Gastrointestinal Graft-versus-host Disease Research Articles

Research Highlights.

Research Highlights.

Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8+ T cells drive gastrointestinal acute graft-versus-host disease.

Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8+ T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8+ T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (TRM) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules (ITGB2), specific chemokines (CCL3 and CCL4L1) and chemokine receptors (CD74), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8+ T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8+ TRM cells during aGVHD in primate transplant recipients.

Broad-Spectrum Antibiotics and Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Transplantation for Acute Leukemia: Association of Carbapenem Use with the Risk of Acute Graft-versus-Host Disease

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD risk in pediatric patients undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before day 0) especially impacted aGVHD risk. For antipseudomonal penicillins, the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad-spectrum antibiotics, should be used judiciously in pediatric HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.

Surgical Treatment of Severe Bowel Obstruction as a Rare Complication Following Allogenic Hematopoietic Stem Cell Transplantation

Gastrointestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) disease are common complications occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and contribute to a high degree of morbidity and mortality associated with allo-HSCT. Herein, we present a patient with severe intestinal GVHD complicated by recurring CMV enteritis, which overall resulted in severe terminal ileum stenosis. The patient underwent laparoscopic ileocecal resection that significantly reduced symptoms and possibly prevented the development of fulminant ileus. Surgical treatment is rarely used in the treatment of gastrointestinal GVHD; however, the current patient history illustrates that patients with inadequate symptom control and severe inflammatory bowel stenosis can be successfully managed with surgery. We also review published case reports on surgical treatment for severe gastrointestinal GVHD.

Safety of Allogeneic Stem Cell Transplantation after PD-1 Blockade for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma: Focus on Immune-Related Adverse Events

Introduction: Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with relapsed and refractory Hodgkin lymphoma (rrHL). However, there is a question of applicability of allo-HSCT for patients previously treated with immune checkpoint inhibitors (ICIs). Initial reports indicate that allo-HSCT in this setting may be associated with increased risk of early transplant-related toxicity, graft versus host disease (GVHD), immune-related adverse events. But subsequently some studies demonstrated acceptable rates of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) after prophylaxis with posttransplantation cyclophosphamide (PTCy). The aim of this study was to define safety and toxicity of allo-HSCT after ICIs for patients with rrHL. Patients and methods: We conducted a retrospective analysis of allo-HSCT results in 23 adult patients with rrHL performed between 2017 and 2019 in RM Gorbacheva Research Institute, Pavlov University. All patients were treated with ICIs before the transplantation (single-agent nivolumab, n=13; nivolumab and brentuximab vedotin, n=5; nivolumab and chemotherapy, n=5). The median time from the last dose of ICIs to allo-HSCT was 83 days (range, 50-350 days) and the median number of cycles was 20 (range, 6-32). Objective response to PD-1 therapy before allo-HSCT was documented in 15 patients (65%) including CR (n=9, 39%) and PR (n=6, 26%). Five patients (22%) had stable disease/disease progression and 3 patients (13%) were transplanted in indeterminate response according to LYRIC criteria. Three (13%) patients had matched HLA-related siblings, 12 patients (52%) had unrelated donors and 8 patients (35%) had haploidentical donors. All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and PTCy-based GvHD prophylaxis. Bone marrow and peripheral blood stem cells was the graft source in 14 (61%) and 9 patients (39%), respectively. All analyses were performed using R 3.6.1 software. Results: At the time of analysis, median follow-up was 14 months (range, 1-26). Engraftment rate was 87%. Two patients had primary graft failure and there was 1 early death due to severe cytokine release syndrome after haploidentical HSCT. The 1-year OS and EFS were 83% (95% CI, 58-93) and 74% (95% CI, 49-87) respectively, whereas the 1-year cumulative incidences of relapse and NRM were 13% (95% CI, 5-39) and 13% (95% CI, 5-38) respectively.Out of the 20 patients with engraftment 15 patients developed acute GVHD including severe (grade III-IV) in 9 patients. All patients had skin aGVHD (stages 1, 2, and 3), 3 patients had gastrointestinal GVHD (stages 2, 3, and 4) and 2 patients had liver GVHD (stages 1 and 2). Four patients with steroid-refractory aGVHD received single-agent ruxolitinib (n=2) or combination of ruxolitinib with extracorporeal photopheresis (ECP) and steroids (n=2). All patients achieved complete response. Ten patients had chronic GVHD including 6 patients with moderate or severe disease. Most commonly skin (90%), mucosa (60%), gastrointestinal tract (30%), liver (20%), lung (10%) and eyes (20%) were involved. Four patients with steroid-refractory cGVHD achieved CR receiving combined immunosuppressive therapy (ruxolitinib and steroids, n=2; combination of steroids, cyclosporine A and ECP, n=2). One patient with severe skin cGVHD (score 3) achieved PR on combination of steroids and ECP, another patient with a severe refractory cGVHD (skin score 3, mucosa score 2 and lungs score 1) achieved stabilization only with third line of therapy (combination of ruxolitinib and imatinib). No cases of GVHD-related mortality were observed. There were no other immune-related adverse events. Conclusions: Our study showed the trend to higher incidence of aGVHD and cGHVD including steroid refractory form after ICIs, however this did not lead to GVHD-related mortality. Introduction of target agents for srGVHD might ameliorate GVHD-related mortality and morbidity in rrHL patients after ICIs. The optimal timing of allo-HSCT and regimen of GVHD prophylaxis are likely to be important in the successful outcome of the transplantation. Disclosures No relevant conflicts of interest to declare.

