Unrelated Donor Hematopoietic Stem Cell Transplantation Research Articles

Increased donor inhibitory KIR are associated with reduced GVHD and improved survival following HLA-matched unrelated donor HCT in paediatric acute leukaemia.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after haematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting. Paediatric acute leukaemia patients were retrospectively analysed, and KIR-KIRL combinations and maximal inhibitory KIR ligand (IM-KIR) scores were determined. Clinical outcomes were examined using a series of graphs depicting clinical events and endpoints. The graph methodology demonstrated that prognostic variables significant in the occurrence of specific clinical endpoints remained significant for relevant downstream events. KIR-KIRL combinations were significantly predictive for reduced grade 3-4 aGVHD likelihood, in patients transplanted with increased inhibitory KIR gene content and IM-KIR = 5 scores. Improvements were also observed in associated outcomes for both ALL and AML patients, including relapse-free survival, GRFS and overall survival. This study demonstrates that NK cell KIR HLA interactions may be relevant to the paediatric acute leukaemia transplant setting. Reduction in aGVHD suggests KIR effects may extend beyond NK cells. Moving forward clinical trials utilizing donors with a higher iKIR should be considered for URD HCT in paediatric recipients with acute leukaemia to optimize clinical outcomes.

Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression

We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1–2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 107/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.

Excellent Outcome Following Haplo-Identical and Unrelated Donor HSCT for Young Patients with Sever Aplastic Anemia Using Reduced Dose TBI and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis

Excellent Outcome Following Haplo-Identical and Unrelated Donor HSCT for Young Patients with Sever Aplastic Anemia Using Reduced Dose TBI and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis

Reduced human leukocyte antigen mismatching is associated with more favourable outcomes after unrelated donor haematopoietic stem cell transplantation.

The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p=.031; hazard ratio [HR] 1.935) and 6 months (p=.004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p=.006; HR 2.642) as well as at 6-month (p=.007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p=.034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1+DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.

Dynamics of Immune Reconstitution after Unrelated Allogeneic Transplantation with Post-Transplantation Cyclophosphamide Compared to Classical Immunosuppression with ATG

Introduction: Post-transplant cyclophosphamide (PTCY), in hematopoietic stem cell transplantation (HSCT), is responsible for the success of haploidentical stem cell transplantation and is also being used in matched transplants such as unrelated transplants, with promising outcomes in graft versus host disease (GVHD). However, we lack data on immune reconstitution with this type of immunosuppression, especially in unrelated transplantation. Immune reconstitution is directly involved with post-transplant morbidity and mortality, being related to GVHD, relapses and infections, such as cytomegalovirus (CMV). Objectives: To evaluate global and CMV-specific immune reconstitution after unrelated donor HSCT, comparing the use of thymoglobulin (ATG) or PTCY protocol. Methods: We prospectively included patients undergoing first unrelated donor HSCT with ATG, methotrexate and tacrolimus or PTCY (50mg/Kg D+3 and D+4), mycophenolate mofetil (MMF) and tacrolimus with patient and/or donor CMV IgG positive. Immune reconstitution analyzes were performed by flow cytometry and CMV-specific recovery by ELISPot technique on days +30, +60, +90 and +180 post HSCT. Results: Thirty-six patients were included in this study, 20 in the ATG group and 16 in the PTCY group (table 1). Only 2 patients were 9x10 match, and the others were 10x10 match. All patients were submitted to preemptive strategy of CMV treatment, without the use of letermovir. Regarding clinical outcomes, neutrophilic engraftment was earlier with ATG (median of 12 days), compared to PTCY (median of 16 days) (p=0.0001). There was no difference between the groups in terms of length of hospital stay (median 33 days in both groups), CMV reactivation (70% in ATG and 75% PTCY, p=0.98), acute GVHD grades II to IV (p=0.26) or grades III-IV (p=0.56), and chronic GVHD (p=0.45), as well as relapse (p=0.3), non relapse mortality (p=0.77) and overall survival (p=0.4). Regarding immune reconstitution we observed an initial expansion of monocytes and NK lymphocytes in both groups and a higher increase in CD8+ T lymphocytes was evidenced, with an inversion of the CD4/CD8 ratio (CD4 14.9% vs 15.5% p=0.9 and CD8 49.7% vs 54.5%p=0.5 in ATG and PTCY respectively). We identified a CD4+/CD8+ double-positive T cell (DP) population, which was higher in PTCY group compared to ATG on days +30 (3.5% vs 10.2%, p=0.009), +90 (3.1% vs 12% p= 0.01) and +180 (5.2% vs 13%, p=0.007, in ATG and PTCY respectively ). On day +30 there were higher proportion of T cells (19.9% vs 9.6% p=0.004), B cells (0.76% vs 0.2%, p=0.006) and NK cells (19.2% vs 8.6% p=0.006) in ATG group compared to PTCY and monocytes were higher in PTCY (31.7 vs 44.5%, p=0.02). On day +180 the proportion of B cell were higher in PTCY (6.1% vs 16.6% p=0.014) and the NK cells were higher in the ATG (22.4% vs 14.7% p=0.021) (Figure 1), with higher CD56dim population in ATG group (46% vs 33.6% p=0.0079), while in PTCY there were a higher NK population CD56high on day +60 (40.3% vs 61%, p=0.014). We identified a peripheral expansion of a CD56negCD16posNKG2Dpos NK cell population, which was higher in the PTCY group on day +180 (3.7% vs 13.2% p=0.017). Regarding CMV-specific immune response, we found no difference between the groups on days +30 (5 vs 5 spots/10 4 PBMC p=0.41), +60 (10 vs 6 spots/10 4 PBMC p=0.38), +90 (13 vs 4 spots/10 4PBMC p=0.33) or +180 (7 vs 6 spots/10 4 PBMC p=0.57). Conclusions: In the context of unrelated HSCT, we found no difference in CMV-specific immune response with the use of PTCY or ATG protocol. Post-transplant immunosuppression with PTCY compared to ATG protocol is related to lower levels of T cells, NK cells and B cells on day +30 and later neutrophil engraftment, but with a higher proportion of double positive T cells on days +30, +90 and +180 and a higher proportion of B cells on day +180. At 6 months after transplantation, a proportionately lower number of NK cells, but higher proportion of CD56negCd16posNKG2D NK population was observed in the PTCY group.

