Chronic Graft-versus-host Disease Research Articles

Genital graft versus host disease in women after allogeneic hematopoietic stem cell transplantation - a single center experience.

Chronic Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT), affecting the female genital tract in 25-66% of the patients. This condition, referred to as Genital GVHD is an underdiagnosed gynecologic comorbidity, that can significantly impair quality of life. We aimed to describe the prevalence and management of genital GVHD following HSCT. This retrospective analysis included women who underwent allogeneic HSCT at a single Bone Marrow Transplantation Unit between 2015 and 2020 and were evaluated at a specialized Vulvo-Vaginal Clinic. Diagnosis and severity of genital GVHD were based on the recommendations by the National Institute of Health (NIH), therapeutic options included topical treatments and surgical interventions. Of the thirty-six patients evaluated, 19.4% were diagnosed with genital GVHD. Patients with genital GVHD were older than those with no-genital GVHD (58.42 vs 47.48years, p = 0.02), and most of them had concurrent multi-organ chronic GVHD (85.71%). Genital GVHD was mostly symptomatic in our cohort (71.42%), clinical findings at the time of diagnosis corresponded with NIH grade 3 (severe disease) in 57.1% of cases. Topical treatments were initiated for all patients with genital GVHD, one required surgical intervention. Genitourinary syndrome of menopause (GSM) was diagnosed among 100% of patients with genital GVHD and among 58.62% of patients without genital GVHD (p = 0.08). In the genital GVHD group, adherence to clinical follow up was limited (43.85%). Genital GVHD should be considered as part of chronic GVHD evaluation after allogeneic HSCT. It is associated with advanced age and the presence of chronic systemic GVHD. Impaired quality of life and limited follow-up within this population emphasize the need for increased awareness and early evaluations.

Multicentre adaptive randomised trial of GvHD prophylaxis following unrelated donor stem cell transplantation comparing Thymoglobulin versus calcineurin inhibitor-based or sirolimus-based post-transplant cyclophosphamide (Methods of T cell Depletion, MoTD trial)

IntroductionGraft-versus-host disease (GvHD) remains a major complication of allogeneic stem cell transplantation (allo-SCT), affecting 30–70% of patients (representing 800 new patients per year in the UK). The risk is higher...

Low dose ATG-Fresenius for GVHD prophylaxis: a comparative study with ATG-Thymoglobulin

BackgroundAnti-Thymocyte Globulin (ATG) is commonly used to prevent graft-versus-host disease (GVHD), but the optimal dosage and type of ATG remains to be determined.ObjectiveWe compared retrospectively the safety and efficacy outcomes of allogeneic transplantation using low-dose ATG-Fresenius (15mg/kg) and ATG-Thymoglobulin (10mg/kg) for GVHD prevention.Study designNinety-eight patients were included, with 46 in the ATG-T group and 52 in the ATG-F group. The median age was 48 years in the ATG-T group (range 20-71) and 50 years in the ATG-F group (range 18-73). Baseline characteristics were similar, with slightly more HLA mismatched donors and single-agent cyclosporine GVHD prophylaxis use in the ATG-T group. Additionally, the ATG-F group had more myeloid leukemia and myelodysplastic syndrome patients, while the ATG-T group had more lymphoma patients.ResultsThe cumulative incidence of acute GVHD (aGVHD) grade II-IV and chronic GVHD (cGVHD) showed no significant differences. Multivariate analysis indicated that donor HLA mismatch influenced aGVHD risk significantly (p=0.005), and myeloablative conditioning increased cGVHD risk. Bacteremia and CMV reactivation rates were similar, but EBV DNA viremia was higher in the ATG-T group (22% vs. 8%, p=0.047), with one case of Post-Transplant Lymphoproliferative Disorder (PTLD) in the ATG-T group. Cumulative incidence of overall survival (OS), relapse incidence, non-relapse mortality (NRM) and GVHD free, Relapse free Survival (GRFS) did not significantly differ.ConclusionsThis study highlights the safety and efficacy of low-dose ATG-F compared to a relatively high dose ATG-T. Prospective studies are necessary to validate the safety and efficacy of low dose ATG-F for GVHD prevention.

