Graft-versus-host Research Articles

Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development.

Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.

CD155 blockade enhances allogeneic natural killer cell-mediated antitumor response against osteosarcoma.

Allogeneic bone marrow transplant (alloBMT) is curative for hematologic malignancies through the graft-versus-tumor (GVT) effect but has been ineffective for solid tumors like osteosarcoma (OS). OS expresses CD155 which interacts strongly with inhibitory receptors TIGIT and CD96 but also binds to activating receptor DNAM-1 on natural killer (NK) cells. CD155 has never been targeted after alloBMT. Combining adoptively transferred allogeneic NK (alloNK) cells with CD155 blockade after alloBMT may enhance a GVT effect against OS. Murine NK cells were activated and expanded ex vivo with soluble IL-15/IL-15Rα. AlloNK and syngeneic NK (synNK) cell phenotype, cytotoxicity, cytokine production, and degranulation against CD155-expressing murine OS cell line K7M2 were assessed in vitro. Mice bearing pulmonary OS metastases underwent alloBMT and alloNK cell infusion with anti-CD155 either before or after tumor induction, with select groups receiving anti-DNAM-1 pretreated alloNK cells. Tumor growth, GVHD and survival were monitored, and differential gene expression of lung tissue was assessed by RNA microarray. AlloNK cells exhibited superior cytotoxicity against CD155-expressing OS compared to synNK cells, and this activity was enhanced by CD155 blockade. CD155 blockade increased alloNK cell degranulation and interferon gamma production through DNAM-1. In vivo, CD155 blockade with alloNK infusion increased survival when treating OS that relapsed after alloBMT. No benefit was seen for treating established OS before alloBMT. Treatment with combination CD155 and anti-DNAM-1 pretreated alloNK ameliorated survival and tumor control benefits seen with CD155 blockade alone. RNA microarray showed mice treated with alloNK and CD155 blockade had increased expression of cytotoxicity genes and the NKG2D ligand H60a, whereas mice treated with anti-DNAM-1 pretreated alloNK cells resulted in upregulation of NK cell inhibitory receptor genes. Whereas blocking DNAM-1 on alloNK abrogated cytotoxicity, blocking NKG2D had no effect, implying DNAM-1:CD155 engagement drives alloNK activation against OS. These results demonstrate the safety and efficacy of infusing alloNK cells with CD155 blockade to mount a GVT effect against OS and show benefits are in part through DNAM-1. Defining the hierarchy of receptors that govern alloNK responses is critical to translating alloNK cell infusions and immune checkpoint inhibition for solid tumors treated with alloBMT. Allogeneic bone marrow transplant (alloBMT) has yet to show efficacy in treating solid tumors, such as osteosarcoma (OS). CD155 is expressed on OS and interacts with natural killer (NK) cell receptors, such as activating receptor DNAM-1 and inhibitory receptors TIGIT and CD96 and has a dominant inhibitory effect on NK cell activity. Targeting CD155 interactions on allogeneic NK cells could enhance anti-OS responses, but this has not been tested after alloBMT. CD155 blockade enhances allogeneic natural killer cell-mediated cytotoxicity against OS and improved event-free survival after alloBMT in an in vivo mouse model of metastatic pulmonary OS. Addition of DNAM-1 blockade abrogated CD155 blockade-enhanced allogeneic NK cell antitumor responses. These results demonstrate efficacy of allogeneic NK cells combined with CD155 blockade to mount an antitumor response against CD155-expressing OS. Translation of combination adoptive NK cell and CD155 axis modulation offers a platform for alloBMT treatment approaches for pediatric patients with relapsed and refractory solid tumors.