Addition of Daclizumab to Standard Graft-Versus-Host Disease Prophylaxis in Patients with Thalassemia Major Undergoing Transplantation from Related Haploidentical Donor and Unrelated Donor Hematopoietic Stem-Cell Transplantation: A Single-Center Retrospective Analysis from China

Background: Previous studies have confirmed that the incidence of graft-versus-host disease (GVHD) remained still very high in patients with thalassemia major (TM) undergoing related haploidentical donor and unrelated donor hematopoietic stem-cell transplantation (HID-HSCT and MUD-HSCT), which seriously affected patients' overall survival and thalassemia-free survival, especially acute GVHD (aGVHD). This study aimed to investigate whether Daclizumab at a dose of 1 mg/Kg on days +7, +14, +28 and +42 reduced GVHD plus standard GVHD prophylaxis (tacrolimus [FK506] plus methotrexate [MTX] and mycophenolate mofetil [MMF]) in TM patients with HID-HSCT or MUD-HSCT. Methods: We retrospectively analyzed our data of TM patients who underwent HID-HSCT or MUD-HSCT at the First Affiliated Hospital of Guangxi Medical University in China from November 2022 to July 2023. TM patients enrolled all received the GVHD prophylaxis which included Daclizumab at a dose of 1 mg/kg on days +7, +14, +28 and +42 plus FK506 (0.03mg/kg/day), MTX (15mg/m 2 on days +1, 10mg/m 2 on days +3, +6, +11), and MMF (250mg/day × 90 days). The primary endpoint was grades 2-4 aGVHD on days +100. Results: Data of 37 patients' transplantation were evaluated. The ratio of male to female was 20 to 17 with a median age of 8 years (range, 3-17 years). Patients were assigned to the HID-HSCT of 24 and the MUD-HSCT of 13. Median follow-up period was 7 months (range, 3 to 11 months). The total of the cumulative incidence rate of grades 2-4 aGVHD was 18.9%, and the rate of grades 3-4 aGVHD was 10.8%. Subgroup analysis showed that the rate of grades 2-4 aGVHD was 20.8% in HID-HSCT and 15.4% in MUD-HSCT, respectively; the rate of grades 3-4 aGVHD was 8.3% in HID-HSCT and 15.4% in MUD-HSCT, respectively. The median days of neutrophil engraftment were +12 days, platelets Implantation days were +14 days. The cytomegalovirus reactivation, Epstein-Barr virus reactivation, fungal infection and septicemia were seen in 16(43.2%), 3(8.1%), 6(16.2%) and 5(13.5%) patients, respectively. One patient in MUD-HSCT died of severe pulmonary infection, but no deaths were attributable to HID-HSCT (Figure 1, Table 1). CONCLUSION: The results of our study analysis suggest that Daclizumab at a dose of 1 mg/kg on days +7, +14, +28 and +42 provides clinically meaningful benefits when added to standard GVHD prophylaxis in TM patients undergoing haploidentical donor and unrelated donor transplantation, including decrease in the incidence rate of aGVHD without sever infection and transplant-related complications. Four doses of Daclizumab should be included in the GVHD prophylaxis of patients with thalassemia major selected for related haploidentical donor and unrelated donor transplantation.

Different Sources of Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Major: Relationship between Immune Reconstitution, Graft-Versus-Host Disease, and Viral Infections

