Unrelated Donor Transplantation Research Articles

High CD34-positive cell dose in matched unrelated donor allogeneic hematopoietic stem cell transplant is not associated with graft-versus-host disease or mortality.

CD34+ stem cells serve as the primary graft source for allogeneic transplants, with a minimum of 2-4 × 106 cells/kg needed for engraftment. There are conflicting data on outcomes at high stem cell doses, with studies limited by few patients receiving doses far above the minimum target. In this retrospective, single-center study of patients with hematologic malignancies who underwent matched unrelated donor transplants, we assessed outcomes for engraftment, survival, relapse, and graft-versus-host disease (GVHD) for the highest CD34+ dose quintile (>13 × 106 cells/kg, n = 36) compared to the remaining patients (n = 139). Similar analysis was performed correlating T cell dose and outcomes. There was no difference between the groups in neutrophil engraftment, with a trend toward faster platelet engraftment. There was no significant difference in mortality (adjusted risk ratio [aRR] = 1.02, 95% confidence interval [CI] = 0.85-1.22), relapse (aRR = 1.10, 95% CI = 0.85-1.42), or overall survival by Kaplan-Meier analysis (p = .44). High CD34+ dose was not associated with higher incidence of acute GVHD (aRR = 0.99 grades II-IV, aRR = 1.18 grades III-IV) or chronic GVHD (aRR = 0.87 overall, RR = 1.21 severe). There was limited correlation between CD34+ and T cell dose (R2 = .073), and there was no significant difference in survival, relapse, or GVHD in the highest T cell dose quintile (n = 33) compared to the remaining quintiles (n = 132). We found no difference in survival, relapse, or GVHD incidence or severity in patients receiving CD34+ doses above prior cutoffs reported in the literature. These data do not support the routine use of graft CD34+ dose reduction.

Long term results of a prospective multicenter observational study on the use of anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation (ATOS study).

ATOS is a prospective observational study evaluating the outcome of patients receiving anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation. Primary endpoint was severe GvHD and relapse-free survival (SGRFS). GvHD prophylaxis consisted of ATLG and CSA/ MTX or MMF. Outcome was compared to the ATLG arm of our prospective randomized phase III multicenter trial trial (RCT) [1, 2]. 165 patients, median age 54 (18; 77) years, with haematological malignancies with early (45.5%), intermediate (17.6%), and advanced (37.0%) disease were included. ATLG dose differed between centers according to local practise (median total ATLG dose of 46 (IQR 32-60, range 15-91) mg/kg). Median follow-up was 70 months. Estimated probabilities at 5 years follow up were for SGRFS 0.27, OS 0.52, DFS 0.43, NRM 0.23, relapse 0.34, acute GvhD °III/IV 0.13, severe chronic GvHD 0.27. OS rates differed dependent on disease status. An effect of the given ATLG dose could not be separated from potential center effects. Despite higher age and more advanced disease in ATOS, outcome was similar to the ATLG arm of our RCT. This long-term, multicenter, experience in routine clinical practice confirms the GvHD-protective effect of ATLG without compromising relapse and non-relapse mortality rates.Clinical Trial Registry: German clinical trials register DRKS00004581.

[Haploidentical donor peripheral blood stem cell transplantation using third-party cord blood compared with matched unrelated donor transplantation for patients with hematologic malignancies].