Hematopoietic stem cell transplantation in inborn errors of metabolism-a retrospective analysis on behalf of the pediatric disease working party from the Brazilian Society of Bone Marrow Transplantation and Cellular Therapy.

Hematopoietic stem cell transplantation (HSCT) is an established treatment for selected patients with inborn errors of metabolism. In this first report from the PDWP-SBTMO, we included 105 patients transplanted between 1988 and 2021 across six Brazilian HSCT centers. The most prevalent diseases were X-linked adrenoleukodystrophy (n = 61) and mucopolysaccharidosis (type I n = 20; type II n = 10), with a median age at HSCT of 8.7 years and 2.1 years, respectively. Most conditioning regimens were myeloablative and busulfan-based. With a median follow-up of 6.7 years, the 5-years overall survival (OS) was 75% (95% CI, 0.65-0.82) with a superior 5-years OS for those transplanted after 2010 (87% vs. 63%, p = 0.01). Higher risk of death was associated with the use of haploidentical donor (HR8.86, p 0.021), unrelated cord blood (HR 8.76, p 0.005), unrelated donor (HR 5.91, p 0.02), and for HSCT performed before 2010(HR 4.16, p = 0.0015). The CI of acute GVHD was 24.8%, while chronic GVHD was 9.5%. Major causes of death were infections (n = 8), GVHD (n = 6), and neurologic progression (n = 3). Despite improvements in transplant outcomes since 2011, challenges persist, emphasizing the need for early diagnosis, timely transplantation and expanding HSCT centers with expertise in the field.

Comparing haploidentical transplantation with post-transplantation cyclophosphamide and umbilical cord blood transplantation using targeted busulfan in children and adolescents with hematologic malignancies

PurposeThis study compared the outcomes of haploidentical-related donor (HRD) and umbilical cord blood (UCB) hematopoietic stem cell transplantation (HSCT) in pediatric patients with hematologic malignancies.MethodsData on patients who underwent HRD HSCT with post-transplant cyclophosphamide (n = 41) and UCB HSCT (n = 24) after targeted busulfan-based myeloablative conditioning with intensive pharmacokinetic monitoring between 2009 and 2018 were retrospectively analyzed.ResultsThe median follow-up durations in the HRD and UCB groups were 7.0 and 10.9 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II–IV and moderate-to-severe chronic GVHD did not differ significantly between the groups. However, the HRD group demonstrated significantly lower rates of acute GVHD grades III–IV (4.9% vs. 29.2%, p = 0.009) and non-relapse mortality (2.6% vs. 34.2%, p < 0.001) but a higher relapse incidence (32.1% vs. 8.8%, p = 0.004) than the UCB group. The 5-year event-free and overall survival rates were 65.8% and 54.2% (p = 0.204) and 78.0% and 65.7% (p = 0.142) for the HRD and UCB groups, respectively. Multivariate analysis identified disease status as a significant risk factor for overall survival (hazard ratio, 3.24; p = 0.016). Additionally, UCB HSCT exhibited a trend toward worse event-free survival compared to HRD HSCT (hazard ratio, 2.63; p = 0.05).ConclusionsThese findings indicate that HRD HSCT with post-transplant cyclophosphamide provides promising outcomes compared to UCB HSCT in pediatric patients, with a trend toward improved survival over a long-term follow-up period exceeding a median of 7 years. Thus, HRD HSCT may be a valuable option for pediatric patients without human leukocyte antigen-matched donors.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for children with chronic GVHD after Hematopoietic Cell Transplantation.

While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplant (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD, and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms. However, children also have the greatest potential for full immune reconstitution, due to thymus recovery that could impact the timing of vaccination with respect to tolerance and restoration of optimal immunity. Developing strategies to mitigate the late effects incurred with, and as a result of cGVHD, is of critical importance. The working group recommends surveillance strategies for late effects in patients with cGVHD, increased utilization of emerging diagnostic tools, integration of monitoring for cGVHD treatment response, development of new treatments, and provides aims for future research endeavors.

Common Hereditary Variants of the APOE Gene and Posttransplant Outcome in Acute Myeloid Leukemia.

