Graft-versus-host Research Articles

Disseminated Varicella-Zoster Virus-Associated Acute Retinal Necrosis in a Post-Bone Marrow Transplant Patient.

This case report highlights the risk of viral infections, particularly acute retinal necrosis (ARN), in patients undergoing immunosuppressive therapy for graft-versus-host disease (GVHD) following bone marrow transplantation. A 45-year-old male with aplastic anaemia who underwent a bone marrow transplantation developed GVHD and was treated with ruxolitinib and tacrolimus. The patient presented with ocular symptoms and was diagnosed with pseudodendritic keratitis in the right eye and ARN in the left eye. The diagnosis was confirmed through PCR analysis of the anterior chamber tap. The patient's right eye symptoms were resolved with topical acyclovir and supportive care, achieving a best-corrected visual acuity of 6/6. Following systemic and intravitreal antiviral therapy, ARN resolved in left eye with thinning and retinal detachment. The patient was not cleared for surgery due to his compromised systemic condition. Our case highlights the disseminated and asymmetric nature of herpes zoster infection in the context of severe immunosuppression. This emphasizes the need to balance effective GVHD treatment and reinforces the importance of ongoing vigilance and timely management of these high-risk individuals.

Phase 1/2 Study of High-Dose Palifermin for GVHD Prophylaxis in Patients Undergoing HLA-Matched Unrelated Donor HCT.

Phase 1/2 Study of High-Dose Palifermin for GVHD Prophylaxis in Patients Undergoing HLA-Matched Unrelated Donor HCT.

Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT.

Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic/Myeloproliferative Overlap Neoplasms.

Myelodysplastic/myeloproliferative overlap neoplasms (MDS/MPN) are rare hematological malignancies. We analyzed the outcomes of 75 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for MDS/MPN. Graft-versus-host disease (GvHD) prophylaxis included post-transplantation cyclophosphamide (PTCy) in 71% of patients, with 44 (59%) receiving a combination of anti-thymocyte globulin (ATG) and PTCy. The median follow-up was 44.4 months. Primary graft failure occurred in three patients (4%). The incidence of grade III-IV acute GvHD at day 100 was 13% (95% CI: 6-22). At 2 years, the incidence of moderate-severe chronic GvHD, non-relapse mortality (NRM), relapse, GvHD-free/relapse-free survival (GRFS), and overall survival (OS) was 31.7% (95% CI 20.7-43.2), 37.9% (26-49), 17.4% (95% CI: 10-27), 24.8% (95% CI: 15-36), and 51.6% (95% CI: 39-63), respectively. PTCy-based GvHD prophylaxis seemed to be associated with improved OS (HR: 0.5, 95% CI: 0.3-0.9, p = 0.03), NRM (HR: 0.4, 95% CI: 0.2-0.9, p = 0.03), and GRFS (HR: 0.5, 95% CI: 0.3-0.8, 0.009). On multivariable analysis, the use of the PTCy-containing regimen seemed to be associated with improved NRM (HR: 0.41; 95% CI: 0.2-0.8; p = 0.03), GRFS (HR: 0.47; 95% CI: 0.3-0.8; p = 0.009), and OS (HR: 0.49; 95% CI: 0.2-0.9; p = 0.03) without an increased risk of relapse.

The impact of ABO compatibility/incompatibility between donor and recipient of allogeneic bone marrow transplant on transplant outcomes.

The impact of ABO compatibility/incompatibility between donor and recipient of allogeneic bone marrow transplant on transplant outcomes.

Allogeneic Hematopoietic Stem Cell Transplantation for Elderly Acute Lymphoblastic Leukemia Patients: A Registry Study From the Société Francophone de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC).

There are very limited data regarding the outcomes of elderly patients with acute lymphoblastic leukemia (ALL) who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). A total of 316 ALL patients aged ≥ 60 years who underwent alloHSCT between 2010 to 2022 were identified in the SFGM-TC registry. The primary objective was to evaluate progression-free survival (PFS), non-relapse mortality (NRM), relapse incidence (RI), and graft-versus-host disease (GvHD)-free relapse-free survival (GRFS), as well as their risk factors. The median age was 63.8 years (range 60-75.8), 49.8% of patients had Philadelphia-positive B-ALL (Ph + ALL), and 70.9% were in first complete remission (CR1) at transplantation. The donor was an unrelated donor in 52.1%, a matched related donor (MRD) in 26.3%, and a haplo-identical donor in 17.7%. Reduced-intensity conditioning (RIC) was administered to 64.6% of patients, while total body irradiation (TBI) was used in 35.8%. The 3-year overall survival (OS) was 46% (95% CI 40%-53%). The 3-year PFS, NRM, RI, and GRFS were 41% (95% CI 35%-48%), 23% (95% CI 18%-28%), 36% (95% CI 31%-42%), and 30% (95% CI 25%-37%), respectively. Multivariable analyses confirmed poorer OS and PFS in patients with advanced disease, with an HR of 1.79 (95% CI 1.22-2.64), p = 0.0032. Additionally, the ALL subtype significantly impacted outcomes, with an HR of 1.99 (95% CI 1.42-2.79) for non-Ph + ALL. This study suggests that alloHSCT is a viable option for elderly ALL patients, as age itself did not impact outcomes. However, advanced disease and non-Ph + ALL were associated with significantly worse survival.

