Introduction The phase II CAST trial published by Alhomsi et al studied the use of PTCY in combination with Abatacept, and short course of tacrolimus(TAC) as GVHD prophylaxis in haploidentical transplant (HID). Results were promising for low incidence of GVHD and superior relapse free survival (RFS) compared to a CIBMTR matched cohort (TCT 2024). Objectives Since Nov 2023, we used the CAST regimen at Mayo Clinic Rochester for patients undergoing matched, mismatched unrelated donor and HID. Here we report our single institution experience of the CAST regimen as GVHD prophylaxis. Methods Patients with insurance approval for Abatacept who received GVHD prophylaxis according to the CAST study were included. Abatacept was dosed on days +5, 14, 28, and 56 post alloHCT. Tacrolimus (TAC) was started on day +5, and tapering was initiated on day 60, while it was discontinued by day 90 in the absence of GVHD. Results A total of 73 patients received the CAST regimen. Median age at transplant was 61-years (IQR 50-68) and 39 (53.4%) were males. Out of the 73 patients, 56 (76.7%) had matched unrelated donor (MUD), 10 (13.7%) had mismatched unrelated donor (MMUD), and 7 (9.6%) had HID. A total of 28 (38.4%) patients received myeloablative conditioning. Graft was 100% T-cell replete PBSC. The most common indications for alloHCT were AML [28 (38.4%) patients], MDS [21 (28.8%) patients], and myelofibrosis [7 (9.6%) patients].Disease risk index (DRI) was high/very high in twelve (16.4%) patients, whereas 49 (67.1%) had intermediate and 5 (6.8%) patients had low DRI. DRI was not available for 7 (9.6%) patients. Among AML patients, 9 (32.1%) were MRD-positive pre-transplant.Median time to ANC engraftment was 15 days (IQR 14-17 days), and median time to platelet engraftment was 20 days (IQR 15-27 days), while one (1.4%) patient developed graft failure.After a median follow-up of 11.9 months (95% CI 10.6 – 13 months), 3 (4.1%) patients developed grade 3-4 acute GVHD, while 8 (10.9%) patients developed chronic GVHD requiring systemic therapy. Of the 3 patients with grade 3-4 acute GVHD, 2 patients had stage 4 GI GVHD and 1 had stage 3 liver GVHD.Median OS and RFS were not reached; 1-year OS was 82.4% (95% CI 73.3 - 92.7%) and 1-year RFS was 69.6% (95% CI 59.5 - 81.5%). A total of 15 (20.5%) patients relapsed, 14 (93.3%) were among MUD group, while only 1 (6.7%) patient relapsed in the MMUD/HID group. The 1-yr GRFS rate was 61.1% (95% CI 50.5 – 73.9%). The 1-yr non-relapse mortality (NRM) for the entire cohort was 8.9% and 1-year cumulative incidence of relapse was 21.5%. Conclusion Here we report the first real world experience of CAST across multiple different donor platforms in a predominantly enriched MUD cohort. Shorter time to engraftment was notable with CAST. CAST was associated with a very low incidence of severe acute and chronic GVHD, which translated into a favorable 1-yr NRM. Longer follow up is required to evaluate long term outcomes.