Objective: To compare the relationship among immune reconstitution, graft-versus-host disease (GVHD), and viral infections in three kinds of hematopoietic stem cell transplantation(HSCT) using different host sources for thalassemia major(TM) patients: matched unrelated donor (MUD) HSCT, haploidentical (Haplo) HSCT with post-transplant cyclophosphamide (PTCy)-based prophylactic therapy, and TCRαβ-T cell-depleted HSCT (TDH). Methods: A total of 191 TM patients in our center between October 2018 and June 2022 were included in this study, comprising three transplant groups: MUD group (n=56), PTCy group (n=45), and TDH group (n=90). Four-color flow cytometry was used to detect the proportions and absolute counts of lymphocyte subsets at the 12th month after transplantation for the three different donor types. The immune reconstitution was analyzed and compared with the occurrence of GVHD and virus infections. Results: 1. Immune Reconstitution: (1) The ratio of helper cells (CD3 +CD4 +)/cytotoxic T cells (CD3 +CD8 +) at the 12 months after transplantation was compared among the three groups. There were statistically significant differences between the TDH and PTCy groups, as well as between the TDH and MUD groups(P=022 and 0.011, respectively). No statistical difference was found between the PTCy and MUD groups (P=0.932). The CD4 +/CD8 + ratio in the TDH group recovered the fastest and had already returned to the normal reference range (0.7-2.7). (2) The comparison of B cells (CD3 -CD19 +) at the 12 months after transplantation showed statistically significant differences between the TDH and PTCy groups, as well as between the MUD and PTCy groups (P=0.049 and 0.034, respectively). No statistical difference was found between the TDH and MUD groups (P=0.447). The recovery of B cells was faster in the TDH and MUD groups, while it was slowest in the PTCy group. (3) The comparison of natural killer cells (NK cells) (CD3 -CD56 +) at the 12 months after transplantation showed statistically significant differences between the TDH and PTCy groups, as well as between the TDH and MUD groups (P=0.048 and 0.000, respectively). No statistical difference was found between the PTCy and MUD groups (P=0.366). The TDH group exhibited the fastest recovery of NK cells. 2. Chronic GVHD (cGVHD): (1) 7/90 cases (7.78%) of cGVHD appeared in the TDH group, 19/45 cases (42.22%) in the PTCy group, and 2/56 cases (3.57%) n the MUD group. (2) No statistical difference showed in the incidence of cGVHD between the TDH and MUD groups (P=0.500). There was a statistical difference in the incidence of cGVHD between the TDH and PTCy groups (P=0.000), as well as between the MUD and PTCy groups (P=0.000). 3. Viral Infection: (1) 22/90 cases (24.44%) of viral infection occurred in the TDH group, 7/45 cases (15.56%) in the PTCy group, and 6/56 cases (10.71%) in the MUD group. (2) Among the 90 cases of TDH group, the CD4/CD8 ratio at the 6 months after transplantation was 0.41±0.24 in the 22 cases with viral infection and 0.69±0.40 in the 68 cases without that. There was a statistical difference in the mean CD4/CD8 ratio between the two divisions in the TDH group (P=0.013). Conclusion:The TDH group exhibited faster immune reconstitution compared to the other two groups, especially in terms of CD4/CD8 ratio, B cells, and NK cells. This may be related to two special factors for patients underwent TDH in our center: a rather high average infusion of CD34 cells (30×10 6/kg) , and the preservation of γδ cells, B cells, and NK cells with the removing of TCRαβ-T cells in the TDH treatment protocol. The TDH and MUD groups showed a lower incidence of cGVHD, while the PTCy group had a higher incidence. The occurrence of viral infection in the TDH group was 24.44%. Also, the lower a CD4/CD8 ratio at the 6 months after transplantation, the higher the incidence of viral infection. Table 1. The Absolute Counts of Lymphocyte Subsets at the 12th Month after Transplantation

Is the Youngest Donor Always the Best Choice to Optimize Outcomes for Matched Unrelated Allogeneic Transplant? Improving Precision Using Novel Statistical Methodology

INTRODUCTION Our recently published research has shown younger donors have superior survival for recipients of allogeneic hematopoietic stem cell transplant (HSCT). But, previously, we had not explored the donor age impact on other outcomes, or the impact of smaller age differences (<4 years) when balanced against other factors. We report results using our recently developed machine learning survival methodology, Nonparametric Failure Time Bayesian Additive Regression Trees (NFT BART). Here we study patient-specific optimization of donor selection for overall survival (OS) and event-free survival (EFS including events of death, relapse, graft failure/rejection, or moderate/severe chronic graft vs. host disease, GVHD). METHODS The patient data was provided by the Center for International Blood and Marrow Transplant Research. Each recipient underwent matched unrelated donor HSCT from 2016 to 2019 and was followed for OS and EFS outcomes up to three years. We trained our NFT BART model on 10,016 patients to provide predictions for OS and EFS. The model was validated on 1,802 patients among whom 699 had archived unrelated donor search records available from the National Marrow Donor Program. We examined donor age, sex/parity, CMV status, DPB1 nonpermissive mismatching, and DQB1 matching, while adjusting for relevant patient characteristics. We further restricted donor factors to those with a >1% positive impact on 3-year OS and/or EFS. Using archived search data for each patient, we examined three optimal strategies for donor selection: OS only, EFS only and a 2:1 weighted average between OS and EFS (denoted OS2:EFS1). The OS2:EFS1 effectively prioritizes optimizing OS while still allowing EFS consideration when the difference in OS predictions between two potential donors is minimal. We calculated predicted OS and EFS outcomes for each patient under all three optimal donor strategies. These predicted outcomes were benchmarked against observed practice by subtracting the predicted outcomes from the actual donor used for the transplant. RESULTS Among donor features, only age (for OS and EFS) and sex (for EFS) had clinically important impacts on outcomes. For OS, the youngest donor provided the best result regardless of patient characteristics: see the waterfall plot presented in Figure 1. As shown, the older the donor, the greater the impact of selection by age. Compared to donors 34+, use of an 18 year-old donor is associated with a substantial increase in OS where all of the recipient OS differentials are above 0.01. Compared to donors 22 to 30, the impact of an 18 year-old donor is negligible. For EFS, donor sex was the dominant factor, with males having a median 4% improvement in EFS at 3 years compared to females, while the difference for 42 vs. 18 was <2%. Optimizing for OS led to selection of the youngest donor regardless of sex, while optimizing EFS led to selection of the youngest male donor. Optimizing OS2:EFS1 generally picked the youngest donor except for selections of a male donor that may be older than the female when the age difference is small (median is 1 year older: Q1=0, Q3=2). In said cases, the OS detriment was minimal (median=-0.0005, Q1=-0.0008, Q3=-0.0003) with a substantial improvement in EFS (median=0.038, Q1=0.031, Q3=0.042) gained by switching to the male donor. Individual patient differences (OS2:EFS1 vs. actual donor) in OS vs. EFS are plotted in Figure 2. CONCLUSION Using our novel NFT BART methodology, we showed that donor selection to optimize HSCT outcomes can be improved by considering both OS and EFS. This weighted optimization strategy balances outcomes, prioritizing OS while also allowing for consideration of EFS when OS is likely similar between donors. Additionally, this supports previous research showing that choosing among donors from 18 to 30 with resultant minimal differences in outcomes that are negligible allowing for more flexibility in donor selection.

Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect.

In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naïve B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers.

Graft-Versus-Host Disease Prophylaxis with Antithymocyte Globulin in Patients Receiving Stem Cell Transplantation from Unrelated Donors: An Observational Retrospective Single-Center Study.

Graft-versus-host disease (GVHD) is one of the most important complications of allogeneic hematopoietic stem cell transplantation. Rabbit antilymphocyte serum (ATG/ATLG) is recommended for GVHD prophylaxis, while its appropriate dosing is debated. We performed a retrospective single-center study to examine the outcome of patients receiving ATG at the dose of 5 mg/kg as GVHD prophylaxis for unrelated donor (URD) HSCT. We collected data from all consecutive adult patients with hematological malignancies who had undergone allogeneic HSCT from URDs at the Stem Cell Transplant Center of the Città della Salute e della Scienza Hospital of Torino between July 2008 and July 2021. The primary aim was to ascertain the cumulative incidence (CI) for acute GVHD (aGVHD) and chronic GVHD (cGVHD); the secondary aim was to ascertain the CI for NRM (Non-Relapse Mortality) and RI (Relapse Incidence), as well the overall survival (OS) and infection incidence within 30 days of transplantation. We included in the analysis 226 patients who collectively underwent 231 HSCTs. The CI of grade II-IV aGVHD was found to be 29.9%, while that of moderate to severe cGVHD was 29.8%. The CI of NRM recorded at 1, 2, and 3 years after transplant was 18.2%, 19.6%, and 20.2%, respectively. The CI of RI at 1, 2, and 3 years from transplant was recorded to be 17.8%, 21.0%, and 21.6%, respectively. The median follow-up was 56 months, while the median OS for the whole cohort was not established; the OS at 1, 3, and 5 years from transplant was 69.6%, 59.3%, and 57.2%, respectively. We registered 88 bacteremias in 82/231 patients (35.5%), while invasive fungal infections occurred in 12/231 patients (5.2%). Our study suggests that the use of ATG at 5 mg/kg is highly effective in limiting the occurrence of both aGVHD and cGVHD, ensuring a low NRM, RI, and infection incidence.

Combination of Cytogenetic Classification and MRD Status Correlates with Outcomes of Autologous Versus Allogeneic Stem Cell Transplantation in Adults with B Cell-Acute Lymphoblastic Leukemia in First Remission