Comparable relapse incidence after unrelated allogeneic stem cell transplantation with post-transplant cyclophosphamide versus conventional anti-graft versus host disease prophylaxis in patients with acute myeloid leukemia: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

We compared relapse incidence (RI) post-unrelated transplantation with post-transplant cyclophosphamide (PTCy) versus no PTCy graft-versus-host disease (GVHD) prophylaxis, in 7049 acute myeloid leukemia (AML) patients in remission, 707 with PTCy, and 6342 without (No PTCy). The patients in the PTCy group were younger, 52.7 versus 56.6 years (p < .001). There were more 9/10 donors in the PTCy group, 33.8% versus 16.4% (p < .001), and more received myeloablative conditioning, 61.7% versus 50.2% (p < .001). In the No PTCy group, 87.7% of patients received in vivo T-cell depletion. Neutrophil and platelet engraftment were lower in the PTCy versus No PTCy group, 93.8% and 80.9% versus 97.6% and 92.6% (p < .001). RI was not significantly different in the PTCy versus the No PTCy group, hazard ratio (HR) of 1.11 (95% confidence interval [CI] 0.9-1.37) (p = .31). Acute GVHD grades II-IV and III-IV, were significantly lower in the PTCy versus the No PTCy group, HR of 0.74 (95% CI 0.59-0.92, p = .007) and HR = 0.56 (95% CI 0.38-0.83, p = .004), as were total and extensive chronic GVHD, HRs of 0.5 (95% CI 0.41-0.62, p < .001) and HR = 0.31 (95% CI 0.22-0.42, p < .001). Non-relapse mortality (NRM) was significantly lower with PTCy versus the No PTCy group, HR of 0.67 (95% CI 0.5-0.91, p = .007). GVHD-free, relapse-free survival (GRFS) was higher in the PTCy versus the No PTCy group, HR of 0.69 (95% CI 0.59-0.81, p = .001). Leukemia-free survival (LFS) and overall survival (OS) did not differ between the groups. In summary, we observed comparable RI, OS, and LFS, significantly lower incidences of GVHD and NRM, and significantly higher GRFS in AML patients undergoing unrelated donor-hematopoietic stem cell transplantation with PTCy versus No PTCy GVHD prophylaxis.

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.

Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice

BackgroundTransplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+ and FL-CD34+CD14−) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice.MethodsNOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14− to generate CB-NOG, FL-NOG and FL-CD14−-NOG, respectively. After 15–20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood and several organs. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs. FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles.ResultsWe show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-NOG mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection.ConclusionOur results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.

Verruciformes Xanthom an der linken Wange bei einer 56-jährigen Patientin – Diagnostik, Therapie und Nachsorge

The oral verruciform xanthoma (OVX) is a rare, benign lesion that occurs predominantly in the masticatory region of the oral cavity. The OVX is small, slow growing, and mostly free of clinical symptoms. The exact pathogenesis is unknown, and a viral etiology such as from a human papillomavirus (HPV) infection has not been proven. Although primarily observed in healthy individuals, there have been cases in patients with autoimmune diseases and with chronic graft-versus-host disease (GvHD). The treatment of choice is complete excision of the lesion. This case report showcases a successful surgical removal of an oral verruciform xanthoma on the left buccal mucosa in a 56-year-old patient with GvHD 14 years after allo-genic stem cell transplantation due to a Non-Hodgkin lymphoma.

Graft-versus-tumor effect of post-transplant cyclophosphamide-based allogeneic hematopoietic cell transplantation.

Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graft-versus-tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification.

Adenovirus- and cytomegalovirus-specific adoptive T-cell therapy in the context of hematologic cell transplant or HIV infection - A single-center experience.

