Haploidentical Donor Transplantation Research Articles

Analysis of efficacy and prognosis of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors. Methods: In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children's Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors. Results: Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis (HR=2.55, 95%CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant (HR=2.96, 95%CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions: Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.

Abstract CT151: Trial in progress:A phase 1 trial of TSC-100 and TSC-101, engineered T cell therapies that target minor histocompatibility antigens to eliminate residual disease after hematopoietic cell transplantation

Abstract Engineered T cell therapies such as CAR-T cell therapies have transformed the treatment of B-cell but not non-B cell hematologic malignancies. Allogeneic hematopoietic cell transplantation (HCT) remains the best curative option for hematologic malignancies but ~40% of patients relapse post-HCT with up to 90% mortality due to residual disease post-HCT. A key challenge in non-B cell malignancies is identifying the right antigens for T cell targeting. Cancer-associated antigens are heterogenous, enabling rapid escape of malignant cells with low antigens, while targeting lineage-specific antigens without distinct expression in malignant versus normal myeloid cells can cause prolonged neutropenia. A potential solution is targeting minor histocompatibility antigens (MiHAs) that are homogenously expressed on all hematopoietic cells and are genetically mismatched between donors and patients undergoing HCT. These mismatches enable T cells to selectively eliminate residual patient hematopoietic cells, normal or malignant, leaving donor cells untouched. TScan has developed allogeneic donor derived T-cell products TSC-100 and TSC-101, targeting MiHAs HA-1 and HA-2 respectively, both presented on HLA-A*02:01. By choosing HCT patients who are HLA-A*02:01 positive (>98% of whom are either HA-1 or HA-2 positive) and donors who are either HLA-A*02:01 or MiHA negative, TSC-100 or TSC-101 can potentially eliminate all residual patient-derived hematopoietic cells after HCT, to prevent disease relapse.Study NCT05473910 is a multi-center, multi-arm, non-randomized controlled Phase 1 umbrella study evaluating the feasibility, safety and preliminary efficacy of TSC-100 and TSC-101. Inclusion criteria (Figure 1) include adults with AML, MDS or ALL eligible for reduced intensity conditioning-based haploidentical donor transplantation from HLA or MiHA mismatched donors. HLA-A*02:01-positive patients undergo HA-1/HA-2 testing and are assigned to either TSC-100 or TSC-101 treatment arms in addition to HCT. HLA-A*02:01-negative patients in the control arm receive HCT alone. Upon count recovery after HCT, patients in treatment arms receive either TSC-100 or TSC-101, administered as single or two doses. Primary endpoints include adverse event profiles and dose limiting toxicities. Secondary endpoints include relapse rates, disease-free survival and overall survival. Exploratory endpoints include surrogates of efficacy such as minimal residual disease (MRD) rates and donor chimerism rates and kinetics. MRD is measured before and after HCT using flow cytometry, NGS and ddPCR. Donor chimerism is measured by standard STR-based and novel high-sensitivity NGS-based assays to quantify residual patient-derived hematopoietic cells. Together, these assays measure elimination of residual patient hematopoietic cells, malignant or normal, and could provide early evidence of biological activity. Citation Format: Monzr Al Malki, Alla Keyzner, Hyung Suh, Uday Popat, Chen Yi-Bin, Saar Gill, Melhem Solh, Joseph Uberti, Iris Isufi, Erica Buonomo, Yun Wang, Jim Murray, Gavin MacBeath, Debora Barton, Shrikanta Chattopadhyay, Ran Reshef. Trial in progress:A phase 1 trial of TSC-100 and TSC-101, engineered T cell therapies that target minor histocompatibility antigens to eliminate residual disease after hematopoietic cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT151.

Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival following Haploidentical Transplant

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.

Impact of Acute and Chronic Graft-Versus-Host Disease (GVHD) on Non-Relapse Mortality and Survival Following Haploidentical Donor Transplantation.

Impact of Acute and Chronic Graft-Versus-Host Disease (GVHD) on Non-Relapse Mortality and Survival Following Haploidentical Donor Transplantation.

The prognosis of haploidentical hematopoietic stem cell transplantation in infants and patients under 3 years old with acute leukemia.

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients<3 years of age remains controversial. Data on haploidentical donor (HID) transplants in this age group is limited. We retrospectively analyzed the prognosis of 97 patients with acute leukemia aged<3 years who underwent HID transplantation at our institute. With a median follow-up of 45 months, the 3-year disease-free survival (DFS), overall survival (OS), and 3-year cumulative incidence rate of treatment-related mortality were 69.3% (95% confidence interval (CI): 59.9%-78.7%), 74.2% (95% CI: 65.2%-83.2%), and 3.6% (95% CI: 0.9%-9.7%) in all 97 patients, respectively. The 3-year DFS and OS rate in patients diagnosed<1 year and patients diagnosed ≥1 year were comparable: 77.8% (95% CI: 62.2%-93.4%) versus 66.3% (95% CI: 55.0%-77.6%, p=.253) and 82.5% (95% CI: 66.3-98.7%) versus 72.8% (95% CI: 61.9%-83.7%, p=.153), respectively. At the last follow-up, 23 patients had died, and 20 had died of relapse. Multivariate analysis revealed that positive pre-HSCT flow cytometric minimal residual disease (hazard ratio 5.605, p=.000) and AML-M7 expression (hazard ratio 2.906, p=.014) were independent adverse prognostic variables for relapse. HID transplantation is potent and safe for infants and young patients with acute leukemia. Relapse is the primary cause of treatment failure.

Reduced Intensity Conditioning (RIC) Transplant with Very Low Dose Evomela Is Safe and Effective in Patients with Hematologic Malignancies Undergoing Haploidentical Donor Transplant.

Reduced Intensity Conditioning (RIC) Transplant with Very Low Dose Evomela Is Safe and Effective in Patients with Hematologic Malignancies Undergoing Haploidentical Donor Transplant.