Objectives: To analyze overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of patients with B cell-acute lymphoblastic leukemia (B-ALL) who received autologous or allogeneic stem cell transplantation and to provide the basis for the choice of transplantation method. Methods: We retrospectively investigated the outcomes of 388 adult patients with B-ALL in our center. The OS, LFS, CIR and NRM rate and the impact of minimal residual disease (MRD) within 3 chemotherapy cycles along with risk classification were explored. Results: Both univariate and multivariate analysis found that negative MRD within 3 chemotherapy cycles was the important factor associated with the prognosis. As to 355 patients who obtained first complete remission (CR1), we divided patients into 3 groups according to the risk stratification and MRD status within 3 chemotherapy cycles. For patients with negative MRD within 3 chemotherapy cycles and standard-risk group, the 3-year OS (82.5% vs 74.1%, P=0.364), LFS (74.5% vs 74.1%, P=0.904), CIR (25.5% vs 17.6%, P=0.648) and NRM rates(0% vs 8.3%, P=0.234) were not significantly different between autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) group（Figure 1）. In patients with negative MRD and high-risk factors, although auto-HSCT group and allo-HSCT group had similar 3-year OS(72.7% vs 68.5%, P=0.436) and LFS rate (62.8% vs 56.0%, P=0.375) , the lower NRM (1.5% vs 25.1%, P=0.000) was offset by higher CIR(35.7% vs 18.9%, P=0.018) in auto-HSCT group compared with allo-HSCT group（Figure 2）. As for other patients with high-risk factors and positive MRD after 3 chemotherapy cycles, the prognosis of auto-HSCT group was evidently worse than those of allo-HSCT group as there was a lower trend of 3-year OS (50.0% vs 66.0%, P=0.077), LFS rate (30.8% vs 47.1%, P=0.398) and significantly higher CIR rate(71.4% vs 39.1%, P=0.018) in auto-HSCT group compared to allo-HSCT group（Figure 3）. MRD within 3 chemotherapy cycles was also related to the selection of allogeneic transplantation methods and pretreatment schemes. The 3-year OS (67.4% vs 60.8% vs 65.2%, p=0.735), LFS (56.3% vs 48.3% vs 58.3%, P=0.538), CIR (21.7% vs 23.3% vs 13.3%, P=0.784) and NRM rate (22.1% vs 28.4% vs 28.3%, P=0.672) were similar in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT), haploid hematopoietic stem cell transplantation (haplo-HSCT) and unrelated donor hematopoietic stem cell transplantation (URD-HSCT) group patients who achieved negative MRD within 3 chemotherapy cycles. While MSD-HSCT group tended to have lower 3-year LFS (33.0% vs 54.1% vs 41.7%, P=0.198) and higher CIR rate (53.2% vs 33.7% vs 46.2%, P=0.233) when comparing with haplo-HSCT and URD-HSCT group patients whose MRD were still positive within 3 chemotherapy cycles. Moreover, in patients who achieved negative MRD within 3 chemotherapy cycles, there was no significant difference in 3-year CIR rate (24.5% vs 23.1%, P=0.784) between TBI group and non-TBI group, but the lower OS (64.2% vs 76.3%, P=0.027) and LFS (54.4% vs 71.3%, P=0.091) was mainly due to the higher NRM rate (17.8% vs 5.6%, P=0.062) in TBI group. For MRD positive patients, TBI group had advantages over non-TBI group, demonstrating a trend of higher 3-year OS (65.0% vs 42.9%, P=0.105), LFS (44.8% vs 27.1%, P=0.138), lower CIR (43.6% vs 63.8%, P=0.106) and similar NRM rate (11.7% vs 9.1%, P=0.671). In addition, we found that 8 most frequently mutated genes were KMT2D、FAT1、NRAS、PAX5、KRAS、SETD2、ASXL1、PTPN11 in 175 patients with preliminary second generation sequencing results（Figure 4）. Mutations in CARD11 and NOTCH signaling pathway were correlated with lower LFS (CARD11: 56.3% vs 16.7%, P=0.002; NOTCH signaling pathway: 59.2% vs 38.8%, P=0.049)（Figure 5）. Conclusions: Auto-HSCT with maintenance therapy after HSCT and non-TBI pretreatment schemes appears to be an attractive treatment option for patients with B-ALL especially for those who achieved negative MRD within 3 chemotherapy cycles. For MRD positive patients, allogeneic transplantation and TBI pretreatment schemes may be more effective. Key words: auto-HSCT, allo-HSCT, acute lymphoblastic leukemia, minimal residual disease Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abatacept As Salvage Therapy for Graft-Versus-Host Disease in Allogenic Hematopoietic Stem Cell Transplantation : A Systematic Review

Introduction Graft vs host disease (GVHD) is one of the major complications after allogenic - Hematopoietic stem cell transplantation (allo-HSCT). It has been reported in around 70 % of patients after allo-HSCT and leads to increased non-relapse mortality (NRM)/transplant-related mortality (TRM) and also contributes to impaired quality of life. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), expressed on the surface of regulatory T cells and activated conventional T cells play a role in inhibiting T cell activation by modulating the costimulatory CD28 signal. The CTLA4-Fc fusion proteins abatacept and belatacept lead to immunosuppression induced by blocking CD28-costimulation. CTLA4Ig (Abatacept) has recently been approved by US Food and Drug Administration for prophylaxis of acute GVHD following mismatched unrelated donor (URD) HSCT. Methods We performed a comprehensive literature search on PubMed and ClinicalTrials.gov. We used the MeSH terms for Abatacept and Stem Cell Transplantation and their associated keywords. The search yielded 153 articles. Screening and data extraction were done according to PRISMA guidelines. After excluding case reports, review articles, 4 clinical studies (n=236) were included. Results: The total number of patients tested in the Abatacept group was 193. (Table 1.) In a retrospective trial by Wertheimer T et al., patients with severe cGVHD receiving abataceptdid not need new immunosuppressive treatments (80%) within 3 months of starting abatacept therapy. Patients with lung involvement (n = 9) showed significant benefit with an overall response rate of 89% based on lung severity score (n = 6), and lung function as measured by FEV1. In the phase II trial by Watkins et al addition of T-cell co-stimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, lead to reduced aGVHD, and improved day +180 severe-aGVHD-free-survival. Incidence of grade 3-4 aGVHD in 8/8-HLA-matched URD, was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). Severe-aGVHD-free-survival (SGFS) was 93.2% (CNI/MTX + abatacept) versus 82% (CNI/MTX + placebo, P = .05). In the smaller 7/8-HLA-mismatched URD cohort, grade 3-4 aGVHD was 2.3% (CNI/MTX + abatacept), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), with improved SGFS (97.7% v 58.7%, P < .001). In retrospective study by Khandelwal, P, et al, addition of Abatacept to post-transplantation cyclophosphamide (PTCy) based haploidentical transplantation for patients with thalassemia major (TM, n=5) and sickle cell disease (SCD, n=5), showed that none of the patients in the abatacept group, had grades III-IV aGVHD by day +100 compared with 50% in the group with standard aGVHD prophylaxis (P = 0.001). Thalassemia-free survival after HSCT was 100% in the patients who received abatacept compared to 62.5% in the cohort with standard aGVHD prophylaxis at follow-up (P = 0.007) .In another study by Jaiswal, et al, patients with refractory aggressive B-cell lymphoma (R-ABCL) following autologous HSCT received CTLA4Ig-based reduced-intensity conditioning and sequential CTLA4Ig-primed donor lymphocyte infusions (DLIs) on days +7, +21, and +35. aGVHD was not seen in any patient and cGVHD was seen in 2 patients. 3 patients had disease-progression at 100 days, progression-free and GVHD-free survival at 2 years was 75%. Conclusion: This systematic review shows that abatacept could be a promising treatment option for GvHD after HSCT. Abatacept is a novel treatment modality to markedly reduce GVHD and infections and yet augment NK cell-mediated cytotoxicity following HSCT. The addition of abatacept to routine GVHD prophylaxis reduced the incidence of GVHD without impacting engraftment or survival. Additional randomized clinical trials are needed to establish the efficacy and safety of to prevent GVHD after HSCT with a larger number of patients to confirm these results.

