Post-transplant Cyclophosphamide For Patients Research Articles

Graft-versus-host-disease prophylaxis with ATG or PTCY in patients with lymphoproliferative disorders undergoing reduced intensity conditioning regimen HCT from one antigen mismatched unrelated donor

Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III–IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed.

Young (35 years) Mismatched Unrelated Donors and Vice Versa for Allogeneic Stem Cell Transplantation with post-Transplant Cyclophosphamide in Patients with Acute Myeloid Leukemia in First Remission: a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Young (<35 years) Haploidentical Versus Old (>35 years) Mismatched Unrelated Donors and Vice Versa for Allogeneic Stem Cell Transplantation with post-Transplant Cyclophosphamide in Patients with Acute Myeloid Leukemia in First Remission: a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Impact of Post-Transplant Cyclophosphamide (PTCY)-Based Prophylaxis in Matched Sibling Donor Allo-HCT for Patients with Myelodysplastic Syndrome: A Study on Behalf of the Chronic Malignancies Working Party of the EBMT

Background Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment option for patients with myelodysplastic syndrome (MDS). The use of PTCY for GVHD prevention is becoming increasingly prevalent across donor types/transplant platforms. However, limited studies have evaluated the efficacy and safety of using PTCY in patients with MDS undergoing matched sibling donor (MSD) allo-HCT. We hereby compare the outcomes of PTCY-based versus (vs.) conventional GVHD prophylaxis in a contemporaneous cohort of MDS patients undergoing MSD allo-HCT from the EBMT registry. Methods A total of 404 MDS patients undergoing first MSD peripheral blood allo-HCT between 2014 and 2020 in 52 participating centers, receiving either PTCY or other GvHD prophylaxis, were included. Primary outcomes were overall survival (OS), progression free survival (PFS), GVHD-free/RFS (GRFS), competing risks analyses for relapse (CIR), non-relapse mortality (NRM), and GVHD. The main comparison was PTCY vs. other types of GvHD prevention. Cox regression analyses with predefined covariates were used to obtain adjusted effect estimates of PTCY in post-transplant results.- Results The median age at allo-HCT was 57 years (IQR 49-62), 66 patients (16.3%) received PTCY, 338 (83.7%) received other prophylaxis. As reported in Figure 1, patient characteristics, disease risk, and pre-transplant status were balanced between the two cohorts. The majority of transplant characteristics were also analogous except for the proportion of adults receiving myeloablative regimens, which was higher in the PTCY group (52.3% vs. 38.2%, P=0.047). PTCY was combined with two additional immunosuppressant agents in 66.7% of the cases, with one additional immunosuppressive drug (generally calcineurin inhibitors (CNI)) in 31.8%, and administered as a single agent in only 1 (1.5%) case. Other prophylaxis mainly combined CNI with either mycophenolate mofetil or methotrexate, and in 162 (47.9%) of the cases, anti-thymocyte globulin was also administered. Post-transplant complications and outcomes are shown in Figure 1. Incidences of Day +28 neutrophil (68% vs. 97%, P=0.011) and platelet (71% vs. 92%, P&amp;lt;0.001) engraftment were lower in patients who received PTCY. The day +100 cumulative incidences (CI) of grade II-IV and III-IV aGVHD, and 5-year CI of extensive cGVHD were 32% (21-43%), 18% (9-27%) and 18% (9-28%) for patients who received PTCY, and 25% (20-30%; p=0.3), 13% (10-17%; p=0.4), 31% (26-36%; p=0.09) for those who did not. The 5-year CIs of cardiac and pulmonary toxicities were similar in both groups (23% (6-40%) vs. 19% (12-25%) (p=0.6) and 23% (8-38%) vs. 27% (21-34%) (p=0.6) in PTCY vs others, respectively). At 5-years after allo-HCT, the estimated OS (51% (39-64%) vs. 52% (46-58%), p=0.6), PFS (48% (36-61%) vs. 46% (40-52%), p=0.9), and GRFS (33% (21-45%) vs. 25% (20-30%), p=0.6), were similar between the two study groups. Nevertheless, patients who received PTCY tended to have lower CIR (20% (10-29%) vs. 33% (28-38%) (p=0.06)), but higher NRM rates (32% (20-43%) vs. 21% (16-25%), p=0.09) than the rest. Next, we performed a multivariable analysis (MVA) of OS, PFS, NRM and CIR (Figure 1). The results observed in the MVA confirmed that using PTCY in patients with MDS undergoing MSD allo-HCT resulted in comparable OS (HR 1.23 (0.77-1.97), p=0.4) and RFS (HR 1.13 (0.73-1.77), p=0.6) to conventional prophylaxis. Furthermore, the diagnosis of a high or very high-risk MDS (according to IPSS-R), and the presence of TP53 mutation at diagnosis were independent predictors of worse post-transplant outcomes. In addition, PTCY-based prophylaxis was associated with a higher NRM (HR 1.79 (1.07-2.98), p=0.03) when adjusted by variables known to be clinically relevant for NRM. Conclusion The use of PTCY in adults undergoing MSD allo-HCT for MDS resulted in comparable OS and RFS rates to conventional GVHD prophylaxis. Allo-HCT performed with PTCY was associated with a longer time to engraftment and comparable incidences of clinically relevant aGVHD. Of note, utilization of PTCY was associated with a non-significant trend to a lower incidence of extensive cGVHD. Furthermore, although a non-significant trend to lower rates of relapse were observed in allo-HCTs performed using PTCY, it use was associated with a higher risk for NRM. Further evaluation of PTCY in the MSD setting for MDS is required.

