Haploidentical peripheral blood stem cell transplantation improves the survival of older patients with myeloid malignancies under low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen for graft-versus-host disease prophylaxis

Haploidentical peripheral blood stem cell transplantation improves the survival of older patients with myeloid malignancies under low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen for graft-versus-host disease prophylaxis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Haploidentical peripheral blood stem cell transplantation improves the survival of older patients with myeloid malignancies under low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen for graft-versus-host disease prophylaxis Xianmin Song, Yannan Jia, Xinxin Xia, yang jun, Yu Cai, Yin Tong, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4734771/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Our study delved into the clinical outcomes of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) for older patients, utilizing a novel low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen to prevent graft-versus-host disease (GVHD). We juxtaposed these outcomes with transplants from matched unrelated/sibling donors (MUD/MSD) for elderly patients with myeloid malignancies from 2016 to 2023. The study encompassed 127 patients, with 40 undergoing MUD/MSD-PBSCT and 87 receiving haplo-PBSCT. The incidences of grades Ⅱ-Ⅳ and Ⅲ-Ⅳ acute GVHD were similar between the two groups, the haplo-PBSCT cohort displayed a promising trend toward reduced incidence of moderate to severe chronic GVHD compared to MUD/MSD-PBSCT (8.19% vs 23.40%, P = 0.067). The 2-year disease-free survival (74.11% vs 59.67%, P = 0.231) and overall survival (76.30% vs 64.00%, P = 0.482) rates were comparable, while haplo-PBSCT exhibited higher graft-versus-host disease-free, relapse-free survival (GRFS) (68.85% vs 46.61%, P = 0.041) and lower cumulative incidences of relapse (CIR) (11.16% vs 31.98%, P = 0.010) compared to MUD/MSD-PBSCT. Our findings underscore the potential of haploidentical transplants with the low-dose ATG/PTCy-based regimen to yield improved GRFS and lower CIR for older patients with hematologic malignancies. Thus, haploidentical donors, especially when coupled with this specified GVHD prevention strategy, emerge as a viable and appealing graft source for elderly patients requiring allo-SCT. Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome Hematopoietic cell transplantation graft-versus-host disease Anti-thymocyte globulin Post-transplant cyclophosphamide Figures Figure 1 Figure 2 INTRODUCTION With the arrival of an aging society, the incidences of elderly myeloid malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) have significantly increased. With the optimization of transplant conditioning regimens and the improvement of supportive care, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become more widely used in the elderly 1 . Human leukocyte antigen (HLA)-matched sibling donors (MSDs) were generally considered the first choice in donor selection, but quite often be limited due to their older age; adult 10/10 HLA-matched unrelated donors (MUDs) are the first-alternative choice, but their availability is limited by taking a long time for selecting a MUD. With the optimization of the T-cell replete haploidentical transplant system, HLA-haploidentical related donors are increasingly used worldwide. However, graft-versus-host disease (GVHD) is still the most important obstacle of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for patients with hematologic malignancies. In the last two decades, the results of haplo-HSCT have been conspicuously improved due to effective prophylaxis strategies for GVHD, such as in vivo T-cell depletion (TCD) with anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy) 2–5 . A dual in vivo TCD strategy under the combination of ATG and PTCy at varying doses were more and more wildly used due to their promising efficiencies 6–9 . Pasic et al. showcased the enhanced efficacy of combining high-dose PTCy (50 mg/kg on days + 3 and + 4) with ATG in older recipients undergoing allo-HSCT 10 . At our center, we have previously employed a pioneering approach by combining low dose ATG (5 mg/kg) with low dose PTCy (one dose of 50 mg/kg)-based regimen (low dose ATG/PTCy-based) in younger patients (median age 37) undergoing haplo-HSCT with a promising efficacy in preventing GVHD 11–13 . To assess whether haplo-HSCT represents a potentially viable alternative for older patients, particularly when utilizing the combination regimen of ATG and PTCy for GVHD prophylaxis, a retrospective comparative analysis was performed to compare the results of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) using a low-dose ATG/PTCy-based regimen for GVHD prevention with those of MUD and MSD transplantation in elderly patients with myeloid malignancies. PATIENTS AND METHODS Patients, donors and grafts The patients aged ≥ 55 years were enrolled in the retrospective study. All the patients were diagnosed with myeloid malignancies and underwent allo-PBSCT at our center from September 2016 to November 2023. Donors included MUDs/MSDs, as well as haploidentical family donors. For MUDs/MSDs, HLA matching required a minimum of 8 out of 10 loci at HLA A, B, C, DRB1, and DQB1 between the donor and recipient. Haploidentical donors were defined by the presence of more than 2 out of the 10 loci mismatched between the recipient and the family donor. Grafts were obtained from mobilized peripheral blood stem cells (PBSCs) using granulocyte-colony stimulating factor (G-CSF). This study received ethical approval from the local ethics committees and was conducted in accordance with the Declaration of Helsinki. Patient data were collected with mandatory written informed consent. Conditioning regimen and GVHD prophylaxis All patients received reduced-intensity conditioning (RIC), which consisted of intravenous busulfan 3.2 mg/kg/day for 2 days, fludarabine 30 mg/m 2 /day and cytarabine (Ara-C) 1 − 1.5 g/m 2 /day for 5 days, and total body irradiation (TBI, 3Gy) on day − 1. GVHD prophylaxis is outlined as follows: ( 1 ) low-dose ATG plus low-dose PTCy-based regimen (low-dose ATG/PTCy-based regimen) 11 : ATG was given at 2.5 mg/kg/d for 2 days (d-2, d-1; a total of 5 mg/kg), and a dose of PTCy (50 mg/kg/d) was given for 1 day on d + 3. Cyclosporine A (CsA) was initiated on d + 4, and administered at 2 mg/kg/d as a continuous infusion. The CsA doses were adjusted to achieve nadir serum levels between 200 and 300 ng/ml. Mycophenolate mofetil (MMF) was orally administered at a dose of 15 mg/kg per time for three times per day (maximum dose 1 g three times a day) from d + 4 to d + 34 in the absence of acute GVHD (aGVHD). ( 2 ) ATG (2.5 mg/kg/d) × 2d + methotrexate (MTX) + CsA + MMF: ATG was administered at a dose of 2.5 mg/kg/d for 2 days, combined with MTX, MMF and CsA. ( 3 ) ATG (1.5 mg/kg/d) × 3d + MTX + CsA + MMF: ATG was given at a dose of 1.5 mg/kg/d for 3 days, combined with CsA, MTX and MMF. MTX was added at a dose of 10 mg/m 2 on day + 1, followed by 5 mg/m 2 on days + 3 and + 6. MMF was given at a dose of 15 mg/kg per time for two times per day for 30 days in MUD and MSD transplantation. CsA was followed the same schedule and dose as described above. Supportive care G-CSF was administered to all patients starting from day + 5 until neutrophil recovery. Prophylactic measures included acyclovir and Posaconazole were provided from the day of conditioning until at least three months after transplant. Quantitative real-time PCR assays for cytomegalovirus (CMV) DNA in serum and Epstein-Barr Virus (EBV) DNA in whole blood were conducted once or twice per week. Patients transplanted before August 2022 with CMV DNA levels exceeding 1000 copies/ml received preemptive therapy with ganciclovir (5 mg/kg, twice daily). Conversely, post-August 2022, 36 patients underwent prophylaxis for CMV reactivation with letermovir following transplantation. For high-risk patients with EBV reactivation, preemptive therapy with rituximab (a single dose of 375 mg/m 2 ) commenced if EBV DNA increased by a log or more within one week or reached above 1×10 5 copies/ml 14 . EBV-related posttransplant lymphoproliferative disease (PTLD) was managed with a reduced dose of immunosuppressive agents and rituximab, administered once per week for a maximum of four courses 15 . Quantitative chimerism monitoring 16 was conducted using short-tandem repeat-based PCR techniques on the CD3-positive cell population from bone marrow. Monitoring occurred at regular intervals every 4 weeks after transplant during the first year. Definitions Neutrophil engraftment was defined as an absolute neutrophil count of ≥ 0.5×10 9 /L sustained for 3 consecutive days post-transplantation without the administration of G-CSF. Platelet engraftment was characterized as the first occurrence of 7 consecutive days with platelet counts exceeding > 20×10 9 /L without the need for platelet transfusion. aGVHD was diagnosed and graded in accordance with the modified Glucksberg grading system for aGVHD 17 . Chronic GVHD (cGVHD) was diagnosed and graded based on the 2014 National Institutes of Health (NIH) consensus criteria, distinguishing between mild, moderate, or severe manifestations, respectively 18 . Statistical analysis Overall survival (OS) was calculated for patients alive at the time of the last follow-up, and disease-free survival (DFS) was defined as the survival period with continuous CR. GVHD-free/relapse-free survival (GRFS) events were defined as without grade Ⅲ-Ⅳ aGVHD, cGVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause after preemptive intervention 19 . The cumulative incidence of aGVHD was documented at day 180, and cGVHD at 2 years post-transplant or at the last follow-up. Death due to other reasons was considered a competing risk for both acute and chronic GVHD. For categorical variables, the chi-square test was employed, and for continuous variables, the Student t-test or Mann-Whitney U test was used. OS, DFS, and GRFS were calculated using the Kaplan-Meier method, while acute and chronic GVHD, non-relapse mortality (NRM), and cumulative incidence of relapse (CIR) were analyzed using competing risk models. Univariate and multivariate analyses were performed using Cox proportional hazards models. Statistical analysis was conducted using SPSS 20.0 and R 3.4.0 software 20 , with a significance level set at P < 0.05. RESULTS Patient characteristics A total of 127 patients aged ≥ 55 years were enrolled in the study, including 87 undergoing haplo-PBSCT, 21 undergoing MSD-PBSCT, and 19 undergoing