Long-Term Data Confirm the Superiority of Total Body Irradiation-Containing Conditioning Regimen in Comparison to a Chemotherapy-Based Preparation in Children with Acute Lymphoblastic Leukemia Above the Age of 4 Years Given an Unmanipulated Allograft. Results of the Forum Randomized Clinical Trial

Background Conditioning regimen plays a crucial role in determining the outcomes of patients with hematological malignancy treated with allogeneic hematopoietic stem cell transplantation (HSCT). In a multicenter, international, randomized, phase 3 clinical Trial (FORUM study), we documented (Peters C, et al. J Clin Oncol 2021) that children with acute lymphoblastic leukemia (ALL) given total body irradiation (TBI) in combination with etoposide had a superior probability of 2-year overall (OS) and event-free survival (EFS) in comparison to patients given either one of two myeloablative chemo-conditioning regimens. In this report, we assessed whether the benefit deriving from the use of TBI was sustained over time. Patients and methods Patients <18 years at diagnosis, 4-21 years at HSCT, in complete morphological remission (CR) pre-HSCT, and with an HLA-compatible related or unrelated donor (UD) were randomly assigned 1:1 to a myeloablative conditioning regimen with fractionated TBI and etoposide or fludarabine, thiotepa, and either busulfan (BU) or treosulfan (TREO). Children transplanted from a matched sibling donor (MSD) received cyclosporine A only as graft-versus-host disease (GvHD) prophylaxis, whereas recipients of UD HSCT also received short-term methotrexate and anti-thymocyte globulin (ATG). Further details on transplant procedure have been described elsewhere (Peters C, et al. J Clin Oncol 2021). Results Between 04/2013 and 12/2018, 413 patients were randomly assigned to receive either TBI (212) or a chemotherapy-based conditioning (201). Compliance with random assignment was 92%. Sixty-five percent of patients were male, 72% had B-cell precursor ALL, 73% were transplanted from a UD, and in 82% of patients bone marrow was the stem cell source employed. Fifty-four percent of patients were in CR1 at time of allograft, while 40% and 4% were transplanted in CR2 and CR3, respectively. Patient's outcomes were updated on February 1st, 2022. With a median follow-up of 3.7 years (range, 0.3-7.9), the 3-year probability of OS of patients allocated to TBI/etoposide or to the chemotherapy-based conditioning regimens was 90±2% and 71±3% (p<0.001), respectively, while that of 3-year EFS was 81±3% and 59±4% (p<0.001). OS and EFS remain comparable in patients receiving BU or TREO in combination with fludarabine and thiotepa. In detail, OS and EFS of the 102 patients given BU, fludarabine and thiotepa were 73±5% and 69±5% respectively, while those of the 99 patients treated with TREO, fludarabine and thiotepa were 62±5% and 61±5%. Multivariate analysis confirmed that the use of chemotherapy-based regimens correlated with worse OS [Hazard Ratio, HR, 2.63, 95% confidence interval, CI, (1.61- 4.31), p<0.001] and EFS [HR 2.30, 95%CI (1.58- 3.35) p<0.001]. Transplantation in >CR1 predicted a worse EFS in multivariate analysis, as well [HR 1.67, 95% CI (1.14- 2.45) p=0.009]. Patients given TBI benefited from a lower cumulative incidence of relapse (Figure 1A), as well as from a lower 3-year cumulative incidence of non-relapse mortality (2+1% vs. 10+2% in the chemo arm, p=0.007). The 3-year cumulative incidence of chronic GvHD was comparable between the 2 arms (15+3% vs. 12+2% in the TBI and chemo arm, respectively, p=n.s.). We also analyzed the probability of GvHD/relapse-free survival (GRFS) considering both relapse and chronic GvHD as events; children prepared with TBI had a better 3-year GRFS probability (Figure 1B) as compared to chemo-prepared patients. Five patients (all transplanted from an UD) developed secondary malignancies: 4 of them had received TBI. Conclusions With a significantly longer follow-up, we confirm that the use of TBI during the conditioning regimen is associated with better outcomes in children and adolescents with ALL above the age of 4 years transplanted in CR, mainly due to a lower risk of leukemia recurrence. The number of cases of secondary malignancies, particularly in patients offered radiotherapy, deserves particular attention and underlines the importance of continuous safety monitoring over time to comprehensively evaluate the long-term sequels observed in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Outcomes of haploidentical peripheral stem cell transplantation with combination of post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) compared to unrelated donor transplantation in acute myeloid leukemia: A retrospective 10-year experience