Reactivation of viral infections, in particular cytomegalovirus (CMV) and adenovirus (ADV), cause morbidity and non-relapse-mortality in states of immune deficiency, especially after allogeneic hematopoietic cell transplantation (allo-HCT). Against the background of few available pharmacologic antiviral agents, limited by toxicities and resistance, adoptive transfer of virus-specific T-cells (VST) is a promising therapeutic approach. We conducted a single-center retrospective analysis of adult patients treated with ADV- or CMV-specific T-cells in 2012-2022. Information was retrieved by review of electronic health records. Primary outcome was a response to VST by decreasing viral load or clinical improvement. Secondary outcomes included overall survival and safety of VST infusion, in particular association with graft-versus-host disease (GVHD). Ten patients were included, of whom four were treated for ADV, five for CMV, and one for ADV-CMV-coinfection. Cells were derived from stem cell donors (6/10) or third-party donors (4/10). Response criteria were met by six of 10 patients (4/4 ADV, 2/5 CMV, and 0/1 ADV-CMV). Overall survival was 40%. No infusion related adverse events were documented. Aggravation of GVHD after adoptive immunotherapy was observed in two cases, however in temporal association with a conventional donor lymphocyte infusion and a stem cell boost, respectively. In this cohort, CMV- and ADV-specific T-cell therapy appear to be safe and effective. We describe the first reported case of virus-specific T-cell therapy for CMV reactivation not associated with transplantation but with advanced HIV infection. This encourages further evaluation of adoptive immunotherapy beyond the context of allo-HCT.

Early Tapering of Cyclosporine Is Feasible in Haploidentical Stem Cell Transplantation: A Single Center Experience.

Cyclosporine-A (CsA) and post transplantation cyclophosphamide (PTCy) are common agents used for graft versus host disease (GVHD) prophylaxis in Haploidentical hematopoietic cell transplantation (haplo-HCT). However, the impact of CsA cessation timing in the posttransplant setting on clinical outcomes is uncertain. We aimed to investigate the impact of a novel approach that integrated early CsA cessation with PTCy utilization. This study was a single arm retrospective study carried out at a tertiary referral hospital hematology and bone marrow transplantation center between 2009 and 2022. The patients who received haplo-HCT with ATG, PTCy and CsA as GVHD prophylaxis were included. CsA was planned for cessation starting at day 45 to day 60. Acute and chronic GVHD were evaluated and graded. CsA blood concentrations and its impact on acute and chronic GVHD was evaluated. Thirty-one patients composed of 19 (61.3%) male and 12 (38.7%) female patients with a median age of 31 years (20-58). Busulfan and TBI based conditioning regimens were the most utilized regimens. The majority of donors were first degree relatives. Stem cell origin was peripheral blood for all patients. GVHD prophylaxis consisted of ATG, CsA and PTCy. Acute GVHD was observed in 9 (29%) cases, whereas chronic GVHD was seen in 3 (9.7%) cases, with 2 of them having overlapping GVHD. Age, gender, number of chemotherapy lines, transplant characteristics, infused CD34 cell count, and engraftment durations were similar among patients with and without GVHD. Patients with GVHD had similar 1st, 2nd, 3rd and 4th week CsA concentrations compared to patients without GVHD (p>0.05). The presence of GVHD was not associated with worse progression free survival and overall survival (p=0.6, p=0.5, respectively). CMV reactivation was more common in the GVHD group. In the current study, we did not find an impact of CsA concentration on GVHD and post-transplant outcomes in Haplo-HCT setting. Therefore, together with the use of PTCy, early CsA cessation can be an option; further studies are needed to understand all aspects of this approach.

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.

The metabolic profiles of patients with autologous hematopoietic stem cell transplantation with graft versus host disease.

e24010 Background: Graft versus host disease (GvHD) is a serious inflammatory complication of hematopoietic stem cell transplant (HSCT) and a leading contributor to morbidity and mortality in HSCT patients. Previous studies have identified increased risk of cardiovascular death in HSCT patients who develop GvHD and characterized echocardiographic changes associated with chronic GvHD. However, details of the metabolic derangements in HSCT patients who develop GvHD remain poorly studied. Methods: This is a retrospective study of patients who underwent HSCT at H. Lee Moffitt Cancer Center and later developed severe chronic GVHD at 1 year. Metabolic data including weight, blood pressure, and lipid profile were recorded at baseline and at 1 year after HSCT. Results: Between January 1, 2010, and December 31, 2020, 1805 patients who received allogeneic HSCT were reviewed. At 1 year, 371 patients (20.5%) had severe GVHD. Compared to baseline, patients had higher total cholesterol (209 vs 183 mg/dL, P &lt; 0.001), high-density lipoprotein (61 vs 47 mg/dL, P &lt; 0.001), and triglycerides (211 vs 163 mg/dL, P &lt; 0.001) at 1 year of follow up. Low-density lipoprotein values were not significantly different (107 vs 102 mg/dL, p = 0.15). Patient weight was significantly less at 1 year (163 vs 183 lbs, p &lt; 0.001). Although blood pressure was not significantly different between baseline and 1 year, more patients were placed on antihypertensive medications at 1 year (50% vs 31%). Conclusions: This study finds that patients who undergo allogeneic HSCT and subsequently develop severe GVHD are at risk for metabolic derangements that may worsen cardiovascular health. We specifically demonstrate an increased need for antihypertensive therapy and elevations in total cholesterol and serum triglycerides. Further research is needed on the impact of these derangements on major adverse cardiac events and the role of cardiovascular risk factor management in these patients.

