Limited Chronic Graft-versus-host Disease Research Articles

Early Engraftment and Immune Kinetics Following Allogeneic Transplant Using a Novel Reduced-Toxicity Transplant Strategy in Children/Adolescents with High-Risk Transfusion-Dependent Thalassemia: Early Results of the ThalFAbS Trial.

Allogeneic hematopoietic stem cell transplantation is challenging for patients with transfusion-dependent thalassemia who have experienced iron overload and received chronic transfusion support. A transplantation strategy including a reduced-intensity preparative regimen and tailored immunosuppression to support donor engraftment and prevent graft-versus-host disease (GVHD) was developed for this population. The combination of a pretransplantation immunosuppression phase with reduced dosing of fludarabine/prednisone, a treosulfan-based preparative regimen with reduced cyclophosphamide dosing, and introduction of a calcineurin/methotrexate-free GVHD prophylaxis/engraftment supporting regimen with abatacept/sirolimus/antithymocyte globulin was tested. In the ThalFAbS trial, a prospective pilot trial (ClinicalTrials.gov NCT05426252) of a transplantation strategy designed for higher-risk patients with transfusion-dependent thalassemia, 12 pediatric patients (4 with alpha thalassemia, 8 with beta thalassemia) were treated with this strategy. Descriptive statistics were used to characterize transplantation outcomes and immune recovery. With a median follow-up of 12 months (range, 4 to 26 months) post-transplantation, all 12 patients had prompt and durable trilineage donor engraftment with low transplantation-related morbidity and acute GVHD and are alive without transfusion support at the time of this report. GVHD was limited to 1 patient with skin-only grade II acute GVHD and 3 patients with limited oral chronic GVHD. Early hematologic and immunologic recovery was achieved, with low rates of transfusion support and infection. Neutrophil recovery occurred at a median of 18 days (range, 15 to 24 days), and platelet recovery occurred at a median of 18 days (range, 12 to 36 days). No patients experienced veno-occlusive disease, transplantation-associated thrombotic microangiopathy, or sepsis. This platform was sufficient to support haploidentical donor transplantation in 2 patients. The ThalFAbS approach is tailored to meet the unique needs of transfusion-dependent thalassemia patients. Delivery of this novel regimen is feasible, and it shows excellent early engraftment and transplantation outcomes. Further follow-up of this cohort and expansion of patient numbers is needed before the findings can be generalized, but early experience is promising.

Effect of graft-versus-host disease on outcomes of HLA-haploidentical peripheral blood transplantation using post-transplant cyclophophamide.

There is limited evidence regarding the association between graft-versus-host disease (GVHD) and reduced relapse in patients who undergo allogeneic hematopoietic stem cell transplantation from haploidentical donors (haplo-HSCT) using post-transplant cyclophosphamide (PTCY). We investigated the association between GVHD and transplant outcomes in 938 patients who received haplo-HSCT using PTCY. Overall survival (OS), relapse rate, and non-relapse mortality (NRM) were evaluated using landmark analysis at the landmark points at 100 and 360 days after HSCT for acute and chronic GVHD, respectively. Grade I-II acute GVHD was not associated with OS (adjusted hazard ratio: 1.15, 95% confidence interval: 0.85-1.57), relapse (1.03, 0.74-1.45) and NRM (1.15, 0.74-1.77). Conversely, grade III-IV acute GVHD was associated with higher NRM (3.16, 1.61-6.19), but no other outcomes. Limited chronic GVHD was not associated with OS (1.11, 0.48-1.95), relapse (1.05, 0.30-3.75) and NRM (1.30, 0.45-3.79). Extensive chronic GVHD was associated with higher NRM (2.40, 1.03-5.57), but no other outcome. In conclusion, any GVHD was not associated with a reduced relapse rate and improved OS, and Grade III-IV acute GVHD and extensive chronic GVHD were associated with higher NRM in patients who received haplo-HSCT using PTCY.

Systematic review and meta-analysis of anti-thymocyte globulin dosage as a component of graft-versus-host disease prophylaxis.

Rabbit anti-thymocyte globulin (ATG) has been used in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for graft-versus-host disease (GvHD) prophylaxis. Since the best dose has not been defined yet, this study aimed to determine the efficacy and safety of different doses of ATG in Allo-HSCT. Data sources were MEDLINE/PUBMED, EMBASE, Cochrane Library, Web of Science, LILACS, and SciELO. Studies were eligible when comparing doses of ATG. The higher dose was in the intervention group. A total of 22 articles (2002-2022) were included. Higher doses (4-12 mg/kg) of ATG-T reduced the incidence of grade III-IV acute GvHD (RR 0.60; 95%CI 0.42-0.84) and limited chronic GvHD (RR 0.64 95%CI 0.45-0.92) compared with lower doses (2-7.5 mg/kg). Higher doses increased the Epstein-Barr virus (RR 1.90 95% CI 1.49-2.42) and Cytomegalovirus reactivation (RR, 1.30; 95% CI 1.03-1.64). Relapse rates were higher in the higher dose group (RR 1.34, 95% CI 1.07-167). The ATG-T dose ≥7mg/kg versus the lower dose showed a number needed to treat 7.4 for acute GvHD III-IV, with a number to harm of 7.7 for relapse at one year in the higher dose group. A dose lower than 7 mg/kg suggests a better risk-benefit ratio than a higher one. Well-designed RCT is needed to define the best risk-benefit doses. Trial registration: Trial registration number: PROSPERO: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020173449.

Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia

The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n=1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P < .001, log-rank test) and limited chronic GVHD (P < .001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, .73, 95% confidence interval [CI], .60 to .87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, .70 to 1.64; P for interaction=.038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.

Mild Acute Graft-Versus-Host Disease Improves Outcomes After HLA-Haploidentical-Related Donor Transplantation Using Posttransplant Cyclophosphamide and Cord Blood Transplantation

Haploidentical-related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) and cord blood transplantation (CBT) are valid alternatives for patients with hematological malignancies when HLA-matched donor transplantation (MDT) is unavailable. However, the effects of graft-versus-host disease (GVHD) on outcomes after these transplants have not been fully elucidated. Therefore, we evaluated the effects of acute and chronic GVHD on transplant outcomes after PTCy-haplo transplants and compared them with CBT and MDT. We included a total of 914 adult patients with hematological malignancies in the Kyoto Stem Cell Transplantation Group registry who received PTCy-haplo (N = 120), CBT (N = 402), and MDT (N = 392), and achieved neutrophil engraftment. A multivariate analysis revealed that grade I–II acute GVHD improved of overall survival (OS) after PTCy-haplo [hazard ratio (HR) = 0.39, P = 0.018] and CBT (HR = 0.48, P < 0.001), but not after MDT (HR = 0.80, P = 0.267) compared with patients without acute GVHD. Grade I–II acute GVHD had a trend toward reducing the risk of nonrelapse mortality (NRM) after PTCy-haplo (HR = 0.13, P = 0.060) and this positive effect was significant after CBT (HR = 0.39, P = 0.003). A negative impact of grade III–IV acute GVHD on NRM was observed after CBT and MDT, but not after PTCy-haplo. Limited chronic GVHD had a positive impact on OS after CBT and MDT, but not after PTCy-haplo. In conclusion, mild acute GVHD improved outcomes after PTCy-haplo and CBT, and limited chronic GVHD improved outcomes after CBT and MDT. These data indicated that the effects of GVHD on transplant outcomes depended on transplant platforms.

Outcome of Patients Undergoing Hematopoietic Cell Transplantation for TP53-Mutated Acute Leukemias and MDS: Effect of Conditioning and GvHD Prophylaxis Regimens Intensity