High GVHD Prevalence in Travel-Based SCT despite Young Patients and HLA Matching

Background: Patients from regions without stem cell transplantation (SCT) facilities often seek treatment abroad and return home for post-transplant care. Although extensive data exist on graft-versus-host disease (GVHD) and its risk factors, information on international SCT patients returning to countries that lack transplant facilities and expertise is scarce and not well documented. Materials and Methods: We screened 149 transplant recipients and analyzed the data of 91 patients who received transplants abroad and were followed up at our center from January 2019 to December 2022. This observational study used data from electronic medical records and employed descriptive statistics, inferential tests, and relative risk calculations with forest plots to analyze the prevalence of GVDH and its key risk factors. Results: Of the recipients, 31.8% were residents of nine countries residing in the UAE, and 67.2% were UAE citizens. Adults comprised 48.3% of the recipients, whereas 51.7% were pediatric patients. Hematological malignancy was the most common indication (49%), primarily in adults. Siblings comprised the majority of donors (52.6%), followed by related (23.09%) and unrelated donors (8.9%). Most patients (69.2%) received HLA-identical transplants, followed by 21.9% who received haplo-identical transplants. Among adults, 62.2% developed GVHD compared to 26% of pediatric patients. Recipients from related HLA-identical donors had a 50% prevalence of GVDH, whereas those from unrelated identical donors had a 71% prevalence. The overall prevalence of GVDH was 50% in 87.9% of patients who received allogeneic SCTs. Conclusion: Despite favorable factors, such as young age and matched related donors, we found a high prevalence of GVDH. Ocular GVHD was less prevalent than expected, and lung GVHD was weakly correlated with established risk factors. Larger multicenter studies are needed to assess and confirm the effect of contributing factors.

Endoscopic findings in the evaluation of gastrointestinal symptoms in pediatric patients post hematopoietic stem cell transplantation.

Endoscopy plays a pivotal role in diagnosing gastrointestinal (GI) symptoms of pediatric patients post hematopoietic stem cell transplantation (HSCT). There is very little data on whether endoscopic findings can predict pathological diagnosis and treatment outcomes in the pediatric population. The primary objective was to determine the association between macroscopic and microscopic findings of endoscopies in pediatric patients post-HSCT. A secondary objective was to evaluate whether macroscopic findings can predict treatment outcomes or differentiate between causes of GI symptoms. This single-center prospective study analyzed the results of endoscopic evaluation in patients aged 18 years or younger, who developed GI symptoms during and after HSCT and required an endoscopy for diagnosis. Macroscopic and microscopic findings of upper and lower endoscopies were reviewed and compared, thus evaluating the correlation between the two. Predetermined sites throughout the GI tract were examined for their macroscopic and microscopic findings, to examine whether their results suggest graft-versus-host disease (GVHD), infection, or both. Patients' change in treatment and clinical response were also assessed. In 22 patients, 249 tissue samples were macroscopically and microscopically evaluated. When abnormal macroscopic findings were present, microscopic findings were present in 86.2% of the cases. In 72.1% of the endoscopic sites with normal macroscopic results, abnormal microscopic findings were present (p value = 0.004, Fisher-Freeman-Halton exact test). This study provides further evidence supporting the correlation between macroscopic and microscopic evaluation in the diagnosis of GVHD post-HSCT, however, normal macroscopic findings do not rule out the presence of GVHD.