Safety and efficacy of low dose versus high dose corticosteroid for graft versus host disease (GVHD): A systematic review.

e24047 Background: Graft-versus-host disease (GVHD) is an immune-mediated complication of allogeneic hematopoietic stem cell transplantations. Current standard dose of corticosteroids used by the most hospitals for GVHD patients is 1-2 mg/kg/day. The prednisone dose used in the treatment of a GVHD has been a matter of debate. In this systematic review, we aimed to compare low dose prednisone to high/standard dose prednisone in terms of multiple prognostic outcomes of the patients undergoing allogenic hematopoietic stem-cell transplantations. Methods: We searched the databases PubMed, Cochrane library, and clinicaltrials.gov for all studies investigating the efficacy and safety of low dose and high dose steroid for GVHD. We set the search strategy incorporating the search terms, Graft-versus-host disease," "low dose cortico-steroid," and "high dose corticosteroid", and operated using the Boolean operators ‘AND’, and ‘OR’. Thus, retrieved articles were then exported on an Excel sheet, and duplicates were removed. After selecting the study based on inclusion criteria, data on study characteristics and biomarker description was extracted on a pre-determined data extraction table on the Microsoft Excel. Results: The search revealed 547 studies and 3 studies that met the eligibility criteria of this review have been included.During relapse, chronic GVHD, mortality, and malignancy outcomes were generally similar between doses, low-dose prednisone showed benefits for leukemia-free, relapse-free, and overall survival. Overall, the randomized trial by Chang et al. found lower risks of HZV and pulmonary infections with low-dose prednisone compared to standard-dose. (Table 1) Other infections were similar between groups. Conclusions: Low-dose prednisone showed similar efficacy to standard-dose for most GVHD outcomes (relapse risk, mortality), with potential benefits on survival, reduced HZV/pulmonary infections, and reduced adverse effect of higher cumulative dose of corticosteroids. [Table: see text]

Outcomes of older adults undergoing allogeneic stem cell transplant with post-transplant cyclophosphamide.