Safe & Effective Reduced Intensity Conditioning Regimen in Patients with Dyskeratosis Congenita

Background: Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by telomerase dysfunction leading to shortened telomeres.1 Recent literature shows only a 23% estimated 10-year survival, secondary to death from pulmonary complications.2 Currently, hematopoietic cell transplantation (HCT) is the only curative therapy for marrow failure but has been limited by mortality related to infection, sinusoidal obstructive syndrome (SOS), graft-versus-host disease (GVHD) and respiratory failure.3,4 The ideal conditioning regimen that optimizes engraftment while maximizing long-term survival is yet to be determined. Methods: We describe three consecutive patients with DC who underwent matched unrelated donor (MUD) allogeneic HCT following a reduced-intensity conditioning regimen similar to protocol NCT03330795 that uses a reduced intensity conditioning (RIC) while maximizing the benefits of shielding vulnerable organs in this populations. These three patients received a RIC regimen of rituximab, alemtuzumab, hydroxyurea, thiotepa, fludarabine, and 250 cGy total body irradiation; patients 1 and 2 received 85% lung shielding and 50% liver shielding. Results: Patient 1 is a 17-year-old male with reduced diffusing capacity of the lungs for carbon monoxide (DLCO), splenomegaly, splenic varices and nodular regenerative hyperplasia (NRH) who presented with pancytopenia. Testing revealed telomeres below the 1st percentile in all WBC subtypes, a PARN c.1257dup heterozygous mutation and a TERC c.17_31 mutation. He underwent a 12/12 MUD HCT and engrafted on Day +18. His course was complicated by poor adherence to medications and visits, and development of skin and GI GVHD, which responded to steroids. He was weaned off of immunosuppression by 11 months post-transplant. Twenty-eight months post-transplant, he remains 100% donor engrafted with no chronic GVHD or organ toxicity, including stable pulmonary function tests (PFT). See figure 1 and 2. Patient 2 is a 16-year-old male with reduced DLCO, splenomegaly and NRH who was diagnosed after his brother (Patient 1). He was found to have very short telomeres in all testable WBC subtypes and the same mutations as his brother. After marrow failure, he underwent a 12/12 MUD HCT, with neutrophil engraftment on Day +16. His course was complicated by sudden noncompliance with tacrolimus at day +100, after which he suffered GI GVHD which responded to steroids. He then developed disseminated adenovirus infection which responded to an adenovirus-specific T-cell infusion. He is now Day +356 after transplant and has been off all immunosuppression for 4 months. He remains >98% donor-engrafted without evidence of GVHD or organ toxicity, and his PFTs have remained stable. Patient 3 is a 16-year-old male with a history of antibody-negative autoimmune hepatitis who later developed pancytopenia. Telomere testing revealed very short telomeres in 4 of the 5 evaluable WBC subtypes. His genetic testing did not uncover a mutation yet identified as pathogenic in DC. He received a 12/12 MUD HCT and engrafted on Day +12. He had skin GVHD which responded to ruxolitinib. He remains 100% donor-engrafted, most recently at 9 months post-transplant without organ toxicity. Conclusions: All patients had timely neutrophil engraftment without SOS or other organ toxicity, despite being at increased risk for organ morbidity due to preexisting liver and lung disease. GVHD was noted, although two of the cases were related to poor adherence, and all responded to treatment. There is sustained donor-engraftment at a median of 637 days (range 356-1186 days) post-transplant.