Objectives: To assess the efficacy of cord blood-assisted haploid peripheral blood stem cell transplantation (haplo-cord-PBSCT) versus unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) in the treatment of malignant hematological diseases. Methods: A retrospective analysis was performed on one hundred and four patients with malignant hematological diseases who underwent haplo-cord-PBSCT and fifty-two patients who underwent UD-PBSCT at Xiangya Hospital of Central South University between January 2016 and December 2021. Results: ①The median implantation time for neutrophils in the haplo-cord-PBSCT and UD-PBSCT groups was 13 (9-22) days and 13 (10-24) days, respectively (P=0.834), whereas the median implantation time for platelets was 15 (7-103) days and 14 (8-38) days, respectively (P=0.816). The cumulative implantation rate of neutrophils at 30 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group was 100% (P=0.314), and the cumulative platelet implantation rate at 100 days after transplantation was 95.2% (95% CI 88.3% - 98.1% ) and 100% (P=0.927), respectively. 30 days after transplantation, both groups of patients achieved complete donor chimerism, and no umbilical cord blood stem cells were implanted. ②The cumulative incidence rates of grade Ⅱ-Ⅳ acute GVHD within 100 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group were 29.1% (95% CI 20.1% -38.1% ) and 28.8% (95% CI 17.2% -41.6% (P=0.965), respectively. The cumulative incidence rates of grade Ⅲ/Ⅳ acute GVHD were 7.8% (95% CI 3.6% -14.0% ) and 9.6% (95% CI 3.5% -19.5% ) (P=0.725). The cumulative incidence rates of 2-year chronic GVHD in the haplo-cord-PBSCT group and the UD-PBSCT group were 45.3% (95% CI 36.1% -56.1% ) and 35.1% (95% CI 21.6% -44.1% ), respectively (P=0.237). The cumulative incidence rates of severe chronic GVHD at 2 years after transplantation were 13.6% (95% CI 7.6% -21.3% ) and 12.9% (95% CI 5.1% -24.3% ), respectively (P=0.840). ③The 2-year CIR after transplantation in the haplo-cord-PBSCT group and UD-PBSCT group were 12.8% (95% CI 7.0% -20.5% ) and 10.0% (95% CI 3.6% -20.2% ), respectively (P=0.341), and the NRM were 14.7% (95% CI 8.4% -22.6% ) and 16.2% (95% CI 7.4% -28.0% ), respectively (P=0.681). ④The 2-year OS rates in the haplo-cord-PBSCT and UD-PBSCT groups after transplantation were 82.2% (95% CI 74.8% -90.3% ) and 75.5% (95% CI 64.2% -88.7% ), respectively (P=0.276). The 2-year DFS rates were 69.9% (95% CI 61.2% -79.8% ) and 73.8% (95% CI 62.4% -87.3% ), respectively (P=0.551). The 2-year rates of GVHD-free/recurrence-free survival (GRFS) were 55.3% (95% CI 44.8% -64.8% ) and 64.7% (95% CI 52.8% -79.3% ), respectively (P=0.284) . Conclusion: The findings of this study indicate that haplo-cord-PBSCT and UD-PBSCT have comparable efficacy and safety in the treatment of malignant hematological diseases and can be used as an alternative treatment options.

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

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

Individualized dose of anti-thymocyte globulin based on weight and pre-transplantation lymphocyte counts in pediatric patients: a single center experience.

Anti-thymocyte globulin (ATG) has become a standard in preventing GVHD in related and unrelated donor transplantation, but there is no consensus on the best administration schedule. The PARACHUTE trial reported excellent CD4 immune reconstitution (CD4 IR) using a dosing schedule based on the patient's weight and pre-conditioning absolute lymphocyte count (ALC). In 2015 we introduced the PARACHUTE dosing schedule for pediatric patients at our center. One hundred one patients were transplanted for malignant and non-malignant diseases. In this non-concurrent cohort CD4 IR+, defined by a single CD4 count >50/µL on day 90, was seen in 81% of patients. The incidence of grade II-IV and III to IV aGvHD was 26.6% and 15.3% and 5% for cGvHD with no severe cases. We found no difference in aGvHD between donor type and stem cell sources. Five-year EFS and OS were 77.5% and 83.5%. Grade III-IV GFRS was 75.2%. CD4 IR+ patients had better EFS (93.1% vs. 77.7%, p = 0.04) and lower non-relapse mortality (2.7% vs. 22.2%, p = 0.002). The PARACHUTE ATG dosing schedule individualized by weight and ALC results in good early immune reconstitution, low incidence of cGvHD, and favorable survival for patients with different disease groups, donor types, and stem cell sources.

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning

BackgroundNo comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. MethodsWe retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. ResultsThe median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III–IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III–IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. ConclusionMMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study.

In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.

Outcomes with HLA-matched unrelated donor versus haploidentical hematopoietic cell transplantation

We investigated the outcomes after adult haploidentical (haplo) and matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) in a single-center study (n = 452) including 276 MUD and 176 haplo transplants. Myeloablative (37%) and reduced-intensity conditioning (63%) were performed. Graft sources included peripheral blood (50%) and bone marrow (50%). GVHD prophylaxis included tacrolimus/methotrexate (53%) and post-transplant cyclophosphamide-based (47%). In MUD versus haplo HCT recipients, a similar incidence of neutrophil engraftment (18 vs 17 days, p = 0.895), grade II-IV acute GVHD (51% vs 50%, p = 0.773), relapse (26% vs 23%, p = 0.578), non-relapse mortality (22% vs 23%, p = 0.817), 1-year disease-free survival (62% vs 63%. p = 0.921), and 1-year overall survival (73% vs 74%, p = 0.744) were observed. Earlier platelet engraftment (22 vs 27 days, p < 0.001) and higher chronic GVHD (45% vs 35%, p = 0.040) were noted in MUD as compared to haplo HCT. Allogeneic transplantation should be done promptly whenever indicated, utilizing either matched unrelated or haploidentical donors.

