Chronic Graft-versus-host Disease Research Articles

Intermediate-Dose Post-Transplantation Cyclophosphamide for Myeloablative HLA-Haploidentical Bone Marrow Transplantation.

High-dose post-transplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase I/II trial (NCT03983850) to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity-score was 3. The phase I dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose-level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n=23), the phase II dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, non-relapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n=5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. Intermediate-dose PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. NCT03983850.

Application of lacrimal gland ultrasonography in the evaluation of chronic ocular graft-versus-host-disease

ObjectiveTo investigate the effectiveness of lacrimal gland ultrasonography in the assessment of chronic ocular graft-versus-host-disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to establish the correlation between the ocular surface and ultrasonographic results.MethodThe cross-sectional study included 57 participants aged 18 and older, who were at least 100 days after allo-HSCT. The study was conducted at the oGVHD clinic of Peking University People’s Hospital between March to June 2023. Patients were categorized into groups according to the International Chronic oGVHD (ICCGVHD) consensus group diagnostic criteria or the 2005 National Institutes of Health (NIH) classification criteria for Chronic GVHD. Demographics and transplantation-related information were collected for all participants, including age, gender, donor-recipient HLA matching, donor-recipient ABO matching, donor-recipient gender combination and duration after allo-HSCT. The disease activity of oGVHD and the severity of ocular surface involvement were assessed using various parameters such as Ocular Surface Disease Index (OSDI), Schirmer test, tear film break-up time (BUT), tear meniscus height, corneal/conjunctival staining and meibomian gland dropout. Lacrimal gland structures were assessed by B-mode and Doppler ultrasonography to measure parameters such as the long diameter, thick diameter, homogeneity and parenchymal vascularization. Statistical analyses were performed to determine differences in ocular surface conditions and lacrimal gland ultrasonographic parameters between groups as well as to determine the correlation between ocular surface condition and lacrimal gland ultrasonographic findings.Result(1) Patients with definite and probable oGVHD exhibited a significantly longer duration after allo-HSCT compared to non-oGVHD patients (H=11.264, p<0.01), The median durations were 247(164,894) days and 525(310,928) days, respectively, compared to 204(169,323.25) days for non-oGVHD patients. (2) Compared to non-oGVHD patients, both definite oGVHD patients and probable oGVHD patients showed lower average of Schirmer test (H=31.188, p<0.01), TBUT (H=11.853, p<0.01), tear meniscus height (H=13.630, p<0.01) and higher average of OSDI (F=27.992, p<0.01), corneal staining scores (χ²=23.66, p<0.05) and temporal conjunctival staining scores (χ²=14.84, p<0.05). (3) The B-mode and Doppler ultrasonography parameters in lacrimal glands including long diameter, thick diameter, homogeneity and parenchymal vascularization did not exhibit significant differences between the three groups. (4) The long diameter in lacrimal ultrasonography had significantly positive correlations with tear meniscus height (r=0.297, p<0.05) and significantly negative correlations with temporal conjunctival staining scores (r=-0.313, p<0.05) and staining total scores (r=-0.285, p<0.05). The thick diameter in lacrimal ultrasonography demonstrated significantly positive correlations with tear meniscus height (r=0.404, p<0.01), and significantly negative correlations with OSDI (r=-0.273, p<0.05), corneal staining scores (r=-0.264, p<0.05), nasal conjunctival staining scores (r=-0.271, p<0.05) and staining total scores (r=-0.312, p<0.05). Homogeneity and parenchymal vascularization were not found to be significantly correlated with ocular surface status.ConclusionThe ocular surface condition in oGVHD patients is worse than that observed in non-GVHD patients. The main manifestations include keratoconjunctival injury and a reduction in tear secretion and tear film stability. These effects appear to be a common result of chemoradiotherapy-induced inflammation and rejection-associated responses. There were no significant differences in the morphology of lacrimal glands as revealed by ultrasonography. This suggests that ocular rejection may not be the primary cause of lacrimal gland changes in oGVHD patients. While ultrasonography can provide insight into tear secretion, its efficacy in diagnosing oGVHD appears limited.