TCR Repertoires in Graft-Versus-Host-Disease (GVHD)-Target Tissues Reveals Tissue Specificity of the Alloimmune Response

TCR Repertoires in Graft-Versus-Host-Disease (GVHD)-Target Tissues Reveals Tissue Specificity of the Alloimmune Response

Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine Following Allogeneic Transplantation in a Phase 1 Clinical Trial

Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine Following Allogeneic Transplantation in a Phase 1 Clinical Trial

Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft Versus Host Disease

Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft Versus Host Disease

Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study

Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study

Chronic Neutrophilic Leukemia - Stem Cell Transplantation in a Very Young Patient

Background: Chronic neutrophilic leukemia (CNL) is a rare BCR/ABL negative myeloproliferative neoplasm (MPN) characterized by sustained, predominantly mature neutrophil proliferation, bone marrow granulocytic hyperplasia, and hepatosplenomegaly. CSF3R mutation is a central diagnostic criterion. Most patients are over the age of 60 and the median survival is estimated at 2 years. No effective standard therapy has been established yet. Case-report: In March 2019 a 29 y/o male presented with cough, arthralgias, and hepatosplenomegaly. His initial WBC was 47.000/µl with 80% neutrophils, few neutrophil progenitors, no monocytosis. Bone marrow was consistent with a myeloproliferative syndrome, particularly CML, however BCR/ABL was negative. Flow cytometry suggested a myelodysplastic syndrome (MDS Score ↑) und with the preliminary diagnosis of mixed MPN/MDS he received one course of azacytidine without response. After this course we received the results of molecular genetic analysis which showed CSF3R c.1853C>T (also pos. for DNMT3A, IDH2, neg. for JAK2, CALR, PDGFRα/β, FGFR1). WBC increased further to 77.000/µl and we initiated hydroxyurea and - after insurance granted coverage - switched to ruxolitinib (initially 10 mg BID, then 15 mg BID). His hepatosplenomegaly responded and WBC came down slowly. In August he started to lose response, WBC rose again, and he needed blood transfusions. Because of his young age we had planned stem cell transplantation from the very beginning. The main purpose of ruxolitinib had been to reduce pre-transplant leukemic burden. Bone marrow from March 2019 showed 2% CD34+ cells, in Sept. 4%, Jan 2020 20-25%, consistent with transformation to AML. There was no family donor. In March 2020 he underwent allogeneic stem cell transplantation from a matched female unrelated donor (MUD allo-SCT 10/10 match) which he tolerated well. Conditioning was busulfan based. His further clinical course was complicated starting d+40 after SZT with °IV gastrointestinal GvHD (no CMV or other infectious agent identified). Immunosuppression had to be escalated using steroids (1 mg/kg BW BID) + ruxolitinib + photopheresis. Eventually AML recurred and the patient deceased on d +81 due to multi organ failure induced by refractory GvHD and AML recurrence. Conclusion: As most described cases of CNL occur in elderly patients reports on stem cell transplantation are rare. Here we present the course of a 29 y/o male who had only a short response to ruxolitinib and hydroxyurea. Both agents did not alter the bone marrow leukemic burden, therefore he proceeded to alloSCT. He did not achieve a sustained remission. We decided to present this case despite the unfortunate outcome because - to our knowledge - there has been no prior report on alloSCT in such a young patient with CNL. Disclosures Matzdorff: Novartis Oncology: Consultancy, Other: Honoraria paid to institution; Amgen GmbH: Consultancy, Other: Honoraria paid to institution; Grifols Deutschland GmbH: Consultancy, Other: Honoraria paid to institution; Swedish Orphan Biovitrium GmbH: Consultancy, Other: Honoraria paid to institution; UCB Biopharma SRL: Consultancy, Other: Honoraria paid to institution; Roche Pharma AG: Other: Family stockownership.