Apolipoprotein E (APOE) has multiple functions in metabolism and immunoregulation. Its common germline variants APOE2, APOE3 and APOE4 give rise to three functionally distinct gene products. Previous studies reported yin-yang roles of APOE2 and APOE4 in immunological processes, but their effects in hematopoietic stem cell transplantation (HSCT) have never been studied. We performed APOE genotyping in two contemporary cohorts of 348 and 447 patients with acute myeloid leukemia (AML) who had received allogeneic HSCT and evaluated associations of recipient and donor APOE genetic variation with posttransplant outcome. Patients who carried at least one APOE2 allele had a higher risk of posttransplant death compared to APOE4 carriers in the discovery (hazard ratio [HR] 2.09, P = .024) and validation cohorts (HR 1.96, P = .040). Detrimental APOE2 effects were driven by an increased risk of severe chronic graft-versus-host disease (GvHD; HRadj 1.85, P = .034) and non-relapse death (HRadj 1.72, P = .044). In non-APOE2 recipients, transplantation of an APOE2-positive allograft was associated with an increased incidence of grade III-IV acute GvHD (HRadj 2.82, P = .012) and severe chronic GvHD (HRadj 2.54, P = .022) compared to APOE2-negative grafts. In summary, the APOE2 allele, typically considered a longevity gene in the general population, was associated with a higher risk of acute GvHD (HRadj 2.75, P = .002), chronic GvHD (HRadj 2.57, P = .001), and posttransplant mortality (HRadj 1.79, P = .004), when present either in the host or transplanted from the donor.

Post-transplant cyclophosphamide plus anti-thymocyte globulin decreased serum IL-6 levels when compared with post-transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation

BackgroundPost-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common prophylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.MethodThe clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023.ResultsForty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).ConclusionSerum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.

Development of the Lee Symptom Scale-Skin Sclerosis for chronic GVHD-associated sclerosis.

Sclerosis is a highly morbid manifestation of chronic GVHD (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome measure (PRO) for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults age ≥18 years with cGVHD-associated sclerosis participated in semi-structured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were employed to evaluate content validity of the items, response options, recall period, and respondent instructions.Thirty-five open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (4) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n=25). Phrasing changes were made to improve relevance and comprehension. One item was removed and two items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale-Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale-Skin Sclerosis. Psychometric testing and determination of minimal clinically important difference are underway in an external cohort to validate the PRO.

The role of fat-soluble vitamins for graft-versus host disease after myeloablative conditioning in allogeneic stem cell transplanted patients

Whether the fat-soluble vitamins A, D, E, and K are associated with development of graft-versus-host disease (GvHD) after allogeneic stem cell transplantation, is unclear. We assessed if the levels of these vitamins were associated with development of GvHD during the first year after transplantation using data from a two-armed randomized nutritional intervention trial. Changes in plasma levels during 1-year follow-up were analyzed using a linear mixed model for repeated measurements. Vitamin A, D, E, and K levels changed significantly the first year in both study arms (p < 0.001). Higher levels of vitamin E over time were associated with less acute GvHD grades 3–4 (OR = 0.997, 95% CI: (0.994, 0.999), p = 0.017). No associations were found with vitamin A, D, E and K levels and chronic GvHD. Multivariable analysis adjusted for treatment group, age, pre-transplant vitamin level and risk factors for GvHD did not change the results. Six weeks post-transplantation, higher levels of vitamin E were associated with less acute GvHD grades 3–4, (p = 0.012). In conclusion, we found an association between higher levels of vitamin E over time and less severe acute GvHD. Whether this reflects a causal relationship warrants further study. ClinicalTrials.gov (NCT01181076).

Donor Regulatory T-Cell Therapy to Prevent Graft-Versus-Host Disease.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity.We enrolled 44 patients on an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg cell therapy manufactured from donor mobilized peripheral blood improves one-year GVHD-free relapse free survival (GRFS) after myeloablative conditioning (trial NCT01660607). We compared this study arm to a concomitant standard of care (SOC) cohort. All donor Treg cell products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a one-year incidence of acute grade III-IV GVHD of 7%, moderate to severe chronic GVHD of 11% and non-relapse mortality rate of 4.5%. The primary endpoint of significantly improved one-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (p = 0.002) with a realized incidence of 36% in the SOC comparitor. For those trial patients whow developed grade II-IV acute GVHD, 91% responded to front-line steroid therapy wheras 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, as compared to rates common to highly variable unmanipulated donor grafts and multi-agent immune suppression.

