Recent updates on allogeneic CAR-T cells in hematological malignancies.

CAR-T cell therapy is known as an effective therapy in patients with hematological malignancies. Since 2017, several autologous CAR-T cell (auto-CAR-T) drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of some kinds of relapsed/refractory hematological malignancies. However, some patients fail to respond to these drugs due to high manufacturing time, batch-to-batch variation, poor quality and insufficient quantity of primary T cells, and their insufficient expansion and function. CAR-T cells prepared from allogeneic sources (allo-CAR-Ts) can be an alternative option to overcome these obstacles. Recently, several allo-CAR-Ts have entered into the early clinical trials. Despite their promising preclinical and clinical results, there are two main barriers, including graft-versus-host disease (GvHD) and allo-rejection that may decline the safety and efficacy of allo-CAR-Ts in the clinic. The successful development of these products depends on the starter cell source, the gene editing method, and the ability to escape immune rejection and prevent GvHD. Here, we summarize the gene editing technologies and the potential of various cell sources for developing allo-CAR-Ts and highlight their advantages for the treatment of hematological malignancies. We also describe preclinical and clinical data focusing on allo-CAR-T therapy in blood malignancies and discuss challenges and future perspectives of allo-CAR-Ts for therapeutic applications.

Interventional antibiotic treatment replacing antibiotic prophylaxis during allogeneic hematopoietic stem cell transplantation is safe and leads to a reduction of antibiotic administration.

Patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) face an elevated risk of infection-related mortality, particularly during the pre-engraftment period. Although systemic antibiotic prophylaxis (SAP) is commonly employed during neutropenia, it is linked to disruptions in the intestinal microbiome, increasing the risk of graft-versus-host disease (GVHD), Clostridium difficile infection (CDI), and colonization with multi-drug resistant (MDR) bacteria. In our retrospective analysis, we evaluated the safety and efficacy of an exclusively interventional antibiotic treatment (IAT) compared to SAP in adult alloHSCT patients. In comparison to SAP, IAT resulted in a significantly reduced duration of antibiotic therapy (24 vs. 18 days, p < 0.001), although the cumulative incidence (CI) of bloodstream infections (BSI) by day + 100 post-HSCT was significantly higher in the IAT group compared to SAP (40% vs. 13%, p < 0.001). However, this did not lead to a significant increase in ICU transfers (13% vs. 6%, p = ns) or a higher CI of non-relapse mortality (NRM) at 3 years (11% vs. 10%, p = ns). With a median follow-up of 1052 days, the 3-year overall survival (OS) rates were 69% and 66% for the SAP and IAT cohorts, respectively (p = ns). The CI of acute GVHD grade II-IV (30% vs. 39%) at 100 days or chronic GVHD of any grade (50% vs. 45%) at 3 years did not differ significantly between the SAP and IAT groups. There was a tendency towards a higher CI of severe chronic GVHD in the SAP cohort (28% vs. 13%, p = 0.08). Our single center experience in conducting alloHSCT without antibiotic prophylaxis but with stringent guidelines for prompt antibiotic intervention demonstrated no disadvantages in terms of OS and NRM. IAT led to significantly reduced consumption of cefotaxime, carbapenem, and glycopeptide antibiotics. In conclusion, our findings suggest that replacing SAP with the proposed IAT procedure is both safe and feasible.

Population pharmacokinetic modeling of vedolizumab for graft-versus-host disease prophylaxis in adults with allogeneic hematopoietic stem cell transplant.

We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.

Immune isolation-enabled nanoencapsulation of donor T cells: a promising strategy for mitigating GVHD and treating AML in preclinical models.

BACKGROUND: In allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking. METHODS: In our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways. RESULTS: Transplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells. CONCLUSIONS: Encapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppress GVHD while preserving the GVL effect.

Aspergillus calidoustus and Talaromyces columbinus infections in chronic graft-versus-host disease.