MUD-PBSCT. All patients in the haplo-PBSCT group and 18 patients from the MUD/MSD-PBSCT group received a low-dose ATG/PTCy-based regimen for GVHD prophylaxis. Eight patients in the MUD-PBSCT group received an ATG (2.5 mg/kg/d) × 2d + MTX + CsA + MMF regimen, while 14 patients in the MSD-PBSCT group received an ATG (1.5 mg/kg/d) × 3d + MTX + CsA + MMF regimen for GVHD prophylaxis. The median age for all the patients was 61 (55–72) years and had no difference between MUD/MRD- and haplo-PBSCT groups ( P = 0.468). AML accounted for 77.2% in all the patients and the frequencies of AML in MUD/MRD- and haplo-PBSCT groups were similar ( P = 0.821). The median age of donors in the haplo-PBSCT group was 34 (range 22–46) years, while in the MUD/MSD-PBSCT group, it was 39 (range 23–69) years ( P < 0.001). The median numbers of mononuclear (MNCs) and CD34 + cells in grafts from haploidentical donors were significantly higher than that from HLA-matched donors ( P < 0.001 for both of MNCs and CD34 + cells). Other characteristics, like as recipient gender, pre-transplantation disease status, ECOG score, HCT-CI score, revised disease risk index (R-DRI), blood type of donors and recipients between the two groups, were similar ( P > 0.05). Median follow-up in the entire cohort was 29.8 months (range 3.4–89.7). The haplo-PBSCT group had shorter follow up (23.5 vs 58.9 months; P < 0.001). The overall characteristics of the patients and donors are summarized in Table 1 . Table 1 Patient Characteristics Characteristics All patients N = 127 MUD/MSD-PBSCT N = 40 Haplo- PBSCT N = 87 P -value Median age at diagnosis, years (range) 61 (55–72) 61.5 (55–72) 61 (55–72) 0.468 ≤ 60 58 (45.7%) 15 (37.5%) 43 (49.5%) >60 69 (54.3%) 25 (62.5%) 44 (50.5%) Sex, n (%) 0.506 Male 69 (54.3%) 20(50.0%) 49(56.3%) Female 58 (45.7%) 20(50.0%) 38(43.7%) Diagnosis, n (%) 0.821 AML 98 (77.2%) 30 (75.0%) 68 (78.2%) MDS 27 (21.3%) 9 (22.5%) 18 (20.7%) CMML 2 (1.5%) 1 (2.5%) 1 (1.1%) ECOG 1.000 0–1 124 124(97.6%) 39(97.5%) 85(97.7%) 2–3 3 (2.4%) 1(2.5%) 2(2.3%) HCT-CI, n (%) 1 (0–3) 1 (0–5) 0.110 0–2 108(85.0%) 37(92.5%) 71(81.6%) ≥ 3 19 (15.0%) 3(7.5%) 16(18.4%) Revised-Disease risk index, n (%) 0.528 Low-Int risk 55 (43.3%) 17(42.5%) 38 (43.7%) High-Very high risk 72 (56.7%) 23 (57.5%) 49 (56.3%) Disease status at transplantation, n (%) 0.901 CR 85 (66.9%) 28 (70.0%) 57 (65.5%) NR 42 (33.1%) 12 (30.0%) 30 (34.5%) Donor-recipient sex matched (n (%) 0.685 Female-male 32 (25.2%) 11 (27.5%) 21 (24.1%) Others 95 (74.8%) 29 (72.5%) 66 (75.9%) Median age at donor, years (range) 34 (22–69) 39 (23–69) 34 (22–46) < 0.001 ABO matched (n (%) 0.398 Matched 61 (48.0%) 17 (42.5%) 44 (50.6%) Mismatched 66 (52.0%) 23 (57.5%) 43 (49.4%) Median mononuclear cells, ×10 8 kg–1 (range) 15.6(4.6–54.0) 12.7(5.0-26.6) 16.5 (4.6–54.0) 0.005 Median CD34 + counts, ×10 6 kg–1 (range) 9.4(0.8–29.5) 6.8(0.8–26.9) 11.3 (1.8–29.5) < 0.001 Median CD3 + counts, ×10 8 kg–1 (range) 3.4 (0.8–13.1) 3.1 (1.6–6.1) 3.4 (0.8–13.1) 0.132 Follow-up in survivors, months (range) 29.8 (3.4–89.7) 58.9(8.5–89.7) 23.5(3.7–75.3) < 0.001 MUD: matched unrelated donor; MSD: matched sibling donor; ECOG: Eastern Cooperative Oncology Group; HCT-CI: hematopoietic cell transplantation comorbidity index; PTCy: posttransplant- cyclophosphamide; CR: complete remission; NR: no response; PBSCT: peripheral blold stem cell transplantation; AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; CMML: chronic myelomonocytic leukemia; Int, intermediate. Bold type indicates statistical significance ( P < 0 .05) Engraftment and GVHD All the patients achieved full-donor chimeirsm at 28 days after transplantation. The median time of neutrophil engraftment in haplo-PBSCT and MUD/MSD-PBSCT groups were 14 (range 10–27) days and 12 (range 10–19) days, respectively ( P = 0.192); while the median time of platelet engraftment was 12 days (6–50), which was prolonged to 14 (range 9–37) days in the MUD/MSD-PBSCT group ( P = 0.040). For all the patients, the cumulative incidences (CIs) of grade Ⅱ-Ⅳ and Ⅲ-Ⅳ aGVHD within 180 days post-transplant were 10.17% and 5.51%, respectively. In the haplo-PBSCT group, the CIs were 9.20% and 4.60%, which were similar to those of 12.26% ( P = 0.605, Fig. 1 a) and 7.50% ( P = 0.490, Fig. 1 b) in the MUD/MSD-PBSCT group. Sixty-six patients in the haplo-PBSCT group and 36 in the MUD/MSD-PBSCT group survived beyond 180 days post-transplant and were available for cGVHD assessment. The CIs of total cGVHD and moderate/severe cGVHD for all the patients at 2 years were 30.52% and 14.60%, respectively. Although there was no statistically significant difference in the overall incidences of cGVHD between the two groups (20.30% vs 33.85%, P = 0.116), the haplo-PBSCT group had a strong trend towards a lower CI of moderate to severe cGVHD at 2 years compared to the MUD/MSD-PBSCT group, with CIs of 8.19% and 23.40%, respectively ( P = 0.067, Fig. 1 c). Relapse Until the last follow-up, 10 patients in the haplo-PBSCT group and 13 in the MUD/MSD-PBSCT group experienced relapse. The median times to relapse were 200 and 132 days for the haplo-PBSCT and MUD/MSD-PBSCT groups, respectively. Notably, the 2-year CIR of 11.16% in haplo-PBSCT group was significantly lower that of 31.98% in MUD/MSD-PBSCT ( P = 0.010, Fig. 1 d). In multivariate analysis, haploidentical transplantation and female donor to male recipient significantly decreased the risk of relapse (haplo vs MUD/MSD: Hazard Ratio [HR] 0.344, 95% Confidence Interval [CI] 0.149–0.795, P = 0.013; female-male vs other: HR 0.164, 95% CI 0.035–0.766, P = 0.022) (Table 2 ). Table 2 Multivariate analyses of outcomes Outcomes Multivariate analysis Hazard ratio (95% CI) P value Relapse Haplo vs MUD/MSD 0.344 (0.149–0.795) 0.013 Sex (male vs female) 3.487 (0.755–16.106) 0.110 Donor-recipient sex matched (female-male vs others) 0.164 (0.035–0.766) 0.022 NRM R-DRI (low-int risk vs high-very high risk) 0.354 (0.114–1.106) 0.074 aGVHD (0-Ⅰ vs Ⅱ-Ⅳ) 0.075 (0.013–0.455) 0.004 Age (≥ 60 vs <60) 4.432 (0.969–20.200) 0.062 CD34 + counts (<6×10 6 /kg vs ≥ 6×10 6 /kg) 8.433(1.217–58.490) 0.058 DFS Pre-transplant status (CR vs NR) 0.644 (0.332–1.249) 0.193 aGVHD (0-Ⅰ vs Ⅱ-Ⅳ) 0.419 (0.158–1.107) 0.079 Donor-recipient sex matched (female-male vs others) 0.660 (0.325–1.337) 0.249 HCT-CI (≥ 3 vs 0–2) 2.708 (0.804–9.122) 0.108 OS aGVHD (0-Ⅰ vs Ⅱ-Ⅳ) 0.329 (0.123–0.877) 0.026 Pre-transplant status (CR vs NR) 0.570 (0.283–1.147) 0.115 HCT-CI (≥ 3 vs 0–2) 4.125 (0.947–17.968) 0.059 GRFS Haplo vs MUD/MSD 0.502 (0.279–1.913) 0.024 Pre-transplant status (CR vs NR) 0.572 (0.316–1.034) 0.064 Age of donor (≤ 40 vs >40) 1.686 (0.811–3.506) 0.162 Bold type indicates statistical significance ( P < 0 .05). Abbreviations: MUD/MSD, matched unrelated/sibling donors; Haplo, haploidentical donors; aGVHD, acute graft-versus-host disease; HCT-CI, Hematopoietic Cell Transplantation–Specific Comorbidity Index; HR, hazard ratio; NRM, non-relapse mortality; OS, overall survival; DFS, disease-free survival; GRFS, Graft-versus-host disease-free, relapse-free survival. Int, intermediate. NRM and infectious complications The 2-year NRM in the haplo-PBSCT and MUD/MSD-PBSCT groups were 14.73% and 5.00%, respectively ( P = 0.116, Fig. 2 a). Among the haplo-PBSCT group, 12 patients experienced NRM, including 10 (11.5% out of 87) with infection, 1 (1.1%) with multi-organ failure, 1 (1.1%) with aGVHD. In the MUD/MSD-PBSCT group, NRM occurred in 2 (5.0% out of 40) patients, predominantly due to infection (Table 3 ). In multivariate analysis (Table 2 ), Ⅱ-Ⅳ aGVHD was the independent risk factor of NRM (0-Ⅰ vs Ⅱ-Ⅳ aGVHD, HR 0.075, 95% CI 0.013–0.455, P = 0.004). Low-int risk in R-DRI classification had a strong trend to lower the risk of NRM (HR 0.354, 95% CI 0.114–1.106, P = 0.074), while age ≥ 60 years (HR 4.432, 95% CI 0.969–20.200, P = 0.062) and CD34 + cells in grafts<6×10 6 /kg (HR 8.433, 95% CI 1.217–58.490, P = 0.058) had strong trends to increase the risk of NRM. Table 3 Cause of NRM and viral infection in the two groups. MUD/MSD-PBSCT N = 40 Haplo-PBSCT N = 87 P-value Causes of NRM Infection 2 (5.0%) 10 (11.5%) 0.403 MOF 0 (0%) 1 (1.1%) 1.000 aGVHD 0 (0%) 1 (1.1%) 1.000 Viral infection CMV viremia 6 (15.0%) 24 (27.6%) 0.090 CMV disease 2 (5.0%) 6 (6.90%) 0.512 EB viremia 7 (17.5%) 17 (19.5%) 0.496 PTLD EBV related 0 (0%) 3 (3.4%) 0.318 CMV: cytomegalovirus, PTLD: post-transplant lymphoproliferative disorder, NRM: non-relapse mortality, MOF: multiple organ failure. aGVHD: acute graft-versus-host disease. Among the total cohort, prophylaxis therapy for CMV reactivation with letermovir was administered to 36 patients (28.3%), including 6 in haplo-PBSCT and 30 in MSD/MUD groups, respectively ( P = 0.050). Interestingly, there was no discrepancy in the incidences of CMV infection and CMV disease within one-year post-transplantation between the haplo- and MUD/MSD-PBSCT groups (27.6% vs 15.0% for CMV infection, P = 0.090; 6.90% vs 5.0% for CMV disease, P = 0.512). The incidences of EB virus infection were comparable between the haplo-PBSCT and MUD/MSD-PBSCT groups (19.5% vs 17.5%, P = 0.496). In the haplo-PBSCT group, 3 patients (3.4%) developed EBV-PTLD, while no cases were reported in the MUD/MSD-PBSCT group (Table 3 ). DFS, OS and GRFS As of the latest follow-up, a total of 26 patients had died: 17 in the haplo-PBSCT group and 9 in the MUD/MSD-PBSCT group. Within the haplo-PBSCT group, 5 patients succumbed to relapse, and 12 patients experienced non-relapse mortality. In the MUD/MSD-PBSCT group, 7 patients died of relapse, while 2 experienced NRM. The haplo-PBSCT group exhibited similar 2-year DFS and OS rates compared to the MUD/MSD-PBSCT group, with rates of 74.11% versus 59.67% ( P = 0.231, Fig. 2 b) and 76.30% versus 64.00% ( P = 0.482, Fig. 2 c), respectively. Notably, the haplo-PBSCT group achieved a significantly higher GRFS compared to the MUD/MSD-PBSCT group, demonstrating rates of 68.85% versus 46.61% ( P = 0.041, Fig. 2 d). In multivariate analysis, grades Ⅱ-Ⅳ aGVHD emerged as a significant predictor of inferior OS. Noteworthy is the finding that haploidentical family donors were associated with improved GRFS (HR 0.502, 95% CI 0.279–1.913, P = 0.024). Although there was no significant difference, CR disease status at pre-transplantation had a strong trend to favor the GRFS (HR 0.572, 95% CI 0.316–1.034, P = 0.064) (Table 2 ). DISCUSSION The success of allo-HSCT for hematological malignancies is significantly dependent on the availability of suitable donors. Haploidentical donors and matched unrelated/sibling donors are crucial donor options. However, the quest for the optimal donor for HCT in elderly patients with myeloid malignancies remains a subject