6559 Background: The two most common disease indications for stem cell transplants (SCTs) are AML and MDS, with average age of diagnoses of 71 and 68, respectively. However, SCTs historically were not offered to older adults because of the associated risks, such as graft-vs-host disease (GVHD). The use of post-transplant cyclophosphamide as an immunosuppressant has been shown to help prevent GVHD. We aimed to compare the effectiveness of GVHD prophylaxis regimens with (post-Cy) and without (non-Cy) cyclophosphamide and to identify characteristics that make patients more likely to be long-term survivors. To our knowledge, studies focusing specifically on patients aged 70+ remain very limited. Methods: This was a retrospective, single-institution study assessing all patients aged 70+ who received an allogeneic SCT between 2009-2023. Our main outcome was GVHD-free, relapse-free survival (GRFS) at endpoints of 1 and 5 years. We also assessed risks of developing clinically significant acute (grade III-IV) and chronic (extensive) GVHD, relapse rate, overall survival (OS), and non-relapse mortality (NRM) at one and five-year endpoints. Results: We evaluated 61 patients aged 70+ (median 75, IQR 5), 23 of whom were female (38%). 42 patients received GVHD prophylaxis with post-Cy and 19 patients received non-Cy regimens (18 ATG-based). Myeloid malignancies were the primary indication for transplant (85%). We stratified patients based on Disease Risk Index, with 64% of patients as intermediate risk and 33% high risk. Unrelated donors contributed 80% of allografts, and 100% of non-Cy patients had a 10/10 HLA-matched donor compared to post-Cy patients having 64% 10/10, 29% haploidentical, and 7% mismatched unrelated donors. Acute GVHD developed in 19% of post-Cy patients, compared to 26% in non-Cy ( p = ns). At one year, the probability of having chronic GVHD was 12% vs 26% in post-Cy vs non-Cy patients ( p = ns). Post-Cy patients had a one-year relapse rate, NRM, and OS of 2%, 52%, and 45%, respectively, whereas non-Cy patients had 5%, 26%, and 68% ( p = ns). Notably, patients treated with both regimens had a similar one-year GRFS (33% post-Cy, 37% non-Cy; p = ns). At five years, OS was 19% vs 32% and GRFS was 14% vs 16% for post-Cy and non-Cy patients, respectively ( p = ns). Conclusions: We observed similar outcomes among patients aged 70+ receiving GVHD prophylaxis with post-Cy compared to non-Cy regimens. Importantly, non-Cy patients had HLA-matched donors, whereas mismatched donors were possible for the post-Cy group. In this way, post-Cy seems to have equalized the outcomes for fully matched and non-matched SCTs by yielding a similar one and five-year GRFS. Patients without a full match would otherwise have a poor outcome. We also found no significant difference in relapse rate, NRM, OS, and five-year GRFS between patients aged 70-74 and ages 75+, showing that numerical age should not be a contraindication to SCT with post-Cy.

Clinical Observation on Haploid Hematopoietic Stem Cells Combined with Umbilical Cord Blood Double Transplantation for Aplastic Anaemia in Children

To explore the efficacy and safety of haploidentical hematopoietic stem cell transplantation combined with umbilical cord blood infusion for the treatment of aplastic anaemia in children. Nine cases of children with aplastic anaemia treated with umbilical cord blood combined with haploidentical hematopoietic stem cell transplantation at the People's Hospital of Henan University of Chinese Medicine from January 1, 2021 to September 15, 2023 with a median age of 11(2-13) years and a median follow up of 18(7.5-21) months were included, and the clinical data were retrospectively analyzed. Hematopoiesis reconstitution, the incidence of graft-versus-host disease(GVHD), infections and survival of the patients were analyzed. All 9 children were successfully implanted. The median time to neutrophil and platelet implantation was 11.11±1.27 d and 12.44±3.36 d, respectively. One case developed acute gastrointestinal GVHD of degree I, which was improved after treatment, and the patient developed superficial gastritis and chronic gastrointestinal GVHD at a later stage, which is currently under clinical follow-up. Acute GVHD of II-IV degree was 0%. Hemorrhagic cystitis in 3 cases, CMV infection in 5 cases and bacterial and fungal infections in 5 cases improved with symptomatic treatment.All 9 children demonstrated complete donor chimerism within 1 month after transplantation, at two years of follow-up, all nine children survived without recurrence or development of grade II-IV GVHD, and there were no children with transplant-related deaths. Haploidentical hematopoietic stem cell transplantation combined with umbilical cord blood transfusion for aplastic anaemia in children has a low incidence and mild degree of GVHD, with significant efficacy, and can be used as a therapeutic option for children without an HLA full donor chimeric match.

Clinical and Economic Impact of CMV Infection in Allogeneic Hematopoietic Stem Cell Transplantation: Perspectives from a Middle-Income Nation.

