New investigational drugs for steroid-refractory acute graft-versus-host disease: a review of the literature.

INTRODUCTION: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains a formidable obstacle in the field of allogeneic hematopoietic cell transplantation (allo-HCT), significantly contributing to patient morbidity and mortality. The current therapeutic landscape for SR-aGVHD is limited, often yielding suboptimal results, thereby emphasizing the urgent need for innovative and effective treatments. AREAS COVERED: In light of the pivotal REACH2 trial, ruxolitinib phosphate, a Janus kinase inhibitor, has gained prominence as the standard treatment for SR-aGVHD. Nevertheless, a considerable number of patients either do not respond to or cannot tolerate this therapy. This review delves into emerging treatments for SR-aGVHD, including mesenchymal stromal cells (MSCs), fecal microbiota transplantation (FMT), CD3/CD7 blockade, neihulizumab, begelomab, tocilizumab, and vedolizumab. While some of these agents have shown encouraging results in early-phase trials, issues such as treatment-related toxicities and inconsistent responses in larger studies highlight the necessity for ongoing research. EXPERT OPINION: Current trials exploring new agents and combination therapies offer hope for fulfilling the unmet clinical needs in SR-aGVHD, potentially leading to more effective and precise treatment strategies.

Human placental mesenchymal stromal cells promote the formation of CD8+CD122+PD-1+Tregs via CD73/Foxo1 to alleviate liver injury in graft-versus-host disease mice.

BACKGROUND: Human placental mesenchymal stromal cells (hPMSCs) are known to limit graft-versus-host disease (GVHD). CD8+CD122+PD-1+Tregs have been shown to improve the survival of GVHD mice. However, the regulatory roles of hPMSCs in this subgroup remain unclear. Here, the regulatory mechanism of hPMSCs in reducing liver fibrosis in GVHD mice by promoting CD8+CD122+PD-1+Tregs formation and controlling the balance of IL-6 and IL-10 were explored. METHODS: A GVHD mouse model was constructed using C57BL/6J and BALB/c mice and treated with hPMSCs. LX-2 cells were explored to study the effects of IL-6 and IL-10 on the activation of hepatic stellate cells (HSCs). The percentage of CD8+CD122+PD-1+Tregs and IL-10 secretion were determined using FCM. Changes in hepatic tissue were analysed by HE, Masson, multiple immunohistochemical staining and ELISA, and the effects of IL-6 and IL-10 on LX-2 cells were detected using western blotting. RESULTS: hPMSCs enhanced CD8+CD122+PD-1+Treg formation via the CD73/Foxo1 and promoted IL-10, p53, and MMP-8 levels, but inhibited IL-6, HLF, α-SMA, Col1α1, and Fn levels in the liver of GVHD mice through CD73. Positive and negative correlations of IL-6 and IL-10 between HLF were found in liver tissue, respectively. IL-6 upregulated HLF, α-SMA, and Col1α1 expression via JAK2/STAT3 pathway, whereas IL-10 upregulated p53 and inhibited α-SMA and Col1α1 expression in LX-2 cells by activating STAT3. CONCLUSIONS: hPMSCs promoted CD8+CD122+PD-1+Treg formation and IL-10 secretion but inhibited HSCs activation and α-SMA and Col1α1 expression by CD73, thus controlling the balance of IL-6 and IL-10, and alleviating liver injury in GVHD mice.

Outcomes with low dose anti-thymocyte globulin based graft versus host disease prophylaxis after mismatched unrelated donor allogeneic hematopoietic cell transplantation.