Advancements in allogeneic haematopoietic stem cell transplant (alloHSCT) procedures have improved patient outcomes over the last two decades, though invasive fungal infections (IFIs) remain a significant risk. The incidence of IFIs in alloHSCT recipients is estimated at 6%, with a mortality rate of 13%, and Aspergillus species are the most common pathogens involved. Posaconazole is effective in preventing IFIs post-transplant and is standard care during neutropenia or when managing graft-versus-host disease (GvHD) with high-dose steroids. However, azole prophylaxis may cause resistant Aspergillus species like A. calidoustus, which are difficult to treat. We report a case from our institution where a patient developed a dual infection with Aspergillus calidoustus and Talaromyces columbinus after alloHSCT and posaconazole prophylaxis. While A. calidoustus is known to cause IFIs in HSCT recipients, T. columbinus represents a previously unreported occurrence in medical literature. This case underscores the importance of a multifaceted diagnostic strategy, integrating BAL diagnosis, mycological cultures, direct microscopy, fungal speciation, susceptibility testing, and biomarkers. These comprehensive approaches are indispensable for accurate pathogen identification and effective management of IFIs with appropriate antifungal agents.

Differences in acute graft-versus-host disease (GVHD) severity and its outcomes between Black and White patients.

BACKGROUND: Acute graft-versus-host disease (GVHD) is a significant complication following hematopoietic stem cell transplantation (HCT). Although recent advancements in GVHD prophylaxis have resulted in successful HCT across HLA barriers and expanded access to HCT for racial minorities, less is known about how race affects the severity and outcomes of acute GVHD. OBJECTIVES: This study examines differences in the clinical course of acute GVHD and the prognostic value of GVHD biomarkers for Black and White recipients. STUDY DESIGN: We conducted a retrospective analysis of patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) database who underwent HCT between 2014 and 2021 to describe the difference in clinical course of acute GVHD and significance of GVHD biomarkers between Black and White recipients. We used propensity score matching to generate a 1:3 matched cohort of 234 Black patients and 702 White patients with similar baseline characteristics. RESULTS: In the first year after HCT Black patients experienced a higher cumulative incidence of grade III-IV acute GVHD (17% vs 12%, P = 0.050), higher non-relapse mortality (NRM; 18% vs 12%, P = 0.009), and lower overall survival that trended toward statistical significance (73% vs 79%, P = 0.071) compared to White patients. The difference in NRM in the first year was even greater among Black patients who developed GVHD than White patients (24% vs 14%, P = 0.041). The distribution of low, intermediate, and high MAGIC biomarker scores at the time of treatment was similar across racial groups (P = 0.847), however, Black patients with high biomarker scores experienced significantly worse NRM than White patients (71% vs 32%, P = 0.010). CONCLUSION: Our data indicate that Black patients are at a higher risk of NRM following HCT, primarily from a higher incidence of severe GVHD. Serum biomarkers at treatment initiation can stratify patients for risk of NRM across races, however Black patients with high biomarker scores had a significantly greater NRM risk. These results suggest a need for strategies that mitigate the higher risk for poor GVHD outcomes among Black patients.

Post-transplantation cyclophosphamide and cyclosporine A versus methotrexate and cyclosporine A for graft-versus-host disease prophylaxis after allogeneic peripheral stem cell transplantation in adult acute myeloid leukemia patients.

BACKGROUND: Different prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors. METHODS: The 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared. RESULTS: The cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, p = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, p = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (p < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, p = 0.470), overall survival (79.1% vs 77.3%, p = 0.986), non-relapse mortality (16.5% vs 16.8%, p = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, p = 0.478) did not differ statistically at 1-year. CONCLUSION: PT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.

Combination of reduced post-transplant cyclophosphamide and early tacrolimus initiation increases the incidence of chronic graft-versus-host disease in human leukocyte antigen-haploidentical peripheral blood stem-cell transplantation.

We evaluated the clinical impacts of the concurrent modification of post-transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)-initiation timing in 61 patients with human leukocyte antigen-haploidentical transplantation. Reduced-dose PTCy (80 mg/kg) was associated with a higher incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) than standard-dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early-initiation Tac (day -1) increased moderate-to-severe chronic GVHD than standard-initiation Tac (day 5) in the reduced-dose PTCy group (p = 0.032), whereas Tac-initiation timing did not impact chronic GVHD in the standard-dose PTCy group. These data indicate that the combination of reduced-dose PTCy and early-initiation Tac can amplify chronic GVHD.