TP53 mutations are seen in ~ 5-10% of hematological malignancies and 25-40% of patients with therapy related myelodysplastic syndrome (MDS) or acute leukemias (AML and ALL). Several studies have demonstrated inferior survival outcomes in patients with TP53-mutated AML/MDS with 3-year overall survival (OS) of 10-20% regardless of chemotherapy used. Furthermore, data on treatment outcomes in patients TP53-mutated disease after allogeneic hematopoietic cell transplantation (HCT) is conflicted with some studies reporting no survival benefit with HCT when compared no HCT(HR 0.97) with 3-year OS of 11%; and other studies showing a trend towards longer survival in those who underwent allogeneic HCT (14.5 months vs 7.9 months; p=0.09).This conflicting results may be at least partially due to heterogeneity in conditioning / graft-versus-host disease (GvHD) prophylaxis regimens. Here, we aimed to describe treatment outcomes in TP53-mutated patients who underwent different combinations of conditioning regimen intensity [fludarabine and melphalan (FM) as reduced intensity conditioning (RIC) or radiation-based myeloablative conditioning (MAC)], and GvHD prophylaxis regimens [post-transplant cyclophosphamide (PTCy) or tacrolimus/Sirolimus (T/S)]. We retrospectively studied 99 patients with TP53 mutated acute leukemias (AML 48.5%, ALL 23.2%) or MDS (28.3%) who underwent HCT with mobilized peripheral blood stem cell (PBSC) as graft source between January 2015 and December 2021. TP53 mutations confirmed by deletion of chr17/17p using FISH/cytogenetics or by HopeSeq NGS were included. Table 1 details patient and HCT characteristics. The median age was 61 years (range: 15-77 years), and 62.6% of patients were males, 87.9% had a KPS >80, 63.6% had a high/very high DRI score and 54.5% had a HCT co-morbidity index ≥3. Donors were matched unrelated or matched sibling in 40.4% and 38.4%, respectively. Conditioning regimen was either radiation (RT) based MAC (n=35; 35.4%) or RIC with FM (n=64; 64.6%). GVHD prophylaxis was PTCy-based in (n=27; 27.3%) and T/S-based in (n=72; 72.7%). For the overall group, 1-year OS, and disease-free survival (DFS) were 48.8% (95% CI: 0.37 -0.59), 36.9% (95% CI: 0.26 -0.47), respectively. Cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) were 36.2% (95% CI: 0.26 -0.46) and 27% (95% CI: 0.18 -0.36), respectively. The cumulative incidence of Day 100 grade 2-4 and 3-4 acute GVHD were 37.4% (95% CI: 0.27 -0.47) and 17.6% (95% CI: 0.10 -0.26). CI of 1 year limited and extensive chronic GvHD were 33.8% (95% CI 0.23 -0.44) and 31.2% (95% CI 0.21 -0.41), respectively. On multivariate analysis, intensity of conditioning or GvHD prophylaxis did not affect OS when FM was compared with RT-based conditioning (HR: 1.14; 95%CI: 0.65-2.1, P=0.64) and PTCy was compared to T/S- based GvHD prophylaxis (HR: 1.41; 95%CI: 0.74-2.67, P=0.27). Conditioning regimen or GVHD prophylaxis intensity did not affect RFS, CIR and NRM. Patients with a DRI score <3 had a better OS (HR: 2.33; 95%CI: 1.25-4.36, P=0.005), RFS (HR: 2.02; 95% CI: 1.15-3.54, P=0.01) and NRM (HR: 3.56, 95% CI: 1.22-10.39, P=0.014) without an impact on relapse rate. Complex Karyotype was associated with lower OS (HR: 2.72, 95%CI: 1.17-6.35, P=0.015) and RFS (HR: 2.19, 95%CI: 1.08-4.44, P= 0.024) but did not increase CIR or NRM. KPS >80 was associated with better OS, RFS and NRM but not CIR. Figure 1 depicts comparable 1-year OS and CIR among different combinations of conditioning regimens and GVHD prophylaxis of FM-PTCy (n=13), FM-T/S (n=51), RT-PTCy (n=14) and RT-T/S (n=21); with p value of 0.57 and 0.96, In this large single center study, patients with TP53 mutant acute leukemias or MDS who underwent HCT at our center had 1-year OS of 48.8%. Patients with better KPS and DRI score of < 3 had better OS with no effect on the risk of relapse. Outcomes of TP53-mutated patients undergoing FM-based RIC was comparable to patients with RT-based MAC regimen regardless of GvHD prophylaxis intensity. Our data provide insight on possible strategies for patient selection and optimization of pre-/post-HCT management and indicates that improving transplant outcomes in patients with TP53-mutated acute leukemias or MDS remains an unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of inborn errors of immunity patients with inflammatory bowel disease phenotype by allogeneic stem cell transplantation.

Patients with inborn errors of immunity (IEI) can suffer from treatment-refractory inflammatory bowel disease (IBD) causing failure to thrive and consequences of long-term multiple immunosuppressive treatments. Allogeneic haematopoietic stem cell transplantation (alloHSCT) can serve as a curative treatment option. In this single-centre retrospective cohort study we report on 11 paediatric and young adult IEI patients with IBD and failure to thrive, who had exhausted symptomatic treatment options and received alloHSCT. The cohort included chronic granulomatous disease (CGD), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency, STAT3 gain-of-function (GOF), Wiskott-Aldrich syndrome (WAS), dedicator of cytokinesis 8 (DOCK8) deficiency and one patient without genetic diagnosis. All patients achieved stable engraftment and immune reconstitution, and gastrointestinal symptoms were resolved after alloHSCT. The overall survival was 11/11 over a median follow-up of 34.7months. Graft-versus-host disease (GVHD) was limited to grade I-II acute GVHD (n= 5), one case of grade IV acute GVHD and one case of limited chronic GVHD. Since treatment recommendations are limited, this work provides a centre-specific approach to treatment prior to transplant as well as conditioning in IEI patients with severe IBD.

Low-Dose ATG Combined with Facybu Conditioning Regimen Followed By Single Unrelated Cord Blood Transplantation in Hematological Malignancies