Unrelated Donors below 35 Years of Age Should be Preferred over HLA-Matched Sibling Donors Older Than 50 Years for Patients with Myeloid Malignancies

Introduction. Selecting the best available stem cell donor is crucial to optimize outcome after allogeneic hematopoietic cell transplantation (alloHCT). For several decades, matched sibling donors (MSD) were considered to be the best choice for all patients. Recently published data suggest that young unrelated donors (UD) may represent a favorable alternative. However, analyses in contemporary disease-specific registry cohorts are still rare. Therefore, we set out to investigate whether young UD provide a benefit for older patients with myeloid malignancies compared to MSD. Patients and Methods. We performed a retrospective study with data of the Deutsches Register Stammzelltransplantation (DRST) on patients 50 years and older who received a first alloHCT for AML, MDS, MDS/MPN or CMML between January 2010 and December 2020. We compared results of patients who were transplanted from MSD aged 50 years or older and young UD aged 35 years or younger who were HLA-compatible for HLA-A, -B, -C, and -DRB1. We evaluated the primary endpoint, event-free survival (EFS), and the secondary endpoints overall survival (OS), cumulative incidence of relapse/progression (CIR), non-relapse mortality (NRM), acute and chronic Graft-versus-Host Disease (GvHD) in multivariable Cox regression models. Results. In total, we analyzed data from 3460 patients. Median patient age was 63.5 years for 2225 patients with UD compared to 60.9 years for 1235 patients with MSD (p&amp;lt;.001). The median donor age was 27 years (range 18-35 years) for UD compared to 58 years (range 50-79 years) for MSD (p&amp;lt;.001). Overall, male donors accounted for 77.9% of UD compared to 49.3% of MSD (p&amp;lt;.001). Fewer male patients had female UD than female MSD (8.6% versus 30%, p&amp;lt;.001). Also, more cytomegalovirus (CMV) seronegative patients had CMV seronegative UD (34.9% versus 23%, p&amp;lt;.001). The percentage of alloHCT with UD increased in recent years, from 46% in 2010 to 72% in 2020 (p&amp;lt;.001). HLA-DQB1-mismatches were reported for 2.5% of UD. HLA-DPB1 matching information was available for 33.6% of UD. We found no differences with respect to the distribution of Karnofsky performance status, disease risk, reduced intensity conditioning (circa 80% of patients) and graft source (almost exclusively PBSC) between the two donor types. GVHD prophylaxis differed significantly, more patients with UD received ATG compared to patients with MSD (87.4% versus 52.9%, p&amp;lt;.001). In univariate comparisons, we observed a trend towards improved EFS (HR 0.91, p=.07; Figure Panel A) and improved OS (HR 0.88, p=.03) for UD compared to MSD transplants. CIR was lower with UD (HR 0.87, p=.04, Figure Panel B) and NRM was not statistically different (HR 0.96, p=.6). The 150-days cumulative incidence of aGVHD was 28.2% for UD versus 31.3% for MSD transplants (p=.09). Corresponding numbers for the 1-year cumulative incidence of cGVHD were 31.3% and 39.4% for UD versus MSD transplants (p=&amp;lt;.001). After multivariable adjustment for patient age, performance status, disease risk, conditioning type, stem cell source, and HLA-DQB1-mismatches, EFS and OS were significantly better for 10/10 UD compared to MSD transplantation with hazard ratios (HR) of 0.86 for EFS (p=.003) and 0.82 for OS (p&amp;lt;.001). After UD alloHCT we found a lower risk of relapse (HR 0.84, p=.018), less chronic GVHD (HR 0.7, p&amp;lt;.001) and a trend towards lower NRM (HR 0.87, p=.07). Conclusions. Selecting HLA-compatible UD over older MSD improves the chances of survival (both OS and EFS) after alloHCT for older patients with myeloid malignancies. This beneficial effect was mediated mainly by a reduced risk for relapse/progression suggesting more potent Graft-versus-Leukemia effects after UD transplantation despite less chronic GVHD.