Photobiomodulation Therapy and Dexamethasone in the Management of Oral Acute Graft-Versus-Host Disease: Case Report

Background: Acute graft-versus-host disease (GVHD) in the oral cavity is a rare complication of hematopoietic stem cell transplantation (HSCT) and treatment has a varying length of time for wound healing. Objective: This case report present a 63-year-old female patient with a diagnosis of acute lymphoid leukemia, submitted a related allogeneic HSCT, which after 6 months evolved with oral acute GVHD, presenting odynophagia, dysphagia, and difficulty of hygiene. Methods: We started the mouthwash dexamethasone and nystatin oral suspension and five sessions of photobiomodulation therapy (PBMT) (660 nm, 100 mW, 0.028 cm2, 2 J, 70 J/cm2, 20 sec/point) has been used with daily applications in the oral cavity (at the lesion sites and in healthy areas). Results: Complete healing of the oral lesions was observed in 5 days although the patient had acute skin and gastrointestinal GVHD. Conclusions: The treatment of oral acute GVHD with PBMT is still rare in the literature, but due to a good result in wound healing with PBMT, we have used this therapeutic option in combination with dexamethasone and have been successful in healing and reducing pain.

Diagnostic disagreement between clinical standard histopathological‐ and retrospective assessment of histopathology‐based gastrointestinal graft‐versus‐host disease in children

No previous paediatric study has evaluated the frequency of diagnostic disagreement between clinical standard histopathological assessment (CSHA) and retrospective, independent, histopathological assessment (RIHA) of gastrointestinal Graft-Versus-Host Disease (GI-GVHD) METHODS: In a retrospective cohort study, based ongastrointestinal biopsies collected from allogeneic HSCT-treated children (<18years) with symptom-based GI-GVHD, we evaluated; disagreement ofhistopathology-based GI-GVHD diagnosis in CSHA vs RIHA, and potential clinical consequences of differences between the assessments. The CSHA-based diagnoses were retrieved from histopathology reports. The RIHA was performed by one pathologist, blinded to the CSHA outcomes and based on the minimal criteria for histopathology-based GI-GVHD diagnosis by the NIH 2014. Seventy children with 92 endoscopic occasions (including 22 re-endoscopies) were enrolled. GI-GVHD was observed in 73% (67/92) of the endoscopies in the RIHA and in 54% (50/92) in the CSHA (P=.014). The RIHA confirmed 94% (47/50) with GI-GVHD and 52% (22/42) with non-GI-GVHD diagnoses, established in the CSHA. Disagreement, that is endoscopic occasions with GI-GVHD solely detected in RIHA or detection of GI-GVHD in CSHA but not in RIHA, was observed in 20/42 (48%) and 3/50 (6%), respectively (McNemar's test,P=.0008). Therisk of a subsequent re-endoscopy was higher in endoscopic occasions with GI-GVHD detected in RIHA but not in CSHA vs if non-GI-GVHD were detected in both readings (P=.005). Our results suggest that in children with symptom-based GI-GVHD without histopathological confirmation in CSHA, a second, NIH 2014 based histopathological assessment should be considered before performing a re-endoscopy.