Non-T-Depleted Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Patients with Relapsed/Refractory Secondary Versus De Novo AML: A Study from the ALWP/EBMT

Background: Secondary acute myeloid leukemia (sAML) is a distinct type of AML. Transplantation, a potentially curative therapy, outcomes are inferior compared to de novo AML. We recently demonstrated (J Hematol Oncol 2023) that results of non-T-cell depleted haploidentical stem cell transplantation (HaploSCT) with post-transplant cyclophosphamide (PTCy) in sAML in complete remission are not significantly different from those in denovo AML. However, the challenge in relapse (Rel)/primary refractory (PR) AML is much higher. Methods:The study aim was to compare the outcomes of HaploSCT with PTCy, performed between 2010 and 2022, in first Rel(Rel1)/PR sAML versus those in Rel1/PR de novo AML. Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. Results: A total of 719 patients (pts) met the inclusion criteria, 129 with sAML and 590 with de novo AML. Median follow-up was 45.6 (IQR] 39.1-57.9) and 43.5 (IQR, 37.5-48.0) months for pts with sAML and de novo AML, respectively (p=0.20). Pts with de novo AML were younger, with a median age of 55.4 (range 18-77.8) versus 61.3 (21-78.8) years, (p&amp;lt;0.0001). The median year of the transplant was 2018 (2010-2011) in pts with sAML and 2017 (2010-2022) in those with de novo AML (p=0.62) and 65.1% and 57.6%, were male (p=0.11). In 81.4% of sAML pts, the antecedent hematological disorder was myelodysplastic syndrome. The cytogenetic risk was categorized as intermediate (58.6% vs 59.4%), adverse (37.4% vs 34.7%), and favorable (4% vs 5.9%) for pts with sAML and de novo AML, respectively (p=0.75) (data missing for 145 pts). A higher percentage of pts with sAML vs de novo AML had PR disease (73.6% vs 58.6%) (p=0.002). HCT-CI was higher in the sAML vs the de novo AML group, with HCT-CI &amp;gt;3 in 40.3% vs 21.9%, respectively (p&amp;lt;0.0001), while the Karnofsky performance status (KPS) did not differ. There was no difference in the frequency of cytomegalovirus (CMV) seropositivity and female donor to male pt combination between the two pt groups. Reduced intensity conditioning was received by 60.2% and 52.2% of the sAML and de novo AML pts, respectively (p=0.1), with thiotepa/busulfan/fludarabine being the most frequent regimen for both groups (38.8% vs 42%, respectively). Graft source was mainly peripheral blood stem cells (PB) in both sAML (69.8.5%) and de novo (66.8%) groups. All pts received PTCy as graft- versus-host disease (GVHD) prophylaxis in combination with immunosuppression, which was cyclosporine A (CSA)/ mycophenolate mofetil in 41.1% vs 52.9% and CSA/tacrolimus in 41.1% vs 33.6% respectively. Cumulative incidence of absolute neutrophil count (ANC) &amp;gt;0.5 x 10 9/L at day 60 was 83.5% vs 88.4% (p=0.13), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was 20% vs 26.9% (p=0.12) and 8.9% vs 10.4%, (p=0.21), respectively. The 2-year (y) total and extensive chronic (c) GVHD were 25.3% vs 20.7% (p=0.27) and 12.5 % vs 10.3% (p=0.46), respectively. In MVA HaploSCT outcomes did not differ significantly between the Rel1 /PR sAML and de novo groups; 2-y non-relapse mortality (NRM) hazard ratio (HR)=1.38 (95% CI 0.96-1.98, p=0.083). Infections and GVHD were the cause of death in 20.8% and 9.3% of pts who died. The HR for 2-y relapse incidence (RI) was 0.68 (95% CI 0.4.7.-1.00, p=0.051) and RI was the main cause of death in 40.9% and 59.3% of pts who died, respectively. The 2-y leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) did not differ between the two groups with HR=0.99 (95% CI 0.76-1.28, p&amp;lt;0.94), HR=0.99 (95% CI 0.77-1.29, p=0.973) and HR=0.99 (95% CI 0.77-1.27, p=0.94), respectively. Adverse-risk cytogenetics was a poor prognostic factor for RI and both higher age (per 10y) and lower KPS were poor prognostic factors for NRM. Adverse-risk cytogenetics and lower KPS were poor prognostic factors for LFS, OS, and GRFS. In addition, pt CMV seropositivity was a poor prognostic factor for OS. Finally, PB grafts were associated with increased risk of all grades and severe aGVHD. Conclusions: In this registry-based retrospective analysis, we observed similar outcomes, of HaploSCT with PTCy for Rel1/PR sAML compared to Rel1/PR de novo AML, with HaploSCT being able to rescue about one-third of the pts. However, relapse is still 43%. The recently approved novel agents for sAML will hopefully further improve sAML outcomes.