Post Transplant Cyclophosphamide (PTCY) in Peripheral Blood Stem Cell Transplant Results in Successful Engraftment and Substantially Low Frequency of Chronic Graft Versus Host Disease (GvHD), without Impaired Cellular Immune Reconstitution

The Post-Transplant Cyclophosphamide (PTCY) approach was first studied in the haploidentical transplant setting, and it resulted in high percentages of engraftment and reduced frequency of acute and mainly chronic GvHD as well as non-relapsed mortality. PTCY is now increasingly being used in HLA-partially and fully matched unrelated, as well as matched related donors. The aim of this study was to investigate the impact of PTCY on the incidence of chronic GvHD, disease relapse and infections because of possible cellular immune impairment. Fifty-one consecutive patients who underwent allogeneic hematopoietic stem cell transplant from an unrelated donor were studied. PTCΥ was administered on days +3 and +4 post-transplant at a dose of 50 mg/kg/day. Additional GvHD prophylaxis included tacrolimus and mycophenolate mofetil starting on day +5. In patients with no evidence of GvHD, immunosuppression was gradually tapered, and eventually stopped by day +90. We evaluated the safety and efficacy of PTCY, focusing on toxicity, engraftment, aGvHD and cGvHD frequency, relapse, non-relapse mortality, survival and immune reconstitution. We performed 51 unrelated donor transplants with PTCY from January 2021 to May 2023 in patients with a median age of 52 (18-69) years. The indication for transplant was AML/MDS (n=36), NHL/CLL, (n=2), pMF (n=2), CML (n=2) και ALL (n=9). Disease risk index (DRI) was intermediate for most patients (34/51), 7 had low and 10 had high DRI. Thirty-seven patients received myeloablative conditioning and 14 reduced-intensity. Overall, three patients were transplanted from a matched sibling, 36 from an 8/8 matched unrelated donor and 12 from an 7/8 HLA-matched unrelated donor. All patients received a peripheral blood graft with a median CD34+ cell dose of 6.97×10e6/kg (3.27-15.82). The most common toxicities observed were mucositis (n=34), diarrhea (n=40), vomit (n=12), liver toxicity (n=3) and acute kidney injury (n=4) - which in all cases were grade Ι-ΙΙ. Engraftment, defined as neutrophils &amp;gt;500/μl, was achieved in 46 cases in a median of 16 (13-27) days. Three patients died before day +28 due to NRM and two additional patients with myelofibrosis and MDS respectively had primary graft failure. The cumulative incidence of aGvHD, grade ΙΙ-IV at 100 days was 46.7% (95%CI: 34.1-63.8). However, aGvHD, grade ΙΙΙ-IV was only 3.9% (95%CI: 1.0-15.5). The cumulative incidence of cGvHD at 18 months was 13,4% (95%CI: 5.8-31.0), with only one case of extensive cGvHD. In a median follow-up of 14.5 (1-28) months, disease free (DFS) was 76,8% (95%CI: 65.5-90.0) at 18 months and overall survival (OS) was 76.3% (95%CI: 64.9-89.8) and 71.6% (95%CI: 58.6-88.3) respectively. There was no statistically significant difference in survival rates for patients who received an HLA mismatched and those who received an HLA-matched unrelated-donor transplant. cGvHD-Relapse-Free Survival was 63.5% (95%CI: 50.3-80.1). Two patients died of their disease and non-relapse mortality was 19.1%. Specifically, 6 patients died of Infections, 1 due to primary graft failure, 1 due to heart failure, and 1 due to Idiopathic Pulmonary Syndrome. Immune reconstitution at month 6 was 420 cells/ul (20-2225) and 179 (13-594) for CD8 and CD4 respectively. At month 12 CD8 and CD4 were 552 (55-3002) and 364 (60-787). 31 viral infections were documented in 28 patients (Respiratory viruses n=13, BKV n=11, CMV n=7). In regard with opportunistic infections, 2 patients had fungal infections and 1 patient atypical mycobacterium. We used PTCY for GvHD prophylaxis in mismatched, full-matched unrelated and matched sibling donor transplants with peripheral blood stem cell graft. This approach was well tolerated. Engraftment was documented in most patients, with a low incidence of grade III-IV aGvHD. Importantly cGvHD, which is the most important barrier in unrelated donor transplant, was substantially low with this method. Cellular immune reconstitution was adequate for CD8 but somewhat impaired for CD4. However, the incidence of viral and opportunistic infections was not increased. Overall, there are implications that PTCY may revert the negative impact of HLA mismatch on the outcomes of unrelated donor transplantation, while it is also a viable option for MUD and MSD transplant.