Severity and organ distribution of graft-versus-host disease with post-transplant cyclophosphamide versus calcineurin inhibitor plus methotrexate/mycophenolate mofetil or sirolimus in allogenic HLA-matched or single-allele mismatched stem cell transplantation.

OBJECTIVE: This retrospective single center study aims to describe changes in the severity and organ-specific distribution of GvHD, by comparing the outcomes of 3 distinct GvHD prophylaxis approaches. METHODS: Between January 2012 and June 2022, 226 patients underwent allogeneic hematopoietic stem cell transplantation from HLA-matched or 1-allele mismatched related or unrelated donors. Fifty-eight (26%) received prophylaxis with calcineurin inhibitor in combination with mycophenolate mofetil or a short course of methotrexate (Cohort-1), 87 (38%) tacrolimus plus sirolimus (Cohort-2), and 81 (36%) post-transplant cyclophosphamide (PTCy) plus tacrolimus (Cohort-3). RESULTS: The incidence of grade II-IV aGvHD was 69% vs. 41.4% vs. 27.2%; p < .01. The most significant reduction with PTCy was observed in both stage 3-4 skin and lower gastrointestinal (GI) involvement (p < .01). The incidence of moderate-to-severe cGvHD at 12 months was 34.5% vs. 34.5% vs. 6.2%; p < .01. Moderate-to-severe skin and GI cGvHD was less common after PTCy (p < .01). The 1-year GvHD-free/relapse-free survival was higher with PTCy (p < .01). CONCLUSIONS: Our study indicates that PTCy-based GvHD prophylaxis reduces the frequency and severity of both acute and chronic GvHD, with a notable decrease in severe GI and cutaneous manifestations. The higher GRFS may result in lower GvHD-related mortality, leading to an improved quality of life among survivors.

Role of Endoscopic Techniques in the Diagnosis of Complications of Allogeneic Hematopoietic Stem Cell Transplantation: A Review of the Literature.

Allogeneic stem cell transplantation (Allo-SCT) implies that a donor and a recipient are not genetically identical. Allo-SCT is used to cure a variety of conditions, including hematologic malignancies using the graft versus tumor effect, nonmalignant hematologic, immune deficiencies, and, more recently, genetic disorders and inborn errors of metabolism. Given the immunosuppressive and myeloablative nature of some of the conditioning chemotherapy regimens used during the Allo-SCT, patients are often at high risk of infection, including viral infections affecting the gastrointestinal tract, following the transplant. Furthermore, other complications such as hepatic sinusoidal obstruction syndrome (SOS) or graft-versus-host disease may occur post-transplant and may require endoscopy to assist in the diagnosis. This review will provide newer insights into the importance of endoscopic techniques in the diagnosis of post-Allo-SCT complications with a focus on safety and timing.

The Impact of Histologic Portal T-Cell Density on the Clinical Outcomes in Hepatic Graft-versus-Host Disease and Autoimmune Liver Diseases.

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8-12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3+ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20+, CD38+, or CD68+ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.

Lower incidence of grade II-IV acute Graft-versus-Host-Disease in pediatric patients recovering with high Vδ2+ T cells after allogeneic stem cell transplantation with unmanipulated bone marrow grafts: a prospective single-center cohort study.