Score to Guide Donor Choice in Haploidentical Stem Cell Transplant Using Post-Transplant Cyclophosphamide for Patients with Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the EBMT

Introduction: There is paucity of information to guide selection of the most appropriate stem cell donor for haploidentical (Haplo) hematopoietic stem cell transplant (HSCT). Patients and Methods: We retrospectively analyzed the characteristics of haploidentical family donors that may affect transplant outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease (GVHD) prophylaxis with postransplant cyclophosphamide (PTCy) registered in the EBMT database. The primary endpoint was GVHD and relapse-free survival (GRFS). Results: Overall, 2200 patients were included with a median age of 56 years (range, 18-75); 1742 (79%) were in complete remission and 1246 (56.6) received reduced intensity conditioning. Regarding donors, the median age was 37 years (range, 8-71), 820 (37%) were females of which 458 (21%) were used for male recipients, 1252 (57%) had positive CMV serostatus, 1631 (74%) donated peripheral blood (PB) and 1638 (75%) had ≥ 4/8 HLA mismatch with the recipient. 100-day acute GVHD grade II-IV and III-IV and 2-year chronic and chronic extensive GVHD were 28% (95% CI 26-30), 11% (95% CI 10-12), 33% (95% CI 31-35) and 14% (95% CI 12-15), respectively. After median follow-up of 24 months, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS), overall survival (OS) and GRFS were 26% (95% CI 24-28), 22% (95% CI 20-24), 52% (95% CI 50-55), 57% (95% CI 55-60) and 41% (95% CI 39-43), respectively. In multivariable analysis, donor-related risk factors with a negative impact on GRFS were older age (HR 1.1; 95% CI 1.04-1.15), use of PB (HR 1.19; 95% CI 1.04-1.37), and female donors to male recipients (HR 1.25; 95% CI 1.09-1.43). We further developed a score that distinguished 4 groups with 0 (241), 1 (913), 2 (863) or 3 (183) donor-related risk factors. GRFS was 57% (95% CI 50-63), 43% (95% CI 39-46), 37% (95% CI 33-40), and 30% (95% CI 23-38), respectively (P &amp;lt; 0.001) (Figure 1). The score was also able to stratify risk groups for acute and chronic GVHD, NRM, LFS and OS. Conclusion: Donor variables have an important impact on AML patient's outcome after Haplo-HSCT using PTCy. With three simple donor characteristics, age, gender and stem cell source, we were able to generate a score that may help to select the most appropriate donor in clinical practice.