Post-transplant cyclophosphamide (PTCy) has emerged as the standard graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (alloHCT). The Endothelial Activation and Stress Index (EASIX) has been shown to be a key determinant of post-transplant outcomes, yet the dynamic trends of post-transplant EASIX scores across GVHD prophylaxis platforms and its prognostic utility remain incompletely defined. We evaluated longitudinal post-transplant EASIX score trajectories in patients receiving PTCy versus calcineurin inhibitor/methotrexate (CNI/MTX)-based prophylaxis and developed an individualized dynamic risk model for post-transplant survival. Log2-EASIX scores from day +20 to day +120 were evaluated using dynamic landmark analysis and combined with the pre-transplant disease risk index (DRI) to develop a dynamic-EASIX DRI risk prediction model which could predict post-transplant mortality. Patients were randomly segregated in a 2:1 ratio into training and validation cohorts to develop and validate the model, respectively. A total of 534 alloHCT recipients were evaluated, of whom 150 (28.1%) received PTCy. In the training cohort, an increasing log2-EASIX score (HR 1.44, P = 0.001) and an increasing log2-EASIX trend/slope (HR 2.81, P = 0.002), both were associated with an inferior 1-year overall survival (OS). The dynamic-EASIX DRI model had a C-index of 0.82 for 1-year and 0.84 for 2-year survival. In the validation cohort, the area under curve for the dynamic-EASIX DRI model was 70.2% and 75.4% for 1 and 2-yr OS, respectively. The dynamic-EASIX DRI model is a novel tool that can be used to risk stratify patients in the post-transplant follow-up period and can be applied irrespective of GVHD prophylaxis.

Post-transplant Cyclophosphamide (PTCy) is becoming the new standard of care for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT). High-dose cyclophosphamide has been associated with cardiac dysfunction through multiple mechanisms. We hypothesized that patients with evidence of coronary artery calcification (CAC) might be at a higher risk for non-relapse mortality (NRM) and inferior survival after receiving PTCy for GVHD prophylaxis. We retrospectively reviewed patients with hematologic diseases undergoing alloHCT using PTCy for GVHD prophylaxis in the Mayo Clinic Enterprise from 2018 to 2022. Patients with non-contrast CT imaging for review for CAC within 1 year (yr) of alloHCT were included in this study, with imaging analyzed by a blinded independent reviewer. Of 204 patients who received PTCy for GVHD prophylaxis, 144 (70.5%) had CT imaging available for CAC review. Seventy-three (50.7%) patients were positive for CAC (+) and 71 (49.3%) were negative for CAC (-). Compared to CAC-, CAC+ patients were older (64 vs 45 years, P < .001) and were more likely to have known coronary artery disease (CAD) before transplant (16.4% vs 1.4%, P = .004), but had a comparable HCT-CI (P=0.17). NRM was higher among patients with CAC+ compared to CAC- at 1 and 2-yr (26.5% versus 8.9%, P = .008), (28.0% versus 8.9%, P = .005), respectively. Univariate competing risk analysis showed that CAC was significantly associated with 2-yr NRM (HR 3.41, 95% CI 1.36-8.54, P = .009) and inferior post-alloHCT survival (2-yr OS rate 51.6% versus 72.3%, P = .01). Multivariate analysis (MVA) confirmed that CAC+ was associated with higher 2-yr NRM (HR 4.37, 95% CI 1.71-11.18, P = .002). While CAC+ did not impact OS in the whole cohort, among elderly patients age ≥60 and without a history of CAD, MVA confirmed that CAC+ was associated with an inferior 2-yr OS (HR 3.67, 95% CI 1.007-13.38, P = .049) and higher NRM (35.5% vs 0%, P = .006). Coronary artery calcification is readily assessable in imaging studies during pretransplant evaluation. Among patients receiving PTCy, CAC was associated with a higher NRM. CAC+ was associated with inferior OS, particularly in elderly patients without a history of coronary artery disease.

ABSTRACT:Allogeneic hematopoietic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MNs) harboring TP53 mutations (TP53mut). The aim of this international study across 7 transplant centers in the United States and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype; 94% of TP53 variants were localized to the DNA-binding domain (DBD). Most common comutations were ASXL1 (7%), TET2 (7%), and DNMT3A (6%). Median post-HCT survival was 1.03 years, and overall survival (OS) at 1 year, 2 years, and 3 years was 51.4%, 35.1%, and 25.1%, respectively. A total of 103 cases (76.9%) met the International Consensus Classification (ICC) criteria for MN with mutated TP53 (referred to as ICC-defined TP53mut MN hereafter). The 3-year OS of ICC-defined TP53mut was significantly shorter compared with that of other TP53mut MNs (3-year OS, 16.9% vs 54.9%; P = .002). ICC-defined TP53mut MNs was independently associated with inferior OS (hazard ratio [HR], 2.62; P = .019). The presence of non-DBD TP53mut only (HR, 3.40; P = .005), DNMT3A comutation (HR, 2.64; P = .016), and pre-alloHCT bone marrow blasts ≥5% (HR, 2.76; P = .006) was independently associated with inferior relapse-free survival (RFS), whereas melphalan-based conditioning was associated with superior RFS (HR, 0.52; P = .005). Combining these variables, we constructed a hierarchical model that stratified patients into low-, intermediate-, and high-risk categories with 1-year RFS of 81.3%, 31.3%, and 6.7%, respectively (P < .001). In conclusion, a subset of MN harboring TP53mut who have low blasts pre-alloHCT and received melphalan-based conditioning derived long-term benefit from alloHCT.