High Amphiregulin Expression in Intestinal Biopsies of Pediatric Patients with Severe Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (GvHD) is a major complication of hematopoietic cell transplantation (HCT). Despite of recent advances in prophylaxis, diagnosis and treatment it is still a serious cause of morbidity and mortality after HCT. Amphiregulin (AREG) is an epidermal growth factor receptor ligand known for restoring damaged intestinal tissue. AREG has been studied as a blood biomarker in acute GvHD and was found predictive of steroid response and mortality. However, the expression of AREG in intestinal tissue in pediatric patients with acute GvHD is unknown. The aim of this study is to analyze and evaluate AREG expression in intestinal tissue biopsies of pediatric patients with GvHD, in comparison to patients with inflammatory bowel disease (IBD) and a control group with no pathological findings to provide insights in the biological tissue expression of this potential diagnostic and prognostic biomarker. We performed a retrospective study with pediatric patients who had an intestinal biopsy performed after HCT between 2010 and 2021, patients who had a diagnosis of IBD and patients with normal findings at the University Children's Hospital Zurich. Intestinal biopsies were stained for AREG. We used a semi-quantitative score ranging from 0 (not present) to 3 (intense) to grade the AREG expression. The grading was performed by a pathologist blinded to the group allocation. Lerner scores were also performed. The median AREG scores between the groups were compared using multivariable linear regression with age and sex as confounders. The study protocol was approved by the Ethical committee of Canton Zürich, Switzerland, number 2022-01037. Overall, 59 biopsies were stained for AREG, 20 after HCT (6 patients with severe GvHD, 5 with mild GvHD and 9 without GvHD), 19 with IBD and 20 controls. The median for the AREG overall grade for control group was 2, for the HCT with severe GvHD group 2.5 (P = .060) and for the IBD group 2.5 (P = .007). The results for the AREG epithelium and lamina propria grades were similar. There were no differences in survival between patients with GvHD with overall AREG scores below and greater or equal to the median of 2.5. This study showed that AREG scores were higher in intestinal biopsies from patients with severe GvHD and IBD compared to controls and patients with mild or no GvHD. Consequently, AREG staining could potentially be used as an additional marker for severe inflammation as seen in GvHD and IBD.

Incidence and Factors Associated with Graft-Versus-Host Disease in the First Year After Allogeneic Peripheral Blood Stem Cell Transplantation.

The use of allogeneic peripheral blood stem cell transplantation (allo-SCT) has increased in Latin America in recent years. In the absence of an matched-related donor (MRD), haploidentical transplantation has emerged as a potentially curative option with increasing availability in the region. Graft-versus-host disease (GVHD) is an important complication with variable incidence rates depending on the type of transplant. The aim of this study was to compare the incidence of acute and chronic GVHD between haploidentical and identical allo-SCT recipients and to analyze factors associated with the development of GVHD during the first year after transplantation. Our retrospective cohort study included adult patients with malignant and nonmalignant hematologic pathologies who received allo-SCT between 2014 and 2022 at a transplant center in Bogota, Colombia. Uni- and multivariate analyses were performed to determine factors associated with the development of GVHD. A total of 152 patients were analyzed, including 108 (71%) transplants from an MRD and 44 (28.9%) transplants from a haploidentical donor. The median age was 45 years. The most common indications for transplantation were acute myeloid leukemia (37.5%) and acute lymphoblastic leukemia (36.2%). The incidence of acute GVHD was greater in the haploidentical transplant group (63.0%) than in the MRD group (36.6%) (p < 0.05). There was no significant difference in the incidence of chronic GVHD between the two groups, with 18% and 33% in transplants from haploidentical donors and MRD, respectively (p = 0.09). The factors associated with the development of acute GVHD were relapse (odds ratio [OR] 0.41; 95% CI, 0.13-1.16), female sex (OR 2.34; 95% CI, 0.93-6.1), and age older than 50 years (OR 2.1; 95% CI, 0.81-5.71). The factors associated with the development of chronic GVHD were haploidentical donor status (OR 0.22; 95% CI, 0.05-0.75) and relapse (OR 0.16; 95% CI, 0.04-0.56). Our study revealed a higher rate of acute GVHD in transplant recipients from a haploidentical donor than in those from MRD, whereas no differences were found for chronic GVHD between the two groups. Sex, age, relapse, and type of transplant were identified as factors associated with the prevalence of GVHD.

Selective H2-O tissue expression reduces risk for graft-versus-host disease in an in vivo transplantation model.

Selective H2-O tissue expression reduces risk for graft-versus-host disease in an in vivo transplantation model.

Effects of Treatment With Premarin Alone and the Combination of Premarin + Beclomethasone in Vaginal Involvement of GVHD After Hematopoietic Stem Cell Transplantation.

Effects of Treatment With Premarin Alone and the Combination of Premarin + Beclomethasone in Vaginal Involvement of GVHD After Hematopoietic Stem Cell Transplantation.