Objective: This study aims to evaluate the efficacy and safety of low-dose ATG combined with FACyBu conditioning regimen for single unrelated cord blood transplantation in hematological malignanciesMethod: From Jul 2013 to Feb 2017, 30 patients of hematological malignancies (15 patients with ALL,11 patients with AML,3 patients with NHL,1 patient with CML ) who underwent unrelated cord blood transplantation were followed up. The median age was 24(3.16-46)years. Seventeen patients were in complete remission(CR) while 13 patients were in progressive stage. All the patients were pretreated with low dose ATG(Fresenius) (24patients 10.0mg/kg/d, 6 patients 5.0mg/kg/d;d-5,d-4) plus FACyBu(a myeloablative FA-BUCY protocol of 25 mg/m2/day Fludarabine and high-dose 2 g/m2/day Cytarabine for 5 consecutive days from day −13 to day −9, 1.8g/m2/day CY from day −8 to day −7, 3.2mg/kg/day BU from day −6 to day −4 and MCCNU 250mg /m2 d-3). Cyclosporine and mycophenolate were applied for Graft-versus-host disease (GVHD) prophylaxis. The GVHD, RFS, nonrelapse mortality, relapse mortality, OS, DFS and graft-versus-host disease-free/relapse-free survival (GRFS) probabilities were investigated. The side effects of the regimens were also evaluated.Result: The median CD34+ cell infusion quantity was 0.17 (0.07-1.26)*106/Kg. the median neutrophil engraftment time was 18(10-27)days and the median platelet engraftment time was 33(15-49)days. The cumulative incidence of grades II-IV acute GVHD was 23.5%. It's interesting that no grade III-IV acute GVHD was observed. The cumulative incidence of limited chronic GVHD and extensive chronic GVHD was 5.0% , 9.1% respectively. The median follow-up time was 10.8(2.6-46.1) months. The nonrelapse mortality, relapse mortality, OS, DFS and GRFS were 27.6%,10.9%,64.5%,64.4% and 61.4%, respectively. For the CR patients, the OS, DFS and GRFS were 85.9%, 85.9%, 80.2%, respectively. While for the nonremission patients, the OS, DFS and GRFS were 38.5%,28.5%, 38.5%Conclusion: The clinical efficacy of low-dose ATG combined with FACyBu conditioning regimen followed by single unrelated cord blood transplantation in hematological malignancies patients is similar to that of alternative allogeneic bone marrow transplantation as reported. The incidence of GVHD was low .The patients who were treated with this regimen experience good quality of life. DisclosuresNo relevant conflicts of interest to declare.

High proportion of terminally differentiated regulatory T cells after allogeneic hematopoietic stem cell transplantation.

It is now well-established that regulatory T cells (Treg) represent a heterogeneous group of CD4+ T cells. Previous studies have demonstrated that Treg homeostasis was impacted by allogeneic hematopoietic cell transplantation (allo-HCT) and particularly so in patients with chronic graft-versus-host disease (GVHD). Here, we first assessed the ability of various Treg subsets to phosphorylate STAT5 in response to IL-2 or IL-7 stimulation in vitro. We then compared the frequencies of different Treg subtypes in healthy controls as well as in allo-HCT patients with or without chronic GVHD. The highest phosphorylated STAT5 (pSTAT5) signal in response to IL-2 was observed in the CD45RO+CD26-CD39+HLA-DR+ Treg fraction. In contrast, naive Treg were mostly less susceptible to IL-2 stimulation in vitro. Following IL-7 stimulation, most Treg subpopulations upregulated pSTAT5 expression but to a lesser extent than conventional T cells. Compared to healthy controls, allo-HCT patients had lower frequencies of the naive CD45RAbrightCD26+ Treg subpopulation but higher frequencies of the most differentiated memory CD45RO+CD26-CD39+ Treg subpopulations. Further, unbiased analysis revealed that six Treg clusters characterized by high expression of CD25, HLA-DR, and ICOS were significantly more frequent in patients with no or with limited chronic GVHD than in those with moderate/severe chronic GVHD.

Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate

Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.

Haploidentical Hematopoietic Stem Cell Transplant Using Post-transplant Cyclophosphamide: A Single-Center Initial Experience in Vietnam.

Haploidentical transplants constitute a potential alternative therapy for patients who urgently need transplantation in the absence of human leukocyte antigen-matched donors. We report a single-center experience regarding the initial results of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) using post-transplant cyclophosphamide (PTCy) at the HCMC Blood Transfusion Hematology (BTH) Hospital. We conducted a retrospective case series study of 23 patients who underwent haplo-PBSCT using PTCy at the HCMC BTH Hospital between January 2014 and January 2021. The refined disease risk index (DRI) was used to stratify the outcomes. We evaluated the engraftment rate, graft-versus-host disease (GVHD), and complications during haploidentical transplantation. Overall survival (OS), disease-free survival (DFS), and GVHD-free relapse-free survival (GRFS) were assessed. The majority of the patients in the present study were diagnosed with acute myeloid leukemia. All patients received reduced-intensity conditioning regimens. The engraftment rate was 86.9%. The median times to neutrophil and platelet engraftment were 17 and 31 days, respectively. Two patients (8.7%) reported severe acute GVHD (grade III-IV), while two patients (8.7%) had grade I-II acute GVHD. Three patients experienced limited chronic GVHD of the skin, requiring topical steroids. The most common complication was bloodstream infection (60.9%). Cytomegalovirus reactivation occurred in 19 patients (82.6%) and 17.4% developed hemorrhagic cystitis. The 1-year relapse rate was 32.5%. The cumulative incidence of non-relapse mortality at 1 year was 17.3%. The 1-year OS and DFS rates were 66.3% and 55.7%, respectively. The 1-year GRFS rate was 49.2%. A high/very high DRI score was associated with worse OS after haplo-PBSCT (P=0.038). Haploidentical transplant using PTCy is a feasible therapy for patients without suitably matched donors in Vietnam. Infection after transplantation remains a challenge and requires effective management.