Gamma delta (γδ) T cells represent a minor fraction of human T cell repertoire but play an important role in mediating anti-infectious and anti-tumorous effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a prospective study to analyze the effect of different transplant modalities on immune reconstitution of γδ T cells and subsets. CD3, CD4 and CD8 T cells were analyzed in parallel. Secondly, we examined the impact of γδ T cell reconstitution on clinical outcomes including acute Graft-versus-Host-Disease (aGvHD) and viral infections. Our cohort includes 49 pediatric patients who received unmanipulated bone marrow grafts from matched unrelated (MUD) or matched related (MRD) donors. The cohort includes patients with malignant as well as non-malignant diseases. Cell counts were measured using flow cytometry at 15, 30, 60, 100, 180 and 240 days after transplantation. Cells were stained for CD3, CD4, CD8, CD45, TCRαß, TCRγδ, TCRVδ1, TCRVδ2, HLA-DR and combinations. Patients with a MRD showed significantly higher Vδ2+ T cells than those with MUD at timepoints +30, +60, +100 (p<0.001, respectively) and +180 (p<0.01) in univariate analysis. These results remained significant in multivariate analysis. Patients recovering with a high relative abundance of total γδ T cells and Vδ2+ T cells had a significantly lower cumulative incidence of grade II-IV aGvHD after transplantation (p=0.03 and p=0.04, respectively). A high relative abundance of Vδ2+ T cells was also associated with a lower incidence of EBV infection (p=0.02). Patients with EBV infection on the other hand showed higher absolute Vδ1+ T cell counts at days +100 and +180 after transplantation (p=0.046 and 0.038, respectively) than those without EBV infection. This result remained significant in a multivariate time-averaged analysis (q<0.1). Our results suggest a protective role of γδ T cells and especially Vδ2+ T cell subset against the development of aGvHD and EBV infection after pediatric HSCT. Vδ1+ T cells might be involved in the immune response after EBV infection. Our results encourage further research on γδ T cells as prognostic markers after HSCT and as possible targets of adoptive T cell transfer strategies.

Potential alternatives to αß-T cells to prevent graft-versus-host disease (GvHD) in allogeneic chimeric antigen receptor (CAR)-based cancer immunotherapy: A comprehensive review.

Currently, CAR-T cell therapy relies on an individualized manufacturing process in which patient's own T cells are infused back into patients after being engineered and expanded ex vivo. Despite the astonishing outcomes of autologous CAR-T cell therapy, this approach is endowed with several limitations and drawbacks, such as high cost and time-consuming manufacturing process. Switching the armature of CAR-T cell therapy from autologous settings to allogeneic can overcome several bottlenecks of the current approach. Nevertheless, the use of allogeneic CAR-T cells is limited by the risk of life-threatening GvHD. Thus, in recent years, developing a method to move CAR-T cell therapy to allogeneic settings without the risk of GvHD has become a hot research topic in this field. Since the alloreactivity of αß T-cell receptor (TCR) accounts for developing GvHD, several efforts have been made to disrupt endogenous TCR of allogeneic CAR-T cells using gene editing tools to prevent GvHD. Nonetheless, the off-target activity of gene editing tools and their associated genotoxicities, as well as the negative consequences of endogenous TCR disruption, are the main concerns of using this approach. As an alternative, CAR αß-T cells can be replaced with other types of CAR-engineered cells that are capable of recognizing and killing malignant cells through CAR while avoiding the induction of GvHD. These alternatives include T cell subsets with restricted TCR repertoire (γδ-T, iNKT, virus-specific T, double negative T cells, and MAIT cells), killer cells (NK and CIK cells), non-lymphocytic cells (neutrophils and macrophages), stem/progenitor cells, and cell-free extracellular vesicles. In this review, we discuss how these alternatives can move CAR-based immunotherapy to allogeneic settings to overcome the bottlenecks of autologous manner without the risk of GvHD. We comprehensively discuss the pros and cons of these alternatives over the traditional CAR αß-T cells in light of their preclinical studies and clinical trials.

Better clinical outcomes and lower triggering of inflammatory cytokines for allogeneic hematopoietic cell transplant recipients treated in home care versus hospital isolation - the Karolinska experience.

After allogeneic hematopoietic cell transplantation (Allo-HCT) and conditioning, patients are typically placed in isolated hospital rooms to prevent neutropenic infections. Since 1998, we've offered an alternative: home care for patients living within a one to two-hour drive of the hospital. In Sweden this approach includes daily visits by an experienced nurse and daily phone consultations with a unit physician. When necessary, patients receive transfusions, intravenous antibiotics, and total parenteral nutrition at home. Our initial study report compared 36 home care patients with 54 hospital-treated controls. Multivariate analysis found that home care patients were discharged earlier to outpatient clinics, required fewer days of total parenteral nutrition, had less acute graft-versus-host disease (GVHD) grade II-IV, and lower transplantation-related mortality (TRM) and lower costs. Long-term follow-up showed similar chronic GVHD and relapse rates in both groups, with improved survival rates in the home care group. A subsequent comparison of 146 home care patients with hospital-treated controls indicated that home care and longer home stays were associated with lower grades of acute GVHD. Home care was found to be safe and beneficial for children and adolescents. Over two decades, 252 patients received home care post-Allo-HCT without any fatalities at-home. Ten-year outcomes showed a 14% TRM and a 59% survival rate. In 2020, an independent center confirmed the reduced risk of acute GVHD grades II-IV for patients treated in home care. Here, we report for the first time that home care patients also demonstrate a less inflammatory systemic cytokine profile. We found higher levels of IFN-γ, IL-2, IL-5, IL-13, GM-CSF, and G-CSF, but lower VEGF in hospital-treated patients, which may contribute to acute GVHD grades II-IV. In conclusion, home-based treatment following Allo-HCT yields multiple promising clinical outcomes and improved systemic inflammatory markers, which may contribute to less development of life-threatening GVHD.