Allogenic hematopoietic stem cell transplantation outcomes of patients aged ≥ 55 years with acute myeloid leukemia or myelodysplastic syndromes in China: a retrospective study

BackgroundElderly patients with acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) have historically had poor prognoses. However, there has been a recent increase in the use of allogenic hematopoietic stem cell transplantation (allo-HSCT) are in this patient population. Nevertheless, the optimal choice of donor type for the patients remains an unmet need. Limited data exist on the use of allo-HSCT in elderly patients with AML/MDS from China. To better understand and optimize the selection of donor type for the elderly patients, particularly for those with refractory or relapsed disease, in comparison with the previous studies in the US and Europe.MethodsOur retrospective study enrolled 259 patients aged over 55 years who underwent their first allo-HSCT between April 2015 and August 2022. These patients were divided into three groups based on donor type: haploidentical related donor group (haploidentical related donor transplantation [HID], n = 184), matched sibling donor group (matched sibling donor transplantation [MSD], n = 39), and matched unrelated donor group (matched unrelated donor transplantation [MUD], n = 36). Statistics were performed with the chi-square test, the log-rank and Fine-Gray tests.ResultsThe median age of the cohort was 57 years (range: 55–75) and 26.25% of patients were over 60 years old. Younger patients had a higher incidence of acute graft-versus-host disease (HR = 1.942, P = 0.035), faster neutrophil recovery (HR = 1.387, P = 0.012), and better overall survival (HR = 0.567, P = 0.043) than patients aged ≥ 60 years across the entire cohort. Patients with refractory or relapsed (R/R) diseases had delayed neutrophil engraftment (P = 0.010, HR = 0.752) and platelet engraftment (P < 0.001, HR = 0.596), higher incidence of relapses (HR = 2.300, P = 0.013), and inferior relapse-free survival (RFS) (HR = 1.740, HR = 0.016) regardless of donor type. When it came to graft-versus-host-disease-free, relapse-free survival (GRFS), MUDs turned out to be superior to HIDs (HR = 0.472, P = 0.026) according to the multivariable analysis. In contrast, we found MSDs had an inferior GRFS to HIDs in parallel (HR = 1.621, P = 0.043).ConclusionThe choice of donor type did not significantly affect the outcomes of allo-HSCT. However, when considering the quality of post-transplant life, MUDs or HIDs from younger donors may be the optimal choice for elderly patients.

Efficacy and Reliability of T-Cell–Depleted Haploidentical Stem Cell Transplantation in Hematologic Disorders: A Retrospective Study

A promising recent strategy for haploidentical transplantation is the depletion of T lymphocytes based on the selective elimination of T cells by manipulation, which enables a very low incidence of nonrelapse mortality and graft-vs-host disease. It is more expensive than conventional unmanipulated methods and requires dedicated transplant centers and sufficient stem cell processing facilities. This retrospective study aimed to evaluate the relapse, survival, and clinical data of the patients and to analyze the outcomes of the technique. The study included 56 adult patients who underwent haploidentical stem cell transplantation via αβ T-cell depletion. The median age of the patients at the time of hematopoietic stem cell transplantation was 41.5 years (range, 20-70 years); 22 patients (39.3%) were women. After the transplantation, half of the patients (50.0%) needed immunosuppressive drugs, and 17.9% of the patients experienced a post-transplant relapse. The mortality rate was 55.4%, and nonrelapse mortality was 25.0%. The 100-day mortality rate was 19.6%. The median overall days was 1101 days (142-3813 days), whereas the median progression-free overall was 302.5 days (11-2479 days). Being older (age >40), having hypertension, having acute liver graft-vs-host disease, and having systemic fungal infection were found as risk factors that significantly increased mortality (with 3.5-, 2.8-, 3.7-, and 2.7-fold increases, respectively). To conclude, T-cell-depleted hematopoietic stem cell transplantation is an effective and reliable technique that has the potential to decrease morbidity and improve relapse-free survival, especially for young patients requiring haploidentical donor transplantation for hematologic malignancy.

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis in HLA-Matched and Haploidentical Donor Transplantation for Patients with Hodgkin Lymphoma: A Comparative Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). This study compared the outcomes of patients with HL undergoing HSCT from HLA-matched donors, including matched sibling donors (MSDs) and matched unrelated donors (MUDs), and haploidentical donors, using PTCy as the GVHD prophylaxis approach in all cohorts. We retrospectively compared outcomes of allo-HSCT from 166 HLA-matched donors (96 sibling and 70 unrelated donors) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the European Society for Blood and Marrow Transplantation database from 2010 to 2020. Compared to HLA-matched HSCT, haploidentical donor HSCT was associated with a significantly lower rate of platelet engraftment (86% versus 94%; P < .001) and a higher rate of grade II-IV acute GVHD (34% versus 24%; P = .01). The 2-year cumulative incidence of nonrelapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to the haploidentical cohort (10% versus 18%; P = .02), resulting in a higher overall survival (OS) rate (82% versus 70%; P = .002). There were no significant differences between the 2 cohorts in terms of relapse, progression-free survival, or GVHD-free relapse-free survival. In multivariable analysis, haploidentical HSCT was associated with an increased risk of grade II-IV acute GVHD and NRM and worse OS compared to HLA-matched HSCT. Our findings suggest that in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical HSCT.