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

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

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).

Outcomes after RIC and Abatacept-Based Acute and Chronic Gvhd Prophylaxis in Allogeneic Transplantation for Sickle Cell Disease - Can Calcineurin Inhibitor Use be Curtailed?

Introduction: Sickle cell disease (SCD) progression can be curtailed by successful allogeneic transplantation from suitable donors. Allogenic transplantation with reduced intensity immune suppressive conditioning (RIC) from sibling or unrelated donors was considered acceptable with the availability of an Human Leucocyte Antigen (HLA)-matched (8/8 loci) or minimally mismatched (7/8) donor on NCT00920972 and in 2018 the study was modified to include abatacept for acute and chronic graft-versus-host disease (GVHD) prophylaxis based on the incidence of severe chronic GVHD noted (13-38%) and the benefits described with abatacept1-3. An interim review of trial results following the modification of GVHD prophylaxis is presented. Methods: Patients with symptomatic SCD who were &amp;lt;21 years of age were enrolled on appropriate study cohorts based on the level of donor match. Cohort 1 included HLA matched donors and cohort 3 included donors mismatched at 1 of 8 major HLA loci (-A, -B, -C, -DRB1) by high resolution typing. Conditioning included alemtuzumab (distal: day -22 to -19), fludarabine (days -8 to -4) and melphalan (day -3). Thiotepa (day -4) was included for mismatched donors. GVHD prophylaxis included tacrolimus (day -1 and tapered 6-9 months later), methotrexate (days +1, 3 and 6) and abatacept (days -1, +5, 14, 28, 60, 90, 180, 270 and 365)4. Though the half-life of the drug is ~30 days, the interval was adjusted after day 100 to every 90 days to curb allogeneic T cell proliferation following complete elimination of the drug. No previous data exists on this approach. Outcomes tracked were GVHD, mortality and graft rejection (GR) (&amp;lt;25% donor myeloid cells/disease recurrence) Results: Nine related donor transplants (4-18 years, median 9y) and 9 unrelated donor transplants (URD) (7-20 years, median 16y) (5 mismatched) were undertaken consecutively after the addition of abatacept to the standard GVHD regimen. The duration of follow-up ranged from 2-59 months (median 44m). GR was noted in 2 patients. One patient with primary GR subsequently rejected a second graft after myeloablative conditioning. Another patient with secondary GR received a CD34-selected boost post-ATG unsuccessfully but stabilized after a flu/cy/ATG regimen and another CD34-selected boost. The most recent engraftment analysis in 17/18 patients is 98% (range, 46 to 100) for myeloid and 94.5% (range, 56 to 100) for lymphoid lineage cells. No patient developed &amp;gt; grade 2 acute or any chronic GVHD in the MSD group. In the URD group 1 patient each developed &amp;gt;grade 2 aGVHD and extensive cGVHD. Of evaluable patients, one remains on systemic immune suppression therapy &amp;gt;18 months post-transplant. The only mortality noted was after 2 subsequent transplants in the patient with GR. Seventeen patients remain disease free post-transplant. Disease free survival (DFS) is 94%. GVHD-free-DFS is 89%. The incidence of viral reactivation was 65% and 17% before and after day +100 respectively. Immune reconstitution was noted to normalize beyond 6-9 months. Conclusion: Transplant is beneficial in SCD, and an expansion of donor sources can help to increase the number of patients rendered disease-free. GVHD risks preclude consideration of allogeneic transplantation. A GVHD-free cure rate of &amp;gt;88% despite risk factors such as age and HLA-mismatch following RIC and abatacept-based GVHD prophylaxis is encouraging for allogeneic transplantation options for children and adolescents with SCD. Long-term follow-up is in progress.