A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation (HaploHCT) with Post-Transplant Cyclophosphamide in Patients with Advanced Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for patients with myelofibrosis (MF); however, a significant obstacle to proceed to HCT is availability a matched donor, especially since MF is most often diagnosed in older adults. The effective development of haploidentical transplant (haploHCT), with post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, has been a major therapeutic advance for patients without an available matched donor. Based on the excellent survival rates seen in older patients with myeloid malignancies using fludarabine/Melphalan-based (Flu/Mel) regimen with PTCy GVHD prophylaxis, we designed a pilot trial (NCT03118492) to evaluate safety and tolerability of reduced intensity condition (RIC) regimen of Flu/Mel and TBI (2Gy) for peripheral blood stem cells (PBSC) HaploHCT with PTCy in patients with advanced MF (Figure 1a). At the time of this report, we have enrolled 17 patients (out of 22) in two cohorts. After treating the first 4 patients in cohort 1 (CH-1), eligibility was updated to exclude accelerated disease, severe pulmonary hypertension, with stricter fluid management for a stricter monitoring and eligibility criteria (cohort 2; CH-2). Our primary objective was to determine safety of this regimen in patients with MF. Key secondary endpoints were grade 2-4 acute GVHD, chronic GVHD, engraftment, overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and relapse. Detailed patient/HCT characteristics are listed in Table 1. Briefly, median age at the time of HCT was 59 years (range: 48-70), and 53% of patients were male. MF diagnosis was primary MF in 53% of patients, and 71% had intermediate-2 risk level. Karnofsky performance status was 80-100 in 94.1% of patients and HCT comorbidity index was 0-2 in 82.4%. Median time from MF diagnosis to HCT was 935 days (range: 27-7651). In CH-1, unacceptable toxicity (UT) was defined as any of the following considered at least possibility related to PTCy: any death; grade 3-4 adverse events (AEs) that does not improve to grade ≤2 within 4 weeks except for hematologic toxicities. For hematologic toxicities, UTs were primary graft failure. Two out of the 4 patients in CH-1 experienced UTs. [UPN1: grade 3 anorexia that did not improve to grade ≤2 within 4 weeks; UPN4: grade 3 kidney injury (per Bearman Scale), and grade 4 neutropenia lasting more than 42 days]. Since &amp;gt;1/6 patients had UTs, per protocol monitoring rules and after a full IRB review, the definition of UT was updated to the following in CH-2: any regimen-related grade 3-4 toxicity per Bearman scale, or for hematologic toxicities, per NCI CTCAE v4.03 toxicity scale, any grade 4 neutropenia associated with fever or infection and lasting for more than 21 days, or grade 4 neutropenia lasting for more than 42 days, or death. In CH-2, one out of 16 patients experienced a UT of acute kidney injury. UPN17 has not reached the 100-day UT period, at the time of this report. One-year OS, PFS and NRM for all patients were 80% (95%CI: 39-95), 68% (95%CI: 30-89) and 21% (95%CI: 3-50), respectively. All patients engrafted (n=12), with the median time to neutrophils engraftment of 19 days (range: 13-23) for CH-1 and 16 days (range: 12-22) for the CH-2. One-year OS for CH-2 was 91% compared to 50% in CH1 and was reduced to 78% and 50% at 2 years, respectively. RFS in CH-2 was 91% at 1 year, and 62% at 2 years compared to 50% in CH-1 at both time points. Relapse was not seen at 1 and 2 years in CH-1, whereas in CH-2 there were no relapses at 1-year but 15% of patients relapsed by the end of year 2. NRM at 100-days was 25% in CH1 vs non in CH-2 and at 2 years-NRM were 50% and 22% in CH-1 and CH-2, respectively. Grade 3-4 GVHD was not seen in either cohort. Similarly moderate and severe chronic GVHD was not seen in either cohort at 1 or 2 years. One and 2 years GRFS was 81 and 61% respectively. In conclusion, early results of this pilot study indicate that HaploHCT in MF patients undergoing HCT is safe and feasible, with low NRM and higher grade acute and chronic GVHD. We are currently accruing in CH2. If successful, this approach can be tested in a multi-center setting as a phase II trial, and likely extend this potentially curative procedure to most patients of minority populations in the United States and to a significant proportion of the Caucasian population without an HLA matched.