AGvHDtrackR and cGvHDtrackR: shiny applications for graft versus host disease management and clinical data collection.

Graft-versus-host disease (GvHD) is one of the most common and troublesome complications after allogeneic hematopoietic stem cell transplantation (HSCT). Despite adequate GvHD prophylaxis, 30-50% of the patients still develop acute or chronic GvHD, often requiring multiple lines of therapy. Therefore, it is crucial to closely monitor the onset and the response of GvHD to therapies to identify the best available treatment for each patient. Currently, some applications (desktop or mobile) that allow to score GvHD severity at the bedside are available. However, none of the published systems is designed to record ongoing therapies and to upload data in a database, which can support both the clinical decision-making process as well as data collection. To this aim, we developed two Shiny apps: aGvHDtrackR for acute GvHD and cGvHDtrackR for chronic GvHD. These applications record GvHD grading alongside the therapies used for each patient and allow to export of the data in a longitudinal patient-specific database. This is of help for the clinical management of patients and for future multicentric studies on GvHD.

The Association of HLA-E Ligand and NKG2 Receptor Variation With Relapse and Mortality After Haploidentical Related Donor Transplantation.

Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown. We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation. We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, nonrelapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression. The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, .49 [95% CI, .26 to .89) contributing to a HR for mortality of .62 (95% CI, .38 to 1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440-rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34 to 3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11 to 1.82) and 1.43 (95% CI, 1.13 to 1.81), respectively. Hazard ratios for nonrelapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06 to 2.41) and HR 1.79 (95% CI, 1.21 to 2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotype was HR 2.52 (95% CI, 1.45 to 4.38) relative to donors with any wt-non CCC/CCC haplotype. The success of haploidentical transplantation may be defined by the cumulative effects of donor NKG2 receptor and patient HLA-E ligand polymorphisms. Patient HLA-E ligand and donor NKG2C-NKG2A receptor haplotypes shed new light on their role in the control of malignancy.

Subsequent Cancers following Non-myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation.

We examined the risk of subsequent malignant neoplasms (SMNs) in 1720 patients with hematologic cancers given allogeneic hematopoietic grafts from 03/1998 to 08/2023 after nonmyeloablative conditioning regimens. With a median follow-up of 12 years, the cumulative incidence of SMNs was 17% (95% CI, [15%, 19%]). Most SMNs (n = 543) were non-melanoma skin cancers seen in 208 patients; unfortunately, information on these cancers was not available in the Surveillance, Epidemiology, and End Results (SEER) database for comparison with such tumors in the general population. However, developing non-melanoma skin cancers was statistically significantly associated with chronic GVHD and, thus, unlikely to be conditioning regimen related. Eighty-six patients (5%) developed 93 other SMNs. This number (93 SNMs) significantly exceeded the expected 73.4 cases in the comparison group (p = 0.03). This increase was driven exclusively by increases in uterine adenocarcinoma (n = 2), squamous lip cancer (n = 5), and squamous penile cancer (n = 2); the latter two cancers were, again, associated with chronic GVHD. Apart from these three tumor types, there were no observed increases in the risk of other tumors compared to those in the general population.