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

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

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

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

Improving Outcomes of Peripheral Blood Stem Cell (PBSC) HLA-Mismatched Unrelated Donor (MMUD) Hematopoietic Cell Transplantation (HCT): Effect of Graft Versus Host Disease (GVHD) Prophylaxis

Human leukocyte antigen (HLA) well matched donor (related or unrelated) has remained the preferred donor source for patients undergoing HCT for hematological disease, but the probability of finding a suitable related or unrelated donor has varied based on ethnic groups. HLA-mismatch unrelated donor (MMUD) transplantation has improved access to HCT in underrepresented minority groups and patients of mixed race. Historically, MMUD HCT has been associated with inferior survival outcomes compared to matched unrelated donor HCT when using conventional platforms of GVHD prophylaxis. (PMID: 31449184, 20538804). Efforts to improve outcomes have investigated the addition of a third agent such as anti-thymocyte globulin (ATG), mini-methotrexate (MTX) or mycophenolate mofetil (MMF). More recently, a study by the National Marrow Donor Program (NMDP) demonstrated the feasibility of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis in MMUD HCT using bone marrow (BM) grafts (PMID: 33905264). Additionally, our group demonstrated promising overall survival (OS) and GVHD-free/relapse-free-survival (GRFS) rates in peripheral blood stem cell (PBSC) MMUD HCT using PTCy based GVHD prophylaxis (PMID: 34156440). Here, we compare outcomes of PBSC MMUD HCT among patients receiving GVHD prophylaxis with either: (1) tacrolimus plus sirolimus (T/S), (2) T/S plus mini-methotrexate (T/S/MTX), or (3) PTCy, MMF, and tacrolimus or sirolimus (PTCy). Patients with various hematologic malignancies that underwent PBSC MMUD HCT (≥5/8 HLA-matched donors) at City of Hope between January 2005 and December 2021 were included in this retrospective review. Of 390 subjects included, GVHD prophylaxis included T/S (n=114), T/S/MTX (n=160), and PTCy (n=116). The median age was 51 (range:15-79), 53.3% of patients belonged to a racial/ethnic minority, and 34.8% (n=136) patients had disease risk index high or very high. Degree of HLA mismatch was 7/8 (91.3%), 6/8 (8.5%), and 5/8 (0.3%). Hematologic diseases included AML (40.3%), ALL (20.3%), MDS/MPN (15.9%), Lymphoma (16.9%), and CML/CMMol (6.7%). Most common conditioning regimens were fTBI-based (34.4%) and melphalan-based (57.2%). HCT comorbidity index was ≥ 3 in 30.8% (n=120), which was most common in PTCy compared to T/S and T/S/MTX: 48.3% vs. 23.7% vs. 23.1%, P&amp;lt;.001. The rate of neutrophil engraftment (15 days vs. 15 days vs 16 days, P=0.002) and platelet engraftment (15 days vs. 16 days vs 27 days, P=0.004) were shorter in T/S compared to T/S/MTX and PTCy, respectively. With median follow-up of 5.4 years (range: 1.0-16.7) the 5-year OS was superior in PTCy (P=0.045) compared to T/S and T/S/MTX: 58.0% (95% CI: 46.6-67.8) vs. 41.1% (95% CI: 31.9-50.1) and 39.6% (95% CI: 32-47.2). The 5-year disease-free survival (DFS) was superior in PTCy (P=0.042) compared to T/S and T/S/MTX: 54.2% (95% CI: 43.3-63.9) vs. 37.1% (95% CI: 28.2-46.0) vs. 37.2% (95% CI: 29.7-44.6), respectively. There was no significant difference in 5-year cumulative incidence of relapse (CIR) in T/S vs. T/S/MTX vs. T/S vs. PTCy: 29.1% (95% CI: 21.0-37.6) vs. 29.5% (95% CI: 22.6-36.7) vs. 22.1% (95% CI: 14.3-31.0), respectively. Additionally, there was no significant difference in 2-year NRM between the cohorts (P=0.459): 24.6% (95% CI: 17.1-32.9) vs. 23.1% (95% CI: 16.9-29.9) vs. 20.4% (95% CI: 13.5-28.4), respectively. The rate of 100-day Grade III-IV acute GVHD were similar between in the cohorts (P=0.321): 19.3% (95% CI: 12.6-27.0) vs. 18.1% (95% CI: 12.6 -24.5) vs. 12.9% (95% CI: 7.6-19.7). When comparing T/S vs. T/S/MTX and PTCy, the incidence of chronic GVHD was less in the PTCy cohort at both 1-year and 2-years (P&amp;lt;.001) with 1-year incidence of 55.0% (95% CI: 45.1-63.7) vs. 61.9% (95% CI: 53.8-68.9) vs. 38.9% (95% CI: 30-47.8), respectively, and 2-year incidence of 58.9% (95% CI: 49.0-67.6) vs. 66.2% (95% CI: 58.3-73.1) vs. 42.7% (95% CI: 33.4-51.6), respectively. To our knowledge, this is the largest reported single center outcome of PBSC MMUD HCT. In this study, we demonstrate the superiority of PTCy based GVHD prophylaxis compared to T/S and T/S/MTX in outcomes of 5-year OS (P=0.045), 5-year DFS (P=0.042), and incidence of chronic GVHD (P&amp;lt;.001). Our experience further supports the superiority of PTCy as the preferred GVHD prophylaxis in the PBSC MMUD HCT setting achieved by lowering chronic GVHD and associated complications.