Effects of Acute and Chronic Graft-versus-myelodysplastic Syndrome on Long-term Outcomes Following Allogeneic Hematopoietic Cell Transplantation.

Potent graft-versus-tumor (GVT) effects associated with graft-versus-host disease (GVHD) might be dependent on hematologic disease type and status. However, the data regarding the impact of GVHD on transplant outcomes for patients with myelodysplastic syndrome (MDS) are limited. We retrospectively evaluated the impact of acute and chronic GVHD on transplant outcomes for a large cohort of adult patients with a low-risk (n = 1,193) and high-risk (n = 1,926) MDS treated by first allogeneic hematopoietic cell transplantation between 2001 and 2017. The multivariate analysis, in which development of GVHD was treated as a time-dependent covariate, showed that acute and chronic GVHD at any grade or severity did not improve overall mortality, relapse, or nonrelapse mortality (NRM) in low-risk MDS. For patients with high-risk MDS, development of limited chronic GVHD was significantly associated with lower overall mortality [HR, 0.66; 95% confidence interval (CI), 0.50-0.86; P = 0.002]. This is probably due to that the reduced risk of relapse with grade III-IV acute GVHD (HR, 0.41; 95% CI, 0.25-0.65; P = 0.0002), or limited (HR, 0.57; 95% CI, 0.39-0.83; P = 0.003) or extensive (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0004) chronic GVHD was offset by increased NRM with grade III-IV acute GVHD or extensive chronic GVHD in high-risk MDS. These data demonstrated a survival benefit of the graft-versus-MDS effect is present only in high-risk MDS patients with limited chronic GVHD.See related commentary by Eckel and Deeg, p. 6404.

BEAM-Campath Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Lymphoma: High Incidence of Long-Term Mixed Donor-Recipient Chimerism and the Response to Donor Lymphocyte Infusions

BiCNU (carmustine), etoposide, Ara-C, melphalan (BEAM) and Campath conditioning was developed to reduce the high transplant-related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy, as well as to some extent a platform for allogeneic stem cell engraftment. Significant numbers of patients appeared to have persistent recipient-derived hematopoiesis, and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM-Campath conditioned allogeneic stem cell transplantation at our center (2003 to 2017) to characterize the patterns of chimerism and patient outcomes. Chimerism was analyzed with short tandem repeat PCR. Mixed donor-recipient chimerism (MDRC) was defined as 5% to 94.9% donor. Fifty-two patients (n=30 male), with a median age of 45 years, were identified with histologic diagnoses of Hodgkin lymphoma (n=13), diffuse large B cell lymphoma (n=7), low-grade non-Hodgkin lymphoma (n=16), mantle cell lymphoma (n=10), and T cell lymphoma (n=6). Pretransplant, 93% achieved complete response (52%) or partial response (41%) with a median of 3 prior therapies (n=3 prior autologous stem cell transplantation). Donors were Matched sibling donors (MSD) (n=21), matched unrelated donors (MUD) (n=24), miss-matched unrelated donors (MMUD) (n=6), and syngeneic (n=1). Acute graft-versus host disease (GVHD) developed in 52% (81% grade I to II) and chronic GVHD (83% extensive) in 12%. MDRC of T cells (MDRCt) developed in 62% (n=32), and 29% (n=15) developed MDRC of myeloid cells (MDRCm) at a median onset of 100 days. Donor lymphocyte infusion (DLI) was given to 17 patients, with a median starting dose of 1×106/kg. The first DLI was given at a median of 225 days post-transplant (range, 99 days to 5.3 years). Of these, 9 developed acute post-DLI GVHD and 2 limited chronic GVHD. Conversion to full donor occurred in 47% MDRCt and 50% MDRCm. Multivariate analysis identified sibling donor type as associated with increased MDRCt (P=.035; hazard ratio [HR], 0.17) and reduced total nucleated cell dose with increased MDRCm (P=.021; HR, 0.76). The median follow-up was 6 years, and 2-year NRM cumulative incidence was 16% (95% confidence interval [CI], 7% to 27%). Ten-year progression and extensive GVHD-free survival was 45% (95% CI, 28% to 61%), and overall survival was 66% (95% CI, 50% to 78%). One-year landmark analysis identified no increased GVHD or relapse risk with MDRCt or MDRCm but reduced nonrelapse mortality (NRM) risk with MDRCt (P=.001). BEAM-Campath allografts for high-risk lymphoma achieve long-term disease-free survival with low rates of GVHD and transplant-related mortality. The frequent development of myeloid MDRC demonstrates that BEAM-Campath is a nonmyeloablative conditioning regimen in almost a third of patients. MDRCt is associated with reduced NRM, but neither MDRCt or MDRCm is associated with increased GVHD or relapse.

Haploidentical related donor vs matched sibling donor allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome aged over 50 years: A single-center retrospective study.