In the evolution of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), In vivo T-cell modulation with concomitant use of anti-thymocyte globulin (ATG) and high-dose post-transplant cyclophosphamide (PTCy) provides a novel promising method on transplant outcomes; however, the long-term effects of this therapy are mostly unknown. We retrospectively compared the long-term outcomes of adult acute myeloid leukemia (AML) patients undergoing a haplo-HSCT (n = 92) with a new modified combination of ATG and PTCy in the context of peripheral blood stem cell (PBSC) and myeloablative conditioning (MAC) with an otherwise similar group of AML patients who received an unrelated donor (URD) HSCT (n = 57) with ATG protocol from February 2010 to December 2020 at our single-center (HORCSCT). Median follow-up was 3.73 and 4.28 years for haploidentical and URD-HSCT, respectively. In haplo-HSCT, the cumulative incidence of grades II-IV and III-IV acute graft versus host disease (aGvHD) and extensive chronic GvHD (cGvHD) was much lower than in URD (27% versus 56% for grades II-IV, 8.7% versus 24.5% for grades III-IV, and 15.4% versus 34.7% for extensive cGvHD, respectively). Five-year overall survival (OS) was 54.03% for haplo and 54.48% for URD (p = 0.927); GvHD-free relapse-free survival (GRFS) was 44.1% and 29.86% (p = 0.149); relapse incidence was 15.79% and 26.95% (p = 0.72); and non-relapse mortality (NRM) was 29.48% and 26.32% (p = 0.73), respectively. Using multivariable analyses, when compared to Haplo, URD was a significant predictor of relapse (HR=1.80, p = 0.039); however, no difference in OS, GRFS, and NRM was noted between haplo and URD. Therefore, given the favorable results with haplo-HSCT and considering donor availability promptly with low cost, it conservatively suggested that haplo-HSCT with the introduced protocol could be viewed as the first alternative for patients with AML in the absence of matched sibling donors.

P1363: OUTCOME OF ADULT HEMATOPOIETIC TRANSPLANT RECIPIENTS AFTER ADMISSION TO INTENSIVE CARE UNIT (ICU): SINGLE CENTRE EXPERIENCE.

Background: Intensive care unit (ICU) admission during hematopoietic stem cell transplant (HSCT) is associated with poor prognosis1,2. Published series report a range of ICU admission rates from 24-40% of transplant patients, most frequent reasons involving septic shock, respiratory failure and veno-occlusive disease3. In addition, patients undergoing HSCT are at a high risk of severe morbidity and mortality associated with COVID-194. Aims: The aim of this study was to analyze outcome of HSCT patients requiring ICU admission in our center. Methods: We retrospectively analysed outcome of 752 patients who underwent HSCT in our centre from January/2008 to June/2021. Data were collected from patients’ clinical histories. Results: 103 (14%) patients required ICU admission (baseline and HSCT characteristics on table). Median time to ICU admission was 42 days (-2-1765). Seven of these patients were admitted to ICU on two occasions giving a total of 110 consecutive ICU admissions available for analysis. Main reason for ICU admission was respiratory distress (74; 67%), mainly due to pneumonia (53%) including a 3% caused by COVID19, pulmonary edema (26%) and pulmonary haemorrhage (8%). Septic shock was second most common cause for ICU admission (26; 24%) due to gram-negative bacilli (47%), fungal (15%) gram-positive bacteria (13%), virus (10%) and others/idiopathic (16%). Other less frequent causes were veno-occlusive disease (11; 10%), hepatic failure/encephalopathy (8; 7%), haemorrhagic complications (6; 5%), cardiorespiratory arrest (2%), GVHD (2%), cardiogenic shock (2%). Of the 110 ICU admissions, 37 (34%) required hemofiltration, of which 30 (81%) died; and 77 (70%) required orotracheal intubation, of which 59 (77%) died. During the 110 ICU admissions, 67 patients (61%) died in the ICU; of these, 40 (37%) received unrelated donor HSCT, 36 (33%) sibling donor, 16 (15%) haploidentical and 17 (16%) autologous. Median ICU length of stay of these patients was 13 days (range 1-76). The cause of death was the same reason for ICU admission. Eighteen (16%) patients were discharged from ICU and died prior to hospital discharge and 24 (22%) survived to hospital discharge and were classified as post-discharge survivors. Of these 24 cases, 19 (79%) remain alive while the others (5; 21%) succumbed to underlying disease or complications post-HSCT. Off note, both patients with COVID19 pneumonia (haploidentical and autologous HSCT respectively) were discharged from ICU and remain alive to date, without major complications. Image:Summary/Conclusion: In our study 14% of transplant recipients required ICU admission, slightly lower than previous reports. Most common cause of admission was respiratory failure, consistent with reported. Mortality rate during ICU admission was 61%; higher death rate observed in allogeneic transplantation and those requiring aggressive ICU treatments such as mechanical ventilation or hemofiltration. Although patients with COVID19 pneumoniae who require ICU admission are usually associated with adverse outcome, in our series they responded successfully to intensive treatment. ICU admission following HSCT is associated with poor prognosis, but should not be considered futile.

