. Risk factors for GVHD include HLA disparity and older age upon organ transplantation. Symptoms of gastrointestinal GVHD are nebulous but can include anorexia, weight loss, and chronic diarrhea. Given the myriad symptoms of GVHD the prudent gastroenterologist must always be aware of this diagnosis. Diagnosis is confirmed via biopsy and scored according to the 2014 revised NIH criteria; she had severe chronic GVHD with an expected two year mortality of 38%.1656_A Figure 1. CT abdomen/pelvis, coronal, white arrow points to diffuse colonic bowel wall thickening1656_B Figure 2. Colon biopsy, black arrow points to apoptotic body1656_C Figure 3. Colon biopsy, black arrows points to crypt attenuation

Proinflammatory Cytokine and Adipokine Levels in Adult Unrelated Marrow Donors Are Not Associated with Hematopoietic Cell Transplantation Outcomes

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). GVHD occurs when donor lymphocytes are activated by inflammatory cytokines and alloantigens. The role of donor biologic characteristics, such as basal inflammation, has not been investigated as a risk factor for GVHD but is theoretically transferrable to the recipient. We evaluated donor serum and plasma concentrations of cytokines and adipokines (IL-1β, IL-6, tumor necrosis factor [TNF]-α, leptin, suppression of tumorigenicity-2, and adiponectin) from test (n = 210) and replication (n = 250) cohorts of matched, unrelated transplant peripheral blood stem cell recipients identified through the Center for International Blood and Marrow Transplantation Research between 2000 and 2011 for hematologic malignancies. Hazard ratios were estimated for acute (grades II to IV and III to IV) and chronic GVHD, overall survival, disease-free survival, transplant-related mortality, and relapse for each cytokine or adipokine, adjusting for significant covariates. The lowest cytokine quartile was considered as the reference group for each model. To account for multiple testing P < .01 was considered the threshold for significance. In the test cohort a borderline significant association was identified between donor serum IL-1β concentrations and grades III to IV acute GVHD in the recipient (P = .01), and a significant inverse association was identified between donor TNF-α concentrations and chronic GVHD (P = .006). These findings were not validated in the replication cohort. Although the initial associations between cytokine levels and allo-HCT outcomes were not validated, the idea that donor characteristics may be transferable to the recipient remains an exciting area for future research.

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

Graft Versus Host Disease Following Intestine Transplantation

Introduction: Graft versus host disease (GVHD) remains one of the most feared medical complications following intestine transplantation (ITx). Few contemporary studies have evaluated the incidence and outcomes of GVHD following ITx. Methods: All ITx performed at our institution from 2003 through 2016 were included in this study and evaluated with the use of a prospectively maintained database. The incidence, associated clinical factors, treatment and outcomes were evaluated for all patients with GVHD. Results: There were 234 transplants performed in 228 patients during this period, including 133 isolated intestine, 59 liver-intestine, 35 multivisceral and 7 modified multivisceral transplants. There were 13 (5.6%) cases of GVHD (6 adults and 7 pediatric) with a median presentation of 77 days (range 14–373) following transplantation. 8 patients received multivisceral or modified multivisceral grafts, 4 patients received isolated intestine grafts, and 1 liver-intestine. 8 patients had native splenectomy at time of transplant and 3 patients had a known immunodeficiency. The most common presentation was a rash (n=8), other clinical manifestations included native GI involvement (n=7), pulmonary involvement (n=3), and bone marrow involvement (n=3). Chimerism data was available for 8 patients and was positive in 7. Immunosuppression was augmented in all cases and median number of treatments/patient was 2 (range 1–4). Treatments included steroids (n=13), thymoglobulin (n=6), alemtuzumab (n=2), extracorporeal photopheresis (n=3), and bone marrow transplant (n=1). The majority of cases 9/13 (69.3%) were fatal despite aggressive treatment. The 5-year survival for patients with GVHD was 30.7% versus 70.5% for patients without GVHD (p=0.001). Statistically significant risk factors for GVHD included multivisceral graft and native splenectomy. Only 1 (7.6%) patient with GVHD had acute rejection compared to 17.7% in the patients without GVHD (p=0.001). Conclusions: Despite modern immunosuppression regimens and advances in treatment, GVHD carries a high mortality. New therapies for GVHD are needed as well as aggressive surveillance protocols in multivisceral graft recipients and patients with a history of splenectomy.

Nonalloreactive T Cells Prevent Donor Lymphocyte Infusion–Induced Graft-versus-Host Disease by Controlling Microbial Stimuli

In mice, graft-versus-host reactions, associated with powerful graft-versus-tumor effects, can be achieved without graft-versus-host disease (GVHD) by delayed administration of donor lymphocyte infusions (DLI) to established mixed chimeras. However, GVHD sometimes occurs after DLI in established mixed chimeric patients. In contrast to mice, in which T cell recovery from the thymus occurs prior to DLI administration, human T cell reconstitution following T cell-depleted hematopoietic cell transplantation is slow, resulting in lymphopenia at the time of DLI. We demonstrate in this study that T cell lymphopenia is an independent risk factor for GVHD following DLI in the absence of known inflammatory stimuli. DLI-induced GVHD was prevented in lymphopenic recipients by prior administration of a small number of nonalloreactive polyclonal T cells, insufficient to prevent lymphopenia-associated expansion of subsequently administered T cells, through a regulatory T cell-independent mechanism. GVHD was not inhibited by T cells with irrelevant specificity. Moreover, administration of antibiotics reduced the severity of GVHD in lymphopenic hosts. Accumulation of DLI-derived effector T cells and host hematopoietic cell elimination were markedly diminished by regulatory T cell-depleted, nonalloreactive T cells. Finally, thymectomized mixed chimeras showed increased GVHD following delayed DLI. Collectively, our data demonstrate that in the absence of known conditioning-induced inflammatory stimuli, T cell lymphopenia is a risk factor for GVHD in mixed chimeras receiving delayed DLI. Our data suggest that the predisposition to GVHD can at least in part be explained by the presence of occult inflammatory stimuli due to the absence of T cells to control microbial infections.