Cytomegalovirus infection (CMV) is a common complication after allogeneic hematopoietic stem cell transplantation (AHSCT). CMV infection increases transplantation costs; however, the extent of the financial burden may vary in different countries. This study aims to determine the clinical and economic impact of CMV infection in patients undergoing AHSCT in a middle-income country. A total of 150 adult and pediatric patients post-AHSCT were included for analysis. In addition to incidence of CMV infections, data on graft versus host disease (GVHD) were also collected. Standard hospital charges for AHSCT and any additional transplantation-related expenditure within 12 months were also retrieved in 104 patients. CMV infection, acute GVHD and chronic GVHD occurred in 38.7%, 60.7%, and 22.0% of patients, respectively. Patients with CMV infections had higher readmission rates compared to those who did not (67.2%vs. 47.8%; p=0.020). Additional expenditure was seen in HLA-haploidentical AHSCT and CMV infection (MYR11 712.25/USD2 504.49; p<0.0001 and MYR5 807.24/USD1 241.79; p=0.036), respectively. This single-center study demonstrated that patients who underwent HLA-haploidentical AHSCT and subsequently developed CMV infection had higher transplantation expenditures compared to those who had matched-related transplantation. Further studies should be conducted to evaluate if primary prophylaxis against CMV is cost-effective, especially in patients who undergo HLA-haploidentical AHSCT.

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

BackgroundDespite 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. MethodsWe 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. ResultsCS12192, 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). ConclusionsCS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.

Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis following mismatched unrelated donor peripheral blood stem cell (PBSC) transplantation.

6503 Background: Our prior prospective multi-center clinical trial (15-MMUD; NCT02793544) estimated 79% overall survival (OS) at one year in adult patients with hematological malignancies undergoing reduced intensity conditioning (RIC), receiving bone marrow (BM) grafts from HLA-mismatched unrelated donors (MMUD), and post-transplant cyclophosphamide (PTCy)-based graft- versus-host disease (GVHD) prophylaxis (Shaw et al, J Clin Oncol 2021). We sought to determine whether OS in adults receiving mobilized PBSC from MMUD would be comparable. Methods: We conducted a prospective, multi-center Phase II study (ACCESS; NCT04904588) to assess the impact of PTCy-based GVHD prophylaxis on OS following MMUD transplantation in adults and children with advanced hematological malignancies. The study included three strata: two for adults based on conditioning regimen intensity [myeloablative (MAC) or RIC] using PBSC, and one pediatric cohort using MAC and BM. Eligible donors were matched at 4-7/8 HLA-loci (HLA -A, -B, -C, and -DRB1) and &lt; 35 years. The primary endpoint was OS at one year following transplantation. We report the results of a planned interim analysis of the first 70 adult patients enrolled on the RIC PBSC stratum. Results: Thirteen sites enrolled 70 patients with the following demographics: median age of 65 years (range 24-77); 50% male; diagnoses: AML (53%), MDS (26%), ALL (7%), other heme malignancies (14%); and patient race/ethnicity: non-Hispanic white (48%). Donor characteristics included: median age 25y (range 18-35); male (44%); and HLA match level: 7/8: 67%; 6/8: 27%; 5/8: 6%. Conditioning regimens included fludarabine (flu) and melphalan (63%), flu/busulfan (20%), other (17%). OS at one year post HCT was 79% (95% confidence interval (CI): 68-87%). Secondary endpoints are provided in the table. Conclusions: Encouraging OS was observed at one year following MMUD PBSC in patients receiving RIC and PTCy. Notably, half of enrolled patients were people of color. OS was similar to our prior study using BM grafts. Rates of GVHD and other complications appear comparable to those in HLA-matched donor recipients, suggesting MMUD HCT could expand access to a potentially life-saving therapy. Accrual to both adult strata of ACCESS is complete, with over 200 patients in follow-up. Accrual to the pediatric stratum continues. Clinical trial information: NCT04904588 . [Table: see text]

Hematopoietic Stem-Cell Transplantation: Exploring the Latest Advances and Gaps in Disparities, Psychosocial and Symptom Management Interventions, and Chronic Graft-Versus-Host Disease Care.