Ruxolitinib for pediatric acute and chronic graft-versus-host disease: a single-center retrospective study of efficacy and safety

Abstract Graft-versus-host disease (GVHD) is a major concern for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Ruxolitinib has been proven effective in treating adult steroid-refractory GVHD; however, studies on pediatric patients are relatively scarce. Thus, this single-center study evaluated the efficacy and safety of ruxolitinib in pediatric patients with steroid-refractory GVHD. We retrospectively reviewed the data of patients aged < 18 years who underwent allogeneic HSCT and received ruxolitinib treatment for either acute GVHD (aGVHD) or chronic GVHD (cGVHD) between 2018 and 2023. Data on the clinical response, concomitant and subsequent medications, adverse events, and outcomes were obtained through medical chart review. Sixteen patients were analyzed in this study: seven with aGVHD and nine with cGVHD. The overall response rate for the 16 patients was 81% (aGVHD, 86%; cGVHD, 77%). The overall survival rate was 56%: (aGVHD, 57%; cGVHD, 55%). For 11 patients with at least stable disease, steroid dosage could be reduced by at least 75%; however, corticosteroids were successfully tapered off in only six patients at the last follow-up. Among four patients with documented lung cGVHD, none experienced lung cGVHD progression at 1-year follow-up. Further, 50% of the patients experienced grade 3 or 4 neutropenia and/or thrombocytopenia, and 56% had viral reactivation. Two patients discontinued ruxolitinib owing to adverse events. Ruxolitinib treatment for pediatric patients with aGVHD and cGVHD is associated with a high overall response rate, significant steroid-sparing effect, acceptable toxicity, and manageable adverse events. However, blood count and viral reactivation should be closely monitored during ruxolitinib use.

Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD.

Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and non-relapse associated mortality following allogeneic hematopoietic cell transplantation (aHSCT). Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. Here, we sought to investigate the DNA demethylase Tet (ten-eleven translocase) methylcytosine dioxygenases 2 (Tet2) and Tet3 in T follicular helper cell (TFH) dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2 deleted donor T-cells did not have improved pulmonary function tests in contrast to the markedly improved pulmonary function in Tet3 deleted donor T-cells. Tet3 deleted donor T-cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency resulted in elevated GATA3 expression in and IL-4 production by TFH cells. TET3 deficient TFH cells supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c allowing mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in-vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH driven Ig class switching and suggest a new approach to mitigate cGVHD.

What should be the optimal dose of post-transplantation cyclophosphamide for GVHD prophylaxis in allogeneic stem cell transplantation?

In this study, we aimed to compare the engraftment days, graft versus host disease (GVHD) development, relapse and overall survival (OS) rates in patients using variable intensity conditioning regimens with two different post-transplant cyclophosphamide (PTCy) doses for hematological malignancies. We retrospectively analyzed 162 patients who have had PTCy at a dose of 25 mg/kg ×2 and 50 mg/kg × 2 between 2018 and 2024. Patients were divided in 2 groups; PTCy dose with 25 mg/kg ×2 (Group 1, n = 45) and PTCy dose with 50 mg/kg ×2 (Group 2, n = 117). The engraftment days, GVHD, relapse and OS rates were compared across groups. All patients had myeloablative conditioning regimens and peripheral stem cell collected transplantation. 61.1 % of patients (n = 99) were alive at the end of the study (60 % (n = 27) in Group1 and 61.5 % (n = 72) in Group 2). In Group 1 the median follow-up was 6.9 months and in Group 2 this was 7 months; the median OS was 15.5 months in Group 1 and 49.5 months in Group 2 but this is not statistically significant (Log rank = 0.796). In Group 1, the engraftment times for platelets was 13 days, for neutrophils 17 days; in Group 2, for platelet this was 18 days; and for neutrophils 17 days; this was statistically significant for platelets but not for neutrophil engraftment (p: < 0.001 and p:0.839, respectively). Eighteen patients (40 %) in Group 1 and twenty-seven (23 %) patients in group 2 had acute GVHD (aGVHD). In Group 1 aGVHD rates were higher than Group 2 (p = 0.031). Seven patients (15.5 %) in Group 1 and 6 (5.12 %) patients in group 2 had chronic GVHD (cGVHD). In Group 1 cGVHD rates were also higher than Group 2 (p = 0.048). Twenty-five patients (55.6 %) in Group 1 and 19 patients (16.2 %) in Group 2 had relapsed disease (p < 0.001). Our study showed that there were no differences in survival across the groups. The platelet engraftment time was shorter for the PTCy 25 mg/kg ×2 doses compared to the post-transplantation 50 mg/kg ×2 doses. Both aGVHD and cGVHD rates were higher in 25 mg/kg ×2 dose treated patients. Relapses occurred more commonly with 25 mg/kg ×2 PTCy dose.