Post-Transplantation Cyclophosphamide-Based Haploidentical versus Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplantation cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin using similar busulfan-based myeloablative conditioning regimens in pediatric acute leukemia. Here we compared the outcomes in children and adolescents with high-risk acute leukemia who underwent HRD HSCT with PTCy (n=35) or MUD HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median duration of follow-up was 3.7 years in the HRD group and 4.6 years in the MUD group. No engraftment failure was observed in either group. There were no significant between-group differences in the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) (34.3% versus 48.9%; P=.142), grade III-IV acute GVHD (2.9% versus 8.9%; P=.272), moderate to severe chronic GVHD (11.4% versus 18.3%; P=.417), relapse (25.6% versus 28.0%; P=.832), and nonrelapse mortality (0% versus 2.2%; P=.420). The 3-year severe chronic GVHD-free/relapse-free survival (GRFS), leukemia-free survival (LFS), and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence interval [CI], 45.8% to 80.0%) versus 49.8% (95% CI, 34.9% to 64.7%; P=.318), 74.4% (95% CI, 58.7% to 90.1%) versus 67.5% (95% CI, 53.4% to 81.6%; P=.585), and 88.6% (95% CI, 78.0% to 99.2%) versus 83.7% (95% CI, 72.5% to 94.9%; P=.968), respectively. In a subgroup analysis of patients with acute lymphoblastic leukemia (HRD, n=17; MUD, n=26), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 49.4% (95% CI, 24.3% to 74.5%) versus 39.5% (95% CI, 19.7% to 59.3%; P=.601), 61.8% (95% CI, 37.5% to 86.1%) versus 63.6% (95% CI, 44.4% to 82.8%; P=.872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1% to 98.3%; P=.445), respectively. In patients with acute myelogenous leukemia (AML) (HRD, n=16; MUD, n=16), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 80.8% (95% CI, 61.2% to 100%) versus 61.9% (95% CI, 37.8% to 86.0%; P=.326), 87.1% (95% CI, 70.2% to 100%) versus 73.9% (95% CI, 51.8% to 96.0%; P=.478), and 93.8% (95% CI, 81.8% to 100%) versus 85.6% (95% CI, 67.0% to 100%; P=.628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrate that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen has outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.

Unrelated donor α/β T cell– and B cell–depleted HSCT for the treatment of pediatric acute leukemia

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe graft-versus-host disease (GVHD). TCRαβ/CD19 depletion may reduce this risk, whereas maintaining graft-versus-leukemia. Outcome data with TCRαβ/CD19 depletion generally describe haploidentical donors, with relatively few URDs. We hypothesized that TCRαβ/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at 2 large pediatric transplantation centers between October 2014 and September 2019. All patients with acute leukemia had minimal residual disease testing, and DP typing was available for 77%. All patients received myeloablative total body irradiation– or busulfan-based conditioning with no posttransplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95% confidence interval [CI], 52%-81%), and leukemia-free survival was 64% (95% CI, 48%-76%), with no difference between lymphoid and myeloid malignancies (P = .6297 and P = .5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence, 21%; 95% CI, 11-34), and 8 patients (cumulative incidence, 15%; 95% CI, 6.7-26) experienced nonrelapse mortality. Grade III to IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Nonpermissive DP mismatch was associated with higher likelihood of acute GVHD (odds ratio, 16.50; 95% CI, 1.67-163.42; P = .0166) but not with the development of chronic GVHD. URD TCRαβ/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.

Cost Utility of Lifelong Immunoglobulin Replacement Therapy vs Hematopoietic Stem Cell Transplant to Treat Agammaglobulinemia

Lifelong immunoglobulin replacement therapy (IRT) is standard-of-care treatment for congenital agammaglobulinemia but accrues high annual costs ($30 000-$90 000 per year) and decrements to quality of life over patients' life spans. Hematopoietic stem cell transplant (HSCT) offers an alternative 1-time therapy, but has high morbidity and mortality. To evaluate the cost utility of IRT vs matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT to treat patients with agammaglobulinemia in the US. This economic evaluation used Markov analysis to model the base-case scenario of a patient aged 12 months with congenital agammaglobulinemia receiving lifelong IRT vs MSD or MUD HSCT. Costs, probabilities, and quality-of-life measures were derived from the literature. Microsimulations estimated premature deaths for each strategy in a virtual cohort. One-way sensitivity and probabilistic sensitivity analyses evaluated uncertainty around parameter estimates performed from a societal perspective over a 100-year time horizon. The threshold for cost-effective care was set at $100 000 per quality-adjusted life-year (QALY). This study was conducted from 2020 across a 100-year time horizon. Immunoglobulin replacement therapy vs MSD or MUD HSCT for treatment of congenital agammaglobulinemia. The primary outcomes were incremental cost-effectiveness ratio (ICER) expressed in 2020 US dollars per QALY gained and premature deaths associated with each strategy. In this economic evaluation of patients with congenital agammaglobulinemia, lifelong IRT cost more than HSCT ($1 512 946 compared with $563 776 [MSD] and $637 036 [MUD]) and generated similar QALYs (20.61 vs 17.25 [MSD] and 17.18 [MUD]). Choosing IRT over MSD or MUD HSCT yielded ICERs of $282 166 per QALY gained over MSD and $255 633 per QALY gained over MUD HSCT, exceeding the US willingness-to-pay threshold of $100 000/QALY. However, IRT prevented at least 2488 premature deaths per 10 000 microsimulations compared with HSCT. When annual IRT price was reduced from $60 145 to below $29 469, IRT became the cost-effective strategy. Findings remained robust in sensitivity and probabilistic sensitivity analyses. In the US, IRT is more expensive than HSCT for agammaglobulinemia treatment. The findings of this study suggest that IRT prevents more premature deaths but does not substantially increase quality of life relative to HSCT. Reducing US IRT cost by 51% to a value similar to IRT prices in countries implementing value-based pricing may render it the more cost-effective strategy.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. DisclosuresKang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.