Although allogeneic hematopoietic cell transplantation (HCT) offers a potential for cure for many patients with advanced hematologic malignancies and bone marrow failure or immunodeficiency syndromes, it is an intensive treatment and accompanied by short- and long-term physical and psychological symptoms requiring specialized care. With substantial advances in therapeutic approaches for HCT and supportive care, HCT survivors experience less morbidity and mortality. However, disparities in both HCT access and outcomes persist, and HCT survivors and their caregivers often lack access to much-needed psychosocial care. Additionally, more medical and psychosocial resources are needed to holistically care for HCT survivors with chronic graft-versus-host disease (GVHD). Hence, this chapter focuses on three areas pertaining to advances and gaps in HCT care: disparities in access to and outcomes of HCT, psychosocial and physical symptom management with supportive care interventions, and GVHD prevention and management.

The Application of PBM Therapy in Patients Subjected to Oral GVHD: A Review.

Background: Oral graft-versus-host disease (GVHD) is characterized by mucosal lesions, salivary gland dysfunction etc., accompanied by pain and oral dysfunction. The efficacy of photobiomodulation (PBM) in managing pain and inflammation has been demonstrated. PBM has been applied in oral GVHD and is regarded as a potent adjunctive therapy. Objective: To review the application of PBM for oral GVHD and summarize its biological mechanisms and recommended parameters. Materials and Methods: The article provides an overview of the therapeutic effects of PBM in oral GVHD cases. It analyzes the biological mechanisms from different aspects and explores the potential prospects of PBM, and appropriate parameters and frequency for GVHD are recommended. Conclusions: The efficacy of PBM in oral GVHD has been demonstrated through symptom alleviation and function improvement. It is recommended as an adjuvant therapy for oral GVHD. However, further research is required to explore optimal devices, parameters, and potential complications associated with using PBM in oral GVHD.

In-hospital outcomes of autologous stem cell transplantation in patients with multiple myeloma with versus without heart failure.

e19511 Background: Autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) is known to improve progression-free survival. However, the outcomes in patients with heart failure (HF) are uncertain. This study aims to compare hospital outcomes in patients with MM undergoing ASCT with and without HF. Methods: The National Inpatient Sample database was used to identify patients with MM undergoing ASCT during hospitalizations between 2016 and 2020. Under IRB exemption, data was extracted using ICD-10 codes. Data were stratified between patient with and without HF. A multivariate regression model was used to estimate the association of HF with ASCT in hospital outcomes, adjusting for statistically significant comorbidities. Results: A total of 30,375 hospitalizations with a diagnosis of MM undergoing ASCT were included, of which 1,535 had HF. On multivariant analysis compared to hospitalization without HF, those with HF had significantly higher risk of in-hospital mortality (adjusted odds ratio [aOR]: 2.20, 95% confidence interval [CI]: 1.49-3.24), graft-versus-host disease (GvHD) (aOR: 4.02, 95% [CI]: 2.48-6.52), transplant complications (aOR: 2.03, 95% [CI]: 1.62-2.56), sepsis (aOR: 2.279, 95% [CI]: 1.95- 2.65), septic shock (aOR: 3.49, 95% [CI]: 2.71-4.48), cardiogenic shock (aOR: 5.33, 95% [CI]: 2.61- 10.9), cardiac arrest (aOR: 3.78, 95% [CI]: 2.24- 6.35) and ventricular arrhythmia (aOR: 2.81, 95% [CI]: 2.08- 3.78). All p-values were &lt;0.001. Additionally, patients with HF had a longer average length of stay (20.48 vs 16.38 days, p&lt; 0.001) and a higher total cost of hospital stay ($245,831 vs $198,732, p&lt;0.001) compared to those without HF. Conclusions: Our findings demonstrated that patients with multiple myeloma undergoing autologous stem cell transplantation, while also having coexisting heart failure (HF), experienced worse outcomes compared to patients without HF. These patients had a higher risk of transplant complications, GvHD, sepsis, septic shock, cardiogenic shock, cardiac arrest, ventricular arrhythmias and mortality. Additionally, these patients experienced a longer hospital stay with higher healthcare costs. Further interventions and research are warranted to improve outcomes in this group of patients.