Post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is now being used beyond haploidentical (HID) allogeneic hematopoietic cell transplant (alloHCT). However, the kinetics of chimerism in patients receiving PTCy and its impact on post-transplant relapse is unknown. In this study we describe the kinetics of donor chimerism in patients receiving PTCy, factors predisposing to mixed donor chimerism, and the associated survival outcomes. Patients undergoing alloHCT at Mayo Clinic, Rochester, from January 2018 to June 2023 were included in the study. Full donor chimerism was defined as donor cell fraction ≥95%, and mixed chimerism as donor cell fraction <95%. Analysis of covariance was used to assess the trend of tacrolimus levels in patients with mixed versus full donor CD3 chimerism. Relapse-free survival (RFS) and overall survival (OS) from transplant were determined using the Kaplan-Meier method. Mixed donor chimerism was considered a time-dependent covariate in multivariate analysis. A total of 500 patients were evaluated; 189 (37.8%) patients received myeloablative conditioning (MAC); 27 (14.3%) of whom received PTCy and 162 (85.7%) received methotrexate (MTX) for GVHD prophylaxis. Among patients receiving PTCy, HID and mismatched donor transplants were significantly associated with a lower risk of mixed CD3 chimerism. In patients receiving PTCy, myeloablative busulfan/fludarabine (BuFlu), compared to non-busulfan MAC regimens, Bu/Flu MAC was associated with an increased risk of d +90 mixed chimerism (OR = 10.47, P = .02). However, reduced intensity (RIC) BuFlu was not associated with an increased risk of mixed CD3 chimerism (OR = 0.71, P = .7). Among patients receiving MAC and PTCy, those with high tacrolimus levels (≥11 mcg/mL) beyond the 2nd wk post-transplant period were more likely to have mixed CD3 chimerism (F1,145 = 4.15, P = .043). In patients receiving MAC and PTCy, d +90 mixed CD3 chimerism was associated with an inferior RFS (1-yr RFS: 89.16% versus 40.0%, P = .009). Multivariate analysis showed that mixed donor CD3 chimerism was associated with an inferior RFS in patients receiving MAC and PTCy (HR: 6.53, 95% CI, 1.18 to 36.15, P = .032). Among patients receiving MAC and PTCy, detection of mixed donor CD3 chimerism at any timepoint after transplant portends an inferior RFS. A high tacrolimus level beyond 2nd week of transplant in this subset of patients was associated with mixed CD3 chimerism. The detection of mixed CD3 chimerism provides an opportunity to implement strategies that may help in decreasing the risk of relapse in this subset of patients.

The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53mut) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53mut (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53mut MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53mut acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v) TP53mut VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53mut AML was associated with significantly poor survival compared to TP53-wild type TP53wt AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53mut MN as a distinct subentity. Secondly, the survival of TP53mut with blast 10–19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53mut with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53mut AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53mut MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.

ABSTRACT:This retrospective analysis aimed to provide evidence-based risk stratification of TP53-mutated (TP53mut) myeloid neoplasms (MNs). Of 580 MNs harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.4%), 92 (15.9%), and 75 (12.9%) were classified as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) with low blasts (MDS-LB), MDS with excess blasts (MDS-EB)-2, and -EB1 according to the revised fourth edition of the World Health Organization (WHO) classification, respectively. Hierarchical analysis identified the following 4 risk groups with distinct survival: (1) MDS-LB, (2) MDS-EB1/EB2/AML VAF <10%, (3) MDS-EB1/EB2 VAF ≥10%, and (4) AML VAF ≥10%. We next evaluated the impact of allelic status, VAF, and complex karyotype (CK). In our cohort, the significance of biallelic status was limited to MDS with <5% blasts and not for blasts 5% to 9%, as proposed by the International Consensus Classification (ICC), or 5% to 19%, as proposed by the fifth edition of the WHO (WHO-5). MDS-EB1 and -EB2 with VAF ≥10% had comparable survival (9.6 vs 7.2 months; P = .12), regardless of allelic status. Contrary to the ICC proposal, MDS-EB1/EB2 with VAF <10% and CK had poor survival compared with those without CK, comparable to MDS-EB1/EB2 with VAF ≥10% (5.6 vs 26.2 vs 6.3 months; P = .003). Survival of TP53mut AML was poor (median 3.9 months) regardless of allelic/CK status. Thus, using ICC or WHO-5 may underestimate prognosis of MDS with blasts 5% to 19% and 5% to 9%, respectively. Collectively, the hierarchical model acknowledges poor survival of 91.9% TP53mut MDS and AML compared with 36.5% and 80.7% by WHO-5 and ICC, respectively.

Background: Disease relapse is a major cause of mortality post allogeneic hematopoietic stem cell transplantion (alloHCT) in patients with myeloid neoplasms (MN). Cytogenetic risk classification is a key prognostic factor in predicting relapse post-transplant. Next generation sequencing (NGS) offers added prognostic insight by identifying relapse-associated mutations. We assessed the impact of mutation type and burden on post-alloHCT relapse risk and relapse-free survival (RFS) in MN patients with non-adverse-risk cytogenetics. Methods: We retrospectively reviewed patients who underwent alloHCT at Mayo Clinic Rochester between 01/01/2018 - 10/01/2023. Eligible patients had MN with non-adverse-risk cytogenetics [Acute myeloid leukemia (AML) with non-adverse-risk cytogenetics per ELN 2022, myelodysplastic syndrome (MDS) with non-high/very high-risk cytogenetics per IPSS-R criteria, and myeloproliferative neoplasms (MPN) (excluding myelofibrosis), chronic myelomonocytic leukemia (CMML), or MDS/MPN overlap with non-complex and non-monosomal karyotypes]. The primary endpoint was 3-year cumulative incidence of relapse (CIR) post-alloHCT, analyzed via competing risk models. RFS was estimated via Kaplan-Meier method. Prognostic mutations were identified using univariate (UVA) and multivariate (MVA) Cox models. A decision tree was used to define mutation-based relapse risk groups. Results: Of 585 patients, 215 (37%) met inclusion criteria; 133 (62%) were male. Median age at diagnosis was 61 years (IQR 53-65.5). Diagnoses included AML (125, 58.1%), MDS (55, 25.6%), CMML (17, 7.9%), MDS/MPN (11, 5.1%), and MPN (7, 3.3%). Median follow-up post-alloHCT was 3.2 years (IQR 1.9-5.2). Donor sources were mostly matched unrelated donors (120; 55.8%), followed by matched related donors (72; 33.5%), haploidentical donors (15; 7%), mismatched unrelated donors (6; 2.8%), and cord blood transplants (2; 0.9%). Most patients reduced intensity/non-myeloablative conditioning (144, 67%), while others received myeloablative (71, 33%). Mutation frequencies were as follows: ASXL1 58 (27.0%), RUNX1 45 (20.9%), FLT3 41 (19.1%), SRSF2 41 (19.1%), DNMT3A 39 (18.1%), STAG2 22 (10.2%), SF3B1 18 (8.4%),BCOR 18 (8.4%), WT1 16 (7.4%), U2AF1 13 (6.0%), ZRSR2 10 (4.7%), TP53 6 (2.8%), EZH2 3 (1.4%). In UVA, mutations in FLT3 (HR 2.15, p=0.018), SF3B1 (SF3B1 HR 3.08, p=0.002), PTPN11(HR 2.93, p=0.032), and WT1 (HR 2.29, p=0.069) were associated with increased risk of 3-year CIR. However, only FLT3 (HR 1.98, p=0.042) and SF3B1 (HR 4.0, p<0.001) retained significance in MVA. SF3B1 correlated with inferior 3-year RFS in UVA (HR 1.99, p=0.034) but not in MVA. Mutations in ASXL1, BCOR, EZH2, RUNX1, SRSF2, STAG2, ZRSR2, U2AF1, and TP53 had no significant impact on CIR or RFS. Harboring ≥2 or ≥3 mutations did not impact CIR or RFS. A decision tree model based on SF3B1, FLT3, DNMT3A, and WT1 mutations stratified patients into 3 risk groups. The high-risk group (n=32; 15%) had 50% 3-year relapse incidence (RI) and included patients with SF3B1 mutations or SF3B1-wildtype (WT) with concurrent FLT3 and DNMT3A mutations. The intermediate-risk group (n=36; 17%) included SF3B1-WT patients with either FLT3 mutations and DNMT3A WT (21% RI), or SF3B-1-WT and FLT3-WT patients with WT1 mutations (33% RI). The low-risk group (n=147; 67%) lacked all 4 mutations and had the lowest 3-year RI of 14%. The 3-year CIR significantly differed across these 3 risk groups (51.9%, 27.3%, and 15.8% in high, intermediate, and low-risk groups respectively; p<0.001). The 3-year RFS was significantly inferior in the high-risk group (35.55%, p=0.001), but similar among intermediate and low-risk groups (67.11% and 63.4%, respectively). Conclusion: In non-adverse risk cytogenetic MN, SF3B1 and FLT3 mutations predicted relapse post-alloHCT. Notably, mutations that were traditionally associated with adverse-risk AML per ELN 2022 (e.g, ASXL1, TP53) were not associated with relapse in this cohort. The discrepancy may reflect exclusion of patients with high-risk cytogenetics, as the prognostic impact of these mutations may depend on co-cytogenetic anomalies. In non-adverse-risk cytogenetics MN, we identified 3 groups of patients based on the presence or absence of SF3B1, FLT3, DNMT3A, and WT1 mutations. Those with mutated SF3B1 or concurrent FLT3/DNMT3A mutations experienced the highest risk of relapse post-alloHCT, translating into inferior RFS. Our findings need to be verified in a larger data registry.

IntroductionPost-transplant Cyclophosphamide (PTCy) is now the standard of care for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplant (alloHCT). High dose cyclophosphamide, as used in PTCy, is associated with cardiac dysfunction through direct toxicity to myocytes and cardiac endothelium. We hypothesize that patients with cardiac risk factors pre-alloHCT, such as presence of coronary artery calcium (CAC), are at higher risk for non-relapse mortality (NRM) and inferior survival after receiving PTCy for GVHD prophylaxis.MethodsWe retrospectively reviewed patients with hematologic diseases who underwent alloHCT and received PTCy for GVHD prophylaxis in the Mayo Clinic Enterprise from 2018 to 2022. Patients who had non-contrast CT imaging for CAC within 1 year of alloHCT were included in this study. Due to the association of age with CAC, age>60 was included in the multivariate analysis (MVA) for both NRM and overall survival (OS). MVA included CAC+, and other factors known to be associated with NRM such as age > 60 years at alloHCT, high HCT-CI and myeloablative conditioning. MVA for 2-year OS included age at alloHCT, haploidentical transplant, high/very high DRI and CAC+.ResultsA total of 204 patients received PT-Cy for GVHD prophylaxis, with 145 patients having available CAC imaging. Seventy-four (51%) patients were positive for CAC (+) and 71 (49%) were negative for CAC (-). As expected, compared to CAC- group, CAC+ patients were significantly older in age (median 64 vs. 45 years, P <0.001), and were more likely to have CAD before transplant (16.2% vs. 1.4%, P=0.008). However, both groups had comparable HCT-CI (P=0.54). Median follow-up after alloHCT was 2 years (95% CI 1.75-2.32 years). NRM at 2-years after alloHCT was significantly higher in CAC+ patients (26.7% vs. 10.4%, P=0.017, Figure 1). OS at 2 years post-alloHCT was lower in CAC+ patients (OS rate 49.1% vs. 75.7%, P=0.002, Figure 2). Univariate competing risk analysis showed CAC to be significantly associated with 2-year NRM (HR 2.74, 95% CI 1.15-6.54, P = 0.02). MVA confirmed CAC+ to be significantly associated with 2-year NRM (HR 2.53, 95% CI 1.04-6.14, P = 0.04). MVA confirmed CAC+ was associated with inferior survival (HR 2.4, 95% CI 1.14-5.06, P = 0.02).Twenty-six (17.9%) patients had NRM by 2 years after transplant with acute respiratory distress syndrome (ARDS)/multiorgan failure (MOF) [10 of 26 patients, 61.5%] as the most common cause of NRM (Table 1). Only 20% CAC+ patients had a positive cardiac HCT-CI, with two having NRM compared to 17 with negative cardiac HCT-CI.ConclusionCoronary artery calcium is readily assessable in imaging studies during pretransplant evaluation, is a surrogate of atherosclerotic burden, and may suggest chronic endothelial injury. Presence of CAC may predict higher risk of NRM and inferior OS in patients receiving PTCy.

This case-control study examines the incidence and risks of myeloid neoplasms in adults treated for B-cell lymphoproliferative disorders or multiple myeloma.

IntroductionAllogeneic stem cell transplant (alloSCT) is considered the therapeutic modality of choice for patients with TP53 mutated (TP53mut) myeloid neoplams (MN). However, outcomes remain poor and factors associated with post-alloSCT survival, in this high-risk cohort, are not known.MethodsWe retrospectively reviewed TP53mut MN patients undergoing alloSCT at Mayo Clinic Enterprise and CALHN, Adelaide, South Australia. TP53mut MN were defined per 2022 ICC guidelines. Multi-hit TP53mut was defined as: 2 distinct TP53mut (each VAF ≥10%) or a single TP53mut with (1) 17p deletion on cytogenetics; (2) VAF of ≥50%; or (3) copy-neutral LOH at the 17p TP53 locus. With an aim to evaluate the impact of complex karyotype (CK) on post-alloSCT outcomes, CK was not considered a multi-hit equivalent. Overall survival (OS) was calculated from the time of alloSCT using Kaplan Meier method. Non-relapse mortality (NRM) and relapse incidence (RI) was determined using competing risk analysis.ResultsOf 87 TP53mut MN patients 32 (36.8%) had AML, 13 (14.9%) had MDS/AML and 42 (48.3%) had MDS. At diagnosis, 73 (83.9%) had CK and 17 (19.5%) patients had two TP53mut. Median TP53 variant allele frequency (VAF) was 38.5% (IQR 17.2–62). Forty-nine (56.3%) patients had multi-hit TP53mut (mhTP53). Median age at alloSCT was 64 (IQR 59-68) years. Median follow-up was 2.9 years. Median OS was 11.7 months, driven primarily by relapse (1-year RI 51.3% and NRM 13.9%). Multivariate analysis (MVA) confirmed mhTP53 (HR 2.37, 95% CI 1.1 – 3.9, P = 0.024) and CK (HR 2.37, 95% CI 1.3 – 4.3, P = 0.005) to be associated with inferior OS, whereas there was a trend towards improved OS with melphalan-based conditioning (HR 0.57, 95% CI 0.32 – 1.04, P = 0.067, Figure 1A). Melphalan-based conditioning was associated with a decreased RI (HR 0.32, 95% CI 0.17–0.60, P <0.001, Figure 1B). In contrast, myeloablative conditioning (HR 2.2, 95% CI 1.13–4.34, P = 0.02) and post-transplant cyclophosphamide (HR 1.84, 95% CI 1.03 – 3.3, P = 0.04) were associated with an increased risk of relapse. Late NRM partially abrogated the benefit of decreased RI seen with melphalan-based conditioning (Figure 2).Given that melphalan was the only modifiable factor associated with a decreased relapse risk, we considered patients with neither mhTP53 nor complex karyotype, but receiving melphalan based conditioning, to have comparatively favorable OS (“standard-risk”). Twelve (13.8%) patients had standard risk, while the remaining 71 (81.6%) patients were considered high-risk. The standard-risk cohort had a significantly longer 3-year OS compared to the high-risk cohort (51.9% vs. 22.3%, P = 0.038, Figure 3).ConclusionMelphalan-based conditioning in patients without mhTP53mut and without complex karyotype may identify a small subset of patients with favorable outcomes in this otherwise high-risk cohort. Larger studies are needed to confirm these findings.

IntroductionNon-permissive HLA-DPB1 mismatch is associated with increased risk of acute graft versus host disease (GVHD), non-relapse mortality (NRM) and inferior overall survival (OS) in matched unrelated allogenic stem cell transplant (alloSCT) recipients. Post-transplant cyclophosphamide (PTCY) is the new standard GVHD prophylaxis regimen. Here, we describe our experience of DPB1 mismatch including allelic level in patients undergoing unrelated matched (MUD) or mismatched (MMUD) alloSCT with PTCY.MethodsWe retrospectively reviewed patients from July 2020 to April 2023 who underwent MUD or MMUD alloSCT and received PTCY with tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Comparative analysis was performed among cohorts determined by DP match status and DP expression levels separately. Kaplan–Meier and log-rank tests were used to estimate OS. NRM and relapse incidence (RI) were calculated using competing risk analysis. R 4.3.1 was used for statistical analyses.ResultsA total of 25 patients [17 (68%) males] were evaluated. Median age at transplant was 62 years (range 30 - 76 years). Eight patients (32%) were DP matched, while 6 (25%) and 11 (44%) patients were DP permissive (P-MM) and non-permissive mismatch (NP-MM), respectively (Table1).In DP NP-MM cohort, 3 patients (27%) developed grade 2 acute GVHD (Skin only required systemic steroid), however none developed steroid refractory GVHD (SR-GVHD). In DP matched cohort, 2 patients (25%) developed grade 2 GVHD with one patient had gastrointestinal SR-GVHD. One patient each in DP NP-MM and DP matched cohorts had moderate-severe chronic GVHD, however the latter did not require systemic therapy.Of the total 9 patients with single DP allele mismatch, 6 (67%) had favorable expression. The DP double allele mismatch group had higher incidence of acute GVHD (57%, 4 of 7 patients) compared to DP match (2 of 8 patients, 25%), DP unfavorable expression (1 of 3 patients, 33%) and none in favorable expression cohorts. No chronic GVHD was noticed in either favorable or unfavorable expression groups.Median follow-up of the entire cohort after alloSCT was 11.4 months (95% CI 7.6 – 36.6 months). Survival at 2-years was similar among DP NP-MM (51.9%) and DP matched cohorts (53.6%) compared to the DP P-MM cohort (83.3%, P = 0.82) (Figure 1). NRM at 1-year after alloSCT was 14.6% vs. 0% vs. 39.4% in the DP match, DP P-MM and NP-MM groups respectively (P = 0.36) (Figure 2).ConclusionPTCY based GVHD prophylaxis is an effective regimen in reducing acute and chronic GVHD for patients with DPB1 non-permissive mismatch and unfavorable expression. There is a trend toward better transplant outcomes in DPB1 permissive mismatch, compared to DPB1 matched and non-permissive mismatch.