Venetoclax therapy in chronic lymphocytic leukaemia patients relapsed after allogeneic haematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains an option for young and fit chronic lymphocytic leukaemia (CLL) patients with high-risk disease features. However, allotransplanted patients are generally excluded from clinical trials, making data regarding the use of venetoclax after alloHSCT extremely rare. We report data from 7 CLL patients who received venetoclax after alloHSCT among 53 Italian centers. These patients underwent alloHSCT between 2006 and 2021 after failing chemoimmunotherapy (7/7), ibrutinib (5/7) and/or idelalisib (1/7). Of note, 3/7 patients had already received venetoclax-based therapy before alloHSCT. Post-allo HSCT venetoclax treatment resulted safe, with adverse events not different from what reported in clinical trials. Importantly, no meaningful impact on graft versus host disease (GvHD) course was observed: 4/7 patients with pre-existing chronic GvHD had no exacerbation after venetoclax start, and only one patient developed GvHD during venetoclax therapy, that was managed as per standard clinical practice. Concerning efficacy, 5/7 patients presented a clinical response to venetoclax, with two patients achieving an undetectable minimal residual disease. To our knowledge, this is the largest reported series of CLL patients treated with venetoclax after alloHSCT. In these heavily pretreated and high-risk patients, previous alloHSCT did not compromise the feasibility of venetoclax therapy, that lacked unexpected toxicities and did not exacerbate GvHD.

Impact of Obesity on GVHD in Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Hematologic Malignancies.

The relationship between obesity and graft-versus-host disease (GVHD) has been studied in both pre-clinical and clinical studies with varying results. We aimed to investigate the impact of obesity, as measured by body mass index (BMI), on the incidence, severity, and response to therapy of GVHD in a contemporary cohort. We conducted a retrospective study of patients undergoing allogeneic hematopoietic cell transplant (HCT) for acute myelogenous leukemia and myelodysplastic syndrome between January 2010 and December 2021 at the Cleveland Clinic. Incidence, grade, organ involvement, and response to therapy of acute and chronic GVHD were compared between patients with obesity (BMI ≥30) and without obesity. Secondary outcomes included relapse, non-relapse mortality (NRM), and overall survival (OS). 531 patients were identified, with a median follow-up of 19 months (range, 7-49). Mean (SD) BMI at time of HCT was 29.1 (6.3) kg/m2. There was no significant difference in demographic and HCT characteristics between patients with obesity (N=199) and without obesity (N=332). Development of any acute (42% vs. 43%) or chronic (29% vs. 30%) GVHD was similar in patients with and without obesity. Patients with obesity were less likely to have gastrointestinal involvement from chronic GVHD (28% vs. 48%, p=0.01). Skin (64% vs 56%), mouth (45% vs 35%) and eye (35% vs 27%) involvements were higher in patients with obesity, although statistically not significant. There were no significant differences in OS, NRM, or relapse. There were no significant differences in incidence of GVHD among patients with and without obesity. Additional studies are needed to further understand potential differences in organ involvement.

Everolimus with or without Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis after Hematopoietic Stem Cell Transplantation in Children with Acute Kidney Injury: A Single-Center Retrospective Analysis.