Graft Versus Host Disease: Management Issues in the Intensive Care Unit.

Graft versus host disease (GVHD) in acute and chronic forms is a frequent post-transplant complication and seen in 50% of patients in acute and up to 70% cases in chronic GVHD setting. Patients with multiorgan involvement and those who are steroid refractory, frequently present with complications arising from this post-transplant complication. These GVHD patients are frequently managed in the Intensive care unit for treatment of air leaks, effusions, management of hypoxemia due to lung GVHD or infections. Close coordination between hematologists and Pulmonary medicine specialists is critical for timely management of these complications to improve patient outcomes.

Treatment of acute and chronic graft-versus-host disease with extracorporeal photopheresis: Update of best practice recommendations from Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and the Italian Transplant Group for Bone Marrow Transplantation, Hematopoietic Stem Cells and Cell Therapy (GITMO).

These guidelines represent a GRADE-method revision of the recommendations produced by the Italian Society of Hemapheresis and Cell Manipulation (SIDEM) and the Italian Transplant Group for Bone Marrow Transplantation, Hematopoietic Stem Cells and Cell Therapy (GITMO) in 2013. Since 2013 several studies have been published that have strengthened the role of ECP in the management of GVHD. Thus, it was deemed appropriate to proceed with an update, with the aim to define uniform criteria for the application of ECP in adult and pediatric patients affected by GVHD throughout the national territory, in line with international guidelines, in maintaining of high standards of safety for patients and quality of the procedures provide. Post-HSCT GvHD therapies other than ECP and ECP therapy of other diseases, such as CTCL, are not covered by these guidelines.The development panel for this guideline includes professionals from various specialties who routinely interact in the management of the patient with GVHD, namely the transfusionist, the adult and pediatric hematologist, and the hospital pharmacist. A hematologist experienced in systematic reviews and GRADE guideline development ccordinated the development process, and an experienced transfusionist coordinated the assignment of tasks and reporting. External reviewers of the guideline included a patient representative.

CAST Regimen for GvHD Prophylaxis: A CIBMTR Propensity Score-Matched Analysis.

Previously, we reported excellent results with the combination of post-transplant cyclophosphamide (PTCy), abatacept and a short course of tacrolimus (CAST) for the prevention of graft-versus-host disease (GvHD) following peripheral blood haploidentical transplantation. To further substantiate these results, we performed a propensity score-matched analysis. Patients enrolled in the CAST trial were matched with patients from a contemporaneous cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR) database who received PTCy, tacrolimus and mycophenolate mofetil, using nearest neighbor propensity score matching. An excellent balance between pairs was achieved as measured by the density distribution and standardized differences of covariates (median 0.09). The rates of acute GvHD grades II-IV at day +120 and one-year GvHD- and relapse-free survival (GRFS) were 16.7% and 66.7% in the CAST cohort versus 28.6% and 47.6% in the control group, respectively. This trend did not reach statistical significance (p= 0.14 and 0.07), possibly due to the small numbers of patients and events. On the other hand, CAST was associated with a statistically significant reduction in the incidence of relapse (9.5% versus 26.2%, p=0.045) with improved disease-free survival (85.7% versus 61.9%, p=0.01). Our data provides a strong impetus to examine CAST in a randomized clinical trial.

Recent advances in acute gastrointestinal graft versus host disease (aGvHD): aspects of steroid-resistant disease.