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a potentially curative therapeutic option for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Increasing data suggest that haploidentical donor (HID) transplantation achieve comparable outcomes with HLA‐matched sibling donor (MSD) in adult AML/MDS. This retrospective study compared the outcomes of AML or MDS patients age ≥50 years underwent HID and MSD transplantation. One hundred and fifty‐six patients were enrolled in this study, including 75 HID and 81 MSD transplantation. The 100‐day cumulative incidence of II‐IV° acute graft‐versus‐host disease (GVHD) was 33.3 ± 5.4% vs 22.2 ± 4.6%, respectively, in HID and MSD groups (P = .066), and III‐IV° acute GVHD was not significantly different between two groups (5.3%±2.6% vs 6.2%±2.7%, respectively, P = .823). The 2‐year cumulative incidence of limited and extensive chronic GVHD was not statistically different in HID and MSD groups (20.9 ± 5.5% vs 18.9 ± 4.8% and 13.0 ± 4.7% vs 19.7 ± 5.0%, P = .889 and P = .269, respectively). The 2‐year cumulative incidences of relapse (27.0 ± 5.6% vs 22.7 ± 5.1%, P = .509), 2‐year overall survival (63.0 ± 5.8% vs 66.7 ± 5.4%, P = .454), 2‐year transplant‐related mortality (17.2 ± 4.6% vs 17.4 ± 4.4%, P = .847), 2‐year progression‐free survival (59.3 ± 5.8% vs 64.5 ± 5.4%, P = .437), 2‐year GVHD‐free relapse‐free survival (42.6 ± 5.9% vs 40.9 ± 5.6%, P = .964) were not significantly different in the two groups. The present data showed equivalent outcomes in AML or MDS patients age ≥50 years underwent HID and MSD transplantation.

Comparison of ATG-thymoglobulin with ATG-Fresenius for Epstein-Barr virus infections and graft-versus-host-disease in patients with hematological malignances after haploidentical hematopoietic stem cell transplantation: a single-center experience

Two anti-thymocyte globulin (ATG) forms are used in graft-versus-host disease (GVHD) prophylaxis during haploidentical hematopoietic stem cell transplantations (haplo-HSCTs): ATG-thymoglobulin (ATG-T) and ATG-fresenious (ATG-F). However, comparable dosages for haplo-HSCT remain unclear. We compared and evaluated the effects of ATG-T (7.5 mg/kg) or ATG-F (20 mg/kg) dosages in a relatively homogenous population in haplotype HSCT settings. Patients administered ATG-T 7.5 mg/kg (n = 81) or ATG-F 20 mg/kg (n = 35) as part of GVHD prophylaxis during haplo-HSCT were enrolled. Incidence and severity of GVHD, Epstein–Barr virus (EBV) infection, and immune cell recovery were compared using the Mann-Whitney U rank test and chi-square test. Cumulative incidences of GVHD, EBV infection and its subgroups, and relapse mortality were computed; overall survival (OS) was analyzed using the Kaplan-Meier method, with the log-rank test used for univariate comparison. Risk factors for OS were analyzed by the Cox proportional hazards model. Incidence and cumulative incidence of all grades of acute GVHD and subgroups were comparable in both groups (all p > 0.05); however, cumulative incidence of any grade and limited chronic GVHD was significantly higher in the ATG-T group (p = 0.002, p = 0.007, respectively). Cumulative incidences of EBV infections, EBV-DNAemia, and EBV-related diseases were similar; relapse mortality and OS rates were comparable between both groups (all p > 0.05). ATG-T dosage (7.5 mg/kg) appeared comparable to ATG-F dosage (20 mg/kg) for haplo-HSCT. Currently approved ATG-T and ATG-F doses appear efficient to balance the risk–benefit ratio of GVHD, OS, relapse mortality, and EBV infection in haplo-HSCT.

International Retrospective Study of Allogeneic Hematopoietic Cell Transplantation (HCT) for Activated Phosphoinositide 3-Kinase Delta (PI3K) Syndrome