BACKGROUND: Anti-thymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis is widely used for mismatched unrelated donor allogeneic hematopoietic cell transplantation (HCT) although optimal dose remains unclear. Although recent literature suggested improved outcomes with PTCy-based regimens when compared to ATG-based regimens these studies used doses of ATG ≥5 mg/kg. Thus, we analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower-dose ATG-based regimens at our center. METHODS: We retrospectively analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower dose ATG-based regimens for all adults undergoing allogeneic HCT at The Ottawa Hospital from 2015 to 2022. Data regarding demographics, conditioning regimen, dose of ATG, rates of GVHD, duration of remission, and survival, were collected and analyzed. RESULTS: Seventy-seven (n = 77) patients (males 62.3%; median age 50 years) underwent allogeneic HCT from MMUD. Majority(81%; n = 63) received 2.5 mg/kg of rabbit ATG and remaining 18.2% (n = 14) received 4.5 mg/kg. Grade II-IV acute GVHD occurred in 24.7% (n = 19) while any chronic GVHD occurred in 32.5% (n = 25) patients. After a median follow-up of 21 months, relapse occurred in 28.6% of patients. Two-year OS, GRFS, CIR, and NRM were 60.6%, 45.3%, 16.9%, and 18.2% respectively. Dose of ATG (2.5 mg/kg vs. 4.5 mg/kg) was not associated with outcomes in either univariate or multivariate analyses. CONCLUSIONS: When compared to published studies using ATG doses ≥5 mg/kg, GVHD prophylaxis using lower dose ATG may potentially lead to improved outcomes in patients undergoing MMUD allogeneic HCT. Further studies are needed to directly compare lower dose ATG to PTCy-based regimens to determine ideal GVHD prophylaxis for these patients.

Oral Mucositis and Nutritional Status in Children Who Underwent Hematopoietic Cell Transplantation: A Comparison Between Nonmalignant and Malignant Primary Diseases.

BACKGROUND: There is a lack of studies analyzing the association between oral mucositis (OM) and nutritional imbalance in children during hematopoietic stem cell transplantation (HSCT). The aim of this study was to compare the risk factors for OM and nutritional imbalance during HSCT in pediatric patients with nonmalignant diseases (NMD) and malignant diseases (MD). METHODS: Data on age, sex, primary disease, transplantation type, conditioning regimen, GVHD prophylaxis, gastrointestinal toxicity, OM, percent body weight loss or gain, nutritional repositioning, and overall survival (OS) were retrospectively collected from the 132 medical records. The data were then compared between patients with NMD (n = 70) and MD (n = 62). RESULTS: OM had a similar severity between the groups. The primary risk factor for OM in the NMD group was the conditioning regimen with busulfan, while in the MD group it was GVHD prophylaxis with cyclosporin and methotrexate. OM did not have an impact on body weight loss or gain in any of the groups. In the NMD, body weight gain due to fluid overload was more pronounced and associated with a lower age range. OS was similar between the groups and was not affected by OM. CONCLUSIONS: OM pattern was similar in pediatric patients with or without MD, but the factors that determined these oral lesions were different. There were disparities in body weight changes between the two groups, and these changes were not associated to OM.

Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation.

Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

Outcome of Cyclophosphamide Treatment Following Hematopoietic Stem Cell Transplantation in a Thalassemia Patient: A Case Study.

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for ß-thalassemia major in children. However, it often induces graft-versus-host-disease (GVHD), which is associated with complications. In the present study, we used cyclophosphamide (Cy) to treat a thalassemia patient post-HSCT to reduce the adverse effects of GVHD. We monitored the numbers and phenotype of granulocytes. In this case study, an 11-year-old female patient, diagnosed with ß-thalassemia major (Pesaro class II), was treated with Cy before and after HSCT with mobilized CD34+ cells. Both the relative and absolute granulocyte counts, as well as CD33+CD11b+ cell counts, increased significantly after HSCT until day 56. However, they suddenly began to decrease after day 56, accompanied by severe diarrhea, skin rash, and a decrease in bilirubin levels compared to day -12. Furthermore, compared to day -12, IL-22 levels increased until day 56, and then decreased, while IDO levels continued to rise after day 56. Our data suggest the potential use of IL-22 and IDO as biomarkers for GVHD assessment. It also indicates that Cy promotes HSCT reconstitution by increasing CD33+CD11b+ cells, which may play a crucial role in reducing GVHD risks. However, further studies are needed to elucidate the mechanism behind GVHD recurrence.