HLA-matched related peripheral blood stem cell and bone marrow transplantation with RIC regimens yield comparable outcomes for adult AML.

Understanding differences in clinical outcomes between PBSCT and BMT is important, and this study compared outcomes of HLA-matched related PBSCT and BMT using reduced-intensity conditioning (RIC) in adult acute myeloid leukemia (AML) patients. Data from 402 patients who underwent either PBSCT (n=294) or BMT (n=108) between 2000 and 2022 were analyzed using the Japanese nationwide registry database. The primary endpoint was overall survival (OS), and secondary endpoints included disease-free survival (DFS), non-relapse mortality (NRM), and GVHD. Results indicated no significant difference in 3-year OS (44.6% for PBSCT vs. 46.9% for BMT, HR 1.173, P=0.299) and DFS (42.1%vs. 41.8%, HR 1.073, P=0.639). PBSCT was more beneficial for avoiding relapse (20.3%vs. 12.4%, HR, 0.715, P=0.059). However, PBSCT was associated with higher NRM (20.3%vs. 12.4%, HR 1.801, P=0.025) due to more frequent, chronic GVHD (HR 1.889, P=0.035). Subgroup analysis did not reveal specific patient groups that benefited more from PBSCT or BMT. Incidence of extensive chronic GVHD and NRM has improved in PBSCT recipients in recent years (2014-2022). We conclude that related PBSCT with RIC regimens offers comparable prognosis to BMT for adult AML patients. Further optimization of prophylactic strategies for chronic GVHD is required to improve outcomes after PBSCT.

Haploidentical Stem Cell Transplantation With Dual Source of Cells and Post-Transplant Cyclophosphamide.

Dual sources of cells (DSC) with peripheral blood stem cell apheresis (PBSC) and surgical bone marrow (BM) for haploidentical hematopoietic cell transplantation (Hid-HCT) are used in China and some Asian countries. The experience of the Baltimore group for haploidentical transplant with post-transplant cyclophosphamide (PT-Cy) and reduced-intensity-conditioning (RIC) regimen used BM as a source of hematopoietic stem cells. We retrospectively analyzed 64 Hid-HCT with DSC and PT-Cy, RIC (n = 57), or myeloablative-conditioning (MAC) (n = 7), from two public health Brazilian centers, with a median follow-up of 23.3 months (6.7-45.4). The 49 malignant patients were 27/46 (58.7%) beyond the first remission or with no complete response, and three patients did not complete disease status evaluation before transplant. Eight of 62 patients (12.9%) had grade 2 or more Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), and two patients had no HCT-CI classified. Cytomegalovirus (CMV) viremia occurred in 26 of 57 (45.6%). The cumulative incidence of 100-day grade III-IV acute GVHD was 12.3% (7/57), with a 95% confidence interval (CI) of 3.8% and 20.8%, and 2-year moderate or severe chronic GVHD was 21.1% (11/52; 95% CI, 10.1%-32.3%). The 2-year relapses were 24.5% for malignant disease (12/49; 95% CI, 12.4%-36.5%). The 2-year overall survival (OS) probability was 54.7% (35/64; 95% CI, 42.5%-66.9%). Benign diseases achieve 2-year OS in 73.3% (11/15; 95% CI, 51%-95.7%) of the patients. The HCT-CI were significant in multivariate analyses for DFS (p = 0.002) and OS in uni- and multivariate analyses (both p < 0.001). The number of CD34+ cells by apheresis collection was significant in multivariate analysis for DFS (p = 0.039). Hid-HCT using PT-Cy, DSC, and RIC is a safe option for benign and malignant diseases.