of ongoing debate. In the present study, the results suggested that haploidentical transplants employing the low-dose ATG/PTCy-based regimen for GVHD prophylaxis significantly reduced the risk of relapse and achieved a better GRFS compared to the conventional MUD/MSD transplants. In recent years, in vivo T-cell depletion with ATG combined with PTCy has seen increasing use across various clinical settings. In a study 7 involving 270 hematologic malignancy patients undergoing RIC PBSCT and using dual T-cell depletion with ATG (total dose of 4.5 mg/kg) and PTCy (50 mg/kg/d for 2 days) as the GVHD prevention regimen, the CIs of grade Ⅱ–Ⅳ and Ⅲ–Ⅳ aGVHD at day + 100 were 20.1% and 4.6%, respectively. The CI of moderate/severe cGVHD at 1 year was 12.4%. A remarkable finding of this study is the absence of statistically significant differences in clinically relevant cGVHD between donor types (30% in Haplo patients, 37.5% in MRD patients, and 31% in UD patients, P = 0.528), suggesting that the combination of ATG and PTCy has the potential to overcome the HLA barrier. Dulery et al. 21 reported on the transplant outcomes of 72 adults with refractory hematologic malignancies treated with PBSCT using ATG (total dose of 5 mg/kg) and PTCy (50 mg/kg for 2 days). They found that haploidentical donors (n = 27) had a lower incidence of grade Ⅱ-Ⅳ aGVHD compared to matched unrelated donors (n = 29), with rates of 11.1% versus 41.4%, respectively ( P < 0.001). While the ATG-PTCy combination has been applied in various HCT indications and with different types of donors, there is limited data supporting its use specifically in patients aged 55 and older with myeloid malignancies. In our study, both the MUD/MSD and haplo-PBSCT groups exhibited lower cumulative incidences of Ⅱ-Ⅳ aGVHD (MUD/MSD-PBSCT: 12.26%, haplo-PBSCT: 9.20%). Specifically, compared to the MUD/MSD-PBSCT group, the haplo-PBSCT group showed a decreasing trend of moderate to severe cGVHD (MUD/MSD-PBSCT: 23.40%, haplo-PBSCT: 8.19%), suggesting that dual T-cell depletion with ATG and PTCy is also feasible in elderly haploidentical transplant patients. Given that the conditioning intensity cannot be too high due to the risk of toxicity in older patients, disease relapse remains a significant problem. Interestingly, a recent study by the European Society for Blood and Marrow Transplantation (EBMT) 22 involving 701 adults aged ≥ 70 years with AML reported a lower relapse incidence among patients using haploidentical donors compared to those using MSD (HR 0.46, 95% CI 0.25–0.80, P = 0.02). This led to prolonged leukemia-free survival (LFS) in the haploidentical donor group (HR 0.62, 95% CI 0.39–0.99, P = 0.04). Other reports showed similar trends in adults with high-risk AML 23, 24 . In line with previous reports, our analysis revealed that the elderly recipients in the haplo-PBSCT group had a significantly lower CIR compared to that in the MUD/MSD group (11.16% vs. 31.98%, P = 0.010). This can possibly be attributed to stronger graft-versus-leukemia effects in haplo-HSCT, due to greater genetic disparity and enhanced function of T and NK cells from haploidentical allografts, leading to more robust anti-leukemia activity 25–28 . Treatment-related complications and mortality are significant concerns for elderly patients when opting for allogeneic transplantation. In elderly patients aged 70 or above with myeloid malignancies, the estimated 2-year NRM is reported to be in the range of 30–35% 29 . In a large retrospective study of 1,080 AML/MDS patients undergoing RIC-HSCT, the 2-year NRM ranged from 22–39% for those aged 55–59, 60–64, and 65 and older, with no significant differences observed between these age cohorts 30 . In a study involving 43 older patients (median age 61 years) with AML/MDS who underwent haplo-SCT with PTCy prophylaxis, the 2-year NRM was reported to be 34% 31 , which is higher than that of 14.73% observed in our study for haplo-PBSCT recipients. This suggests that a low-dose ATG/PTCy-based regimen can be safely used in older individuals undergoing haplo-HSCT, achieving a relatively low NRM for older patients. The multivariate analysis demonstrated that grades Ⅱ-Ⅳ aGVHD were strongly associated with a higher risk of NRM. Additionally, a low-int risk in the R-DRI classification showed a strong trend toward lowering the risk of NRM. Conversely, age ≥ 60 years and CD34 + cell counts in grafts < 6×10 6 /kg exhibited strong trends toward adversely affecting the 2-year NRM. Infection was one of the most important primary causes of transplant-related mortality in both the haplo-PBSCT and MUD/MSD-PBSCT groups. The literatures suggest a higher likelihood of bacterial infection with increasing age 32 . In our elderly patient cohort, the elevated incidence of infections contributing to NRM post-transplantation may be linked to age-related declines in host immune system functionality or diminished thymic T-lymphocyte reconstruction compared to younger patients, resulting in reduced initial T cell circulation 33 . The haplo-PBSCT group experienced an elevated incidence of CMV and EBV virus infections, likely attributed to HLA mismatching between T-cell donors and recipients, along with the dual depletion of T cells resulting from PTCy and ATG. However, no fatalities occurred in the MUD/MSD-PBSCT group due to CMV or EBV infections. In the haplo-PBSCT group, only one patient succumbed to CMV pneumonia. With the increasing use of preventive drugs such as ganciclovir, the incidence of CMV infection is expected to be further controlled. The study by EBMT 22 involving 701 elderly transplant patients with AML reported that patients transplanted from haploidentical donors exhibited higher GRFS rates compared to those who received transplants from matched sibling and unrelated donors. Notably, about 20% of the transplants from haploidentical donors used bone marrow as the cell source, whereas almost all MSD and MUD recipients received peripheral blood stem cells. The lower incidence of cGVHD observed in haplo transplants may be attributed to the use of bone marrow, which is associated with less cGVHD compared to PBSC. Conversely, in our study, all patients received PBSC as the cell source. Our findings indicate that haploidentical transplantation in elderly patients with myeloid malignancies achieves better GRFS rates compared to MUD/MSD-PBSCT. This improved outcome may be attributed to a lower incidence of relapse and reduced rates of cGVHD, likely due to the GVHD prevention regimen consisting of low-dose ATG/PTCy. In conclusion, haploidentical donors, especially when employing the specified GVHD prevention strategy, are a suitable and attractive graft source for patients ≥ 55 with hematologic malignancies in need of allo-SCT. The favorable clinical outcomes observed among recipients of T-cell replete haploidentical transplants should be validated with prospective clinical trials and longer haplo-PBSCT follow up is needed to analyze the impact of this type of donor on long-term outcomes and complications. Declarations COMPETING INTERESTS The authors declare that they have no conflict of interest. ETHICS APPROVAL AND CONSENT TO PARTICIPATE The study was approved by the institutional review committee of the ethics committee of Shanghai General Hospital. All patients gave written informed consent according to the Helsinki declaration. FUNDING This study was funded by the National Natural Science Foundation of China (81570148). AUTHOR CONTRIBUTIONS Y-NJ and X-XX wrote the manuscript. JY, YC, YT, H-YQ, KZ, YZ, CS, LW were involved in patient management and clinical data collection. X-MS revised the manuscript and provided valuable advice. All authors read and approved the final manuscript. ACKNOWLEDGEMENTS We thank the patients who participated and all the nursing staff for providing excellent care for our patients. DATA AVAILABILITY Data will be available upon request to [email protected] . References Phelan R, Chen M, Bupp C, Bolon YT, Broglie L, Brunner-Grady J et al. Updated Trends in Hematopoietic Cell Transplantation in the United States with an Additional Focus on Adolescent and Young Adult Transplantation Activity and Outcomes. Transplant Cell Ther 2022; 28 (7) : 409 e401-409 e410. e-pub ahead of print 2022/04/22; doi: 10.1016/j.jtct.2022.04.012 Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood 2001; 98 (12) : 3456-3464. e-pub ahead of print 2001/11/24; doi: 10.1182/blood.v98.12.3456 Al-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U. Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant 2015; 21 (4) : 604-611. e-pub ahead of print 2014/09/23; doi: 10.1016/j.bbmt.2014.08.014 Apperley J, Niederwieser D, Huang XJ, Nagler A, Fuchs E, Szer J et al. Reprint of: Haploidentical Hematopoietic Stem Cell Transplantation: A Global Overview Comparing Asia, the European Union, and the United States. Biol Blood Marrow Transplant 2016; 22 (3 Suppl) : S15-18. e-pub ahead of print 2016/02/24; doi: 10.1016/j.bbmt.2016.01.006 Handgretinger R. Haploidentical transplantation: the search for the best donor. Blood 2014; 124 (6) : 827-828. e-pub ahead of print 2014/08/12; doi: 10.1182/blood-2014-06-582460 Salas MQ, Atenafu EG, Law AD, Lam W, Pasic I, Chen C et al. Experience Using Anti-Thymocyte Globulin With Post-Transplantation Cyclophosphamide for Graft-Versus-Host Disease Prophylaxis in Peripheral Blood Haploidentical Stem Cell Transplantation. Transplant Cell Ther 2021; 27 (5) : 428 e421-428 e429. e-pub ahead of print 2021/05/10; doi: 10.1016/j.jtct.2021.02.007 Salas MQ, Prem S, Atenafu EG, Datt Law A, Lam W, Al-Shaibani Z et al. Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD. Bone Marrow Transplant 2020; 55 (9) : 1773-1783. e-pub ahead of print 2020/02/07; doi: 10.1038/s41409-020-0813-9 Wang Y, Wu DP, Liu QF, Xu LP, Liu KY, Zhang XH et al. Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients. J Hematol Oncol 2019; 12 (1) : 88. e-pub ahead of print 2019/09/05; doi: 10.1186/s13045-019-0781-y Law AD, Salas MQ, Lam W, Michelis FV, Thyagu S, Kim DDH et al. Reduced-Intensity Conditioning and Dual T Lymphocyte Suppression with Antithymocyte Globulin and Post-Transplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplants for Hematological Malignancies. Biol Blood Marrow Transplant 2018; 24 (11) : 2259-2264. e-pub ahead of print 2018/07/17; doi: 10.1016/j.bbmt.2018.07.008 Pasic I, Lipton JH, Kim DD, Viswabandya A, Kumar R, Lam W et al. Post-transplant cyclophosphamide combined with anti-thymocyte globulin for graft-vs-host disease prophylaxis improves survival and lowers non-relapse mortality in older patients undergoing allogeneic hematopoietic cell transplantation. Ann Hematol 2020; 99 (6) : 1377-1387. e-pub ahead of print 2020/05/10; doi: 10.1007/s00277-020-04033-2 Yang J, Jiang J, Cai Y, Li S, Wan L, Zhu J et al. Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood for patients with hematologic malignancies: a prospective, phase II study. Bone Marrow Transplant 2019; 54 (7) : 1049-1057. e-pub ahead of print 2018/11/18; doi: 10.1038/s41409-018-0382-3 Xu X, Yang J, Cai Y, Li S, Niu J, Zhou K et al. Low dose anti-thymocyte globulin with low dose posttransplant cyclophosphamide (low dose ATG/PTCy) can reduce the risk of graft-versus-host disease as compared with standard-dose anti-thymocyte globulin in haploidentical peripheral hematopoietic stem cell transplantation combined with unrelated cord blood. Bone Marrow Transplant 2021; 56 (3) : 705-708. e-pub ahead of print 2020/09/03; doi: 10.1038/s41409-020-01047-2 Li X, Yang J, Cai Y, Huang C, Xu X, Qiu H et al. Low-dose anti-thymocyte globulin plus low-dose post-transplant cyclophosphamide-based regimen for prevention of graft-versus-host disease after haploidentical peripheral blood stem cell transplants: a large sample, long-term follow-up retrospective study. Front Immunol 2023; 14: 1252879. e-pub ahead of print 2023/11/13; doi: 10.3389/fimmu.2023.1252879 van Esser JW, Niesters HG, van der Holt B, Meijer E, Osterhaus AD, Gratama JW et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 2002; 99 (12) : 4364-4369. e-pub ahead of print 2002/05/31; doi: 10.1182/blood.v99.12.4364 Dierickx D, Tousseyn T, Gheysens O. How I treat posttransplant lymphoproliferative disorders. Blood 2015; 126 (20) : 2274-2283. e-pub ahead of print 2015/09/19; doi: 10.1182/blood-2015-05-615872 Jiang Y, Wan LP, Qin YW, Wang XR, Yan SK, Xie KC et al. Chimerism status is correlated to acute graft-versus-host disease after allogeneic stem cell transplantation. Int J Hematol 2014; 99 (3) : 323-328. e-pub ahead of print 2014/02/01; doi: 10.1007/s12185-014-1510-5 Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15 (6) : 825-828. e-pub ahead of print 1995/06/01; Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21 (3) : 389-401 e381. e-pub ahead of print 2014/12/23; doi: 10.1016/j.bbmt.2014.12.001 Pasquini MC, Logan B, Jones RJ, Alousi AM, Appelbaum FR, Bolanos-Meade J et al. Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials. Biol Blood Marrow Transplant 2018; 24 (6) : 1274-1280. e-pub ahead of print 2018/01/13; doi: 10.1016/j.bbmt.2018.01.002 Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 2007; 40 (4) : 381-387. e-pub ahead of print 2007/06/15; doi: 10.1038/sj.bmt.1705727 Dulery R, Menard AL, Chantepie S, El-Cheikh J, Francois S, Delage J et al. Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors. Biol Blood Marrow Transplant 2018; 24 (5) : 1013-1021. e-pub ahead of print 2018/01/18; doi: 10.1016/j.bbmt.2018.01.005 Maffini E, Ngoya M, Galimard JE, Harbi S, Kroger N, Platzbecker U et al. Allogeneic hematopoietic cell transplantation for patients with AML aged 70 years or older in first remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2023; 58 (9) : 1033-1041. e-pub ahead of print 2023/06/30; doi: 10.1038/s41409-023-02027-y Salvatore D, Labopin M, Ruggeri A, Battipaglia G, Ghavamzadeh A, Ciceri F et al. Outcomes of hematopoietic stem cell transplantation from unmanipulated haploidentical versus matched sibling donor in patients with acute myeloid leukemia in first complete remission with intermediate or high-risk cytogenetics: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 2018; 103 (8) : 1317-1328. e-pub ahead of print 2018/05/12; doi: 10.3324/haematol.2018.189258 Luo Y, Xiao H, Lai X, Shi J, Tan Y, He J et al. T-cell-replete haploidentical HSCT with low-dose anti-T-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT. Blood 2014; 124 (17) : 2735-2743. e-pub ahead of print 2014/09/13; doi: 10.1182/blood-2014-04-571570 Guo H, Chang YJ, Hong Y, Xu LP, Wang Y, Zhang XH et al. Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation. Cell Mol Immunol 2021; 18 (5) : 1172-1185. e-pub ahead of print 2021/01/08; doi: 10.1038/s41423-020-00597-1 Yabe T, Azuma F, Kashiwase K, Matsumoto K, Orihara T, Yabe H et al. HLA-DPB1 mismatch induces a graft-versus-leukemia effect without severe acute GVHD after single-unit umbilical cord blood transplantation. Leukemia 2018; 32 (1) : 168-175. e-pub ahead of print 2017/06/28; doi: 10.1038/leu.2017.202 Shaw BE, Gooley TA, Malkki M, Madrigal JA, Begovich AB, Horowitz MM et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110 (13) : 4560-4566. e-pub ahead of print 2007/08/30; doi: 10.1182/blood-2007-06-095265 Hambach L, Spierings E, Goulmy E. Risk assessment in haematopoietic stem cell transplantation: minor histocompatibility antigens. Best Pract Res Clin Haematol 2007; 20 (2) : 171-187. e-pub ahead of print 2007/04/24; doi: 10.1016/j.beha.2006.09.002 Muffly L, Pasquini MC, Martens M, Brazauskas R, Zhu X, Adekola K et al. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States. Blood 2017; 130 (9) : 1156-1164. e-pub ahead of print 2017/07/05; doi: 10.1182/blood-2017-03-772368 McClune BL, Weisdorf DJ, Pedersen TL, Tunes da Silva G, Tallman MS, Sierra J et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010; 28 (11) : 1878-1887. e-pub ahead of print 2010/03/10; doi: 10.1200/JCO.2009.25.4821 Ciurea SO, Shah MV, Saliba RM, Gaballa S, Kongtim P, Rondon G et al. Haploidentical Transplantation for Older Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant 2018; 24 (6) : 1232-1236. e-pub ahead of print 2017/09/18; doi: 10.1016/j.bbmt.2017.09.005 Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int 2009; 22 (11) : 1041-1050. e-pub ahead of print 2009/07/25; doi: 10.1111/j.1432-2277.2009.00927.x Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica 2011; 96 (2) : 298-306. e-pub ahead of print 2010/10/12; doi: 10.3324/haematol.2010.029702 Additional Declarations The authors have declared there is NO conflict of interest to disclose. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4734771","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":327301505,"identity":"f55dc3e6-2349-4d44-b3ac-c9d1c314ffa4","order_by":0,"name":"Xianmin 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Wan","suffix":""}],"badges":[],"createdAt":"2024-07-13 10:25:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4734771/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4734771/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62328424,"identity":"6de43060-c4d2-4daf-8be3-823518e35bc2","added_by":"auto","created_at":"2024-08-13 03:14:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":260101,"visible":true,"origin":"","legend":"\u003cp\u003eRates of grades Ⅱ-Ⅳ acute graft-versus-host disease (GVHD), grades Ⅲ-Ⅳ acute GVHD, moderate to severe chronic GVHD, andcumulative incidences of relapse (CIR) according to treatment group. Rates of grades Ⅱ-Ⅳ acute GVHD (a), grades Ⅲ-Ⅳ acute GVHD (b), moderate to severe chronic GVHD (c), CIR (d).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4734771/v1/ef954bed692942430807623f.png"},{"id":62327551,"identity":"c2e1665a-c96e-4874-9f01-cf22ae59bc44","added_by":"auto","created_at":"2024-08-13 03:06:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":336356,"visible":true,"origin":"","legend":"\u003cp\u003eClinical outcomes of patients 2 years after transplantation by treatment group. (a) The probabilities of non-relapse mortality (NRM). (b) The probabilities of disease-free survival (DFS). (c) The probabilities of overall survival (OS). (d) The probabilities of graft-versus-host disease-free, relapse-free survival (GRFS).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4734771/v1/d11b92be7634f30b4588a1e5.png"},{"id":62329209,"identity":"30bbb9c6-45e0-46d2-a4e6-a8810239f869","added_by":"auto","created_at":"2024-08-13 03:23:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1262865,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4734771/v1/97af0d15-838d-495c-9d21-face4477bd53.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Haploidentical peripheral blood stem cell transplantation improves the survival of older patients with myeloid malignancies under low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen for graft-versus-host disease prophylaxis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eWith the arrival of an aging society, the incidences of elderly myeloid malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) have significantly increased. With the optimization of transplant conditioning regimens and the improvement of supportive care, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become more widely used in the elderly \u003csup\u003e1\u003c/sup\u003e. Human leukocyte antigen (HLA)-matched sibling donors (MSDs) were generally considered the first choice in donor selection, but quite often be limited due to their older age; adult 10/10 HLA-matched unrelated donors (MUDs) are the first-alternative choice, but their availability is limited by taking a long time for selecting a MUD. With the optimization of the T-cell replete haploidentical transplant system, HLA-haploidentical related donors are increasingly used worldwide. However, graft-versus-host disease (GVHD) is still the most important obstacle of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for patients with hematologic malignancies.\u003c/p\u003e \u003cp\u003eIn the last two decades, the results of haplo-HSCT have been conspicuously improved due to effective prophylaxis strategies for GVHD, such as \u003cem\u003ein vivo\u003c/em\u003e T-cell depletion (TCD) with anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy) \u003csup\u003e2\u0026ndash;5\u003c/sup\u003e. A dual \u003cem\u003ein vivo\u003c/em\u003e TCD strategy under the combination of ATG and PTCy at varying doses were more and more wildly used due to their promising efficiencies \u003csup\u003e6\u0026ndash;9\u003c/sup\u003e. Pasic et al. showcased the enhanced efficacy of combining high-dose PTCy (50 mg/kg on days\u0026thinsp;+\u0026thinsp;3 and +\u0026thinsp;4) with ATG in older recipients undergoing allo-HSCT \u003csup\u003e10\u003c/sup\u003e. At our center, we have previously employed a pioneering approach by combining low dose ATG (5 mg/kg) with low dose PTCy (one dose of 50 mg/kg)-based regimen (low dose ATG/PTCy-based) in younger patients (median age 37) undergoing haplo-HSCT with a promising efficacy in preventing GVHD \u003csup\u003e11\u0026ndash;13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo assess whether haplo-HSCT represents a potentially viable alternative for older patients, particularly when utilizing the combination regimen of ATG and PTCy for GVHD prophylaxis, a retrospective comparative analysis was performed to compare the results of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) using a low-dose ATG/PTCy-based regimen for GVHD prevention with those of MUD and MSD transplantation in elderly patients with myeloid malignancies.