Exploring Clonal Hematopoiesis in Chronic Graft Versus Host Disease Patients: A Comprehensive Study

Introduction Clonal hematopoiesis (CH) is a prevalent condition characterized by the presence of genetic mutations in hematopoietic cells, without being associated with any overt hematological malignancy. Emerging evidence has linked CH to various health complications, potentially contributing to higher morbidity rates in cancer survivors and individuals with chronic inflammatory diseases. Increased inflammation has been identified as a consequence of CH-related mutations, which may underlie these risks. Chronic graft versus host disease (cGVHD), debilitating complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), is a multisystem inflammatory disease. However, to date, the relationship between CH and cGVHD remains poorly understood. This study aims to investigates the potential role of CH in increasing the risk of developing cGVHD. Methods Research was conducted on patients who met the following inclusion criteria; (1) adult (age ≥ 18 years) acute myeloid leukemia (AML) patients who had previously consented to blood banking at a human resources bank and signed a residual specimen research agreement (IRB: H-2202-100-1302); (2) received allo-HSCT between Jul 2013 and Oct 2020; (3) experienced cGVHD of any NIH severity; (4) had peripheral blood sample taken after the occurrence of cGVHD but without relapse at that time, evidenced by &amp;gt;95% donor chimerism. The sequencing of 24 CH-related genes reported to date was performed at a sequence depth of ≥1000X, and the results were reported with a sensitivity of 99.9% and an accuracy of 99.9%. Analysis was conducted on patients with Variant Allele Frequency (VAF) ranging from 2.0% to less than 30.0%, classifying them as CH positive. Result A total of 134 patients who met the inclusion criteria were included in the analysis. The mean age at matched sibling donors (MSD) (n=41, 30.6%), unrelated donors (UD) (n=38, 28.4%) and haplo-identical donors (HID) transplants (n=55, 41.0%) was 48, 45 and 43 years for recipients, respectively, with no statistically significant difference (p=0.220). However, there was a significant difference in the mean age of donors, with 45, 32 and 32 years for MSD, UD and HID transplants, respectively (p&amp;lt;0.001). Among the cGVHD patients, 11.9% (16/134) tested positive for CH. The majority of these CH+ patients had a DNMT3A mutation (11) followed by TET2 (2), ASXL1 (1) and PPM1D (1). Between the CH- and CH+ groups, there were no statistically significant differences in age (both recipient and donor), gender, and clinical outcomes including relapse and death. A trend towards a higher incidence of CH+ was observed in patients receiving HID transplants, with 3/41 (7.3%) for MSD, 3/38 (7.9%) for UD, and 10/55 (18.2%) for HID, although this difference was not statistically significant (p=0.177). In addition, we could not observe the differential impact of donor age on the incidence of CH+ after allo-HSCT. The distribution of CH was further analyzed based on clinical outcomes, dividing patients into severe cGVHD and non-severe cGVHD groups. The results showed that patients with a mutation in the TET2 gene, which contributes to CH, accounted for 6.9% (2/29) of the total patients in the severe cGVHD group, while it was 0% (0/105) in the non-severe cGVHD group. Next, we compared CH data from cGVHD patients to a cohort of 5205 healthy individuals in Korea, where a CH positivity rate of 7.9% was observed. We found a statistically significant increase in the odds ratio for CH positivity in the overall cGVHD population after adjusting for age. The highest detection of CH, including the DNMT3A gene, was observed when adjusting for recipient age (odds ratio of CH 2.41[1.39-4.19], p= 0.002) and when adjusting for donor age (odds ratio of CH 3.79[2.10-6.83], p= 0.001). Conclusion In this study, we found that 11.9% of cGVHD AML patients who underwent allo-HSCT tested positive for CH, with DNMT3A mutation being the most common. There was a trend towards a higher incidence of CH+ in HID transplant although it was not statistically significant. Compared to healthy individuals, cGVHD patients had a significant higher risk for CH positivity, particularly when adjusting for age. For the deeper understanding of CH's role in post-transplant complications, further analysis with incorporating the data regarding baseline genetic information from recipients and donors and non-cGVHD patients after allo-HSCT would be warranted.