Effectiveness of ibrutinib in the management of chronic GVHD.

Chronic graft-versus-host disease (cGVHD) represents a significant adverse event that may ensue following allogeneic hematopoietic stem cell transplantation (Allo-HSCT). In patients resistant to corticosteroids, which is the first-line treatment for cGVHD, ibrutinib is being evaluated as a potential treatment option. In this study, we aimed to share the findings of our multicenter study regarding the outcomes of ibrutinib treatment in patients with corticosteroid-resistant cGVHD who had previously received multiple systemic therapies. A retrospective analysis was conducted to examine the clinical characteristics and outcomes of patients who received ibrutinib treatment for corticosteroid-resistant cGVHD after Allo-HSCT. A total of 24 patients diagnosed with cGVHD who received ibrutinib treatment were included in the study. The median age of the patients was 34.5 (20-67). The included patients were followed for a median of 6 (1-30) months. All patients had stem cells collected from the peripheral blood. Fifty percent of the patients had multiple organ involvement, while the other 50 % had single organ involvement. The most frequently affected organs were skin and liver. On average, patients received four (3-5) lines of systemic therapy before ibrutinib treatment. At week 24 of ibrutinib treatment, 10 patients (41.7 %) had a complete response, and 10 patients (41.7 %) had a partial response; at week 48, 8 patients (33.3 %) had a complete response, and 10 patients (41.7 %) had a partial response. The most common hematological side effect after ibrutinib treatment was thrombocytopenia in 5 out of 24 patients, while the most common non-hematological side effect was CMV infection in 6 out of 24 patients. In patients with corticosteroid-resistant cGVHD, ibrutinib treatment has been demonstrated to be an efficacious option exhibiting an elevated overall response rate and a tolerable side effect profile.

G-CSF-primed bone marrow transplantation experience in 350 matched sibling donor grafts for Severe Thalassemia.

For matched related hematopoietic cell donor transplantation (HCT) for non-malignant diseases most centres prefer bone marrow (BM) over peripheral stem cell (PBSC) grafts due to increased risk of chronic GVHD associated with the latter. BM generally entails delayed neutrophil and platelet recovery compared to PBSC transplants. G-CSF-primed bone marrow (G-BM) has been associated with faster hematological recovery while retaining a decreased risk of GVHD. Moreover, it may allow for reduced marrow collection volumes. We retrospectively analysed our experience with G-BM as graft source from July 2015 to February 2023 across 350 consecutive first matched sibling transplants in children with severe thalassemia in four centres in India. We observed that G-BM is associated with rapid hematological recovery with relatively low rates of CMV reactivation (16%), low rates of moderate to severe GVHD (grade 3-4 acute GVHD was 5% and moderate to severe chronic GVHD was 3%), reduced marrow collection volumes (12.5 ml/Kg of donor's weight), and thus is potentially safer for both donors and recipients compared with standard bone marrow. This observation was made in a relatively homogenous cohort of multiply transfused patients with thalassemia who are at high risk of rejection. None of the donors required third-party blood transfusion irrespective of donor-recipient weight discrepancy. Our experience suggests that G-BM is associated with prompt engraftment and very low rates of moderate or severe GVHD. It also appears to be safe for donors and decrease the risk for third-party red cell transfusions. Finally, its relatively easy and inexpensive to collect. G-BM should be strongly considered as a preferable graft source in matched-related donor transplantations for thalassemia and potentially other transplant indications.

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.