Hematopoietic stem cell transplantation (HSCT) serves as a therapeutic intervention for various pediatric diseases. Acute and chronic graft-versus-host disease (GVHD) are decisive determinants of successful allogeneic HSCT. The immunosuppressive agent cyclosporin A (CsA) is most often used to prevent GVHD in pediatric patients, but it is known to be nephrotoxic. Acute kidney injury (AKI) affects 21% to 84% of pediatric HSCT recipients, compromising clinical outcomes. This retrospective single-institution analysis scrutinized the practice of substituting nephrotoxic CsA with an everolimus/mycophenolate mofetil (MMF) combination as GVHD prophylaxis in 57 patients with AKI (n = 53) or central nervous system side effects due to calcineurin inhibitor (CNI) treatment (n = 4) following first allogeneic HSCT. This retrospective cohort study analyzed the clinical courses of 57 children who were switched from CNI-based GVHD prophylaxis (CsA or tacrolimus in single cases) to the everolimus/MMF combination (n = 48) or everolimus alone (n = 9) after undergoing their first allogeneic HSCT at the Charité University Medicine Berlin. Serving as a control group were 74 patients undergoing their first allogeneic HSCT during the same period who did not receive everolimus at any time post-transplantation. Patients undergoing mismatched family donor transplantation without subsequent CNI treatment for GVHD prophylaxis were excluded. Study endpoints encompassed the retention parameter course subsequent to the GVHD prophylaxis switch, overall survival (OS), and incidences of underlying disease relapse and acute and chronic GVHD in both treatment groups. Renal function improved significantly after switching from CsA to the everolimus/MMF combination. Crucially, the transition to everolimus did not adversely affect OS following HSCT (hazard ratio [HR], 1.6; 95% confidence interval [CI], 0.74 to 3.5; P = .23), especially for patients with nonmalignant diseases (HR, 1.4; 95% CI, 0.34 to 5.9; P = .64). The incidences of grade III-IV acute GVHD (HR, 1.82; 95% CI, 0.45 to 7.4; P = .40) and severe chronic GVHD (HR, 2.76; 95% CI, 0.69 to 11.0; P = .15) were comparable in patients treated with the everolimus/MMF combination and those receiving standard CsA treatment in the control group. OS in patients with malignant underlying diseases was lower in the everolimus group (HR, 2.7; 95% CI, 1.1 to 6.9; P = .03), however, event-free survival was similar in patients with an underlying malignant disease treated with either the everolimus/MMF combination or CsA (HR, 0.87; 95% CI, 0.39 to 1.9; P = .73). Renal function improved significantly in patients who switched their immunosuppression regimen from CsA to everolimus with or without MMF cotreatment after diagnosis of AKI. Patient outcomes in the everolimus group were comparable to those in the control group. This study provides compelling real-world clinical evidence to support replacing CsA with the everolimus/MMF combination in the management of AKI following HSCT in children.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Aged 70 Years and Older: A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potential cure for many hematological malignancies. Historically, older adults were not considered eligible for allo-HCT due to increased toxicity and mortality concerns. This systematic review and meta-analysis aim to explore the outcomes of allo-HCT in patients aged 70 years or older. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a comprehensive literature search was performed on PubMed, Cochrane Register of Controlled Trials, and Clinicaltrials.gov using MeSH terms and keywords for "Hematopoietic Stem Cell Transplantation" AND "Outcome Assessment" from the date of inception to June 30, 2024. Our search produced 102 articles. After excluding irrelevant and review articles during primary and secondary screening, eight original studies reporting outcomes of allo-HCT in patients aged 70 years or older were included. The survival data were retrieved from Kaplan-Meier (KM) curves using an online plot digitizer tool to calculate the overall survival (OS) and disease-free survival (DFS). The pooled KM curves were plotted and analyzed using the "MetaSurvival" package of R software version 4.2.1. Proportions and 95% confidence intervals (CIs) were extracted as well. A total of 2519 patients aged 70 years or older with allo-HCT were included in the analysis. The included patients' age ranged from 70 to 84 years, and 68% were male. Median follow-up was 23.2 (0.4 to 122.5) months. The combined median OS was 14.84 months (95% CI: 11.61 to 19.50), with OS rates at 6, 12, 24, and 36 months of 71.8%, 54.5%, 41.9%, and 34.9%, respectively. The estimated pooled mean OS was 28.62 months (95% CI: 23.41 to 31.44). The pooled median DFS was 10.54 months (95% CI: 7.93 to 14.17), with DFS rates at 6, 12, 24, and 36 months of 61.5%, 47.5%, 37%, and 30.6%, respectively. The estimated pooled mean DFS was 24.45 months (95% CI: 18.30 to 23.74). The relapse rate ranged from 28% to 55.6%, while non-relapsed mortality ranged from 5.6% to 42%. The acute graft versus host disease (GvHD) incidence varied from 9.3% to 32%, while chronic GvHD rates ranged from 10% to 43%. Allo-HCT provides promising outcomes for patients aged 70 or older with transplant-eligible diseases. Disease progression, followed by infections, is the leading cause of mortality, underscoring the need for improved post-transplant care, including optimized GvHD regimens and strategies to reduce infection risk.

A retrospective study of an irradiation-based conditioning regimen and chidamide maintenance therapy in T-ALL/LBL

ABSTRACT Objectives T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL. Methods We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170–1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1). Conclusion Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated.

FDA-approved therapies for chronic GVHD.

Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. Chronic GVHD can affect multiple organs and reduces quality of life, and treatment can cause serious side effects. In the last ten years, the drugs ibrutinib, ruxolitinib, belumosudil and axatilimab were FDA-approved for cGVHD. Here we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA-approval, and future directions for clinical research.