Acute Graft versus Host Disease (aGvHD) is a common immunological complication occurring in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Moreover, aGvHD is associated with a higher risk of infections and metabolic complications, affecting non-relapse mortality. Progress in transplantation has changed the prophylactic and therapeutic strategies of aGvHD and improved patient outcomes. The standard first-line therapy remains steroids, with a response rate of about 50%. The Janus Kinase 2 (JAK2) inhibitor, ruxolitinib, is an effective second-line therapy. The management of patients who developed a disease that is refractory to steroids and ruxolitinib, especially in the severe gastrointestinal forms of aGvHD, is not validated and remains an unmet medical need. In the article, we present the current clinical practice, as well as the latest advances targeting pathophysiological pathways of GvHD and gut microbiota, which may be a potential future of aGvHD therapy.

The role of interleukin-2 in graft-versus-host disease pathogenesis, prevention and therapy.

Graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), posing substantial risks to patient survival. In the late follow-up phase of transplanted patients, GVHD is also a major cause of morbidity and disability, mostly due to low response to first-line steroids and the lack of effective standard therapies in the second line. This review provides a description of GVHD pathogenesis, with a focus on the central role of Interleukin-2 (IL-2). IL-2 is one of the critical mediators in the complex pathogenesis of GVHD, contributing to the intricate balance between regulatory T cells (Tregs) and effector T cells (Teffs). Due to this pivotal role, several studies investigate the potential of IL-2 as a therapeutic option for GVHD management. We discuss the outcomes of low-dose IL-2 therapies and their impact on Treg proliferation and steroid dependency reduction. Additionally, the effects of combining IL-2 with other treatments, such as extracorporeal photopheresis (ECP) and Treg-enriched lymphocyte infusions, are highlighted. Novel approaches, including modified IL-2 complexes and IL-2 receptor blockade, are explored for their potential in selectively enhancing Treg function and limiting Teff activation. The evolving understanding of IL-2's pivotal role in immune regulation presents promising prospects for applying treatment and prevention strategies for GVHD.

Lower Weight-Based Mycophenolate Mofetil Dosing is Associated with Superior Outcomes after Haploidentical Hematopoietic Cell Transplant with Post-transplant Cyclophosphamide.

Mycophenolate mofetil (MMF) is commonly included in post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis after haploidentical (haplo) hematopoietic cell transplant (HCT). In the non-PTCy setting, higher MMF dose/kg has been shown to reduce rates of acute graft-versus-host disease (GVHD). When used in conjunction with PTCy, MMF is dosed at 15 mg/kg three times daily up to a maximum dose of 3 g/day. Thus, patients who weigh ≥67 kg receive 3 g/day and a variable dose/kg of MMF. We investigated the impact of MMF dose/kg on clinical outcomes following haploidentical PBSCT with PTCy-based GVHD prophylaxis. All consecutive adult patients with hematologic malignancies receiving haploidentical T cell replete peripheral blood stem cell transplant (PBSCT) with PTCy/MMF and either tacrolimus or sirolimus at the Moffitt Cancer Center or City of Hope between April 2014-August 2020 were included. For analyses, MMF dose relative to patient actual body weight (mg/kg/day), was stratified into categories of low (<29 mg/kg/day), low intermediate (29-34 mg/kg/day), high intermediate (35-41 mg/kg/day), and high (>41 mg/kg/day). Three hundred eighty-six patients were included. Of these, 54 patients received low dose, 73 low intermediate, 137 high intermediate and 122 high dose MMF by relative weight exposure. In multivariate analysis, low MMF dose exposure was associated with reduced rates of relapse in comparison to the high dose group (HR = 0.45, 95% CI: 0.21 to 0.94, P = .03). This led to superior PFS among patients with low compared to high MMF dose exposure (HR = 0.58, 95% CI: 0.34 to 0.99, P = .045). MMF relative dose exposure was not associated with engraftment, GVHD, nonrelapse mortality, or OS. In this study of patients receiving haploidentical PBSCT with PTCy based GVHD prophylaxis, low MMF dose/kg was associated with improved rates of relapse and PFS. Future prospective studies should investigate optimal dosing strategies of MMF when given with the PTCy regimen.