Severe Hypercholesterolemia Associated with Steroid-Refractory Acute Liver GVHD: Unusual Complication of Allogeneic Hematopoietic Cell Transplantation

Severe hypercholesterolemia is an uncommon complication of allogenic hematopoietic cell transplantation (HCT). Treatment options for hypercholesterolemia due to liver graft-versus-host disease (GVHD) are limited because many antilipidemic medications are known to worsen hepatic functions. We report our experience on a case of a 38-year-old male with Philadelphia chromosome positive acute lymphoblastic leukemia presenting with steroid-refractory hepatic and lower gastrointestinal acute GVHD after matched sibling donor peripheral blood myeloablative HCT who developed severe hypercholesterolemia (>1,000mg/dl). The patient was effectively treated with extracorporeal photopheresis for GVHD and severe hypercholesterolemia resolved after weeks of therapy with lipoprotein apheresis.

Fecal microbiota transplantation for graft-versus-host disease in children and adults: methods, clinical effects, safety

Was to evaluate clinical efficacy, adverse events and changes in the gut microbiome after fecal microbiota transplantation (FMT) in patients with gastrointestinal (GI) form of graft-versus-host disease (GVHD). The prospective single-center study in R.M. Gorbacheva institute included 27 patients with GI GVHD after allogeneic stem cell transplantation. 19 patients received FMT, 8 patients received placebo. Clinical scales for GI autoimmune diseases were used to evaluate response. Microbiome alterations were assessed with multiplex PCR. After FMT higher overall bacterial mass (р=0.00088), higher bacterial numbers ofBifidobacteriumspp. (р=0.021),Escherichia coli(р=0.049) andBacteroides fragilisgr. (р=0.000043) compared to placebo group. Also higher bacterial mass was observed in patients with clinical response (р=0.0057). The bacterial mass after procedure in non-responders was compared to the placebo group (р=0.31). Partial response of GVHD was achieved faster in the FMT group compared to placebo (median 4 days vs 48 days,p=0.014). Complete response was observed in 8 (42%), 14 (74%) and 16 (84%) at 30, 60 and 90 days respectively, while in the placebo group only 0%, 1 (13%) and 4 (50%) achieved complete response at the same time points. The incidence and severity of adverse events was comparable between FMT and the placebo group. FMT in patients with refractory GI GVHD was associated with favorable clinical outcomes and recovery in certain marker bacterial populations. Multiplex PCR can be used to assess an engraftment of a donor microbiota. FMT in GI GVHD was not associated with life-threatening adverse events, but further studies are required to validate clinical efficacy.

Nutrition Support Practices of Hematopoietic Stem Cell Transplantation Centers in Mainland China.

It has been identified that malnutrition can influence the immune system and time of engraftment, and it's also associated with increased incidence of complications, prolonged length of hospital stays, and transplant mortality and morbidity in patients undergoing hematopoietic stem cell transplantation (HSCT), so dynamic nutrition care is highly important. The aim of this study was to better understand the differences between clinical nutrition practices and international recommendations as well as possible barriers to the use of nutrition support in HSCT patients. An evidence-based nutrition support pathway was constructed through a systematic literature review to identify evidence and recommendations relating to the relevant issues. Then, a questionnaire consisting of 28 questions that focused on the 4 topics, namely, assessment and screening for malnutrition, nutrition support interventions, nutrition support in gastrointestinal graft-versus-host disease (GVHD) and neutropenic diet was developed by the study authors and used for data collection. Responses of 18 HSCT centers from 17 provinces were received. General assessment for malnutrition was performed at 72% (13/18) centers. Parenteral nutrition (PN) was given as the first option to HSCT patients in the majority of centers, despite the fact that current guidelines recommend enteral nutrition (EN) over PN. As many as 72% (13/18) of the centers considered a neutropenic diet in the management of HSCT patients, but only one center had a formal neutropenic diet protocol in place for transplant recipients. Criteria for initiating nutrition support in patients with gastrointestinal GVHD were heterogeneous among the centers, and PN was the most widely used technique. The survey results revealed significant heterogeneity with regard to nutrition support practices among the centers, as well as between the practices and the guidelines. Standard nutrition support guidelines or protocols for nutrition support practices were absent in most of the centers.