Clinical outcomes of patients receiving three versus four doses of methotrexate with concomitant antithymocyte globulin in match unrelated donor allogeneic stem cell transplant: A single-center experience.

Methotrexate (MTX) doses on days +1, +3, +6, and +11 after match unrelated donor allogeneic stem cell transplant (MUD HSCT) is a common graft-versus-host disease (GVHD) prophylaxis regimen. However, the overlapping toxicity of MTX with conditioning chemotherapy sometimes warrants the omission of the fourth dose of MTX. Prior single-institution studies showed conflicting results comparing the outcomes of patients who received three versus four doses of MTX, but to our knowledge, the effect of concomitant antithymocyte globulin (ATG) has not been reported. Charts of patients who underwent MUD HSCT between 2009 and 2023 were reviewed. Patients received rabbit ATG (Thymoglobulin), given at 0.5 mg/kg on day -3, 2 mg/kg on day -2, and 2.5 mg/kg on day -1. MTX is given at 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11. Severe mucositis was the most common indication for day +11 MTX omission (82%). We identified 292 patients (116 in 3 dose cohort and 176 in 4 dose cohort). Median follow-up was 23 months (range 1-151). Patients in the 4 doses cohort were more frequently male (68% vs. 50%, p < 0.01), received a reduced intensity conditioning regimen (38.0% vs. 22%, p < 0.01), were older (median 58 vs. 54 years, p = 0.02), and received a transplant in the earlier era (median HSCT year 2014 vs. 2018, p < 0.01). A statistically significant difference was not evidenced between the cohorts for the following outcomes: acute GVHD (aGVHD) (HR 1.1, 95% CI 0.9-1.5), chronic GVHD (cGVHD) (HR 1.3, 95% CI 0.8-1.6), relapse-free survival (RFS) (HR 1.0, 95% CI 0.6-1.5), non-relapse mortality (NRM) (HR 1.4, 95% CI 0.9-2.2), and overall survival (OS) (HR 1.2, 95% CI 0.9-1.7). Both cohorts had similar median time to neutrophil engraftment at 14 days. When ATG is incorporated, omission of day +11 MTX does not significantly impact the rate of engraftment or cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS.

The impact of MICB mismatches in unrelated haematopoietic stem cell transplantation.

MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I-related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon-based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA-genes, sub-stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA-matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA-B mismatches have to be accepted.

Abstracts of the Cell Therapy Transplant Canada 2023 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May-2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as "Award Recipient" within the relevant category. We congratulate all the presenters on their research and contributions to the field.

[Current state of graft-versus-host disease prophylaxis with PTCy for allogeneic hematopoietic stem cell transplantation].

There is growing recognition of post-transplant cyclophosphamide (PTCy) as the new standard prophylaxis for graft-versus-host disease (GVHD) in HLA-matched peripheral blood stem cell transplants with reduced intensity conditioning, based on recent results of randomized phase III trials of PTCy. Allogeneic hematopoietic cell transplantation (HCT) with PTCy is thought to have GVHD-dependent and -independent graft-versus-tumor (GVT) effects. Its GVHD-dependent effects may be attenuated by PTCy-induced alloreactive T cell dysfunction and preferential recovery of regulatory T cells after HCT, but its GVT effects do not appear to be significantly impaired in patients in remission or with indolent disease. As patients not in remission are often also candidates for transplantation in Japan, it will be necessary to use PTCy as a platform to establish a strategy that could also be effective in patients not in remission and to revise the donor selection algorithm.

Haploidentical HSCT in the Treatment of Pediatric Hematological Disorders.

Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent hematopoietic stem cell transplantation (HSCT) in the absence of an HLA-matched donor. Haploidentical HSCT (haplo-HSCT) can be an effective treatment for non-malignant pediatric disorders, such as primary immunodeficiencies or hemoglobinopathies, by enabling a much quicker selection of the appropriate donor for virtually all patients, low incidence of graft-versus-host disease (GVHD), and transplant-related mortality (TRM). Moreover, the outcomes of haplo-HSCT among children with hematological malignancies have improved radically. The most demanding tasks for clinicians are minimizing T-cell-mediated alloreactivity as well as early GVHD prevention. As a result, several T-cell depletion approaches, such as ex vivo T-cell depletion (TCD), and T-cell replete approaches, such as a combination of anti-thymocyte globulin (ATG), post-transplantation cyclophosphamide (PTCy), cyclosporine/tacrolimus, mycophenolate mofetil, or methotrexate, have been taken up. As more research is needed to establish the most beneficial form of therapy, haplo-HSCT is currently considered an alternative donor strategy for pediatric and adult patients with complications like viral and bacterial infections, invasive fungal disease, and GVHD.

Encephalitozoon hellem infection after haploidentical allogeneic hematopoietic stem cell transplantation in children: a case report.

Background: Encephalitozoon hellem (E. hellem) infection is a zoonotic disease, rarely observed in individuals, causing various clinical manifestations including diarrhea, keratoconjunctivitis, cystitis, etc. E. hellem infection after hematopoietic stem-cell transplantation (HSCT) is a rare, serious complication. Case presentation: Herein, we present a case of E. hellem infection developing during HLA-haploidentical HSCT in a 9-year-old boy who suffered from aplastic anemia. On 15 days after HSCT, the patient developed recurrent and prolonged fever, diarrhea and hematuria. It is challenging to differentiate whether the symptoms mentioned in this case are caused by graft-versus-host disease (GVHD) or a specific infection. Based on the result of metagenomic next-generation sequencing (mNGS) and clinical observation, the patient was diagnosed as E. hellem infection, and received albendazole and decreased the immunosuppressive treatment. Finally, he had recovered. Conclusion: We should pay attention to the uncommon disease caused by the E. hellem infection after HSCT, especially in cases with immune reconstitution unrecovered. Among those rare infection, mNGS can be performed for better understanding the source of infection and targeted therapy, which can benefit the patients.

Impact of chronic graft-versus-host disease on non-relapse mortality and survival.

Chronic graft-versus-host-disease (cGVHD) is one of the primary causes of morbidity and mortality for patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HCT). In recent years, advancements in allo-HCT have allowed a broader range of patients to receive transplant, particularly older patients. We sought to assess the impact of cGVHD on outcomes in patients undergoing allo-HCT, for older patients as compared to their counterparts. We performed a retrospective analysis of all patients who underwent allo-HCT 1999-2018. Our results showed that those patients who developed cGVHD by D + 180 had an increased risk and incidence of NRM as compared to those patients without cGVHD. There was no significant difference in outcomes for those patients with cGVHD by age (≥60 years old [yo] and <60 yo). These findings suggest the significant morbidity of cGVHD, regardless of age.

Impact of Graft-Versus-Host Disease on Relapse and Nonrelapse Mortality Following Posttransplant Cyclophosphamide-Based Transplantation.

Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.

Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

CS12192: A novel selective and potent JAK3 inhibitor mitigates acute graft-versus-host disease in bone marrow transplantation.

BACKGROUND: Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases. METHODS: We evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model. RESULTS: CS12192, starting at a concentration of 0.5 µM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05). CONCLUSIONS: CS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.

Optimizing Outcomes in Mismatched Unrelated Donor Allogeneic Transplantation: Post-Transplant Cyclophosphamide's Dual Impact on Graft versus Host Disease Incidence and Overall Survival: Retrospective Analysis on Behalf of Polish Adult Leukemia Group.