Effect of HLA-DPB1 Mismatch on Incidence and Severity of Chronic Graft-Versus-Host Disease Following Haploidentical Transplantation

Chronic graft-versus-host disease (cGVHD) is an important cause of late morbidity and mortality after haploidentical donor transplantation (HIDT), occurring in up to one-third of patients. The treatment of cGVHD can continue for years and can significantly impact quality-of-life in long-term transplant survivors. Therefore, it is important to identify risk factors that are associated with the incidence and severity of cGVHD. To this end, we investigated 335 consecutive recipients of HIDT utilizing post-transplant cyclophosphamide (PTCy) from 2005-2021, with a particular focus on class II HLA mismatches given prior published associations of HLA-DR and -DP mismatches with HIDT outcomes. HIDT recipients had a median age of 50 (19, 80). PBSC was the graft source in 81%, and conditioning was myeloablative in 49%. Whereas the incidence and severity of cGVHD did not differ between transplants with or without an HLA-DRB1 or -DQB1 allele-level mismatch, the presence of an HLA-DPB1 mismatch was associated with higher 1-yr incidence of all-grade (32% vs. 22%, p=0.07) and moderate-to-severe (22% vs. 12%, p=0.011) cGVHD (see figure). The effect of HLA-DPB1 mismatch on cGVHD was independent of permissiveness by the T cell epitope (TCE) algorithm or the vector of the mismatch (bidirectional, GVH- or HVG-only). In multivariate analysis, an HLA-DPB1 mismatch was associated with an increased risk of moderate-to-severe cGVHD (HR 2.05, p=0.044), while controlling for other covariates (CMV status, year of transplant). Other class II loci (HLA-DRB1 and HLA-DQB1) mismatching were not associated with chronic GVHD incidence in MVA. In summary, the presence of an HLA-DPB1 mismatch is associated with an increased incidence of moderate-to-severe cGVHD following PTCy-based HIDT. This effect, of course, must be balanced by the protective effect of a TCE nonpermissive HLA-DPB1 mismatch on relapse and survival, when selecting the optimal haploidentical donor.

Impact of an HLA-DPB1 Non-Permissive Mismatch By the Revised T Cell Epitope (TCE)-Core Algorithm on Survival Following Haploidentical Donor Transplantation (HIDT) with Post-Transplant Cyclophosphamide (PTCy)

The presence of an HLA-DPB1 non-permissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following HIDT utilizing post-transplant cyclophosphamide (PTCy). A revised model (TCE-core) which further separates TCE “group 3” alleles into “core”(C) and “non-core” (NC) alleles has been developed (Arrietta-Bolanos et al. Blood 2022). In this new model, a formerly permissive mismatch (PMM) resulting from “group 3” alleles in both donor and recipient are now considered a C-NPMM if one or more of those alleles is NC (see figure), and the total number of NPMMs by the TCE-core model results from adding these C-NPMMs to conventional NPMM. In order to study the impact of an HLA-DPB1 NPMM by the TCE-core model on outcomes following PTCy-based HIDT, we evaluated 242 consecutive HIDT recipients with ALL, AML or MDS transplanted between 2005 - 2021 at a single institution, (median age 51 [19,80], 38% non-White, 32% DRI high/v. high). We further examined the effect of the vector of non-permissiveness (see figure), hypothesizing that a NPMM in the GVH or bidirectional direction may have a more significant impact on relapse and survival than an HVG-only NPMM. Median follow-up was 62 [23, 199] months. A NPMM was seen in 129 donor-recipient pairs (53%), of which 65 (27%) were either in the GVH-only or bidirectional vector. In univariate analysis, a trend for improved 5-yr OS was seen in the context of a TCE-core NPMM vs. matched/PMM HLA-DPB1 (59% vs. 49%, p=0.06). Restricting TCE-core NPMM to the GVH/bidirectional vector further improved 5-yr OS (64% vs. 49%, p=0.023, see figure). Compared to an HVG-only NPMM, a GVH/bidirectional NPMM was associated with a significantly lower 5-yr risk of relapse (23% vs. 45%, p=0.016). In Cox multivariable analysis, adjusted for disease risk index, regimen intensity and donor age, a GVH/bidirectional mismatch was associated with improved OS (HR 0.62, 95% CI 0.38-0.99, p=0.047), compared with HLA-DPB1 match/PMM. Although not statistically significant, a trend was also seen for DFS (HR 0.69, 95%CI 0.44-1.09, p=0.11) and relapse (HR 0.63, 95%CI 0.35-1.14, p=0.12). Compared with an HVG-only TCE-core NPMM, a GVH/bidirectional NPMM was associated with significantly lower relapse (HR 0.48, 95%CI 0.26-0.89, p=0.020). In summary, the presence of TCE-core GVH/bidirectional NPMM is associated with less relapse and significantly improved OS following PTCy-based HIDT. This association should be confirmed in a large registry analyses and potentially incorporated in future donor selection algorithms.

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.

Haploidentical Donor Transplants with Cytokine Release Syndrome Have Increased Risk of Clinically Significant Early CMV Reactivation Compared with Matched Donor Transplants Receiving Post-Transplant Cyclophosphamide

Background: Post-transplant cyclophosphamide (PTCy) enables safe haploidentical stem cell transplantation by reducing graft-versus-host-disease (GVHD) but is associated with an increased risk of reactivation of Cytomegalovirus (CMV). PTCy has more recently been adopted for matched-donor transplants, where early CMV reactivation may also be more common. This suggests that CMV reactivation is a function of PTCy rather than donor source. However, other studies comparing the rates of CMV in transplants using PTCy-based prophylaxis suggested disparity in donor source may contribute to CMV reactivation. Aim: The goal of this single-centre, retrospective study was to determine if donor type had any impact on CMV reactivation in the setting of PTCy-based GVHD prophylaxis. Methods: The Alfred Hospital Bone Marrow Transplantation Unit has used PTCy for GVHD prophylaxis in both haploidentical and matched-donor allogeneic stem cell transplants (alloSCT) since 2015. A local database search identified 119 allogeneic peripheral blood alloSCT recipients receiving PTCy-based GVHD prophylaxis between February 2015 and December 2022. Matched-donor alloSCTs also received cyclosporin from Day +5 while haploidentical alloSCTs also received tacrolimus and mycophenolate from Day +5. One patient was excluded due to CMV viremia at the time of transplant. Recipients who were CMV seropositive received therapeutic dose valganciclovir 900 mg twice daily from the start of conditioning until the day prior to stem cell infusion. Prophylactic valganciclovir (900 mg daily) was planned upon engraftment for seropositive recipients and those receiving stem cells from a seropositive donor. CMV DNA PCR was performed weekly for the first 100 days post-transplant and beyond when clinically indicated. CMV viremia was defined as any positive CMV PCR (&amp;gt; 34.5 copies/mL) within the first 100 days post-transplant. Therapeutic valganciclovir was initiated for CMV viral loads (VL) &amp;gt; 1,000 copies/mL or earlier for rapidly rising VLs. Cytokine release syndrome (CRS) was defined as fever &amp;gt; 38 degrees Celsius between stem cell infusion and PTCy on Day +3 without an alternate explanation and graded according to CTCAE criteria. CMV donor and recipient negative transplants were excluded from the analysis of the impact of donor disparity on CMV reactivation. Statistical analyses included Fisher's Exact test, one-way ANOVA and Binomial Logistic Regression. Results: Transplant characteristics according to donor source were similar apart from conditioning intensity, where recipients of haploidentical stem cells were more likely to receive myeloablative conditioning (Table 1). The cumulative incidence of moderate-severe chronic GVHD was significantly higher in matched sibling transplants but overall, 12-month GVHD-free and relapse-free survival were similar. As previously reported, CRS (overall and grades II-IV) was significantly more common in haploidentical transplants. Day 100 CMV viremia rates were not statistically different between donor groups. However, haploidentical transplants trended for earlier CMV reactivation (p=0.08), and were significantly more likely to rise above 250 copies/mL (Table 1 and Figure 1). Consequently, haploidentical transplant recipients received significantly more anti-CMV therapy (p=0.009). Multivariable analysis identified haploidentical donor as a major risk factor for CMV &amp;gt; 250 (odds ratio, OR 1.24, p=0.011) and &amp;gt; 1,000 copies/mL (OR 1.41, p=0.032) while transplant for AML/MDS was negatively associated with CMV &amp;gt; 250 (OR 0.19, p=0.009) and CMV &amp;gt; 1,000 copies/mL (OR 0.16, p=0.003). CRS was significantly associated with CMV &amp;gt; 1,000 copies/mL (OR 3.33, p=0.032) but this was no longer significant in multivariable analysis due to the association with haploidentical donor transplantation. Conclusion: This single-center retrospective comparison of PTCy-based transplants shows that haploidentical transplants have increased risk of early and clinically significant reactivation of CMV. Potential explanations include increased immunosuppression with mycophenolate and the presence of CRS, where inflammatory cytokines may de-repress the CMV major immediate early promoter. Selecting this high-risk group (haploidentical transplants with CRS) may be a cost-effective use of letermovir, which can be initiated prior to engraftment.

Impact of HLA-DQ Heterodimer Group (G1/G2) Mismatch on Relapse and Survival Following Haploidentical Donor Transplantation

The role of HLA-DQ matching in transplant outcomes after post-transplant cyclophosphamide (PTCy)-based haploidentical donor transplantation (HIDT) remains unclear. DQB1 alleles can be grouped into group 1 (DQB1*02/03/04) or group 2 (DQB1*05/06) based on the ability of their corresponding β chains to form stable heterodimers with α chains of specific DQA1 alleles (Petersdorf et al. Blood 2022). For transplant recipients expressing a G1G1 or G2G2 genotype, additional HLA-DQ diversity is achieved through successful DQα-β transdimerization from the other parental chromosome, resulting in up to 4 unique HLA-DQ molecules. We hypothesized that an HLA-DQ group G1/G2 mismatch (mm) would reduce relapse and improve survival following PTCy-based HIDT, and that the effect may be more significant in G1G1 or G2G2 (vs. G1G2) recipients due to a higher number of heterodimer mismatches. A total of 242 consecutive patients with ALL (n=71), AML (n=125) or MDS (n=46) receiving a PTCy-based HIDT from a single institution were analyzed (median age 51 (19,80), 38% non-White, 32% DRI high/v. high). PBSC was the graft source in 87%, and conditioning was myeloablative in 57%. Recipient HLA-DQ group genotype was G1G2, G1G1, and G2G2 in 50%, 29% and 21%, respectively. Donor-recipient HLA-DQ alleles were G1/G2 group matched in 49% of all transplant recipients (49% and 48% in G1G2 and G1G1/G2G2 recipients, respectively). Baseline patient, disease and transplant characteristics were well matched in the HLA-DQ G1/G2 group matched vs. mm transplants. Median follow-up was 62 [23, 199] months. In univariate analysis, 5-year DFS was 56% vs. 43%, p=0.12 for HLA-DQ group mm vs. matched, respectively. Corresponding rates of relapse were 31% vs. 41%, p=0.18. As predicted, the protective effect of a group mm was stronger in recipients with a G1G1 or G2G2 (vs. G1G2) genotype (see figure). In G1G1/G2G2 recipients, 5-yr DFS (55% vs. 34%, p=0.017) and relapse (29% vs. 49%, p=0.038) was improved for HLA-DQ group mm vs. matched, respectively. In multivariable analysis, controlled for disease risk index, regimen intensity, donor age, and sex match, an HLA-DQ G1/G2 group mm was associated with significantly improved OS (HR 0.64, p=0.022), DFS (HR 0.65, p=0.020) and relapse risk (HR 0.60, p=0.021), an effect even more pronounced when restricted to G1G1/G2G2 recipients - OS (HR 0.48, p=0.006), DFS (HR 0.46, p=0.002) and relapse (HR 0.41, p=0.003). In contrast, there was no beneficial effect of an HLA-DQ group mm in transplant recipients with a G1G2 genotype. In summary, an HLA-DQ G1/G2 group mm significantly decreases relapse risk and improves survival in the half of HIDT recipients characterized by a G1G1 or G2G2 genotype. Our results may have considerable importance for donor selection in these patients. Furthermore, this finding reinforces the existing literature, suggesting that HLA-DQ matching follows a different paradigm than other class II antigens.

Selecting the Right Alternative Donor: Comparison of Outcomes of HLA-Mismatched Alternative Donor Hematopoietic Cell Transplantations in Adult Patients with Acute Lymphoblastic Leukemia Regarding KIR-Ligand Mismatch

Background: Allogeneic hematopoietic cell transplantation from cord blood (CBT) or haploidentical donor (HIDT) has proved to be a viable option for patients unable to find a human leukocyte antigen (HLA)-matched conventional donor. However, few single-centered studies have compared outcomes of the two alternative donor transplantations in adult acute lymphoblastic leukemia (ALL). Aim: Our aim is to compare outcomes of adult ALL patients treated with CBT with those treated with HIDT. Secondly, we tried to find out factor that could be considered in selecting donor for alternative donor transplantation to improve clinical outcomes. Methods: We compare outcomes of adult ALL patients treated with CBT (n=134) between 2008 and 2022 with those treated with HIDT (n=47) between 2018 and 2022.Conditioning regimen for CBT consisted of total body irradiation (12Gy) plus cytarabine (9g/m 2) plus fludarabine (150mg/m 2). Graft-versus-host disease (GVHD) prophylaxis was attempted using tacrolimus and mycophenolate mofetil. For HIDT, we used reduced toxicity conditioning (RTC) regimen including fludarabine (150mg/m 2) plus busulfan (6.4mg/kg). GVHD prophylaxis was done with ATG 1.5mg for 4 days plus short course methotrexate (MTX) (15mg/m 2) plus tacrolimus. Killer cell immunoglobulin-like receptor (KIR) ligand mismatch was calculated in both GVH and HVG direction using HLA-KIR ligand database, and its effect on clinical outcomes of alternative donor transplantation was investigated. Results: In HIDT, CD34+ cell count (´10 6/kg) was significantly higher (7.4 vs. 0.1, P&amp;lt;0.001), and the patients were older (49 vs. 33.5, P&amp;lt;0.001) compared to CBT. Other characteristics, such as cytogenetic risk and leukocyte count at diagnosis, did not show significant difference between the two groups. Incidence of acute GVHD II-IV (51.1% vs. 50.0%), III-IV (25.5% vs. 17.9%), and moderate to severe chronic GVHD (10.8% vs. 11.0%) between HIDT vs. CBT were similar. After median follow-up of 39.4 months (range: 5.5-167.4), HIDT showed higher cumulative incidence of relapse (CIR) compared to CBT (47.9% vs. 18.9%, P&amp;lt;0.001), which remained true even after stratifying by age subgroup (Age&amp;lt;40: P=0.033, Age≥40: P=0.002). Conversely, CBT showed higher non-relapse mortality (NRM) than HIDT (22.8% vs. 9.0%, P=0.038), but the same was true only in the older age subgroup (Age&amp;lt;40: P=0.484, Age≥40: P=0.002). These effects summed up to produce comparable results in estimated 3-year disease-free survival (DFS) of CBT and HIDT (58.4% vs. 43.5%, P=0.103), especially in the older subgroup (38.7% vs. 40.7%, P=0.897). Multivariate analysis also revealed that HIDT was related with higher relapse (HR 3.47; 95%CI 1.92-6.27, P&amp;lt;0.001), and CBT with higher NRM (HR 4.18; 95%CI 1.42-12.3, P=0.009). GVH direction KIR ligand mismatching worked for lower 3-year DFS in CBT (40.3% vs. 74.4%, P=0.007), although CIR and NRM did not show significant difference (27.8% vs. 15.6%, P=0.178; 35.0% vs 18.4%, P=0.057, respectively). On the other hand, the mismatch resulted in lower incidence of acute GVHD II-IV (32.0% vs. 54.2%, P=0.011). The trend remained when such effect was investigated separately in CBT and HIDT, but it was not statistically significant (33.3% vs. 53.1%, P=0.082; 28.6% vs. 57.6%, P=0.053, respectively). Conclusions: Our data shows higher NRM in CBT, and unexpected higher relapse rate in HIDT. Age of the patient should be considered when choosing CBT, because in older patients CBT showed notably worse NRM compared to HIDT. Higher incidence of relapse in HIDT may be attributable to ALL disease characteristics itself or insufficient elimination of leukemic cells by RTC regimen with stronger GVHD prophylaxis. Similar to what is known in acute myeloid leukemia, GVH direction KIR incompatibility showed protective effect against acute GVHD in ALL. However, the mismatch resulted in worse DFS in ALL patients treated with CBT, but not in those treated with HIDT. Possible explanation to this phenomenon is that the number of NK cells in cord blood was insufficient for mismatch-induced graft-versus-leukemia effect, while its immune response against infected cells was suppressed by the same mechanism that resulted in lower acute GVHD. Keywords: Acute lymphoblastic leukemia, Cord blood transplantation, Haploidentical donor transplantation, HLA-mismatched transplantation, Killer-cell immunoglobulin like receptor

HLA 1 Allele-Mismatched Unrelated Vs Haploidentical Donor Transplants in Acute Myeloid Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative treatment for acute Myeloid Leukemia (AML) patients. When there is no HLA-identical sibling or unrelated donor, alternative donors such as 1 allele-mismatched unrelated donors (1-MMUD) or haploidentical donors (HID) may be considered. While there have been reports that the outcomes of these two donors are comparable with those of HLA-matched unrelated donors, there is limited data directly comparing the outcomes between 1-MMUD and HID transplantation. Therefore, we conducted an analysis of the outcomes of allo-HSCT from 1-MMUD and HID in AML patients. This study is a retrospective cohort study at a single institution, including patients with AML who underwent first allo-HSCT in complete remission (CR) or CR with incomplete hematologic recovery between 2002 and 2022, from 1-MMUD or HID. For HID transplantation, patients were administered fludarabine 30mg/BSA for 4 days, intravenous busulfan 3.2mg/kg for 2 days, and depending on the condition, they received either total body irradiation (TBI) at 400cGy or fractionated TBI at 800cGy (400cGy for 2 days). Graft-versus-host disease (GVHD) prophylaxis for HID transplantation consisted of antithymocyte globulin total 5.0mg/kg, methotrexate 5mg/BSA 3 or 4 times, and calcineurin inhibitors. In 1-MMUD transplantation, various myeloablative or reduced-intensity conditioning regimens were used. All patients received T-cell replete peripheral blood stem cells. A total of 108 patients who underwent 1-MMUD transplantation and 447 patients who underwent HID transplantation were included. The 1-MMUD group showed a tendency to be younger (median 42 years vs. 51 years, Wilcox rank-sum test p &amp;lt; 0.01) and had a lower proportion of ABO-matched transplantations (28.7% vs. 51.7%, Chi-square test p &amp;lt; 0.01). Other patient characteristics were similar between the two groups. In terms of survival, the median OS in the 1-MMUD group was 60.1 months, and in the HID group was 58.7 months, showing no significant difference between the two groups (Log rank test p = 0.81). Similarly, the median RFS was 54.8 months in the 1-MMUD group and 40.9 months in the HID group, with no statistically significant difference (Log rank test p = 0.96). The cumulative incidence of relapse and NRM at 60 months after allo-HSCT showed no significant difference between the two groups, with 26.1% and 25.7% for relapse and 23.9% and 26.3% for NRM in the 1-MMUD and HID groups, respectively (Gray's test p for relapse: 0.81, p for NRM: 0.82). Although the cumulative incidence of grade 2 or higher acute GVHD did not show a significant difference between the two groups (38.0% in 1-MMUD, 45.4% in HID, Gray's test p = 0.41), the incidence of chronic GVHD was significantly higher in the HID transplantation group (63.6%) compared to the 1-MMUD transplantation group (52.0%) (Gray's test p &amp;lt; 0.01). Finally, in a multivariate Cox model In conclusion, both 1-MMUD and HID can be considered equivalent alternative donors, and caution should be exercised regarding the occurrence of chronic GVHD in HID transplantation. Further comparisons between the two donors, including in different settings such as post-transplantation cyclophosphamide, warranted.

Donor Age Matters in Haploidentical Donor Transplantation Rather Than in Matched Unrelated Donor Transplantation in Older Adults with Acute Myeloid Leukemia

Allogeneic hematopoietic cell transplantation (HSCT) has curative potential for Acute myeloid leukemia (AML). Given that the median age of acute myeloid leukemia (AML) patient is 68 years, the majority of HSCT candidates in AML are inevitably elderly patients. Advances in alternative donor HSCT and reduced intensity conditioning have expanded the opportunities for elderly patients to undergo HSCT. Previously, we reported HSCT outcomes of older adults with AML according to donor type, showing comparable outcomes among haploidentical donor (HID), matched unrelated donor (MUD) and matched sibling donor group, with especially superior survival in the MUD group ( Transplantation and Cellular Therapy 2021; 27: 774.e1-774.e12.). Since donor age has been shown to be a significant factor in HSCT outcomes, we investigated the HSCT outcomes of older AML HSCT recipients from HID according to donor age, and compared to those of MUD HSCT recipients. We retrospectively evaluated older adults with AML aged 60 and above, who underwent first HSCT at Catholic Hematology Hospital between 2007 and 2022, in complete remission (CR) or CR with incomplete hematologic recovery. We analyzed the HSCT outcomes (Overall Survival [OS], Relapse-Free Survival [RFS], and Graft-versus-Host Disease [GVHD], Relapse-Free Survival [GRFS]) in patients who underwent either HID or MUD HSCT. A total of 204 patients were included, with 117 (57.4%) in the HID group and 87 (42.6%) in the MUD group. For MUD HSCT, conditioning regimens consisted of cyclophosphamide 120 mg/kg combined with 1320 cGy of fractionated total body irradiation (TBI) or busulfex [12.8 mg/kg], or busulfex [6.4 mg/kg] and fludarabine [150 mg/m2] with 400 cGy of fractionated TBI. Conditioning for HID HSCT comprised of busulfex [6.4 mg/kg] and fludarabine [150 mg/m2] with 400-800 cGy of fractionated TBI. Rabbit antithymocyte globulin was administered at a dose of 1.25 mg/kg/day on days -3 to -2 for MUD HSCT and days -4 to -1 for HID HSCT. There was no significant difference in the clinical characteristics between the MUD and the HID groups, except donor age (MUD vs. HID: median 28 years vs. 37 years, p &amp;lt;0.01). In the survival analysis, 196 patients whose donor age was identified were included. The difference in survival based on donor age was striking. Patients who received transplantation from donors aged below 35 showed superior outcomes compared to those with donors aged 35 and above (Figure A). The impact of donor age on survival differences was also pronounced in RFS (Figure B). However, the differences based on donor age were mitigated in terms of GRFS (Figure C), suggesting that donor age may play a role in the occurrence of GVHD and relapse. In the cumulative incidence analysis, there was a significant difference in relapse and non-relapse mortality between patients who received HID HSCT from younger donors aged below 35, patients who received HID HSCT from older donors aged 35 and above, and patients who received MUD HSCT. The patients who underwent MUD HSCT showed a significantly higher relapse rate than those who underwent HID HSCT regardless of donor age. HID HSCT patients with older donors (aged 35 and above) showed significantly higher non-relapse mortality than the other two groups. In the analysis of cumulative incidence of GVHD, with death as a competing risk, patients who underwent MUD HSCT showed lower incidence of acute GVHD than those who underwent HID HSCT (Figure D). Our data showed equally promising outcomes of HID HSCT from a younger donor (age &amp;lt;35) compared to MUD-HSCT, suggesting the necessity for more sophisticated strategies to improve survival outcomes in HID HSCT from older donors. Further studies comparing donor age are warranted in various transplantation settings.

Graft-Versus-Host Disease (GvHD) Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation (haplo-PBSCT) Using Abatacept in Combination with Post-Transplant Cyclophosphamide (PTCy)

Background: Multiple studies demonstrated the efficacy of PTCy in achieving successful multiple-HLA-antigen mismatched (haploidentical) donor transplantation. However, acute GvHD (aGvHD) remains a major cause of morbidity and mortality after transplantation. Furthermore, many patients (pts) experience severe cytokine release syndrome (CRS) immediately after haplo-donor transplantation, which may be a greater risk after haplo-PBSCT. We hypothesized that adding co-stimulation blockade with abatacept (Abat) starting before transplantation to a standard GvHD prophylaxis regimen of PTCy, tacrolimus, and mycophenolate mofetil in haplo-PBSCT would be safe and effective in aGvHD prevention and decrease the incidence of cytokine release syndrome (CRS) associated with use of this cell source. Methods: This retrospective study included 50 recipients of haplo-PBSCT between 1/1/20, and 3/31/23, who received standard PTCy GvHD prophylaxis with (PTCY/Abat, n=22) or without (PTCy, n=28) the addition of Abat at a planned dose of 10 mg/kg/dose IV on days -1, +5, +14 (n=10) and +28 (n=12). Choice of donor, conditioning regimen, and use of Abat were per physician discretion. The PTCy GvHD regimen and pre- and post-transplant care of all pts were as previously described (Baker et al. Biol Blood Marrow Transplant. 2016;22:2047-55). Survival development of aGvHD or chronic GvHD (cGvHD), and engraftment success and kinetics were evaluated. CRS (Lee, et al. Blood 2014;124:188-95), aGvHD (Magic criteria, Harris et al. Biol Blood Marrow Transplant. 2016;22:4-10) and cGvHD (NIH consensus criteria, Jagasia et al. Biol Blood Marrow Transplant 2015;21:389-401) were scored per citations. Results: In total, 22 pts received PTCy/Abat. Ten pts did not receive day +28 Abat for insurance reasons. Twenty-eight pts received PTCy without abatacept. Pt characteristics and CRS grading are described in the Table. Although distributions of diagnosis, sex, and pt or donor ages were similar between cohorts, there was some imbalance, particularly in higher use of TBI myeloablative conditioning regimen for PTCy cohort (Table). The median follow-up of survivors is 10 months. In this analysis we found a non-significant trend to lower incidence (65% vs 88% p=0.079) and severity of CRS for PTCy/Abat recipients vs PTCy recipients (Table). Only 1 of 20 evaluable PTCy/Abat recipients developed grade 2 CRS vs 6 of 26 PTCy pts. PTCy/Abat recipients achieved faster ANC engraftment (median: 15 days, 95% CI: 14-16 vs 17 days, 95% CI: 16-18; p&amp;lt;0.0001 (Figure 1A)) and platelet recovery (median: 15 days, 95% CI 13-22 vs 24 days 95% CI 19-29; p=0.002). No pt in either group developed 1 o or 2 o graft failure. Median peripheral blood CD3 chimerism at day +28 was 100% (range, 57-100%) for PTCy/Abat pts and 100% (range, 85-100%) for PTCy pts. The cumulative incidence of any aGvHD was 71% for PTCy/Abat pts vs 73% for PTCy pts, (p=0.9). Grade II or III aGvHD occurred in 13/21 and 1/21 evaluable PTCy/Abat pts, and 12/26 and 3/26 evaluable PTCy pts, respectively. No grade IV or liver aGvHD occurred in either group. The median time of onset of aGvHD was 54 days for PTCy/Abat pts and 36 days for PTCy pts (p= 0.08). The cumulative incidence of any grade cGvHD trended higher in the PTCy/Abat group (81% vs 50% p=0.052). Also, the PTCy/Abat group had a higher incidence of severe grade cGvHD (6/13 vs 2/10 evaluable pts). The 200-day cumulative incidence of relapse was 35% for PTCy/Abat and 11% for PTCy (p=0.2). No statistically significant differences in overall survival, or relapse-free survival (Figure 1B) were detected for these two populations. Conclusions:The addition of Abat starting before haplo-PBSCT did not interfere with the aGvHD and engraftment protective effects of PTCy in this cohort. Abat initiated before PBSC infusion may reduce the risk and severity of CRS and was associated with earlier neutrophil and platelet recoveries. Although the incidence of aGvHD did not differ between the two groups, time of onset trended later among PTCy/Abat recipients. Larger pt populations will be needed to determine more accurately the effects of adding Abat to PTCy on relapse risk and cGvHD incidence and severity.

A Real-World Efficacy of Letermovir Primary Prophylaxis for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single-Center Retrospective Analysis

Introduction: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. Methods: We retrospectively analyzed 167 consecutive patients who underwent allo-HSCT between August 2022 and May 2023, who received LET 240 mg/day, to evaluate the efficacy and safety of LET in primary prophylaxis for clinically significant CMV infection (csCMVi), defined as CMV disease or CMV viremia reactivation, in real-world situations in China. Results: Among the enrolled 167 patients, 95.21% (159/167) of patients underwent a haploidentical donor (HID) transplant and 4.79% (8/167) a matched unrelated donor (MUD) transplant. 96.41% of the recipients were CMV seropositive, and only 6 recipients were CMV seronegative but donor seropositive. The median interval from allo-HSCT to the administration of LET was 7 (2-55) days. A total of 121 patients received LET within 14 days after HSCT. With the median follow-up 162(74-397) days post-HSCT, the incidence of CMV viremia was 11.98% (20/167). 3 patients developed CMV viremia after discontinuation of LET medication. Among the 20 patients with CMV viremia, the median duration of preemptive therapy was 9 (3-28) days, and the peak level of CMV-DNA was 1867 (1228-22383) copies/ml. Only 1 patient developed refractory CMV viremia with prolonged preemptive anti-CMV treatment. No patients were diagnosed with clinically significant CMV disease. Patients who developed CMV viremia or not were similar with respect to the CMV IgG status of the recipient at HSCT, donor CMV IgG, and GVHD incidence. Notably, the CMV viremia incidences of patients who received LET within 14 days and after 14 days post-HSCT were 7.44% and 23.91%, respectively (p=0.005). The incidence of EBV viremia was 17.16% (29/169), and 9 developed PTLD. The six-month overall survival was 93.4±2.1% in all patients who received LET prophylaxis. Meanwhile, LET prophylaxis was well tolerated. No drug-related death or permanent discontinuation was reported due to toxicity. Conclusion: Letermovir was effective and safty as primary prophylaxis of csCMVi, particularly initiating early post-HSCT.

Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis in HLA-Matched and Haploidentical Donor Transplants for Patients with Hodgkin disease: A Comparative Study of the LWP EBMT

INTRODUCTION Post-transplant cyclophosphamide (PTCy) has proven to be a highly effective strategy in preventing graft-versus-host disease (GVHD) in haploidentical (haplo) hematopoietic stem cell transplantation (HSCT), but it is being increasingly used in HLA-matched transplants. The outcomes of haplo HSCT with PTCY in various hematologic malignancies, particularly in relapsed/refractory Hodgkin disease (HD), have shown promising results, challenging those obtained in transplant patients from HLA-matched donors without PTCy. However, there is limited information on the impact of donor types on the outcomes of patients with HD undergoing allogenic HSCT when using homogeneous GVHD prophylaxis with PTCy. To address this knowledge gap, we have conducted an extensive study using the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (LWP-EBMT) registry. The aim of this study was to compare the outcomes of patients with HD undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haplo donors, using PTCy as GVHD prophylaxis approach in all cohorts. PATIENTS AND METHODS Inclusion criteria All adults (≥ 18 years) patients diagnosed with HD who underwent their first HSCT between January 2010 and December 2020 from either a MSD, MUD or haplo, and whose data were reported to the EBMT registry were included. For the purposes of this study, only transplants who received PTCy-based as GVHD prophylaxis were considered. Statistical Analysis The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, PFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and packages were used. RESULTS Patient and Transplantation Characteristics Patient, disease and transplant-related characteristics of the 860 patients are summarized in Table 1. Engraftment The cumulative incidence (Cum Inc) of neutrophil recovery at day 30 was 95% (95% CI, 93-96) in the HLA-matched group and 96% (95% CI, 91-98) in the haplo cohort (p=0.18). The 60-day Cum Inc of platelet recovery in similar order was 94% (95% CI, 88-97) and 86% (95% CI, 83-88) (p&amp;lt;0.001). GVHD The Cum Inc of acute GVHD grade II-IV at 100 days in the HLA-matched and the haplo cohorts was 24% (95% CI, 17-31) and 34% (95% CI, 30-37), respectively (p=0.01), whereas for grade III-IV it was 8% (95% CI, 4-13) and 10% (95% CI, 8-13), (p=0.44). In multivariable analysis (table 2), haplo was associated with an increased risk of acute GVHD grades II-IV, when compared with HLA-matched (HR 0.65; 95% CI, 0.46-0.93; p=0.01). Other variables are shown in table 2. The 2-year Cum Inc of chronic GVHD in the HLA-matched and haplo cohorts was 26% (95% CI, 19-33) and 27% (95% CI, 24-31), respectively (p=0.75). Other variables are shown in table 2. NRM and relapse The Cum Inc of NRM at 2 years was 10% (95% CI; 6-16) for HLA-matched and 18% (95% CI; 15-21) for haplo (p=0.02). In multivariable analysis (table 2), haplo was associated with an increased risk of NRM, when compared to HLA-matched (HR 0.5; 95% CI, 0.28-0.89; p=0.01). Other variables are shown in table 2. The Cum Inc of relapse at 2 years was 22% (95% CI; 15-29) for HLA-matched and 24% (95% CI; 20-27) for haplo (p=0.81). Other variables are shown in table 2. Survival The 2-year OS for the HLA-matched and haplo cohorts was 82% (95% CI; 75-88) and 70% (95% CI; 67-74), respectively (p=0.002). In multivariable analysis (table 2), compared to HLA-matched, haplo (HR, 0.51; 95% CI, 0.34-0.77; p=0.001) was associated with worse survival. Other variables are shown in table 2. The 2-year PFS was similar between HLA-matched and haplo (66%; 95% CI, 58-74; and 58%; 95% CI, 54-62, respectively; p=0.17). Other variables are shown in table 2. Comparison of outcomes for MSD and MUD With regards to the donor type, most posttransplant outcomes did not exhibit significant differences, except for a higher incidence of grades II-IV acute GVHD in the MUD group (33%; 95% CI, 32-44) compared to the MSD group (17%; 95% CI, 10-25) (p=0.01). CONCLUSION Our study shows that in patients with HD undergoing HSCT with PTCy for GVHD prophylaxis, no significant differences in 2-year PFS were observed between HLA-matched and haplo. A higher risk of acute GVHD and NRM is associated with haplo, leading to lower OS compared to HLA-matched transplantation.