COVID‐19 in bone marrow transplant recipients: reflecting on a single centre experience

Covid-19 disease is caused by a novel SARS-CoV-2 virus and has been declared a pandemic on the 9th of March by WHO. Hallmark of COVID-19 management is supportive care and there is still no convincing evidence on a treatment which will reduce mortality. Severe COVID-19 associated sepsis characterized by acute respiratory distress syndrome (ARDS), secondary bacterial pneumonias thrombotic complications, myocarditis, and gastrointestinal involvement are more prevalent in those with comorbidities such as hypertension, diabetes, cardiac disease, cancer and age>70 years (Liang et al; 2020, Guan et al; 2019).

Prognostic plasma biomarkers of early complications and graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation.

Early complications post hematopoietic stem cell transplantation (HSCT) such as sinusoidal obstruction syndrome (SOS) and graft versus host disease (GVHD) can be life threatening. Although several biomarkers have been identified to correlate with these complications and their response to treatment, these are yet to be used in clinical practice. Here, we evaluated circulating endothelial cells (CECs) (n = 26) and plasma biomarkers (ST2, REG3α, VCAM1, ICAM1, TIM3) (N = 210) at early time points, to determine their association with early complications post‐HSCT. Elevated CEC counts at the end of conditioning was associated with GVHD, indicating endothelial damage during HSCT. Plasma levels of REG3α, VCAM1, ICAM1, and TIM3 on day 14 (D14) and D14 ICAM1 and D28 ST2 were significantly higher in patients with SOS and aGVHD, respectively. Upon sub‐group analysis, D28 ST2, D14/D28 REG3α, and D14 ICAM1 levels were significantly higher in patients with gastrointestinal GVHD, while D28 ST2 was higher in those with skin/liver GVHD. High ST2 levels on D28 was significantly associated with non‐relapse mortality (NRM) and overall survival. Our results suggest that elevated ST2 levels on D28 could predict the likelihood of developing aGVHD and could influence NRM and OS.

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.

Clinical relevance of endoscopy with histopathological assessment in children with suspected gastrointestinal graft-versus-host disease.

Endoscopy with histopathological assessment is an established practice to confirm gastrointestinal graft-versus-host disease (GI-GVHD). However, the clinical relevance of this approach in children is incompletely evaluated. In a retrospective cohort study, we investigated the frequency of treatment changes in response to histopathological findings in all children (<18years) in Sweden who underwent endoscopy for suspected GI-GVHD (2000-2013) after receiving hematopoietic stem cell transplantation. Sixty-eight children with ninety-one endoscopic occasions were enrolled. At the time of endoscopy, anti-GI-GVHD treatment was ongoing in 71% (65/91). In 18% (12/65) with ongoing treatment, no histopathological evidence of GI-GVHD or another cause to justify anti-GI-GVHD treatment was found. In 48% (44/91), endoscopy with histopathological assessment led to changes in the treatment regimen. Re-endoscopy was more frequent among those with treatment changes, versus unchanged treatment, 39% (17/44) and 13% (6/47), respectively (P=.007). Histopathological findings generating treatment changes were as follows: GI-GVHD in 68% (30/44), normal histology in 25% (11/44), and an alternative diagnosis in 7% (3/44). In conclusion, this study supports that endoscopy with histopathological assessment should be considered in all children with suspected GI-GVHD.