Allogeneic hematopoietic cell transplantation (allo-HSCT) stands as an effective treatment method for various hematologic malignancies. However, graft-versus-host disease (GvHD), an intricate immunological phenomenon where donor immune cells target recipient tissues, remains a significant challenge, particularly in mismatched unrelated donors (MMUD). Post-transplant cyclophosphamide (PTCy) has emerged as a promising immunosuppressive strategy, revolutionizing haploidentical transplantation and demonstrating promise in MMUD settings. Background/Objectives: This study aimed to evaluate the impact of PTCy on MMUD allo-HSCT outcomes, specifically its effects on GvHD incidence and overall survival, compared to anthitymocyte globulin (ATG). Methods: One hundred seventy-four patients were classified into three groups based on the type of transplantation: PTCy-haplo (114/174; 65.5%), PTCy-MMUD (23/174; 13.2%), and ATG-MMUD (37/174; 21.2%). Results: Our findings showed that PTCy-MMUD significantly reduced acute GvHD occurrence compared to PTCy-haplo and ATG-MMUD approaches (p = 0.006). The delayed onset of acute GvHD in the PTCy-MMUD group suggests a more controlled immune reconstitution, contributing to the lower incidence. Importantly, PTCy-MMUD exhibited enhanced five-year overall survival rates, aligning with the notion that reduced GvHD correlates with improved patient outcomes (p = 0.032). Conclusions: We believe that this study contributes valuable insights into PTCy-MMUD's management, underscoring its potential to significantly reduce GvHD incidence and enhance survival outcomes. Although further investigations and clinical trials are warranted, this research underscores the promising role of PTCy-based GvHD prophylaxis in improving MMUD allo-HCT success.

Immunomodulation of salivary gland function due to cancer therapy.

Functional salivary glands (SG) are essential for maintaining oral health, and salivary dysfunction is a persistent major clinical challenge. Several cancer therapies also have off-target effects leading to SG dysfunction. Recent advances highlight the role of SG immune populations in homeostasis, dysfunction and gland regeneration. Here, we review what is known about SG immune populations during development and postnatal homeostasis. We summarize recent findings of immune cell involvement in SG dysfunction following cancer treatments such as irradiation (IR) for head and neck cancers, immune transplant leading to graft-versus-host-disease (GVHD) and immune checkpoint inhibitor (ICI) treatment. The role of immune cells in SG in both homeostasis and disease, is an emerging field of research that may provide important clues to organ dysfunction and lead to novel therapeutic targets.

Factors influencing overall survival and GvHD development after allogeneic hematopoietic stem cell transplantation - single centre experience.

BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a substantial therapeutic procedure for the treatment of a wide spectrum of severe diseases. Despite advancements in treatment and supportive care, alloHSCT still carries a considerable mortality risk, primarily caused by graft-versus-host disease (GvHD). Our retrospective analysis aimed to identify the factors influencing overall survival and GvHD development in HLA-identical sibling alloHSCT. We have analyzed patients' and donors' age, AB0 compatibility, recipient-donor gender match, stem cell source, time from the diagnosis to alloHSCT, conditioning regimen type, GvHD prophylaxis, and relapse. PATIENTS AND METHODS: Our study included 96 patients (54 male, 42 female) who underwent HLA-identical sibling alloHSCT. The median follow-up was 64.5 months (range 1-218 months), and the median age of both recipients and donors was 34 years. Malignant hematological diseases were the most common indications for alloHSCT. RESULTS: GvHD and its complications accounted for the highest number of deaths (N = 24; 46.2%), followed by relapse (N = 18; 34.6%). Acute GvHD developed in 30 patients (31.3%), while chronic GvHD occurred in 25 patients (26.0%), resulting in a total of 45 patients (46.9%) experiencing GvHD. Male recipients with female donors had significantly worse overall survival compared to other patients (P = 0.01; HR = 2.33). Overall survival was better in patients transplanted within 1 year from the diagnosis compared to those transplanted after 1 year (P = 0.03; HR = 1.93). No factor reached statistical significance regarding the impact on acute GvHD, chronic GvHD, or overall GvHD. CONCLUSION: We confirmed that sex mismatch, specifically in the case of a female donor and a male recipient, significantly negatively affects overall survival after alloHSCT. Additionally, overall survival is significantly shorter when the interval between the diagnosis and alloHSCT exceeds one year.