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

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

Role of Splenic Irradiation Prior to Transplant for Myelofibrosis: A Global Collaboration

JAK inhibitors and novel agents have shown promising reduction of spleen size in newly diagnosed myelofibrosis. However, not all patients will respond or they eventually progress at some point. Despite hematopoietic cell transplantation (HCT) being the only curative treatment option to date, splenomegaly prior to HCT remains a particular challenge. On the other hand, numbers of patients eligible for HCT continue to increase worldwide, and thus management of splenomegaly becomes more and more relevant. One approach to reduce spleen size prior to HCT could be splenic irradiation. However, evidence on its role remains scarce. We took advantage of a global collaboration between European, US, and Latin American centers to investigate the role of splenic irradiation as part of the HCT platform for patients with myelofibrosis. Radiation therapy had to be given within 3 months prior to or be part of conditioning therapy for HSCT. Detailed information on irradiation as well as post-HCT safety profiles was collected in addition to usual patient-, disease-, and transplant-related variables. This global collaborative study included 52 patients, of whom 71% had primary myelofibrosis, 17% post polycythemia vera and 12% post essential thrombocythemia myelofibrosis. Median age at HCT was 60 years (range, 32-76). Risk category according to DIPSS prior to irradiation was intermediate-1 in 20%, intermediate-2 in 52%, and high in 28%. Driver mutation status was JAK2 in 44%, CALR in 40%, MPL in 4%, and triple negative in 12%. Four patients had portal vein thrombosis before irradiation. Ruxolitinib before irradiation was received by 76% and 4% received fedratinib. Reduced intensity conditioning HCT was received by 73% and 85% were matched related or matched unrelated donor transplants. Median time from irradiation to HCT was 2 weeks (range, 0.9-12 weeks) and median spleen size prior to irradiation was 23 cm (range, 14-35). Spleen size was measured by ultrasound in 70%, CT scan in 20%, and physical examination in 10%. Median total irradiation dose was 7 Gy (range, 3-12), fractionated in a median of 5 administrations (range, 2-12). Splenic irradiation resulted in a significant spleen reduction prior to HCT but was also associated with significant reduction in platelet and leukocyte counts ( Table). Spleen size did not correlate with blood counts prior or after irradiation. Higher platelet count prior to irradiation correlated with higher counts after irradiation (r=0.83; P&amp;lt;0.001). There was no correlation between irradiation dose and post-irradiation hematological toxicities. Only 1 patient had non-hematological adverse events (tumor lysis syndrome). Neutrophil engraftment was achieved by 90% within a median of 18 days after HCT and platelet engraftment was achieved by 81% within a median of 38 days. Median follow-up of the total cohort was 2.7 years and 3-year overall survival was 66% (95% CI, 52-80%; Figure). Non-relapse mortality was 27% (95% CI, 15-39%) and cumulative incidence of relapse was 11% (95% CI, 2-20%; Figure). Incidence of acute GVHD grade II-IV and chronic GVHD was 25% and 38%, respectively. Increased spleen size (as continuous variable) prior to irradiation was associated with worse outcome (P=0.05), showing 3-year survival of 73% for spleen ≤25cm vs 42% for &amp;gt;25cm, and non-relapse mortality of 58% vs 14%, respectively (P=0.02). No effect of spleen size after irradiation on outcomes was observed. All 4 patients with portal vein thrombosis died (2-year survival 25%). A multivariable model showed that larger spleen size before irradiation, lower hemoglobin levels, CALR/MPL-unmuated driver mutation genotype, and presence of portal vein thrombosis were significantly associated with worse survival ( Table). This first international and largest study to date on splenic irradiation as part of the HCT algorithm for patients with myelofibrosis and splenomegaly showed a significant impact of spleen size on overall survival and non-relapse mortality, while relapse rates were low. In addition, lower hemoglobin levels and presence of portal vein thrombosis at time of irradiation predicted worse outcomes.

Sirolimus Is an Acceptable Alternative to Tacrolimus for Graft-versus-Host Disease Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT.