Post-transplant Cyclophosphamide Research Articles

A Novel Post-Transplant Regimen for Selectively Promoting Unrelated Cord Blood Engraftment in Haploidentical-Cord Transplantation in Childhood Leukemia: A Single-Arm, Dual-Center Trial

Background Our previous studies indicated that complementary transplantation that was combined with a haploidentical peripheral blood stem cell (PBSC) transplant (haplo-SCT) and unrelated cord blood (UCB) transplant using a post-transplant cyclophosphamide (PTCy) regimen was applicable in children with acute leukemia. A better leukemia-free survival (LFS) was found in the UCB engraftment group, however, the engraftment of PBSC or UCB was unpredictable in the setting of complementary transplantation. Here, we conducted a prospective single-arm dual-center trial to investigate the effect of post-transplant cyclophosphamide plus fludarabine regimen for selectively promoting UCB engraftment in haploidentical-cord transplant. Methods This updated conditioning regimen was performed in two hospitals in China, including a total of eligible 78 pediatric patients who were enrolled from September 2019 to October 2022. The median follow-up was 24 months. This study is in progress. Meanwhile, 55 historically consecutive patients from December 2012 to June 2019 were included for comparison. The updated conditioning regimen (PT-Cy/Flu group) consisted of fludarabine (40mg/m 2, d-5 to d-3 and d+3, d+4), busulfan (100mg/m 2, d-6 to d-3), haplo-PBSC (d0), PTCy (50mg/kg, d+3, d+4) and UCB (d+6). The fludarabine was applied at d-6 to d-2 in the original conditioning regimen (PT-Cy group). In addition to PTCy, tacrolimus or cyclosporine and mycophenolate mofetil were administered as prophylaxis of GVHD. The primary aim was the UCB engraftment rate. In addition, the 2-year mid-term inspection included overall survival (OS), LFS, non-relapse mortality (NRM), graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS), and cumulative incidence of acute and chronic GVHD. Results The characteristic of patients were shown in Table 1. In brief, 47 (60.3%) acute myeloid leukemia and 27 (34.6%) acute lymphoblastic leukemia pediatric patients were included. 64 (82.1%) patients achieved first complete remission (CR1) before SCT. The median of PBSC mononuclear cells was 20.0×10 8/kg and CD34 + cells was 12.1×10 6/kg, while the median of CB total nuclear cells was 5.0×10 7/kg and CD34 + cells was 1.8×10 5/kg. Eventually, 73 (93.6%) patients in the PT-Cy/Flu group achieved full UCB engraftment by short tandem repeat (STR) detection, while the UCB engraftment rate was 24 (43.6%) in the PT-Cy group (p<0.001). The OS of the PT-Cy/Flu group was 88.6% ± 4.0% (95%CI 81.2% - 96.7%), which was significantly higher than the PT-Cy group [60.0% ± 6.6% (95%CI 48.4% - 74.5%), p<0.001] (Figure 1A). Of note, the LFS was markedly higher in the PT-Cy/Flu group compared to PT-Cy group [83.2% ± 4.3% (95%CI 75.2% - 92.0%) vs. 54.2% ± 6.8% (95%CI 42.4% - 69.2%), p<0.001] (Figure 1B). However, there was no statistical difference in NRM between the PT-Cy/Flu and PT-Cy groups (7.7% ± 0.1% vs 12.7% ± 0.2%, p=0.326). Moreover, similar cumulative incidence of III-IV acute GVHD and severe chronic GVHD were found between groups (Figure 1C, D). Finally, the GRFS of the PT-Cy/Flu was obviously better than the PT-Cy group [70.1% ± 5.9% (95%CI 59.5% - 82.5%) vs 39.4% ± 7.6% (95%CI 27.0% - 57.5%), p=0.025] (Figure 1E). Conclusion These results suggested that the novel post-transplant cyclophosphamide plus fludarabine regimen can be considered as a strategy for selectively facilitating UCB engraftment and improving LFS in haploidentical-cord transplant in children with acute leukemia.

Patterns of Graft-Versus-Host Disease (GvHD) Prevention and Management in the Eastern Mediterranean (EM) Region: A Worldwide Network for Blood & Marrow Transplantation (WBMT) Survey

Introduction: GvHD is a significant cause of morbidity and mortality in recipients of allogeneic hematopoietic cell transplant (HCT). The prevention, management, and treatment of GvHD vary in different regions worldwide. This WBMT study aims to better understand the current clinical practices of GvHD prevention and management around the globe. This study presents our survey results in the Eastern Mediterranean Region. Methodology: This is a cross-sectional survey-based study involving hematopoietic cell transplant (HCT) centers in the EM region. Participants of the survey were programs' directors or their designees. The survey comprised two parts; the first part aimed to study the practices of GvHD prevention, whereas the second part aimed to study GvHD management and treatment. The survey was distributed and filled out between December 2022 and May 2023. Results: Thirty participants from 28 institutions responded. Participants were from eleven different countries in the EM region. Fourteen participants (50%) filled it for combined pediatrics and adult HCT programs. The remaining participants filled it for programs performing HCT, either only in adult (27%) or pediatrics (23%) patients. The majority of participants indicated that cyclosporine and methotrexate combination is the most used GvHD prophylaxis therapy in both myeloablative and reduced intensity HCT in their centers. Cyclosporine was the predominantly used calcineurin inhibitor (CNI), followed by tacrolimus. All centers using cyclosporine indicated that they monitor its level, with 200-300 mcg/L being the target in 66% of the survey. Cyclosporine was typically given for 2-12 months after HCT, with around 80% of centers stopping it at 3-4 months post-HCT in recipients with malignant indications and around 90% of centers stopping it around 6-12 months post-HCT in recipients with non-malignant indications. When tacrolimus is used, results showed that it is typically used for similar duration to cyclosporine. Twenty-nine participants reported using post-transplant cyclophosphamide (PTCy) in their centers, with seven centers (24%) reporting its use in indications other than haploidentical transplants. Additionally, the results show that PTCy is typically used in combination with other medications, with 53% of participants reporting that it is used along with mycophenolate mofetil and cyclosporine and only one participant reported its use as a single agent. Seven participants (23%) reported that PTCy is typically used in doses less than 50 mg/kg. In patients with established GvHD, steroids were most commonly used alone as a first-line therapy in acute and chronic GvHD. The majority of centers report re-introducing or continuing the immunosuppressive agent used in GvHD prevention, with few centers indicating that they switched to another CNI. 64% and 55% of centers indicated that they have a standard-operating procedure (SOP) for steroid-refractory acute GvHD (aGvHD) and chronic GvHD (cGvHD), respectively. Only two centers reported involving steroid-refractory GvHD patients in clinical trials. Second-line therapy for steroid-refractory aGvHD and cGvHD varies significantly between centers depending on the type of GvHD and organ involved. In steroid-refractory aGvHD, ruxolitinib was the most frequently listed agent to be considered in the second line, regardless of the involved organ. Ruxolitinib was followed by Extracorporeal photopheresis in Skin aGvHD, Budesonide in lower GI tract aGVHD, and Mycophenolate Mofetil in liver aGvHD. In cGvHD, ruxolitinib was also the most frequently listed medication. However, more significant variability between centers was noted in treating organ-specific cGvHD. Conclusion: GvHD prevention and management practices vary between the different EM region centers. Some variations could be related to access to some medications. This might indicate the need for more evidence-based practices in preventing and managing GvHD and possibly adjusting the guidelines according to access and availability of some medications. WBMT is currently working on understanding the global patterns of GvHD practices in other regions and, ultimately, a global comparative study of all data combined.

Safety and Efficacy of Orca-Q with Haploidentical Donors for the Treatment of Advanced Hematologic Malignancies without the Use of Post-Transplant Cyclophosphamide

Srour, Salhotra, Lowsky and Abedi contributed equally as authors BACKGROUND Allogeneic stem cell transplantation (SCT) can be curative for several high-risk hematologic malignancies, but access was previously limited to patients with a fully matched donor. The introduction of post-transplant cyclophosphamide (PTCy) GvHD prophylaxis has increased the use of haploidentical donors (haplo) for patients who lack an HLA-matched donor. However, clinical outcomes associated with PTCy-based regimens remain challenging due to increased relapse rates (particularly in the setting of reduced intensity conditioning) and the adverse event profile including higher incidence of mucositis, cytokine release syndrome (CRS), delayed engraftment & T cell reconstitution, infections, early cardiotoxicity events and death from organ failure (Dulery 2021, Abboud 2021, Nagler 2022, Hoover 2022, Bolaños-Meade 2023). Additionally, the incidence of chronic GvHD after haplo SCT with PTCy is 24 - 33% at 1 year in various historical cohorts. Orca-Q -an investigational precision engineered cell therapy biologic- represents an alternative strategy which may be administered with single agent prophylaxis and does not require PTCy. The cellular composition of Orca-Q includes enriched CD34+ stem cells, combined with specific T-cell subsets, and is intended to reconstitute the blood and immune systems. METHODS Adult patients with high-risk hematologic malignancies eligible for MAC SCT were enrolled on the haplo donor dose expansion arm of a multicenter phase1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA-A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received MAC conditioning and single agent GVHD prophylaxis with tacrolimus (starting on day -1 and taper day +60). Orca-Q was manufactured centrally at Orca Bio Manufacturing Site in Sacramento, CA from G-CSF mobilized peripheral blood apheresis. RESULTS Orca-Q was successfully manufactured and delivered to all subjects with a vein-to-vein time (time between end of donor apheresis to start of recipient's Orca-T infusion) of < 72 hours. A total of 33 patients (21 AML, 10 ALL, 2 CML) were included. Median age was 43 (range, 21 - 63) years, 73% were male. Median follow-up was 375 (range, 73 - 1384) days. Sixteen patients received TBI-based MAC; 17 received busulfan-based MAC (Table). All patients engrafted with median time of 12.0 (range, 8 - 25) and 15.5 (range, 8 - 79) days for neutrophil and platelet engraftment, respectively. Two patients had secondary graft failure. Two patients had Grade 1 CRS; 1 patient had Grade 2 CRS. Grade 2+ aGvHD through Day 180+ occurred in 15% of patients. Grade 3-4 acute GvHD (aGvHD) was rare with only 1 event of grade 3 aGvHD and no grade 4 aGvHD. No patients had moderate-to-severe cGvHD. Estimated incidence of CTCAE grade 2 and > grade 3 infections were 9% and 15% at 1 year, respectively. 5 patients died (2 from relapsed disease) during the study period. NRM was 9% at 1 year. The 1-year relapse-free survival, GvHD-and-relapse free survival (Figure), and overall survival at 1 year was 82%. CONCLUSIONS Our findings reveal promising safety and efficacy outcomes using Orca-Q cell therapy for haplo-SCT despite the use of MAC with only single-agent tacrolimus, and without PTCy. With median follow-up of approximately 1 year, no patients experienced moderate or severe cGvHD, the low AE profile in the haplo setting remains favorable, and 1 year GvHD-free, relapse-free survival of 83% is very encouraging. This phase 1 study continues to enroll patients across the US. REFERENCES Abboud R, Wan F, Mariotti J, et al. Bone Marrow Transplant. 2021;56(11):2763-2770. Bolaños-Meade GM, Hamadani M, Wu J. N Engl J Med. 2023; 388(25):2338-2348. Duléry R, Mohty R, Labopin M, et al. JACC CardioOncol. 2021; 3(2):250-259. Hoover A, O'Leary D, Cao Q, et al. Blood. 2022; 140 (Supplement 1):282-283 Nagler A, Tsirigotis P. Bone Marrow Transplant. 2022; 57(11):1640-1641.

MMF Is Associated with Worse OS in CMV Seropositive AML Patients Undergoing MUD HCT with Calcineurin-Inhibitor-Based Gvhd Prophylaxis

Background: Calcineurin-inhibitor (CNI) with mycophenolate mofetil (MMF) or methotrexate (MTX) is commonly used as graft-versus-host disease (GVHD) prophylaxis for HLA-matched hematopoietic cell transplantation (HCT) but MMF, which targets both T- and B-lymphocytes, is associated with higher risk for cytomegalovirus (CMV) reactivation [ Blood Adv.2023;7(8):1394-1403]. We investigated whether overall survival (OS) differed with MMF- vs MTX-based GVHD prophylaxis according to recipient CMV serostatus and underling HCT disease indication. Methods: We evaluated 3105 patients with acute myeloid leukemia (AML, n=1572), acute lymphoblastic leukemia (ALL, n=453) or myelodysplastic neoplasms (MDS, n=1080) who underwent HLA-matched unrelated donor (MUD) peripheral blood (PB) HCT from 2008-17 using a publicly available Center for International Blood and Marrow Transplant Research (CIBMTR) dataset. Four groups were compared: MTX/ CMV+ (n=1527), MTX/ CMV- (n=916), MMF/ CMV+ (n=395), and MMF/ CMV- (n=267). All patients also received tacrolimus; none received post-transplant cyclophosphamide (PTCy). Primary outcome was OS. Results: The median (interquartile range) age was 57 (45-64), 56 (45-64), 62 (54-68), and 61 (50-67) years in the respective 4 groups. Within each group, most patients had AML or MDS. Disease status was mostly early or intermediate (51-63%). About half had HCT-CI > 2. In vivo T cell depletion was used in 41%, 65%, 48% and 52%, respectively. More patients in the MTX groups received myeloablative conditioning (58% and 55%, respectively), while reduced intensity/non-myeloablative conditioning was more common in the MMF groups (73% and 65%, respectively). In multivariate models stratified by disease, we noted significantly worse OS in CMV+ patients who received MMF, but this effect was restricted to AML. Among AML patients, OS was only 31% (95% confidence interval [CI] 25-37) among the MMF/CMV+ group, but was higher and not significantly different for the MMF/CMV- (54%, 95% CI 45-63) and MTX/CMV+ (51%, 95% CI 48-55) groups compared to the MTX/CMV- group (58%, 95% CI 53-63) [ Figure 1, Table 1] In ALL, GVHD prophylaxis type/CMV serostatus had no significant association with OS. In MDS, CMV+ patients had worse OS (HR 1.2, 95% CI 1.01-1.4, p=0.03) than CMV- patients irrespective of GVHD prophylaxis (MMF/CMV+ vs MTX/CMV+: HR=1.1, 95% CI 0.8-1.4, p=0.5). Donor CMV serostatus had no impact on these associations. Data on CMV reactivation and causes of death were not available; however, our data suggest that the inferior OS in AML was driven mostly by higher non-relapse mortality and some increase in relapse (data not shown). To evaluate how the use of PTCy prophylaxis might impact the interaction between MMF and recipient CMV+ serostatus, we next analyzed a separate CIBMTR MUD PB-HCT cohort that received PTCy/CNI/MMF prophylaxis (N=242; AML, n=136, ALL, n=42; MDS, n=64) and assessed the effect of CMV serostatus on OS. A majority (95%) received HCT from 2015-18. Our results showed that CMV+ recipients had a significantly worse OS than CMV- recipients, but only in AML (HR 2.7, 95% CI 1.1-6.4, p=0.03) and not in ALL (HR 0.4, 95% CI 0.1-1.5, p=0.2), or MDS (HR 0.7, 95% CI 0.3-1.5, p=0.3). As all patients in this cohort received PTCy/CNI/MMF, we were unable to assess the independent impact of MMF and CMV serostatus in this setting. Nevertheless, these data suggest similar trends as seen in the CNI cohort (without PTCy), where the inferior OS in the MMF/CMV+ group was noted only in AML patients. Conclusion: Our data suggest that the use of MMF with CNI-based prophylaxis (without PTCy) should be avoided in AML CMV+ patients. Why this adverse effect of CMV seropositivity and MMF prophylaxis is restricted to AML patients, and not seen in ALL, and whether the same applies to PTCy-prophylaxis with/without MMF, needs further investigation but could be due to CMV-induced expansion of NK cells [ Béziat. Blood. 2013; Foley. Blood. 2012] which mediates alloreactivity against AML but not ALL [ Ruggeri Blood 1999] and is suppressed by MMF more than MTX [ Ohata. BBMT. 2011].

Favorable Outcomes for High-Risk MDS and Oligoblastic AML with MDS-Related Changes with Reduced Intensity Allogeneic Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide

Introduction: Newer classification systems label myelodysplastic syndrome (MDS) with 10-20% blasts and acute myeloid leukemia (AML) with MDS-related changes (AML-MR) on a continuum as they share common biologic features. The prognostic implication of blast percentage is less clinically relevant particularly in diseases with high-risk molecular features such as MDS/AML with TP53 mutations. The recently introduced Molecular International Prognostic Scoring System (IPSS-M) allows for a more personalized prognosis for MDS patients (pts) than the prior revised IPSS (IPSS-R), but it is less clear if this translates to better therapeutic choices or outcomes for pts. Allogeneic bone marrow transplantation (BMT) remains the only potentially curative approach. Increasingly clinical trials of novel compounds combined with hypomethylating agents (HMAs) have not shown improved efficacy over single agent HMAs, necessitating further study of BMT approaches for durable disease control across the spectrum of disease biology. No uniform approach to the conditioning regimen and GVHD prophylaxis for this pt population has proven superior. In the current study, we describe the outcomes of BMT with post-transplant cyclophosphamide (PTCy) for patients with high-risk MDS and oligoblastic AML-MR, and analyze the prognostic implication of their chromosomal and molecular profiles within the international scoring systems. Patients and methods: This is a retrospective analysis of patients with 5-30% blasts and IPSS-R ≥3 who underwent BMT with PTCy at Johns Hopkins Hospital between 1/2013 and 12/2020. Next generation sequencing (NGS) was performed within 12 months of diagnosis. Kaplan-Meier analysis was performed to evaluate overall survival (OS) and relapse-free survival (RFS). Competing risks analysis was performed to evaluate the incidence of relapse and non-relapse mortality (NRM). Cox-regression models were performed in univariate analyses with false discovery rate adjustment and then subsequently conducted for multivariable analyses to identify statistically significant and independent prognostic factors. Results: Ninety-four consecutive patients (65% male) were identified with a median age of 61 (range 22 - 75) years at diagnosis. Median follow-up was 4.8 years (range 5 days-9.6 years) post BMT. Two-thirds (63%) underwent haploidentical transplantation, and 91% received reduced intensity conditioning with Fludarabine, Cyclophosphamide, and TBI. Median age at BMT was 65 years (range 22 - 76). The median time from diagnosis to BMT was 7.9 months. 52 (57%) received HMA based treatment and 36 (39%) intensive chemotherapy prior to BMT. Graft failure occurred in 6 patients (6.4%) The 5-year OS rate was 53% (95% CI: 43%-65%), the 5-year RFS rate was 47% (95% CI: 38%-59%) ( Figure 1A). The incidence of relapse was 21% (95% CI: 13% - 30%) at 1 year and 31% (95% CI: 21% - 40%) at 2 years after BMT ( Figure 1B). NRM rate in the first-year was 7% (95% CI: 2%-13%) and 11% (95% CI: 4%-17%) in the first two years ( Figure 1B). The incidence of acute GVHD (aGVHD) grades 3 to 4 was 3.2%, whereas chronic GVHD (cGVHD) presented in 12 patients (12.7%) with only 2 patients (2.1%) having moderate to severe disease based on the NIH grading criteria. Univariate analysis showed that higher IPSS-R (HR 1.68, 95% CI 1.39 - 2.04), poor or very poor karyotype risk (HR 7.48, 95% CI 3.49 - 16.02), complex karyotype (HR 3.72, 95% CI 2.01 - 6.88), higher IPSS-M (HR 1.72, 95% CI 1.38 - 2.14), TP53 mutations (HR 6.53, 95% CI 3.36 - 12.7) and RAS mutations (HR 4.96, 95% CI 1.7 - 14.5) were associated with worse OS. IPSS-R was significantly correlated with the patients' response to bridge therapy (OR 1.34, P=0.036). IPSS-R, IPSS-M, poor or very poor karyotype risk, complex karyotype, TP53 and any RAS mutations and response to bridge therapy were independently associated with worse OS and RFS ( Table 1, Figure 1C). Conclusion: This retrospective analysis supports that BMT with PTCy is a durable approach for patients with high-risk MDS and oligoblastic AML-MR leading to high OS and RFS associated with a promising safety profile with low NRM and severe GVHD incidence. IPSS-R, IPSS-M, karyotype and response to bridge therapy are independent predictors of OS and RFS post-BMT. The presence of TP53 and/or RAS mutations defines a sub-group of patients with dismal outcomes representing an unmet need within this patient population.

Inb-100: A Pilot Study of Donor Derived, Ex-Vivo Expanded/Activated Gamma-Delta T Cell (EAGD) Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-Transplant Cyclophosphamide (PTCy)

Background: Gamma-delta (gd) T cells are MHC unrestricted lymphocytes that recognize and lyse malignant cells in allogeneic settings. Although haploidentical transplant with PTCy has reduced the risk of graft-versus-host disease (GvHD); the incidence of relapse remains up to 50% at year 1. Early post-transplant infusion of haploidentical EAGD cells may decrease relapse risk through a graft-versus-leukemia (GvL) effect without severe GvHD. We present updated clinical and correlative data from our Phase I trial using our recommended phase 2 dose (RP2D). Methods: Adults with newly diagnosed or relapsed ALL, CML, AML undergoing first haploidentical transplant with reduced-intensity flu/cy/TBI conditioning received EAGD intravenously within 7 days of neutrophil engraftment. Peripheral blood was collected at EAGD infusion and monthly through day 90, with additional collections every 6 months through 1 year. Primary endpoints include dose-limiting toxicities (DLT), grade (G) 3-4 adverse events including GvHD with secondary endpoints of relapse and overall survival. Biologic parameters included multiparameter flow cytometric immunophenotyping and additional serum cytokine analysis using the Olink ® 48 target panel. Results: 14 subjects were enrolled with 4 treated at Dose Level (DL) 1 of 1 x 10 6 EAGD/kg and 6 subjects treated at the RP2D of DL2 (3 x 10 6 EAGD/kg). Untreated subjects included: One screen failure, a manufacturing failure, one subject who died prior to dosing, and one subject who received an out of study specification product. Treated subjects were 60% male, median age of 68, and primarily AML subjects in CR1. RP2D was defined by an acceptable toxicity profile, no DLT's, prolonged RFS and elevated gd levels. Peripheral lymphodepletion persisted through the first 100 days post-BMT followed by T cell recovery from a CD45+CD27-effector phenotype to central and effector memory phenotype. Notably, DL2 showed significant increases in gd T cell count recovery at days 60, 100 and 180 post-BMT vs. DL1 and historically untreated Haplo/PTCy patients, p = <0.05. NK cells remained within the low normal range and <3% of circulating T cells were Tregs. Preliminary serum cytokine analysis revealed elevated IL-6 and IL-15 in serum post- transplant prior to EAGD infusion, but dropped to normal median levels at day 60, 20-30 days after EAGD infusion. One subject received intermittent hypomethylating therapy for emergence of recipient chimerism. Treatment emergent AE's included transient WBC and ANC decreases (100% each), platelet count decrease and anemia (88.9% each) and maculopapular rash, hypomagnesemia and blood creatine increased (55.6% each). EAGD related toxicities were primarily G1-2, included G1-2 skin acute GvHD and gastrointestinal GvHD, and one case of G3 platelet count decrease. Treatment related serious AE's of G3 nausea and G2 rash were reported. No DLTs, neurotoxicity, cytokine release syndrome or treatment related deaths were reported. Conclusions: Post-BMT infusion of donor-derived, EAGD cells has demonstrated manageable safety with no infusional toxicity or ≥G3 acute GvHD or extensive chronic GvHD. Durable relapse free survival at a maximum of >3 years in subjects with poor risk cytogenetics and adverse clinical risk factors combined with ongoing homeostatic reconstitution of increasing gd T cell effectors post-BMT suggests this therapy may be an effective measure in mitigating relapse after HaploBMT. NCT03533816

Abatacept-Prophylaxis Based Haploidentical Transplantation May Allow Sustained Engraftment and Offset Gvhd in Non-Malignant Disorders

Introduction: Non-malignant disorders (NMD) derive no benefit from graft-versus-host disease (GVHD) after allogeneic hematopoietic transplantation (HCT). Transplantation designed to optimize engraftment and immune reconstitution while minimizing GVHD and organ toxicities is desirable. Post-transplant cyclophosphamide (PTCy) decreases severe chronic GVHD risk in radiation-containing regimens for NMD when combined with serotherapy (anti-thymocyte globulin) (PMID: 22955919; PMID: 30500440). Abatacept effectively offsets GVHD following unrelated donor (URD) HCT (PMID: 33449816; PMID: 32813873). Based on these reports, NCT03128996 was developed for haploidentical transplantation in NMD after radiation-free reduced intensity conditioning (RIC) combining PTCy + Abatacept for GVHD prophylaxis. Serotherapy does not contribute to GVHD prophylaxis in this RIC approach. Outcomes focused on safety and GVHD- free donor engraftment in children with NMD and no better donor options. Method: Conditioning included alemtuzumab (day -22 to -19), fludarabine (day -8 to -4), melphalan (day -3) and thiotepa (day -4) as previously published (hydroxyurea prior to RIC was used in proliferative marrow disorders) (PMID: 32813873). Stem cell source was bone marrow (BM) or CD34-selected peripheral blood cells with a fixed CD3 cell dose of 1x10^6/kg recipient weight. GVHD prophylaxis included tacrolimus (day -1, with wean beginning 6-9 months post-HCT), PTCy on days +3 and +4, mycophenolate mofetil until day +28, and monthly abatacept doses until 13 months post-HCT. Survival, safety, donor chimerism, GVHD incidence, and incidence of post HCT infection were primary outcome measures. Results: Eleven patients 6 to 24 years old (median 9 years) underwent HCT for adrenoleukodystrophy ( 2), sickle cell disease (SCD) ( 6), aplastic anemia ( 1), second transplant for severe combined immunodeficiency ( 1) and STAT 5B gain-of-function mutation ( 1). Eight were trial participants and 3 treated according to trial guidelines. All patients tolerated abatacept infusions and engrafted with neutrophil recovery (>500/cu mm) at a median of 17 days (range 15-24 days). As of 7/31/2023, median follow up is 411 days (range 83-1979 days). The mean myeloid and T-cell chimerisms at D100 (n=10) and 1 year (n=6) were 97.8%+/- 5.3 and 96.3% +/- 6.4 and 98.6% +/- 3.3 and 95% +/-8.7, respectively. One patient with SCD has low myeloid engraftment (24%) at 7 months post-HCT (lymphoid 91%); a stem cell boost is planned after immune suppression with fludarabine/Cytoxan/ATG (PMID: 35798858). Viral reactivation was noted in 4 patients, none developed CMV disease or EBV post-transplant lymphoproliferation. One patient developed grade 1 acute GVHD. Of 6 evaluable patients, one developed localized chronic skin GVHD. This patient remains on systemic immune suppression beyond 13 months (ruxolitinib). The overall and GVHD-free survival at 1-year post HCT in evaluable patients (N=6) is 100 % and 83%, respectively. Conclusion: Promising preliminary results in this cohort support continuation of the trial with longer term follow-up. The effective suppression of GVHD without serious infectious complications in the first year post-HCT is encouraging. Virus reactivation was however noted early post-HCT and requires monitoring and prophylaxis. Incorporating abatacept into GVHD prophylaxis was successful in achieving desired outcomes; the phase 1 portion of the study is completed and the phase 2 trial and follow-up are ongoing.

Post-Transplant Cyclophosphamide Eliminates Disparity in GvHD-Free, Relapse-Free Survival and Overall Survival between 8/8 Matched and 7/8 Mismatched Unrelated Donor Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies

Background: Post-transplant cyclophosphamide (PTCy) has become a standard of care for graft-versus-host disease (GvHD) prophylaxis in recipients of human leukocyte antigen (HLA)-matched and mismatched unrelated donor (MMUD) allografts, generating new opportunities for successful hematopoietic cell transplantation (HCT) regardless of patient ancestry. The National Marrow Donor Program (NMDP)-sponsored 15-MMUD study, which used PTCy-based GvHD prophylaxis (PMID 3390526), demonstrated encouraging overall survival (OS) in adult patients receiving MMUD bone marrow grafts matched at ≤7/8 HLA alleles. Currently, the follow-up ACCESS study (NCT04904588) will determine if similar outcomes can be achieved using MMUD peripheral blood stem cell allografts. As part of its 5-year strategic plan, the NMDP aims to determine the extent of differences in GvHD-free, relapse-free survival (GRFS) between 8/8 and 7/8 URD allografts using PTCy and seeks to develop approaches over time to close the presumed gap in URD outcomes. Methods: The primary objective was to compare GRFS between 8/8 and 7/8 URD HCT using the Center for International Blood & Marrow Transplant Research (CIBMTR) database. After analyzing primary results, secondary objectives were added to compare GRFS, OS, and other clinical outcomes among 8/8 URD, 7/8 URD, and haploidentical-related donor (Haplo) HCT. The study included adult patients (age≥18y) with hematologic malignancies (ALL, AML, MDS) undergoing first URD or Haplo HCT between 2017-2020 using PTCy-based GvHD prophylaxis. Kaplan-Meier curves were used to estimate probability of GRFS and OS. Cox regression examined the independent effect of HLA match controlling for other clinical factors on outcomes referenced to 8/8 URD HCT. A priori clinically selected factors considered as possible confounders in the regression model included disease risk index, comorbidity risk, pre-HCT Karnofsky score, conditioning regimen intensity, graft source, donor/recipient CMV serostatus, year of HCT, donor/recipient age and race/ethnicity. Final models were stratified by factors violating the proportional hazards assumption. Factors were eliminated in a backwards fashion if p-values were >0.10 unless inclusion affected the hazard ratio (HR) of HLA match by more than 10%. Interactions were tested against a p-value of <0.01. Results: Table 1 shows demographics for the three patient cohorts: Haplo (n=2772), 8/8 URD (N=1517), and 7/8 MMUD (N=540). Notable differences among the cohorts included: 8/8 URD recipients had younger, predominantly Caucasian donors and were more likely to receive myeloablative conditioning. Haplo recipients had more donor/recipient CMV seropositivity and received more reduced intensity conditioning. Otherwise patient characteristics were similar. Contrary to our expectations, multivariable regression analysis (MVA) showed no significant differences in either GRFS or OS between recipients of 8/8 and 7/8 URD HCT at 1, 2 and 3-years post-HCT ( Figure 1). Outcomes, including relapse and NRM, between 8/8 and 7/8 URD HCT were similar irrespective of conditioning intensity. However, 8/8 URD HCT associated with lower two-year moderate/severe chronic GvHD than 7/8 URD [1.30 (1.00-1.68), p=0.049]. We next compared GRFS and OS among 8/8 and 7/8 URD and Haplo at 3y after HCT. On MVA, GRFS [HR 1.15 (1.04-1.26), p=0.005] and OS [HR 1.15 (1.03-1.29), p=0.013] were significantly better in 8/8 URD compared to Haplo HCT. Differences between 8/8 URD and Haplo appeared to be driven by significantly higher NRM [HR 1.46 (1.22-1.74), p<0.001)] and two-year moderate/severe chronic GvHD [HR 1.28 (1.07-1.54), p=0.007] in Haplo. No significant differences were seen in GRFS or OS at 3 years when comparing 7/8 URD to Haplo. Causes of death among donor types were similar with primary disease relapse/progression, infection and organ failure being the most frequent. Conclusions: Use of PTCy-based GvHD prophylaxis seems to have resolved previously observed differences in GRFS and OS between 8/8 and 7/8 URD HCT. HCT using an 8/8 URD HCT, if available, continues to be the best option for patients lacking a matched sibling donor. Further studies comparing Haplo to 7/8 URD HCT are warranted, but will require larger numbers of 7/8 URD HCT. Both mismatched donor sources substantially increase access to HCT for patients regardless of their ancestry.

Patterns of CMV infection after letermovir withdrawal in recipients of posttransplant cyclophosphamide–based transplant

AbstractReactivation of latent cytomegalovirus (CMV) is increased in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with seropositive CMV using posttransplant cyclophosphamide (PT-Cy)–based graft-versus-host disease (GVHD) prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy–based allo-HCT, including 157 patients with CMV, of whom 80 completed letermovir prophylaxis without csCMVi and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range [IQR], 160-250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (95% confidence interval, 14.3-32.8). There were no episodes of CMV end-organ disease. Hypogammaglobulinemia before letermovir discontinuation was predictive of csCMVi (hazard ratio, 0.33; 95% confidence interval, 0.12-0.93; P = .03), whereas T-cell and B-cell reconstitution before letermovir withdrawal were not predictive of csCMVi. Higher numbers of natural killer cells were found before letermovir withdrawal in patients who experienced csCMVi (median, 202 vs 160; P = .03). In recipients with seropositive CMV, CD3+CD4–CD8+ T-cell reconstitution was faster in patients with CMV regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV-specific adaptive immunity in patients with persistent hypogammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.

Results of the Astral Study: A Prospective Phase II Clinical Study of the German Lymphoma Alliance to Assess the Efficacy and Toxicity of High-Dose Chemotherapy Followed By Allogeneic Stem Cell Transplantation As Treatment of Primary Progressive and Relapsed Aggressive Non-Hodgkin Lymphoma

Introduction Patients with relapsed and refractory (r/r) aggressive B- or T-cell lymphoma have a dismal prognosis. Registry analyses as well as one preceding prospective clinical study demonstrated durable disease control through graft-versus-lymphoma activity conferred by allogeneic stem cell transplantation (alloSCT) in this population and suggests this modality being a preferred treatment option after failing of less toxic approaches. Recently, allogeneic SCT has been shown to result in long term PFS in r/r large B-cell lymphoma (LBCL) with preceding CAR-T treatment. Despite the current achievements in treatment of r/r LBCL by introducing anti CD19 CAR-T as a treatment modality appproximately 60% need further approaches to achieve long term progression free survival (PFS). Here we represent the results of a prospective clinical trial of allogeneic SCT in r/r aggressive B- and T-cell lymphoma using a thiotepa based conditioning regimen. Methods ASTRAL is a national, multicenter, prospective phase II study of the German Lymphoma Alliance (GLA). Eligible were patients aged 18 or older with relapsed or primary progressive aggressive B- or T-cell lymphoma who had a fully matched (10/10) related or unrelated donor available. Patients underwent myeloablative conditioning regimen with Fludarabine 125 mg/m², Thiotepa 15 mg/kg and Cyclophosphamide 120 mg/kg (FTC). GVHD prophylaxis and posttransplant immunosuppression was done by local standards. The primary objective was to determine the efficacy and toxicity of the defined conditioning therapy followed by allogeneic stem cell transplantation. The primary endpoint was progression free survival at 1 year. Key secondary efficacy endpoints included rate of complete remissions (CR), rate of partial remissions (PR), overall response rate (OR), rate of progressive disease (PD), relapse rate, event free survival (EFS) and overall survival (OS) at 1 year and non-relapse mortality (NRM). Results From June 2019 until December 2021 in total 60 patients were enrolled. The demographic data are presented in table 1. The majority of patients (70%) had B-cell lymphomas. Patients had received a median of 3 prior lines (range 1-6), including autoSCT in 42% of all patients and CAR-T in 29% of the B-cell patients. The rate of primary progressive disease before salvage therapy was 27% (29% B-cell and 22% T-cell). 83% (50/60) still had measurable disease (no CR) prior to FTC, thereof 81% with B-cell (34/42) and 89% with T-cell lymphoma (16/18) and 13 (22%) had high intermediate and high IPI. After alloSCT, CR was achieved in 45% of patients with B-cell and in 67% with T-cell lymphoma, respectively. The overall response rate was 53%, 48% for B-cell lymphoma and 67% T-cell lymphoma. After a median observation time of 30 months, 1-year PFS was 40% [95%-CI: 28%-52%] (38% [23%-53%] (B-cell) vs. 44% [21%-67%] (T-cell) (figure 1). EFS was identical to PFS. After one year 15 patients (25%) had progressive disease or relapse, thereof 13 patients (29%) with B-cell lymphoma and two with T-cell lymphoma (11%). Thirty-seven patients died. Main cause of death was treatment related 19/37 (51%), including 8/19 deaths due to toxicity of the conditioning therapy (6 infections, 1 respiratory failure and 1 neurotoxicity). 12/37 (32%) patients died lymphoma related, 4/37 (11%) patients died of a SARS-Cov-2 infection, and two causes of death were unknown. 1-year OS was 43% [31%-56%] (40% [26%-55%] (B-cell) vs. 50% [27%-73%] (T-cell)). 1-year NRM was 35% [23%-47%] (31% [17%-45%] (B-cell) vs. 44% [20%-68%] (T-cell)). Most of the patients with grade 3-5 adverse events had infections 40/60 (67%), renal disorders 17/60 (28%) and oral mucositis 14/60 (23%). Conclusions This is the second prospective trial on alloSCT for r/r aggressive lymphoma ever performed, demonstrating that alloSCT can provide sustained disease control in heavily pretreated patients. Also in the modern era, including patients who failed CARTs the strong anti-lymphoma activity of allogeneic SCT is shown in the low relapse/progression rate and the long term PFS. FTC conditioning avoids the toxicities of busulfan-based regimens but fosters neuro- and other toxicities, especially when given at 15mg/kg. Still, NRM remains a challenge and warrants exploration of novel transplant strategies, such as modulation of conditioning intensity and GVHD prophylaxis, e. g. post-transplant cyclophosphamide.

Post-Transplant Cyclophosphamide, Tacrolimus or Cyclosporine a and Mycophenolate Mofetil Compared to Anti-Thymocyte Globulin tacrolimus or Cyclosporine a and Methotrexate Combinations As Graft- versus -Host Disease Prophylaxis Post Allogeneic Stem Cell Transplantation from Sibling and Unrelated Donors in Patients with Acute Myeloid Leukemia: a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow

Background: Recently, the BMT CTN 1703 phase III study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as graft- versus-host disease (GVHD) prophylaxis post allogeneic transplantation (HSCT), demonstrating a lower incidence of severe acute (a) GVHD and chronic (c) GVHD and better GVHD-free, relapse-free survival (GRFS). The control arm did not include anti-thymocyte globulin (ATG), used in many centers for GVHD prophylaxis. Methods: The study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) to ATG combined with TAC or CSA and MTX (ATG/TAC or CSA & MTX) in acute myeloid leukemia (AML) patients (pts) undergoing HSCT from matched siblings (MSD) or 9-10/10 unrelated donor (UD) in first complete remission (CR1). Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. . Results: 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC or CSA & MTX as GVHD prophylaxis. Median follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p<0.0001). The median year of the transplant was 2018 (2010-2020) and 2016 (2007-2020) (p<0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) versus 51.5 (8-77.8) years (p=0.024). The diagnosis was de novo AML in 84.1% vs 85.3% and secondary (s) AML in 15.9% vs. 14.7% (p=0.49). The cytogenetic risk was categorized as intermediate (70.9% vs. 67.1%), adverse (22.2% vs. 25.7 %), and favorable (6.9% vs. 7.2%) for pts in the PTCy/TAC or CSA & MMF and ATG/TAC or CSA & MTX groups, respectively (p=0.35) (data missing for 2214 pts). Karnofsky performance status (KPS) did not differ between the groups. There was a higher frequency of pt cytomegalovirus (CMV) seropositivity and female (F) donor to male (M) pt combination in the PTCy/TAC or CSA & MMF group, 77.8% vs. 71.8% (p=0.009) and 18.4% vs. 14.4% (p=0.029). More pts in the PTCy/TAC or CSA & MMF group received reduced intensity conditioning (RIC) 51.5% versus 41.1% in the ATG/TAC or CSA & MTX group, respectively (p<0001). Day 60 neutrophil engraftment (ANC >0.5 x 10 9/L) was 98.7% vs. 98.6% (p=0.84). Day 180 incidence of a GVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p=0.92) and 8.1% vs. 6% (p=0.1), in pts receiving PTCy/TAC or CSA & MMF versus the ATG/TAC or CSA & MTX GVHD prophylaxis, respectively. The 2-year (y) total and extensive chronic (c) GVHD were 33.7% vs. 30% (p=0.09) and 10.7 % vs. 11.2% (p=0.81), respectively. GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD (grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios (HRs) =1.15 (95% CI 0.86-1.53, p=0.35), HR=0.87 (95% CI 0.56-1.34, p=0.52), HR=0.91 (95% CI 0.7-1.18, p=0. 47 and HR=1.51 (95% CI 0.96-2.36, p=0.074). Two-y NRM was significantly lower in pts that received PTCy/TAC or CSA & MMF versus ATG/TAC or CSA & MTX for GVHD prophylaxis, HR=1.57 (95% CI 1.07-2.3, p=0.022). Other HSCT outcome parameters did not differ between the groups. The HR for 2-y RI was 0.99 (95% CI 0.77-127, p=0. 93). The HRs for 2-y leukemia-free survival (LFS), overall survival (OS), and GRFS were HR=1.15 (95% CI 0.94-1.42, p<0.18), HR=1.18 (95% CI 0.94-1.49, p=0.16) and HR=1.12 (95% CI 0.93-1.36, p=0.22), respectively. Donor type and conditioning regimen were poor prognostic factors for grade II-IV, III-IV aGVHD, and total and extensive cGVHD. For cGVHD, additional poor prognostic factors were F donor to M pt combination and pt CMV seropositivity. Poor prognostic factors for LFS, OS, and GRFS were 9/10 UD, age (by 10 y), sAML, adverse-risk cytogenetics, lower KPS, and pt CMV seropositivity. For NRM, factors were the same apart from cytogenetics risk which was not a prognostic factor. In addition, time from diagnosis to HSCT was a prognostic factor for NRM and RI. Other poor prognostic factors for RI were lower KPS and pt CMV seropositivity. Conclusions: In this registry-based retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC or CSA and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. NRM was significantly lower with the PTCy-based GVHD prophylaxis, while all other transplant outcome parameters were similar.

Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome with T-Cell Replete Peripheral Blood Haploidentical Transplantation

Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and one-year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report outcomes from our study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, MDS, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100 (first 20 patients) or 180 (second 22 patients), followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS, relapse, GRFS, and overall survival. Results: Forty-two patients were enrolled and underwent transplantation on study between November 2019 and December 2022, median days of follow up was 453 days (range 142-1259). The patient population had a median age of 60 years (20 - 73 years) with the majority of patients having AML (AML 60%, ALL 21%), MDS 10%, MF 5%, NHL 4%). All patients with AML, MDS, or ALL were in a complete morphologic remission, although 45% had disease by either cytogenetics, next generation sequencing, or measurable residual disease assay (flow cytometry for AML/MDS, NGS for ALL). There were no cases of grade III-IV acute GVHD. The cumulative incidence of grade II acute GVHD on day 100 was 17.3% (95% CI, 7% - 31%), day 180 was 20.5% and day 365 was 20.5%. There were no cases of severe CRS with 90% of patients having grade 1 CRS and 10% having no CRS. No anti-IL6R or steroid therapy was used. There were no cases of primary graft failure. The cumulative incidence of relapse at 1 year was 10% (95% CI, 3% to 22%) and at 2 years was 14% (95% CI, 5% to 29%). In patients who survived without relapse to day 100, the 1-year cumulative incidence of moderate or severe chronic GVHD was 5% (95% CI 1% - 17%). The refined GRFS at day +180 was 85% (95% CI 69% - 93%) and at day +365 was 79% (95% CI 62% - 89%). Overall survival at 180 days 87% (95% CI 72% - 94%) and at 1 year was 80% (95% CI 63% - 90%). Analysis of peripheral blood mononuclear cells at day +28, +60, and +100, revealed that patients on itacitinib, compared with control haplo-HCT patients, had lower numbers of CD4 and CD8 central memory T cells, lower numbers of CD4 and CD8 naïve T cells, and higher numbers of classical monocytes, nonclassical monocytes, and both myeloid and plasmacytoid dendritic cells. In itacitinib treated patients, T-cell subsets expressed lower LAG3 and PD-1 and higher TIGIT, while monocytes expressed higher HLA-DR, CD80, and CD86. Conclusions: Itacitinib with PB haplo-HCT was safe with low rates of acute and chronic GVHD, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. The addition of Jak inhibition to standard PtCy based GVHD prophylaxis was associated with encouraging rates of GRFS and OS on this pilot and expansion study. Patients on itacitinib have unique immune reconstitution characteristics both in terms of PBMC counts and signaling markers within subsets.

Comparison of Non-Relapse Mortality after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Versus Single Umbilical Cord Blood Transplantation for Hematologic Disease

Introduction: Unrelated cord blood transplantation (UCBT) and haploidentical stem cell transplantation with post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (PTCy-haplo) are alternative options for patients with hematologic disease lacking a human leukocyte antigen (HLA)-matched donor. Non-relapse mortality (NRM) after UCBT may vary depending on the cord blood CD34+ cell count, but no study has accounted for CD34+ cell count when comparing the outcomes after UCBT and PTCy-haplo. Therefore, we analyzed transplant outcomes after UCBT and PTCy-haplo in patients with hematologic disease from data of a nationwide registry that included cord blood CD34+ cell count. Methods: Patients with hematologic disease receiving first UCBT or PTCy-haplo between 2014 and 2020 were identified from the nationwide registration data of the Japanese Data for Hematopoietic Cell Transplantation. Acute GVHD-related mortality was defined as death caused primarily by GVHD or occurred secondary to GVHD, and infection-related mortality as death due to graft failure or infection but not acute GVHD. Patients treated by UCBT were stratified by the median CD34+ cell count for comparison (0.84 × 10 5/kg). Results: A total of 7,499 patients were enrolled and classified into 3 groups: PTCy-haplo (n = 1,142), UCBT with high CD34+ cell count (UCB-H; ≥ 0.84 × 10 5/kg, n = 3,185), and UCBT with low CD34+ cell count (UCB-L; < 0.84 × 10 5/kg, n = 3,172). Patients in the PTCy-haplo group were slightly younger than UCB-H and UCB-L patients (median age: 54 vs. 56 and 55 years). The PTCy-haplo group also included a greater proportion of males than the UCB-H group (62.4% vs. 50.0%) but not the UCB-L group (64.2%). A greater proportion of PTCy-haplo patients had a PS score of 0 (53.2% vs. 46.2% and 45.6%), a hematopoietic cell transplantation-specific comorbidity index of 0 (57.6% vs. 52.7% and 54.4%) and donor-specific anti-HLA antibody (2.7% vs. 1.0% and 1.6%), received reduced-intensity conditioning (58.0% vs. 40.5% and 41.6%), calcineurin inhibitor with mycophenolate mofetil (88.5% vs. 38.6% and 38.4%), and underwent transplantation in the later period (82.0% vs. 54.6% and 50.7%). There were no significant differences in disease-risk index between groups. At 2 years post-transplantation, NRM and overall survival (OS) were significantly better in the PTCy-haplo group than the UCB-H and UCB-L groups (NRM: 18.8% vs. 21.6% and 25.3%, P < 0.001; OS: 56.2% vs. 53.3% vs. 49.6%, P < 0.001). Neutrophil engraftment rate at 42 days was also significantly higher in the PTCy-haplo group than the UCB-H and UCB-L groups (93.7% vs. 87.5% and 82.9%, P < 0.001). The PTCy-haplo group less frequently developed grade II-IV (26.4% vs. 37.3% and 34.4%, P < 0.001) and III-IV acute GVHD (7.0% vs. 12.2% and 10.5%, P < 0.001). While neither the differences in NRM nor that in OS remained significant between PTCy-haplo and UCB-H groups in multivariable analysis (NRM: hazard ratio [HR], 1.18, 95% confidence interval [CI], 0.99-1.41, P = 0.073; OS: HR, 1.05, 95% CI, 0.94-1.17, P = 0.42), significant differences were maintained between PTCy-haplo and UCB-L groups (NRM: HR, 1.35, 95% CI, 1.13-1.61, P = 0.001; OS: HR, 1.12, 95% CI, 1.00-1.26, P = 0.042). Regarding the cause-specific mortality, infection-related mortality was also significantly lower in the PTCy-haplo group compared to UCB-H and UCB-L groups (8.1% vs. 11.1% and 13.6%, P < 0.001) while GVHD-related mortality did not differ among groups (5.0% vs. 5.2% and 4.9%, P = 0.69). Conclusion: UCBT-H resulted in similar NRM and OS as patients receiving PTCy-haplo, whereas outcomes were worse in UCBT-L. These findings indicate that high CD34+ cell count in cord blood is a critical criterion for alternative donor selection.

Post-Transplant Cyclophosphamide, Abatacept, and Vedolizumab to Prevent Graft-Versus-Host Disease after Hematopoietic Stem Cells Transplantation from Haploidentical Donors in Children with Acute Leukemia: Results of a Prospective Trial

Introduction Graft-versus-host disease (GvHD) remains a crucial complication associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). High-dose post-transplantation cyclophosphamide (PTCy) targets alloreactive donor T cells proliferating early after HSCT, promotes regulatory T cells, and prevents severe GVHD. The effectiveness of PTCy-based regimens varies depending on the graft source and intensity of the preparative regimen. Improvement of GVHD control with novel targeted agents, added to the backbone of PTCy, could further increase the safety of HSCT and reduce the morbidity and complications of standard regimens of pharmacological immune suppression. In this pilot trial, we evaluated the safety and efficacy of abatacept and vedolizumab in unmanipulated haploidentical transplantation among children with leukemia. Materials and methods A total of 54 pts with acute leukemia (AML- 18, ALL-36, 26 female, 28 male, the median age at HSCT - 7,4 years (0,4-16,8), underwent unmanipulated allogeneic bone marrow (BM) (n=53) or peripheral blood stem cell (PBSC)(n=1) transplantation between March 2022 and May 2023. All donors were haploidentical relatives, represented Disease status at transplant was CR1 in 25 pts, CR³2 in 29 pts. For all patients, it was the 1-st transplantation. All patients received myeloablative conditioning, either TBI-based (n=30) or 24 treosulfan-based (n=24), with either cyclophosphamide (n=47) or etoposide (n=7) as a second agent. Prophylaxis of graft-versus-host-disease (GVHD) consisted of CsA from day-1 to day 180, 50 mg/kg of Cph on days +3 and +4, abatacept at 10 mg/kg on days +5, +14, +28, +45, +60 and vedolizumab at 10 mg/kg (capped at 300 mg) on days -1, +14, +28. The median dose of CD34+ cells was 4,7 x10 6/kg (range 1,2-17), and the CD3 dose was 42 x10 6/kg. Results Primary engraftment was achieved in 53 (98%) pts; the median time to neutrophil and platelet recovery was 20 and 23 days, respectively. All engrafted pts had verified morphologic remission and achieved complete donor chimerism by day +30. One patient failed to engraft, relapsed, and required rescue with a second HSCT from an alternative donor. The regimen was generally well tolerated. Acute toxicity consisted of grade III-IV mucositis (n=5); grade II-III hemorrhagic cystitis (n=4); grade III-V veno-occlusive disease (n=2) (all cases of VOD developed after pre-HSCT use of inotozumab); bloodstream infections (n=8). Four patients were admitted to the intensive care unit due to septic events or VOD. The median follow-up time for survivors was seven months (range: 1 -15). Transplant-related mortality was 2% (95% CI:0,3-14): one patient with ALL previously treated with inotozumab died in CR due to consequences of severe VOD on day + 60. The cumulative incidence of aGVHD grade II-IV was 36% (95% CI, 25 - 52), and grade 3-4 was 9% (95% CI, 4 - 22). In 13 cases, aGVHD was limited to skin: grade 2 (n=12), grade 4 (n=1), in two cases to the gut: grade 3(n=1), grade 4(n=1), three patients had skin and gut GVHD: grade 2 (n=2), grade 3(n=1) and one had skin and liver GVHD grade 3. The cumulative incidence of gut aGVHD grade II-IV was 9% (95% CI, 4 - 22). Eleven patients with GVHD responded to first-line immunosuppressive treatment, while 8 received additional therapy. The cumulative incidence of relapse was 11% (95%CI:5-26) in the entire cohort. EFS and OS were 89% (95%CI: 79-97) and 98% (95%CI: 94-100). The GVHD- and relapse-free survival was 78% (95%CI:67-88). Conclusion Our data suggest that adding vedolizumab and abatacept to the PTCy-based GVHD prophylaxis backbone is well tolerated and may reduce the incidence of gut GVHD among children with acute leukemia grafted from haploidentical donors. This approach can be further developed to reduce exposure to calcineurin inhibitors and deploy additional anti-leukemia effectors after HSCT.

Allogeneic Hematopoietic Cell Transplantation for Vexas Syndrome: Results of a Multicenter Study from the Chronic Malignancies and Autoimmune Disease Working Parties of the EBMT

VEXAS is a new entity encompassing a variety of clinical manifestations spanning from autoimmune/auto-inflammatory to hematologic conditions including MDS, plasma cell dyscrasias, and recurrent thrombosis. Somatic mutations of the X-linked UBA1 gene in hematopoietic stem and progenitor cells constitute the molecular underpinnings of VEXAS, typically occurring in men during the 6 th decade of life. Over the last 2 years since its first description, VEXAS has elicited wide medical interest resulting in the identification of pleomorphic clinical phenotypes, which make this syndrome a “big masquerader” and a clinical diagnostic challenge. Treatment strategies aim at suppression of the UBA1-mutant clone (e.g., with azacitidine or allo-HCT) or blockade of the downstream pleiotropic effects of hypercytokinemia. However, no treatment guidelines exist to date, and patients may manifest life-threatening inflammatory symptoms frequently refractory to many therapies. As few literature reports have described the successful use of transplant, we here report the outcomes of patients with VEXAS in a multicenter EBMT registry-based study. Leveraging a multidisciplinary liaison of EBMT and key rheumatology centers across Europe, we disseminated a survey to gather further information on patients with VEXAS undergoing allo-HCT to explore overall survival (OS), transplant-specific outcomes, and reversal of the VEXAS clinical phenotype. We evaluated a total of 13 patients, all males and with a median age of 58 years (IQR, 52-63) at the time of transplant. The majority had concomitant MDS (n=10) while 2 presented with only autoinflammatory manifestations, and 1 had MPN. In line with the genomics of the disease, UBA1 mutations consisted of missense substitutions at the Met41 hotspot in 10 cases (n=6 Thr/3 Val/1 Leu), splice site (n=2 c.118-2A>C, c.118-1G>C), and the rare p.Ser56Phe at a median VAF of 73% (IQR, 45-84). All patients presented with anemia and had concomitant rheumatologic manifestations ( Fig1A) requiring specific treatment. VEXAS symptoms preceded the diagnosis of MDS/MPN in all but one case. Cytogenetics was normal in all VEXAS/MDS cases, which also displayed lower-risk IPSS-R scores with a median bone marrow blast of 2% (IQR, 1-4). Allo-HCT was performed at a median of 46 months (IQR, 22-59) from VEXAS onset. Before transplant, patients received a variety of both rheumatological (steroids/anti-interleukins) and hematological (azacitidine/ruxolitinib) treatments, with a high refractoriness (median number of lines 5, range 1-13). In all cases, stability of the clinical phenotype with no flares/uncontrolled manifestations was achieved at the time of the procedure. Conversely, in 3 MDS cases, clonal progression with acquisition of additional chromosomal alterations [+8, +21, t(12;16)] was evident. Overall, 62% of patients had a Karnofsky score >80% and low/intermediate (< 3) HCT-CI scores. Donor choice consisted of matched related in 23%, matched unrelated in 54%, mismatched related in 15%, and mismatched unrelated in 8% of the cohort. Peripheral blood was the preferred stem cell source in all but one case and conditioning regimen consisted of a variety of fludarabine-based strategies (n=4 MAC, n=9 RIC). GvHD prophylaxis was based on post-transplant cyclophosphamide (n=4), or serotherapy (n=8 ATG, n=1 alemtuzumab), in combination with cyclosporine and short-course methotrexate (n=5) or mycophenolate (n=4). All patients engrafted at a median time of 16 and 14 days for neutrophils and platelets, respectively. Overall, 92% of patients achieved full donor chimerism at last-follow-up. Grade II-IV acute GvHD occurred in 23% of cases, whereas only 1 patient presented with chronic extensive GvHD, which resolved 1-year after transplant. With a median time of 19 months (IQR, 8-42) from allo-HCT, 2-year OS was 82% ( Fig1B). Of note, 1 patient died because of infection and 1 because of CNS toxicity, whereas all cases with prolonged follow-up (>10 months) displayed resolution of the VEXAS clinical phenotypes and were able to discontinue immunosuppression between 2-8 months post-transplant. Allo-HCT remains the only curative option for MDS and is used to treat rheumatologic conditions refractory to conventional treatments. We present the largest series of allografted VEXAS cases. Given the hemato-inflammatory nature of the disease, allo-HCT may be a viable option in selected patients.

Effect of Immunopeptidome Gap Caused By Recipient-Donor HLA Mismatch in Umbilical Cord Blood Transplantation and HLA-Haploidentical Hematopoietic Stem Cell Transplantation

Introduction The immune response by alloreactive T cells plays a crucial role in allogeneic hematopoietic stem cell transplantation (allo-HCT), causing not only graft-versus-leukemia but also harmful graft-versus-host disease (GVHD). Human leukocyte antigens (HLA), which are highly polymorphic and differ widely among individuals, are the key molecules that present antigens to T cells. This individual variation in antigen-presenting capacity, the immunopeptidome, is thought to be assessable as HLA evolutionary divergence (HED) between alleles. Several autoimmune diseases are explained by HED, and HED is reported to be associated with outcome in HLA-matched allo-HCT. Thus, HED can be a useful indicator of potential immune reactivity. HLA-mismatched allo-HCT, including umbilical cord blood transplantation and HLA-haploidentical allo-HCT (Haplo-HCT), has been increasing in recent years. The combination of HLA mismatch alleles varies from case to case, thus speculating that it causes individual differences in immune responses is easy. HLA mismatches have long been known to be associated with recurrence and GVHD, but a few risk assessment studies have focused on the immunopeptidome gap due to each HLA mismatch in individual cases. Aim This study aimed to examine the prognostic impact of the gap of immunopeptidome in mismatched HLA between recipient and donor in HLA-mismatched allo-HCT. Methods Allo-HCT was performed on 317 patients at our institution from 2006 to 2022. Of the 272 patients with evaluable allele data, 123 patients who underwent more than 3 alleles HLA-mismatched allo-HCT were retrospectively analyzed. Graft sources included cord blood (n=69, 56.1%) and haploidentical stem cells derived from peripheral blood (n=54, 43.9%). The median age at allo-HCT was 44 (range: 16-67) years and the median observation period was 545 [8-5551] days. Diagnoses include acute myeloid leukemia (n=61, 49.6%), acute lymphoblastic leukemia (n=24, 19.5%), malignant lymphoma (n=24, 19.5%), myelodysplastic syndrome (n=10, 8.1%), and others (n=4, 3.2%). The conditioning regimens was non-myeloablative (n=89, 72.4%). GVHD prophylaxis for 54 Haplo-HCT was anti-thymocyte globulin in 27 (50%) and post-transplant cyclophosphamide in 27 (50%) patients. The immunopeptidome gap of HLA mismatch (HED-mis) was evaluated between each mismatched allele. Grantham distance, which predicts amino acids from HLA allelic information and attempts to measure evolutionary distance based on the chemistry of the two amino acids, was used to calculate HED-mis. HLA allele data were drawn from clinical records. Tobias Lenz et al. produced the calculator program (https://hladiv.net/). HED-mis for each HLA class I: HLA-A (HED-mis A), HLA-B (HED-mis B), and HLA-C (HED-mis C) were calculated to evaluate acute and chronic GVHD (aGVHD and cGVHD), cumulative relapse rate (CIR), and overall survival (OS). Result The median [range] of HED-mis for 123 patients was 0.13 [0.00-13.70] for HED-mis A, 7.15 [0.00-11.25] for HED-mis B, and 4.19 [0.00-7.58] for HED-mis C. Patients were divided into 4 groups at each HED-miss value quartile: Q1, Q2, Q3, and Q4. Non-Q4 (Q1, Q2 and Q3 with the lower gaps) and Q4 with the highest gap of HED-mis A, B, and C were compared to confirm the effect of gap size. Univariate analysis revealed that non-Q4 of HED-mis B was associated with increased aGVHD 2-4 up to 100 days after all-HCT, compared to Q4 (non-Q4 49.8% vs. Q4 25.0%, p=0.017), but was unrelated to the incidence of severe aGVHD 3-4 ( p=0.58). Q4 of HED-mis A demonstrated no difference in aGVHD 2-4 compared to non-Q4 ( p=0.20) but was associated with increased severe aGVHD 3-4 (non-Q4 of 0.06% vs. Q4 of 20.7%, p=0.019, Table and Figure). Similarly, multivariate analysis adjusted for each HED-mis, graft, and conditioning revealed that Q4 of HED-mis A was a risk factor for severe aGVHD 3-4 (hazard ratio [HR]: 3.85, p=0.015), and non-Q4 of HED-mis B was a risk factor for developing aGVHD 2-4 (HR: 3.64, p=0.017). HED-mis C was unrelated to any grade aGVHD, but Q4 of HED-mis C may have a better 2-year CIR in univariate (20.3%, vs. in non-Q4, 46.2%, p=0.055) and multivariate analyses (HR: 0.34, p=0.051). No association was found with each HED gap and each quartile for cGVHD and OS. Conclusion Gaps in the immunopeptidome of HLA-mismatched alleles, especially in HLA-A, should be considered in severe aGVHD development during donor selection.

CR1 Favors PTCy-haplo over UCB in Allogeneic Stem Cell Transplantation for Adult Patients with AL

[Introduction] HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCB) are alternative to HLA-matched hematopoietic stem cell transplantation (HSCT). However, advantage of PTCy-haplo versus UCB has not been determined in patients with acute lymphoblastic leukemia (ALL). Thus, we compared post-HSCT outcomes of PTCy-haplo and UCB in adult patients with ALL to determine patient subgroups who benefit from PTCy-haplo. [Methods] We analyzed data on adult patients (≥16 years) with ALL who underwent HSCT with PTCy-haplo or single-unit UCB between January 2013 and December 2021, using the Japanese nationwide registry database. Endpoints of the analysis included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), engraftments, acute and chronic graft-versus-host disease (GVHD), and infections. In addition to multivariate analysis, propensity score matching was performed as a sensitivity analysis. [Results] We analyzed 1999 patients (PTCy-haplo, 330; UCB, 1669). Median age at HSCT was 44.5 years (range, 16-73) in PTCy-haplo and 45 years (range, 16-74) in UCB group. The proportion of patients who underwent HSCT in the first complete remission (CR1) (PTCy-haplo, 50.3%; UCB, 48.8%) and median time from diagnosis to HSCT (PTCy-haplo, 7.8 months; UCB, 7.7 months) were comparable between the groups. Regarding conditioning, the proportion of those who received myeloablative conditioning (PTCy-haplo, 50.6%; UCB, 54.8%), or conditioning with total body irradiation (PTCy-haplo, 82.4%; UCB, 79.3%) were comparable between the groups. Multivariate analyses showed that PTCy-haplo recipients had comparable 3-year OS (54.1% vs. 52.3%; adjusted hazard ratio [aHR], 0.93; p = 0.51) and DFS (49.7% vs. 47.1%; aHR, 1.06; p = 0.60) with UCB recipients. PTCy-haplo recipients had a significantly higher 3-year relapse rate (32.2% vs. 26.4%; aHR, 1.47; p = 0.01), but had a significantly lower 3 -year NRM (18.1% vs. 26.5%; aHR, 0.70; p = 0.03) as compared to UCB along with significantly faster neutrophil (median, 16 days vs. 20 days) and platelet (median, 30 days vs. 42 days) engraftments, and lower incidence of viral, fungal and bacterial infections. There was no significant difference in cumulative incidence of acute GVHD (30.9% vs. 36.4%, grade II-IV at 100 days; p = 0.15), or chronic GVHD (22.5% vs. 20.9% at 3 years; p = 0.85) between the two groups. These comparable OS and DFS between the two groups were confirmed after minimizing differences in patient characteristics with propensity score matching analysis (Figure 1A). Then, to identify patient subgroups who benefit from PTCy-haplo rather than UCB transplant, we performed subgroup analyses of OS. Significantly favorable effects of PTCy-haplo over UCB were observed in patients with CR1 at HSCT (HR, 0.66; p = 0.03). Indeed, propensity score matching analysis showed that PTCy-haplo recipients had a significantly higher 3-year OS (76.4% vs. 67.6%; HR, 0.57; p = 0.01) and DFS (70.5% vs. 60.6%; HR, 0.66; p = 0.03) than UCB recipients, along with a significantly lower NRM (12.9% vs. 26.3%; HR, 0.39; p < 0.01), and a comparable relapse rate (16.6% vs. 13.1%; HR, 1.41; p = 0.25) with UCB. These results suggest that the low NRM in PTCy-haplo transplant outweighs potential concerns of relapse among patients transplanted in CR1 (Figure 1B). By contrast, in patients with ≥ 2 nd CR or non-CR at HSCT, survival benefits of PTCy-haplo were not observed. [Conclusions] Our results suggest that while both PTCy-haplo and UCB are suitable alternative donor sources for adult ALL patients without HLA-matched donors, in patients with CR1, selection of PTCy-haplo rather than UCB improves post-transplant prognosis.

Patient Characteristics and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy arising from plasmacytoid dendritic cells. It commonly presents as skin lesions with or without bone marrow, lymph node, central nervous system (CNS), or systemic involvement. Limited retrospective data have shown durable remissions after allogeneic (allo) hematopoietic cell transplantation (HCT). Methods: In this retrospective single-center analysis, we evaluated outcomes of 31 BPDCN patients treated with allo-HCT between September 2000 and June 2023 at our institution. Results: Median age of our cohort was 52 years [range 16-76 y]. Patient characteristics are summarized in the attached Table. Only 6 patients (19%) had their disease confined to skin and 4 (13%) had CNS/CSF involvement at diagnosis. Four patients (13%) had prior hematologic malignancies (HM), and 9 patients (29%) had a cytogenetic abnormality at baseline. Thirteen (42%) patients, who were evaluated by a next-generation sequencing Leukemia Mutation Panel, had TET2 mutation. Median time from diagnosis to HCT was 6.2 (3.2-42.4) months. Eight (26%) patients received tagraxofusp, matched unrelated donor was the most common donor type (39%), and fludarabine + busulfan-based conditioning was used in 17 (55%) patients. Post-transplant cyclophosphamide (PTCy) was used for GVHD prophylaxis in 23 (74%) patients. Median follow up was 23.9 (0.9-119.9) months. One-hundred day and 1-year non-relapse mortality was 9.7% and 23.1%, respectively. Grade 2 acute GVHD was seen in 9 patients (29%), and no grade 3-4 GVHD has been seen so far. Limited or extensive chronic GVHD was seen in 6 (21%) of 28 evaluable patients. Only 6 of the 31 (19%) allo-HCT patients progressed after HCT. Two-year PFS and OS was 56% and 67%, respectively. Patients receiving allo-HCT in first remission had significantly better median PFS (not reached vs. 11.3 months; p=0.034) and OS (not reached vs. 12.6 months; p=0.045). Conclusions: These results demonstrate the safety and efficacy of allo-HCT in BPDCN. Patients undergoing allo-HCT in first remission had significantly better outcomes. Prospective studies are needed to better define the role of allo-HCT in BPDCN.

Budesonide Added to Post-Transplantation Cyclophosphamide, Tacrolimus and Mycophenolate Mofetil for Prevention of Graft-Versus-Host Disease

Background: Topically active corticosteroids have been shown to effectively treat inflammatory bowel disease with a systemic steroid-sparing effect. However, previous studies have not demonstrated their efficacy in preventing graft-versus-host disease (GVHD) when combined with the standard GVHD prophylaxis regimen consisting of calcineurin inhibitors and methotrexate. We hypothesized that the addition of orally administered ileal-controlled-release budesonide to the post-transplant cyclophosphamide (PTCy)-based regimen could effectively prevent severe acute gastrointestinal GVHD. In this study, we present outcomes of the first 43 consecutively treated patients (pts) with the PTCy-tacrolimus (T), mycophenolate mofetil (M) and budesonide (B) (PTCy-TMB) as a GVHD prophylaxis regimen after allogeneic stem cell transplantation (alloSCT). Methods: Pts with hematologic malignancies received their first alloSCT at our institution between 05/2020-04/2023. Thirty one pts received conditioning with fludarabine (160 mg/m 2) + melphalan (100-140 mg/m 2) + TBI (2-4Gy) or thiotepa 5 mg/kg. Twelve pts received fludarabine (150mg/m 2) + cyclophosphamide (29mg/kg) and TBI 4Gy ± ATG (4.5 mg/kg). GVHD prophylaxis consisted of Cy (50 mg/kg on D+3 and +4), T (trough goal 6-10 ng/mL), M (15mg/kg TID) and budesonide (3 mg TID) starting on D+5 and continued until D+90 followed by a weekly taper if no acute GVHD (aGVHD) occurred. T was continued for at least 6 months followed by a taper, unless otherwise indicated. Results: The median age was 50 years (range 22-73), 39 pts had hematologic malignancies including AML (N=14), ALL (N=11) and NHL (N=8). Seven pts (16%) classified as high/very-high DRI. The median of HCT-CI was 4 (range 0-7). Donors were haploidentical (N=32), MSD (N=8), MUD (N=1), MMSD (1) and MMUD (N=1). PBSCs were used in 28 pts (65%). Thirty pts (70%) received RIC regimens. Median follow-up was 407 days (range 91-996 days). At day 100, the cumulative incidence (CI) of grade 2 aGVHD was 7.0% (95%CI 1.8-17.2), while none developed grade 3-4 aGVHD (Figure 1). One patient had severe chronic GVHD (bronchiolitis obliterans) with CI at 2 years of 3.2% (95%CI 0-14.0). The CI of any systemic steroid use at D+100 and D+180 was 30.2% (95%CI 17.4-44.1) and 44.8% (95%CI 28.9-59.5), respectively. Among the pts who received treatment for aGVHD, the median cumulative systemic steroid exposure (in prednisone equivalents) was 1,318 mg (IQR 623-3,775) at D+100 and 1,325 mg (IQR 525-1,640) at D+180, with a median treatment duration of 40 days (IQR 25-110). At 1 year, the OS, PFS, GRFS, relapse and NRM were 79.6% (95%CI 61.4-89.9), 69.8% (95%CI 51.6-82.3), 66.6% (95%CI 48.4-79.8), 15.3% (95%CI 6.2-28.2) and 14.9% (95%CI 5.3-29.1), respectively. The 1-year CI of newly diagnosed/worsening hyperglycemia and Cushing syndrome was 18.2% (95%CI 7.9-31.9) and 5.0% (95%CI 0.9-14.2), respectively. 3 pts (7%) required insulin treatment. The median absolute lymphocyte count (ALC) at day 30, 90 and 180 was 200/mcL, 300/mcL and 500/mcL, respectively, with no differences in the median ALC at D+180 among pts with and without GVHD. Median cell numbers of CD3 +, CD3 +/CD4 +, CD3 +/CD8 +, CD19 + and CD56 + at 1, 3, 6 months post-transplant were D+30 - 63/mcL, 18/mcL, 34/mcL, 1/mcL, 87/mcL, D+90 - 111/mcL, 64/mcL, 34/mcL, 9/mcL, 216/mcL and D+180 - 269/mcL , 78/mcL , 126/mcL , 7/mcL, 189/mcL, respectively. After 10/2022 pts were tested routinely for Reg3α and ST2 (baseline and retested if developed any signs/symptoms of aGVHD). Among 18 tested pts at baseline, the median number (range) of Reg3α and ST2 at baseline was 28 ng/mL (16-90) and 23,308 pg/mL (4,678-56,226), respectively. Three low-risk pts developed grade 1 aGVHD (N=2) and grade 2 aGVHD (N=1). Fourteen pts with GI sign/symptoms after transplant showed median number (range) of Reg3α and ST2 of 78 ng/mL (16-837) and 34,904 pg/mL (13,329-160,000), respectively. Only one pt with high-risk aGVHD algorithm developed grade 2 aGVHD (Figure 1). Conclusions: The addition of budesonide to PTCy-based GVHD prophylaxis regimen (PTCy-TMB) is feasible and appears to be effective in preventing severe GI aGVHD, without compromising transplant outcomes and immunologic reconstitution.

Evaluation of the Use of Post-Transplant Cyclophosphamide in Patients Diagnosed of Myelodysplastic Syndrome Who Undergo Allogenic Hematopoietic Cell Transplantation

INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative strategy for patients with MDS. Although the outcomes of allo-HCT performed in MDS patients have improved, transplant toxicity remains a relevant limitation for determining this patient's eligibility and transplant success. The use of PTCY for GVHD prevention is becoming a common practice in the allo-HCT community. At our institution, as in many others, PTCY-based prophylaxis has been progressively used, irrespective of the selected donor type. PTCY effectively prevents the onset of GVHD. However, its use is also associated with increased infectious complications, delayed engraftment, and specific organ toxicities. Little is known, however, about the efficacy and safety of using PTCY in patients with MDS undergoing allo-HCT. This study reports the results of comparing the outcomes of PTCY-based versus (vs.) conventional prophylaxis in a cohort of MDS patients undergoing allo-HCT. METHODS This study includes the 69 patients with MDS who underwent their first allo-HCT at our institution in the years 2010 to 2022. Retrospective data were updated in June 2023. The study cohort was divided into two groups according to the GVHD prophylaxis used in the transplant platform (PTCY-based vs. other prophylaxis) in order to compare their respective outcomes. RESULTS The baseline characteristics of the study cohort according to the GVHD prophylaxis are shown in Table 1. Overall, the median age was 59, with 17 (24.6%) patients older than 65. According to the IPSS-R score, 11 (15.95%) patients were classified into the high-risk group, and 20 (29%) into the very-high-risk group. Fifteen (21.7%) adults underwent allo-HCT upfront, and 54 (78.3%) received prior treatment with either chemotherapy-based 7 (10.1%) or HMA-based regimens 49 (71%). Most of the baseline characteristics were balanced between the two study groups, except for the proportion of allo-HCT using 9/10 mismatched unrelated and haploidentical donors, which was higher in the PTCY group (50.0% vs. 10.3%, p<0.001). Post-transplant results are shown in Table 1. All patients engrafted. The medians of days to neutrophil (20 vs. 16, p<0.01) and platelet (15 vs. 12, p<0.01) engraftment were longer in patients who received PTCY. The use of PTCY resulted in similar rates of grades II-IV (Day +100 cumulative incidence (CI): 40.0% vs. 30.8%, p=0.56), in higher incidence of III-IV aGVHD (20.0% vs. 5.1%, p=0.052), and in lower rates of moderate/severe cGVHD (0% vs. 37.0%, p<0.001). Post-transplant outcomes were similar in patients who received PTCY and in those who did not. The 2-years OS, RFS, NRM, CIR and GRFS of patients who received PTCY were 44.2%, 42.7%, 35.5%, 21.8% and 40.4%; for those patients that did not receive these numbers were 64.1%, 61.5%, 15.4%, 23.1% and 30.8% ( Table 1). A multivariate analysis was performed to compare the effects of PTCY in post-transplant results (aGVHD CI, OS and NRM), controlling for covariates whose omission could bias the results of the univariate comparisons. As shown in Table 2 when controlled by donor type, patients who underwent allo-HCT with PTCY had comparable risk for presenting grades II-IV (HR 0.94, P=0.89) and III-IV aGVHD (HR 2.57, P=0.20) than patients without PTCY. The null hypothesis that patients with MDS and PTCY prophylaxis had similar transplant outcomes than those with conventional prophylaxis was not rejected: OS (HR 1.36, p=0.45), NRM (HR 2.28, p=0.21) and CIR (HR 0.39, p=0.27). The multivariate analysis also revealed that older patients (HR 1.11, p=0.01) and patients transplanted in a worse performance status (KPS<90) (HR 3.40, p=0.006) had worse OS secondary to higher risk for NRM. In addition, patients classified into the very-high-risk group (HR 10.88, p<0.001), and patients with a higher number of blasts prior to allo-HCT (HR 1.26, p=0.06) all had a higher risk for disease relapse. CONCLUSION The use of PTCY in adults undergoing allo-HCT for MDS resulted in comparable post-transplant outcomes than the use of more conventional prophylaxis but lowered the rates of moderate/severe cGHVD. Higher risk for NRM was documented in older adults and in patients with worse performance status. Furthermore, patients with a very-high-risk MDS, according to R-IPSS, were exposed to higher risk for relapse irrespective of the intensity of the conditioning regimen used as part of the transplant platform.