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients, donors and grafts\u003c/h2\u003e \u003cp\u003eThe patients aged\u0026thinsp;\u0026ge;\u0026thinsp;55 years were enrolled in the retrospective study. All the patients were diagnosed with myeloid malignancies and underwent allo-PBSCT at our center from September 2016 to November 2023. Donors included MUDs/MSDs, as well as haploidentical family donors. For MUDs/MSDs, HLA matching required a minimum of 8 out of 10 loci at HLA A, B, C, DRB1, and DQB1 between the donor and recipient. Haploidentical donors were defined by the presence of more than 2 out of the 10 loci mismatched between the recipient and the family donor. Grafts were obtained from mobilized peripheral blood stem cells (PBSCs) using granulocyte-colony stimulating factor (G-CSF). This study received ethical approval from the local ethics committees and was conducted in accordance with the Declaration of Helsinki. Patient data were collected with mandatory written informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eConditioning regimen and GVHD prophylaxis\u003c/h2\u003e \u003cp\u003eAll patients received reduced-intensity conditioning (RIC), which consisted of intravenous busulfan 3.2 mg/kg/day for 2 days, fludarabine 30 mg/m\u003csup\u003e2\u003c/sup\u003e/day and cytarabine (Ara-C) 1\u0026thinsp;\u0026minus;\u0026thinsp;1.5 g/m\u003csup\u003e2\u003c/sup\u003e/day for 5 days, and total body irradiation (TBI, 3Gy) on day \u0026minus;\u0026thinsp;1.\u003c/p\u003e \u003cp\u003eGVHD prophylaxis is outlined as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) low-dose ATG plus low-dose PTCy-based regimen (low-dose ATG/PTCy-based regimen) \u003csup\u003e11\u003c/sup\u003e: ATG was given at 2.5 mg/kg/d for 2 days (d-2, d-1; a total of 5 mg/kg), and a dose of PTCy (50 mg/kg/d) was given for 1 day on d\u0026thinsp;+\u0026thinsp;3. Cyclosporine A (CsA) was initiated on d\u0026thinsp;+\u0026thinsp;4, and administered at 2 mg/kg/d as a continuous infusion. The CsA doses were adjusted to achieve nadir serum levels between 200 and 300 ng/ml. Mycophenolate mofetil (MMF) was orally administered at a dose of 15 mg/kg per time for three times per day (maximum dose 1 g three times a day) from d\u0026thinsp;+\u0026thinsp;4 to d\u0026thinsp;+\u0026thinsp;34 in the absence of acute GVHD (aGVHD). (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) ATG (2.5 mg/kg/d) \u0026times; 2d\u0026thinsp;+\u0026thinsp;methotrexate (MTX)\u0026thinsp;+\u0026thinsp;CsA\u0026thinsp;+\u0026thinsp;MMF: ATG was administered at a dose of 2.5 mg/kg/d for 2 days, combined with MTX, MMF and CsA. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) ATG (1.5 mg/kg/d) \u0026times; 3d\u0026thinsp;+\u0026thinsp;MTX\u0026thinsp;+\u0026thinsp;CsA\u0026thinsp;+\u0026thinsp;MMF: ATG was given at a dose of 1.5 mg/kg/d for 3 days, combined with CsA, MTX and MMF. MTX was added at a dose of 10 mg/m\u003csup\u003e2\u003c/sup\u003e on day\u0026thinsp;+\u0026thinsp;1, followed by 5 mg/m\u003csup\u003e2\u003c/sup\u003e on days\u0026thinsp;+\u0026thinsp;3 and +\u0026thinsp;6. MMF was given at a dose of 15 mg/kg per time for two times per day for 30 days in MUD and MSD transplantation. CsA was followed the same schedule and dose as described above.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSupportive care\u003c/h2\u003e \u003cp\u003eG-CSF was administered to all patients starting from day\u0026thinsp;+\u0026thinsp;5 until neutrophil recovery. Prophylactic measures included acyclovir and Posaconazole were provided from the day of conditioning until at least three months after transplant. Quantitative real-time PCR assays for cytomegalovirus (CMV) DNA in serum and Epstein-Barr Virus (EBV) DNA in whole blood were conducted once or twice per week. Patients transplanted before August 2022 with CMV DNA levels exceeding 1000 copies/ml received preemptive therapy with ganciclovir (5 mg/kg, twice daily). Conversely, post-August 2022, 36 patients underwent prophylaxis for CMV reactivation with letermovir following transplantation. For high-risk patients with EBV reactivation, preemptive therapy with rituximab (a single dose of 375 mg/m\u003csup\u003e2\u003c/sup\u003e) commenced if EBV DNA increased by a log or more within one week or reached above 1\u0026times;10\u003csup\u003e5\u003c/sup\u003e copies/ml \u003csup\u003e14\u003c/sup\u003e. EBV-related posttransplant lymphoproliferative disease (PTLD) was managed with a reduced dose of immunosuppressive agents and rituximab, administered once per week for a maximum of four courses \u003csup\u003e15\u003c/sup\u003e. Quantitative chimerism monitoring \u003csup\u003e16\u003c/sup\u003e was conducted using short-tandem repeat-based PCR techniques on the CD3-positive cell population from bone marrow. Monitoring occurred at regular intervals every 4 weeks after transplant during the first year.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eNeutrophil engraftment was defined as an absolute neutrophil count of \u0026ge;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L sustained for 3 consecutive days post-transplantation without the administration of G-CSF. Platelet engraftment was characterized as the first occurrence of 7 consecutive days with platelet counts exceeding\u0026thinsp;\u0026gt;\u0026thinsp;20\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L without the need for platelet transfusion. aGVHD was diagnosed and graded in accordance with the modified Glucksberg grading system for aGVHD \u003csup\u003e17\u003c/sup\u003e. Chronic GVHD (cGVHD) was diagnosed and graded based on the 2014 National Institutes of Health (NIH) consensus criteria, distinguishing between mild, moderate, or severe manifestations, respectively \u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eOverall survival (OS) was calculated for patients alive at the time of the last follow-up, and disease-free survival (DFS) was defined as the survival period with continuous CR. GVHD-free/relapse-free survival (GRFS) events were defined as without grade Ⅲ-Ⅳ aGVHD, cGVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause after preemptive intervention \u003csup\u003e19\u003c/sup\u003e. The cumulative incidence of aGVHD was documented at day 180, and cGVHD at 2 years post-transplant or at the last follow-up. Death due to other reasons was considered a competing risk for both acute and chronic GVHD. For categorical variables, the chi-square test was employed, and for continuous variables, the Student t-test or Mann-Whitney U test was used. OS, DFS, and GRFS were calculated using the Kaplan-Meier method, while acute and chronic GVHD, non-relapse mortality (NRM), and cumulative incidence of relapse (CIR) were analyzed using competing risk models. Univariate and multivariate analyses were performed using Cox proportional hazards models. Statistical analysis was conducted using SPSS 20.0 and R 3.4.0 software \u003csup\u003e20\u003c/sup\u003e, with a significance level set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 127 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;55 years were enrolled in the study, including 87 undergoing haplo-PBSCT, 21 undergoing MSD-PBSCT, and 19 undergoing MUD-PBSCT. All patients in the haplo-PBSCT group and 18 patients from the MUD/MSD-PBSCT group received a low-dose ATG/PTCy-based regimen for GVHD prophylaxis. Eight patients in the MUD-PBSCT group received an ATG (2.5 mg/kg/d) \u0026times; 2d\u0026thinsp;+\u0026thinsp;MTX\u0026thinsp;+\u0026thinsp;CsA\u0026thinsp;+\u0026thinsp;MMF regimen, while 14 patients in the MSD-PBSCT group received an ATG (1.5 mg/kg/d) \u0026times; 3d\u0026thinsp;+\u0026thinsp;MTX\u0026thinsp;+\u0026thinsp;CsA\u0026thinsp;+\u0026thinsp;MMF regimen for GVHD prophylaxis.\u003c/p\u003e \u003cp\u003eThe median age for all the patients was 61 (55\u0026ndash;72) years and had no difference between MUD/MRD- and haplo-PBSCT groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.468). AML accounted for 77.2% in all the patients and the frequencies of AML in MUD/MRD- and haplo-PBSCT groups were similar (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.821). The median age of donors in the haplo-PBSCT group was 34 (range 22\u0026ndash;46) years, while in the MUD/MSD-PBSCT group, it was 39 (range 23\u0026ndash;69) years (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median numbers of mononuclear (MNCs) and CD34\u003csup\u003e+\u003c/sup\u003e cells in grafts from haploidentical donors were significantly higher than that from HLA-matched donors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both of MNCs and CD34\u003csup\u003e+\u003c/sup\u003e cells). Other characteristics, like as recipient gender, pre-transplantation disease status, ECOG score, HCT-CI score, revised disease risk index (R-DRI), blood type of donors and recipients between the two groups, were similar (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Median follow-up in the entire cohort was 29.8 months (range 3.4\u0026ndash;89.7). The haplo-PBSCT group had shorter follow up (23.5 \u003cem\u003evs\u003c/em\u003e 58.9 months; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The overall characteristics of the patients and donors are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;127\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMUD/MSD-PBSCT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHaplo- PBSCT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age at diagnosis, years (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e61 (55\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.5 (55\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61 (55\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.468\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e58 (45.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43 (49.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e69 (54.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44 (50.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e69 (54.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20(50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49(56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e58 (45.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20(50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38(43.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnosis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.821\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e98 (77.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (75.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68 (78.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e27 (21.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (22.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (20.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e124 124(97.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39(97.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e85(97.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3 (2.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(2.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT-CI, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e108(85.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37(92.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71(81.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e19 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(7.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16(18.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRevised-Disease risk index, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.528\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-Int risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e55 (43.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17(42.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38 (43.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-Very high risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e72 (56.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (57.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease status at transplantation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e85 (66.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (70.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57 (65.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e42 (33.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (30.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (34.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor-recipient sex matched (n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.685\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale-male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e32 (25.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (27.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (24.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e95 (74.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (72.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66 (75.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age at donor, years (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e34 (22\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (23\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34 (22\u0026ndash;46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eABO matched (n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.398\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e61 (48.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (42.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44 (50.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMismatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e66 (52.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (57.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43 (49.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian mononuclear cells, \u0026times;10\u003csup\u003e8\u003c/sup\u003e kg\u0026ndash;1 (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e15.6(4.6\u0026ndash;54.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.7(5.0-26.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.5 (4.6\u0026ndash;54.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian CD34 \u003csup\u003e+\u003c/sup\u003e counts, \u0026times;10\u003csup\u003e6\u003c/sup\u003e kg\u0026ndash;1 (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e9.4(0.8\u0026ndash;29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.8(0.8\u0026ndash;26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.3 (1.8\u0026ndash;29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian CD3 \u003csup\u003e+\u003c/sup\u003e counts, \u0026times;10\u003csup\u003e8\u003c/sup\u003e kg\u0026ndash;1 (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3.4 (0.8\u0026ndash;13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.1 (1.6\u0026ndash;6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.4 (0.8\u0026ndash;13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up in survivors, months (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e29.8 (3.4\u0026ndash;89.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.9(8.5\u0026ndash;89.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23.5(3.7\u0026ndash;75.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eMUD: matched unrelated donor; MSD: matched sibling donor; ECOG: Eastern Cooperative Oncology Group; HCT-CI: hematopoietic cell transplantation comorbidity index; PTCy: posttransplant- cyclophosphamide; CR: complete remission; NR: no response; PBSCT: peripheral blold stem cell transplantation; AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; CMML: chronic myelomonocytic leukemia; Int, intermediate.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eBold type indicates statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0 .05)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEngraftment and GVHD\u003c/h2\u003e \u003cp\u003eAll the patients achieved full-donor chimeirsm at 28 days after transplantation. The median time of neutrophil engraftment in haplo-PBSCT and MUD/MSD-PBSCT groups were 14 (range 10\u0026ndash;27) days and 12 (range 10\u0026ndash;19) days, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.192); while the median time of platelet engraftment was 12 days (6\u0026ndash;50), which was prolonged to 14 (range 9\u0026ndash;37) days in the MUD/MSD-PBSCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040).\u003c/p\u003e \u003cp\u003eFor all the patients, the cumulative incidences (CIs) of grade Ⅱ-Ⅳ and Ⅲ-Ⅳ aGVHD within 180 days post-transplant were 10.17% and 5.51%, respectively. In the haplo-PBSCT group, the CIs were 9.20% and 4.60%, which were similar to those of 12.26% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.605, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea) and 7.50% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.490, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) in the MUD/MSD-PBSCT group. Sixty-six patients in the haplo-PBSCT group and 36 in the MUD/MSD-PBSCT group survived beyond 180 days post-transplant and were available for cGVHD assessment. The CIs of total cGVHD and moderate/severe cGVHD for all the patients at 2 years were 30.52% and 14.60%, respectively. Although there was no statistically significant difference in the overall incidences of cGVHD between the two groups (20.30% \u003cem\u003evs\u003c/em\u003e 33.85%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.116), the haplo-PBSCT group had a strong trend towards a lower CI of moderate to severe cGVHD at 2 years compared to the MUD/MSD-PBSCT group, with CIs of 8.19% and 23.40%, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.067, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRelapse\u003c/h2\u003e \u003cp\u003eUntil the last follow-up, 10 patients in the haplo-PBSCT group and 13 in the MUD/MSD-PBSCT group experienced relapse. The median times to relapse were 200 and 132 days for the haplo-PBSCT and MUD/MSD-PBSCT groups, respectively. Notably, the 2-year CIR of 11.16% in haplo-PBSCT group was significantly lower that of 31.98% in MUD/MSD-PBSCT (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). In multivariate analysis, haploidentical transplantation and female donor to male recipient significantly decreased the risk of relapse (haplo \u003cem\u003evs\u003c/em\u003e MUD/MSD: Hazard Ratio [HR] 0.344, 95% Confidence Interval [CI] 0.149\u0026ndash;0.795, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; female-male \u003cem\u003evs\u003c/em\u003e other: HR 0.164, 95% CI 0.035\u0026ndash;0.766, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analyses of outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003cem\u003e(95% CI)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaplo \u003cem\u003evs\u003c/em\u003e MUD/MSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.344 (0.149\u0026ndash;0.795)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male \u003cem\u003evs\u003c/em\u003e female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.487 (0.755\u0026ndash;16.106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor-recipient sex matched (female-male \u003cem\u003evs\u003c/em\u003e others)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.164 (0.035\u0026ndash;0.766)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNRM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR-DRI (low-int risk \u003cem\u003evs\u003c/em\u003e high-very high risk)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.354 (0.114\u0026ndash;1.106)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD (0-Ⅰ \u003cem\u003evs\u003c/em\u003e Ⅱ-Ⅳ)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.075 (0.013\u0026ndash;0.455)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026ge;\u0026thinsp;60 \u003cem\u003evs\u003c/em\u003e \u0026lt;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.432 (0.969\u0026ndash;20.200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD34\u003csup\u003e+\u003c/sup\u003e counts (\u0026lt;6\u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg \u003cem\u003evs\u003c/em\u003e\u0026thinsp;\u0026ge;\u0026thinsp;6\u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.433(1.217\u0026ndash;58.490)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-transplant status (CR \u003cem\u003evs\u003c/em\u003e NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.644 (0.332\u0026ndash;1.249)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD (0-Ⅰ \u003cem\u003evs\u003c/em\u003e Ⅱ-Ⅳ)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.419 (0.158\u0026ndash;1.107)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor-recipient sex matched (female-male \u003cem\u003evs\u003c/em\u003e others)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.660 (0.325\u0026ndash;1.337)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT-CI (\u0026ge;\u0026thinsp;3 \u003cem\u003evs\u003c/em\u003e 0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.708 (0.804\u0026ndash;9.122)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.108\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD (0-Ⅰ \u003cem\u003evs\u003c/em\u003e Ⅱ-Ⅳ)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.329 (0.123\u0026ndash;0.877)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-transplant status (CR \u003cem\u003evs\u003c/em\u003e NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.570 (0.283\u0026ndash;1.147)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCT-CI (\u0026ge;\u0026thinsp;3 \u003cem\u003evs\u003c/em\u003e 0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.125 (0.947\u0026ndash;17.968)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGRFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaplo \u003cem\u003evs\u003c/em\u003e MUD/MSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.502 (0.279\u0026ndash;1.913)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.024\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-transplant status (CR \u003cem\u003evs\u003c/em\u003e NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.572 (0.316\u0026ndash;1.034)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of donor (\u0026le;\u0026thinsp;40 \u003cem\u003evs\u003c/em\u003e \u0026gt;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.686 (0.811\u0026ndash;3.506)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eBold type indicates statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0 .05).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: MUD/MSD, matched unrelated/sibling donors; Haplo, haploidentical donors; aGVHD, acute graft-versus-host disease; HCT-CI, Hematopoietic Cell Transplantation\u0026ndash;Specific Comorbidity Index; HR, hazard ratio; NRM, non-relapse mortality; OS, overall survival; DFS, disease-free survival; GRFS, Graft-versus-host disease-free, relapse-free survival. Int, intermediate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eNRM and infectious complications\u003c/h2\u003e \u003cp\u003eThe 2-year NRM in the haplo-PBSCT and MUD/MSD-PBSCT groups were 14.73% and 5.00%, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.116, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Among the haplo-PBSCT group, 12 patients experienced NRM, including 10 (11.5% out of 87) with infection, 1 (1.1%) with multi-organ failure, 1 (1.1%) with aGVHD. In the MUD/MSD-PBSCT group, NRM occurred in 2 (5.0% out of 40) patients, predominantly due to infection (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In multivariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), Ⅱ-Ⅳ aGVHD was the independent risk factor of NRM (0-Ⅰ \u003cem\u003evs\u003c/em\u003e Ⅱ-Ⅳ aGVHD, HR 0.075, 95% CI 0.013\u0026ndash;0.455, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Low-int risk in R-DRI classification had a strong trend to lower the risk of NRM (HR 0.354, 95% CI 0.114\u0026ndash;1.106, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.074), while age\u0026thinsp;\u0026ge;\u0026thinsp;60 years (HR 4.432, 95% CI 0.969\u0026ndash;20.200, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.062) and CD34\u003csup\u003e+\u003c/sup\u003e cells in grafts\u0026lt;6\u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg (HR 8.433, 95% CI 1.217\u0026ndash;58.490, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.058) had strong trends to increase the risk of NRM.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCause of NRM and viral infection in the two groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD/MSD-PBSCT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHaplo-PBSCT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCauses of NRM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (11.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMOF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViral infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMV viremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.090\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMV disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (6.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.512\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEB viremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (19.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.496\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTLD EBV related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.318\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCMV: cytomegalovirus, PTLD: post-transplant lymphoproliferative disorder, NRM: non-relapse mortality, MOF: multiple organ failure. aGVHD: acute graft-versus-host disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the total cohort, prophylaxis therapy for CMV reactivation with letermovir was administered to 36 patients (28.3%), including 6 in haplo-PBSCT and 30 in MSD/MUD groups, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.050). Interestingly, there was no discrepancy in the incidences of CMV infection and CMV disease within one-year post-transplantation between the haplo- and MUD/MSD-PBSCT groups (27.6% \u003cem\u003evs\u003c/em\u003e 15.0% for CMV infection, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.090; 6.90% \u003cem\u003evs\u003c/em\u003e 5.0% for CMV disease, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.512). The incidences of EB virus infection were comparable between the haplo-PBSCT and MUD/MSD-PBSCT groups (19.5% \u003cem\u003evs\u003c/em\u003e 17.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.496). In the haplo-PBSCT group, 3 patients (3.4%) developed EBV-PTLD, while no cases were reported in the MUD/MSD-PBSCT group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDFS, OS and GRFS\u003c/h2\u003e \u003cp\u003eAs of the latest follow-up, a total of 26 patients had died: 17 in the haplo-PBSCT group and 9 in the MUD/MSD-PBSCT group. Within the haplo-PBSCT group, 5 patients succumbed to relapse, and 12 patients experienced non-relapse mortality. In the MUD/MSD-PBSCT group, 7 patients died of relapse, while 2 experienced NRM. The haplo-PBSCT group exhibited similar 2-year DFS and OS rates compared to the MUD/MSD-PBSCT group, with rates of 74.11% versus 59.67% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.231, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb) and 76.30% versus 64.00% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.482, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec), respectively. Notably, the haplo-PBSCT group achieved a significantly higher GRFS compared to the MUD/MSD-PBSCT group, demonstrating rates of 68.85% versus 46.61% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). In multivariate analysis, grades Ⅱ-Ⅳ aGVHD emerged as a significant predictor of inferior OS. Noteworthy is the finding that haploidentical family donors were associated with improved GRFS (HR 0.502, 95% CI 0.279\u0026ndash;1.913, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024). Although there was no significant difference, CR disease status at pre-transplantation had a strong trend to favor the GRFS (HR 0.572, 95% CI 0.316\u0026ndash;1.034, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.064) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe success of allo-HSCT for hematological malignancies is significantly dependent on the availability of suitable donors. Haploidentical donors and matched unrelated/sibling donors are crucial donor options. However, the quest for the optimal donor for HCT in elderly patients with myeloid malignancies remains a subject of ongoing debate. In the present study, the results suggested that haploidentical transplants employing the low-dose ATG/PTCy-based regimen for GVHD prophylaxis significantly reduced the risk of relapse and achieved a better GRFS compared to the conventional MUD/MSD transplants.\u003c/p\u003e \u003cp\u003eIn recent years, in vivo T-cell depletion with ATG combined with PTCy has seen increasing use across various clinical settings. In a study \u003csup\u003e7\u003c/sup\u003e involving 270 hematologic malignancy patients undergoing RIC PBSCT and using dual T-cell depletion with ATG (total dose of 4.5 mg/kg) and PTCy (50 mg/kg/d for 2 days) as the GVHD prevention regimen, the CIs of grade Ⅱ\u0026ndash;Ⅳ and Ⅲ\u0026ndash;Ⅳ aGVHD at day\u0026thinsp;+\u0026thinsp;100 were 20.1% and 4.6%, respectively. The CI of moderate/severe cGVHD at 1 year was 12.4%. A remarkable finding of this study is the absence of statistically significant differences in clinically relevant cGVHD between donor types (30% in Haplo patients, 37.5% in MRD patients, and 31% in UD patients, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.528), suggesting that the combination of ATG and PTCy has the potential to overcome the HLA barrier. Dulery et al. \u003csup\u003e21\u003c/sup\u003e reported on the transplant outcomes of 72 adults with refractory hematologic malignancies treated with PBSCT using ATG (total dose of 5 mg/kg) and PTCy (50 mg/kg for 2 days). They found that haploidentical donors (n\u0026thinsp;=\u0026thinsp;27) had a lower incidence of grade Ⅱ-Ⅳ aGVHD compared to matched unrelated donors (n\u0026thinsp;=\u0026thinsp;29), with rates of 11.1% versus 41.4%, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). While the ATG-PTCy combination has been applied in various HCT indications and with different types of donors, there is limited data supporting its use specifically in patients aged 55 and older with myeloid malignancies. In our study, both the MUD/MSD and haplo-PBSCT groups exhibited lower cumulative incidences of Ⅱ-Ⅳ aGVHD (MUD/MSD-PBSCT: 12.26%, haplo-PBSCT: 9.20%). Specifically, compared to the MUD/MSD-PBSCT group, the haplo-PBSCT group showed a decreasing trend of moderate to severe cGVHD (MUD/MSD-PBSCT: 23.40%, haplo-PBSCT: 8.19%), suggesting that dual T-cell depletion with ATG and PTCy is also feasible in elderly haploidentical transplant patients.\u003c/p\u003e \u003cp\u003eGiven that the conditioning intensity cannot be too high due to the risk of toxicity in older patients, disease relapse remains a significant problem. Interestingly, a recent study by the European Society for Blood and Marrow Transplantation (EBMT) \u003csup\u003e22\u003c/sup\u003e involving 701 adults aged\u0026thinsp;\u0026ge;\u0026thinsp;70 years with AML reported a lower relapse incidence among patients using haploidentical donors compared to those using MSD (HR 0.46, 95% CI 0.25\u0026ndash;0.80, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). This led to prolonged leukemia-free survival (LFS) in the haploidentical donor group (HR 0.62, 95% CI 0.39\u0026ndash;0.99, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). Other reports showed similar trends in adults with high-risk AML \u003csup\u003e23, 24\u003c/sup\u003e. In line with previous reports, our analysis revealed that the elderly recipients in the haplo-PBSCT group had a significantly lower CIR compared to that in the MUD/MSD group (11.16% \u003cem\u003evs.