Mutations resulting in increased PI3K signaling confer increased risk of B cell lymphoma, recurrent infections, poor viral control, and autoimmunity. Allogeneic HCT is curative, but the optimal approach to HCT for these patients is still evolving as experience grows. Herein, we present the clinical outcomes of 27 patients transplanted for activating PI3K mutations. Required approvals were obtained by contributing centers. Nineteen <i>PIK3CD</i> patients and 8 <i>PIK3R1</i> patients received 22 and 10 HCTs respectively, at median age 12 years (range 2-66) at time of first HCT. Significant pre-HCT comorbidities were common, Fig 1. Conditioning platforms varied in intensity; most included serotherapy (84%). With median survivor follow up of 26.3 months from first HCT (range 2.4-71.8), overall survival was 85% (3 infectious deaths and 1 due to organ toxicity); graft failure (GF)-free survival (GFFS) was estimated at 80% at 1 year but declined to 68% by 2 years, Fig 2. Neutrophil engraftment occurred at median 15.5 days (range 11-33) with autologous recovery in 1 patient at day +14 and another deceased prior to engraftment. Four engrafted patients are alive and well despite mixed donor chimerism (<95%). Nine (33%) patients required 24 total subsequent unplanned donor cell infusions (DCI) for mixed chimerism (n=15), poor graft function (n=2), infection (n=1), GF (n=3), malignancy relapse (n=1), or to improve immune reconstitution (n=2). Grade 2-4 acute graft versus host disease (GVHD) occurred in 27% patients, with Grade 3-4 acute GVHD and limited self-resolved chronic GVHD in 1 (4%). Organ toxicities and infectious complications are summarized in Fig 3; CMV infection requiring treatment occurred in 11 (41%) patients with disease in 3 (11%). Serotherapy use, conditioning intensity, and degree of donor human leukocyte antigen (HLA) match were not significantly associated with cumulative incidence of GF or subsequent unplanned DCI (with death as a competing risk), while mTOR inhibitor use post-HCT was associated with subsequent unplanned DCI for graft augmentation or GF (p=0.006). An mTOR inhibitor was used within the year following 12 HCTs, for primary GVHD prophylaxis (n=7) or to treat disease manifestations or GVHD; loss of chimerism and/or need for subsequent DCI occurred in 9 of these. Patients with activating PI3K mutations are at overall significant risk of GF or need for subsequent DCI. While we found no association with GF or DCI for discrete elements such as serotherapy use, donor source, or conditioning intensity, small numbers preclude conclusions regarding the optimal HCT approach, and more HCTs with longer follow up are needed to refine these preliminary findings. Post-HCT mTOR inhibitor exposure was associated with need for subsequent unplanned DCI, perhaps by providing a survival advantage to host lymphocytes, and may thus be detrimental in these patients during the early post-HCT timeframe.

A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

<h3>Background</h3> The optimal regimen for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. Post-transplant cyclophosphamide (PT-Cy) mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. We investigated the benefit of PT-Cy in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. <h3>Methods</h3> We conducted a phase II clinical trial of PT-Cy for GVHD prophylaxis following MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 to +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. <h3>Results</h3> There were 39 patients enrolled in the study. The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). The most commonly used conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV. The incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of these were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1-year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. <h3>Conclusion</h3> The use of one dose of PT-Cy in combination with MMF and tacrolimus is effective in preventing acute severe GVHD in myeloablative PBSC MUD HSCT recipients. We observe modest control over chronic GVHD with this regimen which may be explained by giving one dose of PT-Cy only. We report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD and may play a vital role in mismatched unrelated donor transplants as well.

Non-Myeloablative Bone Marrow Transplant with Post-Transplant Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Transfusion Dependent Thalassemia: Results of an International Consortium (VGC2)

<h3>Background</h3> Post-transplant cyclophosphamide (PTCy) enables allogeneic hematopoietic cell transplant (Allo-HCT) across the human leukocyte antigen barrier. Allo-HCT for severe transfusion dependent thalassemia is restricted in its application due to limited donor availability, graft rejection, and regimen-related toxicities. We explored the use of a common non-myeloablative (NMA) conditioning regimens with PTCy based graft-versus-host disease (GvHD) prophylaxis for matched related, haploidentical, and unrelated donors in the setting of a collaborative consortium. <h3>Methods</h3> A multicenter learning collaboration involving 3 centers used an augmented NMA conditioning with PTCy developed by John Hopkins group (Bolaños-Meade, Blood 2012). All patients received common conditioning regimen consisting of ATG 4.5 mg/kg, fludarabine 150 mg/m², cyclophosphamide 29 mg/kg, thiotepa (10 mg/kg on day -7) and TBI 200 cGy. Graft versus host disease (GvHD) prophylaxis was PTCy 50 mg/kg on days +3 and +4, MMF, and sirolimus. To improve engraftment rates, all patients received preconditioning with hydroxyurea 30mg/kg x 60 days (Figure 1). Most patients received G-primed bone marrow as stem cell source. Two patients received matched related donor (MRD), 4 patients haploidentical, and 3 patients matched unrelated donor (I-MUD, 2-mismatched MUD) bone marrow transplants (Figure 2). <h3>Results</h3> A total of 9 patients with transfusion dependent thalassemia were included with a median follow-up time of 371 days. One case of primary graft failure was seen in the haploidentical cohort at D+32; 89% (8/9) patients successfully engrafted. Two cases each of mild gut and skin acute GvHD and one case each of limited gut and skin chronic GvHD were seen in transplanted patients. No cases of grades III-IV acute or severe, chronic GvHD were seen. All patients are alive, thalassemia free survival (TFS) was 100% in the MRD and M/MUD recipients, but 75% (3/4) in the haploidentical cohort. There was no statistical difference between groups in regards to neutrophil or platelet engraftment, age, TNC or CD34+ cell dose. No engrafted patient required long-term immunosuppression therapy, and all remain transfusion independent. <h3>Conclusion</h3> We have shown the feasibility of NMA conditioning with PTCy plus thiotepa for severe transfusion dependent thalassaemia. A phase II study will help determine the optimal regimen with least toxicity and improved thalassaemia free survival.

Partially CD3+-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy.

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3+/CD19+ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.

Post-Transplant Cyclophosphamide Improved Outcomes of HLA Mismatched Hematopoietic Stem Cell Transplantation in Children with β-Thalassemia Major

Background:Hematopoietic stem cell transplantation(HSCT) is currently the only treatment shown to provide an effective, definitive cure for β-thalassemia major (TM). All over the world a major constraint is the lack of access to this therapy related to the lack of a suitable donor. Matched related donors are generally available only for a third of patients with TM.The need for alternative donors has therefore been explored in several ways-partially mismatched related donors, related haploidentical transplants,and matched or mismatched unrelated donors.Persisting concerns regarding high rejection rates and graft versus host disease (GVHD) need to be addressed through the evaluation of novel protocols in current and future studies.The effect of alloreactive clone destruction in post-transplant cyclophosphamide (Cy, PTCy) transplant resulted in low GVHD and high relapse but nice immuno-recovery and immuno-tolerance by keeping antivirus and regulatory T cells. Therefore, we developed a novel protocol for TM patients received HSCT form HLA mismatched donors. Patients and methods:Twenty patients received HSCT form HLA mismatched donors between May 2014 and May 2017,with median follow-up time of 38 months (range: 2-65months).The median age at transplant was 8 years (rang:4-13years). Of them, 15 patients received unrelated- donor peripheral blood stem cell transplant(UD-PBSCT) consisted of 13 HLA 9/10(HLA-A loci,DRB loci and DRQ loci mismatched are 8,2and2,respectively) and 2 HLA 8/10(1 HLA-A and DRB loci mismatched and 2 HLA-DRB and DRQ loci mismatched), another 5 patients received HLA 9/10 related-donor peripheral blood stem cell transplant (RD- PBSCT) consisted of 3 HLA-A loci and 2 HLA-DRB loci mismatched.Among them,3 patients received adopting bone marrow(BM) and/or unrelated-donor cord blood(UD-CB). Conditioning regimen included Thymoglobuline on day -10 to -8, Cy on day-7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. GVHD prophylaxis consisted of Cy on day+3 to +4, Mycophenolate mofetil and Tacrolimus from day+6. BM or UCB was infused on day+1.GVHD prophylaxis consisted of Cy on day+3 to+4, Mycophenolate mofetil and Tacrolimus from day+5. Results:The median infused total nucleated cell (TNC) dose was 24.8×108/kg (range: 9.0-40.2×108/kg). The median dose of infused CD34+ cells was 13.88×106/kg (range 2.89-38.76× 106/kg). All twenty patients had a successful engraftment with &amp;gt; 95% donor-derived cells by day 30 after transplantation.The median time to neutrophil recovery was 21 days (range 16-36days). The platelet and hemoglobin engraftment times were 14 days (range10-65days) and 15 days (range 8-48days), respectively.The cumulative incidences of grades Ⅱ-III acute GVHD (aGVHD) was 10.0% (2/20 patients).No patient developed grade IV aGVHD after transplantation. No extensive or limited chronic GVHD(cGVHD) was diagnosed among any patients in the group.The incidences of CMV and EBV antigenmia were 10.0% (2/20) and 0%(0/20), respectively. All of the 20 patients were alive without TM, and overall survive(OS)and thalassemia free survive (TFS) were 100% and 100%, respectively.We also compared the outcomes of PTCy protocol with fifty-two patients with β-TM received one or two locis HLA mismatched HSCT by use of the NF-08-TM protocol(see Li et al., Blood 2012).OS and TFS were higher in the PTCy group(100%vs.90.4%,p&amp;lt;0.05 and 100%vs.86.5%,p&amp;lt;0.05, respectively;).No patients in the PT Cy protocol group had GR, whereas 2 patients had GR in the NF-08-TM protocol group (0.00% vs.3.84%,p&amp;lt;0.05,respectively ).Of the 50 patients who had a successful in the NF-08-TM protocol group engraftment,aGVHD occurred in 8 patients and the incidence of grade Ⅱ-III and IV aGVHD were 6% and 6% (3/50 and 3/50 patients), respectively. One pulmonary cGVHD was diagnosed in the NF-08-TM protocol group and one patient died of IV GVHD.Compared to the NF-08-TM protocol group, patients in PTCy protocol group had a lower incidence of aGVHD(10.00% vs.16.00%,p&amp;lt;0.05), especially IV aGVHD (0.00% vs.6.00%, p&amp;lt;0.05). Conclusion: PTCy protocol leaded to 100% OS and TFS with low GR and GVHD rate compared with the NF-08-TM protocol in patients with β-TM who received HSCT form HLA mismatched donors. A large-cohort study with extending follow-up time should be developed in the future. Disclosures No relevant conflicts of interest to declare.