Constrictive Pericarditis as a Rare Manifestation of Graft-Versus-Host Disease: A Case Report.

Graft-versus-host disease (GVHD) is a serious inflammatory complication that can arise after allogeneic transplantation, characterized by donor T-cells attacking the recipient's tissues. While cardiac complications are infrequent, they are more commonly observed in cases of chronic GVHD and may manifest as pericardial effusion, cardiac tamponade, and various arrhythmias. Additionally, chronic GVHD can result in constrictive pericarditis (CP) due to the accumulation of fluid and scarring. A 25-year-old Iranian man developed CP 14 years after undergoing allogenic stem cell transplantation. Following inadequate response to medical therapy, he underwent a pericardiectomy. Pathological examination during follow-up revealed fibrosis and mild chronic inflammation. This report aims to add another case of cardiac manifestation associated with GVHD to the current literature. The main message emphasizes the urgent need for prompt diagnosis and effective pericardiectomy, which can be life-saving. Surgical referral should always be an option, and post-operative immunomodulation is crucial.

Overcoming NK-mediated rejection by anti-3rd-party central memory veto CD8 T cells through downregulation of DNAM-1 on alloreactive NK cells.

Overcoming NK-mediated rejection by anti-3rd-party central memory veto CD8 T cells through downregulation of DNAM-1 on alloreactive NK cells.

Early cardiac events after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. subanalysis exploring cardiac toxicity conducted on behalf of GETH-TC

IntroductionHaploidentical allogeneic hematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCY) has become a standard approach for patients lacking HLA-matched donors. While effective in reducing graft-versus-host disease (GVHD), concerns about PTCY-associated cardiovascular toxicity remain. This study investigates the incidence, predictors, and impact of early cardiac events (ECE) in haplo-HCT recipients.MethodsWe conducted a retrospective, multicenter analysis of 268 patients with acute myeloid leukemia (AML) treated with anthracycline-based induction regimens and undergoing their first haplo-HCT with PTCY (50 mg/kg/day on days +3 and +4) between 2011 and 2022. ECEs, defined as any new cardiac event within 100 days post-transplant, were analyzed using cumulative incidence functions considering death and relapse as competing risks. Risk factors and the impact on non-relapse mortality (NRM) and overall survival (OS) were assessed via univariate and multivariate regression models.ResultsThe median patient age was 57 years (range: 18–79), and pre-transplant comorbidities included hypertension (22.4%), dyslipidemia (13.1%), diabetes mellitus (6.7%), and prior cardiac history (14.2%). ECEs occurred in 23 patients (8.6%) at a median of 19 days post-transplant (IQR: 5–66), with a day +100 cumulative incidence of 8.6% (95% CI: 6.1–12.3). The most frequent complications were pericardial effusion/pericarditis (43.5%), arrhythmias (30.4%), and heart failure (17.4%). Severe ECEs (CTCAE grade 3–4) were observed in 30.4% of cases, and four deaths (17.4%) were directly attributed to ECEs. Univariate analysis identified dyslipidemia (HR: 3.87, p=0.001), hypertension (HR: 2.76, p=0.015), and moderate-severe veno-occlusive disease (HR: 4.94, p=0.002) as significant predictors of ECE. ECEs were associated with lower OS (HR: 1.78, p=0.04) and higher NRM (HR: 2.87, p=0.005).DiscussionWhile the incidence of ECEs following haplo-HCT with PTCY was relatively low, their occurrence significantly worsened transplant outcomes. These findings underscore the importance of cardiovascular risk assessment and structured cardiac monitoring to mitigate complications in haplo-HCT recipients.

Comprehensive up-to-date analysis on TCRαβ/CD19-depleted hematopoietic stem cell transplantation in pediatric hematological malignancies.

Comprehensive up-to-date analysis on TCRαβ/CD19-depleted hematopoietic stem cell transplantation in pediatric hematological malignancies.

Ruxolitinib in the treatment of acute corticosteroid-refractory graft-versus-host disease: a scoping review.

Ruxolitinib in the treatment of acute corticosteroid-refractory graft-versus-host disease: a scoping review.