\u003c/em\u003e 31.98%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010). This can possibly be attributed to stronger graft-versus-leukemia effects in haplo-HSCT, due to greater genetic disparity and enhanced function of T and NK cells from haploidentical allografts, leading to more robust anti-leukemia activity \u003csup\u003e25\u0026ndash;28\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTreatment-related complications and mortality are significant concerns for elderly patients when opting for allogeneic transplantation. In elderly patients aged 70 or above with myeloid malignancies, the estimated 2-year NRM is reported to be in the range of 30\u0026ndash;35% \u003csup\u003e29\u003c/sup\u003e. In a large retrospective study of 1,080 AML/MDS patients undergoing RIC-HSCT, the 2-year NRM ranged from 22\u0026ndash;39% for those aged 55\u0026ndash;59, 60\u0026ndash;64, and 65 and older, with no significant differences observed between these age cohorts \u003csup\u003e30\u003c/sup\u003e. In a study involving 43 older patients (median age 61 years) with AML/MDS who underwent haplo-SCT with PTCy prophylaxis, the 2-year NRM was reported to be 34% \u003csup\u003e31\u003c/sup\u003e, which is higher than that of 14.73% observed in our study for haplo-PBSCT recipients. This suggests that a low-dose ATG/PTCy-based regimen can be safely used in older individuals undergoing haplo-HSCT, achieving a relatively low NRM for older patients. The multivariate analysis demonstrated that grades Ⅱ-Ⅳ aGVHD were strongly associated with a higher risk of NRM. Additionally, a low-int risk in the R-DRI classification showed a strong trend toward lowering the risk of NRM. Conversely, age\u0026thinsp;\u0026ge;\u0026thinsp;60 years and CD34\u003csup\u003e+\u003c/sup\u003e cell counts in grafts\u0026thinsp;\u0026lt;\u0026thinsp;6\u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg exhibited strong trends toward adversely affecting the 2-year NRM.\u003c/p\u003e \u003cp\u003eInfection was one of the most important primary causes of transplant-related mortality in both the haplo-PBSCT and MUD/MSD-PBSCT groups. The literatures suggest a higher likelihood of bacterial infection with increasing age \u003csup\u003e32\u003c/sup\u003e. In our elderly patient cohort, the elevated incidence of infections contributing to NRM post-transplantation may be linked to age-related declines in host immune system functionality or diminished thymic T-lymphocyte reconstruction compared to younger patients, resulting in reduced initial T cell circulation \u003csup\u003e33\u003c/sup\u003e. The haplo-PBSCT group experienced an elevated incidence of CMV and EBV virus infections, likely attributed to HLA mismatching between T-cell donors and recipients, along with the dual depletion of T cells resulting from PTCy and ATG. However, no fatalities occurred in the MUD/MSD-PBSCT group due to CMV or EBV infections. In the haplo-PBSCT group, only one patient succumbed to CMV pneumonia. With the increasing use of preventive drugs such as ganciclovir, the incidence of CMV infection is expected to be further controlled.\u003c/p\u003e \u003cp\u003eThe study by EBMT \u003csup\u003e22\u003c/sup\u003e involving 701 elderly transplant patients with AML reported that patients transplanted from haploidentical donors exhibited higher GRFS rates compared to those who received transplants from matched sibling and unrelated donors. Notably, about 20% of the transplants from haploidentical donors used bone marrow as the cell source, whereas almost all MSD and MUD recipients received peripheral blood stem cells. The lower incidence of cGVHD observed in haplo transplants may be attributed to the use of bone marrow, which is associated with less cGVHD compared to PBSC. Conversely, in our study, all patients received PBSC as the cell source. Our findings indicate that haploidentical transplantation in elderly patients with myeloid malignancies achieves better GRFS rates compared to MUD/MSD-PBSCT. This improved outcome may be attributed to a lower incidence of relapse and reduced rates of cGVHD, likely due to the GVHD prevention regimen consisting of low-dose ATG/PTCy.\u003c/p\u003e \u003cp\u003eIn conclusion, haploidentical donors, especially when employing the specified GVHD prevention strategy, are a suitable and attractive graft source for patients\u0026thinsp;\u0026ge;\u0026thinsp;55 with hematologic malignancies in need of allo-SCT. The favorable clinical outcomes observed among recipients of T-cell replete haploidentical transplants should be validated with prospective clinical trials and longer haplo-PBSCT follow up is needed to analyze the impact of this type of donor on long-term outcomes and complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCOMPETING INTERESTS\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/strong\u003e \u003cp\u003e The study was approved by the institutional review committee of the ethics committee of Shanghai General Hospital. All patients gave written informed consent according to the Helsinki declaration.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFUNDING\u003c/h2\u003e \u003cp\u003eThis study was funded by the National Natural Science Foundation of China (81570148).\u003c/p\u003e\u003ch2\u003eAUTHOR CONTRIBUTIONS\u003c/h2\u003e \u003cp\u003eY-NJ and X-XX wrote the manuscript. JY, YC, YT, H-YQ, KZ, YZ, CS, LW were involved in patient management and clinical data collection. X-MS revised the manuscript and provided valuable advice. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e \u003cp\u003eWe thank the patients who participated and all the nursing staff for providing excellent care for our patients.\u003c/p\u003e\u003ch2\u003eDATA AVAILABILITY\u003c/h2\u003e \u003cp\u003eData will be available upon request to [email protected].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePhelan R, Chen M, Bupp C, Bolon YT, Broglie L, Brunner-Grady J\u003cem\u003e et al.\u003c/em\u003e Updated Trends in Hematopoietic Cell Transplantation in the United States with an Additional Focus on Adolescent and Young Adult Transplantation Activity and Outcomes. \u003cem\u003eTransplant Cell Ther \u003c/em\u003e2022; \u003cstrong\u003e28\u003c/strong\u003e(7)\u003cstrong\u003e: \u003c/strong\u003e409 e401-409 e410. e-pub ahead of print 2022/04/22; doi: 10.1016/j.jtct.2022.04.012\u003c/li\u003e\n\u003cli\u003eLuznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. \u003cem\u003eBlood \u003c/em\u003e2001; \u003cstrong\u003e98\u003c/strong\u003e(12)\u003cstrong\u003e: \u003c/strong\u003e3456-3464. e-pub ahead of print 2001/11/24; doi: 10.1182/blood.v98.12.3456\u003c/li\u003e\n\u003cli\u003eAl-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U. 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The aging of the immune system. \u003cem\u003eTranspl Int \u003c/em\u003e2009; \u003cstrong\u003e22\u003c/strong\u003e(11)\u003cstrong\u003e: \u003c/strong\u003e1041-1050. e-pub ahead of print 2009/07/25; doi: 10.1111/j.1432-2277.2009.00927.x\u003c/li\u003e\n\u003cli\u003eCastermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R\u003cem\u003e et al.\u003c/em\u003e Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. \u003cem\u003eHaematologica \u003c/em\u003e2011; \u003cstrong\u003e96\u003c/strong\u003e(2)\u003cstrong\u003e: \u003c/strong\u003e298-306. e-pub ahead of print 2010/10/12; doi: 10.3324/haematol.2010.029702\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hematopoietic cell transplantation, graft-versus-host disease, Anti-thymocyte globulin, Post-transplant cyclophosphamide","lastPublishedDoi":"10.21203/rs.3.rs-4734771/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4734771/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOur study delved into the clinical outcomes of haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) for older patients, utilizing a novel low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen to prevent graft-versus-host disease (GVHD). We juxtaposed these outcomes with transplants from matched unrelated/sibling donors (MUD/MSD) for elderly patients with myeloid malignancies from 2016 to 2023. The study encompassed 127 patients, with 40 undergoing MUD/MSD-PBSCT and 87 receiving haplo-PBSCT. The incidences of grades Ⅱ-Ⅳ and Ⅲ-Ⅳ acute GVHD were similar between the two groups, the haplo-PBSCT cohort displayed a promising trend toward reduced incidence of moderate to severe chronic GVHD compared to MUD/MSD-PBSCT (8.19% \u003cem\u003evs\u003c/em\u003e 23.40%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.067). The 2-year disease-free survival (74.11% \u003cem\u003evs\u003c/em\u003e 59.67%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.231) and overall survival (76.30% \u003cem\u003evs\u003c/em\u003e 64.00%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.482) rates were comparable, while haplo-PBSCT exhibited higher graft-versus-host disease-free, relapse-free survival (GRFS) (68.85% \u003cem\u003evs\u003c/em\u003e 46.61%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041) and lower cumulative incidences of relapse (CIR) (11.16% \u003cem\u003evs\u003c/em\u003e 31.98%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) compared to MUD/MSD-PBSCT. Our findings underscore the potential of haploidentical transplants with the low-dose ATG/PTCy-based regimen to yield improved GRFS and lower CIR for older patients with hematologic malignancies. Thus, haploidentical donors, especially when coupled with this specified GVHD prevention strategy, emerge as a viable and appealing graft source for elderly patients requiring allo-SCT.\u003c/p\u003e","manuscriptTitle":"Haploidentical peripheral blood stem cell transplantation improves the survival of older patients with myeloid malignancies under low-dose antithymocyte globin (ATG)/post-cyclophosphamide (PTCy)-based regimen for graft-versus-host disease prophylaxis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-13 03:06:52","doi":"10.21203/rs.3.rs-4734771/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1818588-f480-4d5c-9571-a740da237b9f","owner":[],"postedDate":"August 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34640359,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":34640360,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome"}],"tags":[],"updatedAt":"2024-08-13T03:06:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-13 03:06:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4734771","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4734771","identity":"rs-4734771","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}