Novel Tear Biomarkers in Ocular Graft Versus Host Disease Associated with Th1/Th2 Immune Responses: A Case Series and Literature Review

Ocular graft versus host disease (oGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation and may be associated with dry eye disease and chronic inflammation and fibrosis. Immune dysregulation, particularly the Th1/Th2 imbalance, plays a key role in the progression of oGVHD. This case study presents two oGVHD patients (a 20-year-old with acute oGVHD and a 59-year-old with chronic oGVHD), analyzing clinical dry eye parameters (Schirmer test I, tear film break-up time, Ocular Surface Disease Index (OSDI), and kerato-conjunctival staining) alongside tear biomarkers. A 27-plex tear cytokine analysis was performed using the Luminex200 platform, assessing various biomarkers against a control group-defined normal range. Key biomarkers included beta2-microglobulin (β2-MG), complement components, chemokines, growth factors, and both pro-inflammatory and anti-inflammatory cytokines, as well a series of soluble ligand and receptors. The study identified distinct biomarker progression patterns during topical corticosteroid treatment in the acute oGHVD patient, suggesting potential shifts in Th1/Th2 responses as the disease progressed. Notably, the soluble CD27, TNF-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), chemokine ligand 2 (CCL2), and IL-1β, initially elevated, normalized during treatment, while tear-soluble Fas remained highly elevated (&gt;400-fold). Conversely, soluble TRAIL, which was initially at very low levels (100-fold lower), increased during treatment and reached normal tear levels, coinciding with improvements in the clinical ocular inflammation symptoms and OSDI score. This case study also highlights potential differences between acute and chronic oGVHD, particularly in the distinct patterns of novel tear biomarkers such as CD27, TRAIL/TRAIL-R2, and CCL2. Enhancing our understanding of biomarker dynamics may improve disease monitoring and pave the way for personalized management strategies to improve patient outcomes.

MIF functional polymorphisms are associated with acute GVHD progression and steroid-refractoriness

IntroductionApproximately 50% of allogeneic hematopoietic stem cell transplantation (HSCT) Q6 recipients develop graft versus host disease (GVHD). Glucocorticoids (GC) are the first line of treatment for both acute and chronic GVHD. Failure to respond to GC [steroid-refractory (SR)] encompasses a very poor outcome with high mortality. Macrophage migration inhibitory factor (MIF) is released during transplantation and triggers enhanced and prolonged immune reactions. Persistently elevated levels of MIF have been shown to override both endogenous and exogenous antiinflammatory effects of GC.MethodsTwo functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were analyzed in 86 patients who underwent allogeneic HSCT. We also measured MIF serum levels at different time points before and after HSCT.ResultsFrequencies of MIF high-expression -794 CATT7 containing genotypes were increased in patients with grade III-IV acute GVHD (aGVHD) (36.8%) compared with patients that did not develop aGVHD (5.8%) and patients with grade II aGVHD (0%), (p=0.0019, 0.0080 respectively). We also demonstrated that the frequencies of the MIF-794 CATT7 and -173 C containing genotypes, were significantly associated with steroid-refractory aGVHD (46.6%, 60% respectively) compared to steroid-responsive aGVHD (0%, 5.3% respectively), (p=0.0011, P=0.0007 respectively). We further showed that MIF circulating levels preceded onset of severe aGVHD.DiscussionOur findings suggest that genetically controlled high expression MIF genotypes are associated with aGVHD worsening and could serve as a biomarker enhancing identification and treatment of steroid-refractory disease.

Truncated form of human CD19 antigen as a suicide gene to control T-cell alloreactivity: ΔCD19.

Donor lymphocyte infusion (DLI) is employed to either treat or prevent relapse in patients with hematologic malignancies, as well as to accelerate recovery of adaptive immunity, after allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the increased use of DLI, there is renewed interest in the development of approaches able to prevent graft-versus-host disease (GvHD) reaction. In this study, we describe a novel and effective safety switch represented by the truncated form of the human CD19 antigen (ΔCD19) used to transduce T lymphocytes (hΔCD19 Tcells). We demonstrated that the exposure of ΔCD19-T-cells to an anti-hCD19-hCD3 T-cell bispecific T-cell engager (BiTE) molecule (structurally identical to blinatumomab, an agent largely used in the treatment of B-cell acute lymphoblastic leukemia) resulted into a prompt elimination of hCD19+/CD3+ cells both in vitro and in an in vivo animal model of mice developing a xenograft reaction mimicking GvHD after infusion of in vitro-activated/expanded human T cells. Importantly, the administration of the anti-hCD19-hCD3 BiTE molecule in the animal model, from one hand led to the improvement of signs and symptoms of GvHD, as well as of the overall-survival of the mice, and from the other, after a drug washout, was associated with the resurge of ΔCD19-T-cells without reoccurrence of GvHD. Our study provides evidence that the ΔCD19 suicide gene used in combination with an anti-hCD19-hCD3 T-cell BiTE molecule could represent a valid and effective strategy to control GvHD occurring after the infusion of donor T lymphocytes.