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&amp;lt;0.001). Post-transplant results are shown in Table 1. All patients engrafted. The medians of days to neutrophil (20 vs. 16, p&amp;lt;0.01) and platelet (15 vs. 12, p&amp;lt;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&amp;lt;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&amp;lt;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&amp;lt;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.

Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT.

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II-IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III-IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT

We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.

Outcomes of HLA-mismatched HSCT with TCRαβ/CD19 depletion or post-transplant cyclophosphamide in patients with inborn errors of immunity – an EBMT inborn errors working party analysis

HLA-mismatched donor HSCT is an increasingly utilized approach for patients with inborn errors of immunity (IEI) lacking a matched donor, thanks to the development of in-vivo T-cell depletion with post-transplant cyclophosphamide (PTCY) or in-vitro TCRαβ/CD19 depletion (TCRab). Our study analyzed the outcome with these approaches in patients with IEI. Pediatric patients who received a first HSCT between 2011 and 2019 from haploidentical related or ≤9/10 HLA-mismatched unrelated (MMUD) donors were included in this retrospective study.We included 296 patients, 139 with PTCY and 157 with TCRab, who received HSCT at a median age of 1.4 years (0.1–19.6) from haploidentical donors (n = 282) or MMUD (n = 14). There were significant differences in patient characteristics: PTCY recipients had a higher rate of pre-HSCT infections (p = 0.002), and organ damage (p < 0.001), had lower performance scores (0.008), and were transplanted more recently (p = 0.001). Owing to the approach, there was a higher proportion with busulfan-based conditioning and multi-drug GVHD prophylaxis, and a lower proportion with serotherapy in the PTCY group; and lower CD34+ but higher CD3+ numbers were infused to PTCY recipients (all p < 0.001). Neutrophil and platelet engraftment occurred significantly earlier after TCRab depletion (p < 0.001). Acute GVHD°III-IV occurred in 10.3% of patients, more frequently after PTCY (p = 0.022), while 14.3% of patients required secondary cellular therapy (boost, DLI, 2nd HSCT), more frequently after TCRab (p = 0.026). Adenoviremia was more frequent (p = 0.012) and veno-occlusive disease (p = 0.015), acute kidney injury (p = 0.028), autoimmune cytopenia (p = 0.032), and pulmonary complications (p = 0.011) less frequent after TCRab. Overall survival at 3 years was 81% (95%CI: 75–88%) and 70% (63–78%; p = 0.001) after TCRab and PTCY, respectively, while event free survival (graft failure, extensive chronic GVHD) was 69% (62–77%) and 63% (55–71%), respectively. In univariate analysis, use of PTCY, conditioning other than busulfan or treosulfan, pre HSCT organ damage, preHSCT infections and number of preHSCT morbidities correlated negatively with overall survival.This study of HLA-mismatched HSCT in IEI demonstrated better overall but not event-free survival after TCRab, but patients with PTCY had significantly higher rates of preHSCT risk factors. We conclude that both approaches are feasible and efficacious in patients with IEI lacking an HLA-matched donor.

393 - ABO Incompatibility Did Not Impact Outcomes after Haploidentical Bone Marrow Transplantation with Posttransplant Cyclophosphamide for Patients with Sickle Cell Disease: Single Center Experience

393 - ABO Incompatibility Did Not Impact Outcomes after Haploidentical Bone Marrow Transplantation with Posttransplant Cyclophosphamide for Patients with Sickle Cell Disease: Single Center Experience

Possible prognostic impact of WT1 mRNA expression at day + 30 after haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide for patients with myeloid neoplasm: a multicenter study from the Okayama Hematological Study Group.

Previous studies have revealed that relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be predicted by monitoring Wilms' tumor 1 (WT1) mRNA expression. However, only a few studies have investigated patients who received human leukocyte antigen-haploidentical stem cell transplantation with posttransplant cyclophosphamide (PTCY-haplo). In this study, we investigated the relationship between WT1 mRNA levels and clinical outcomes in the PTCY-haplo group, and compared them with those in the conventional graft-versus-host disease prophylaxis group (conventional group). We retrospectively analyzed 130 patients who received their first allo-HSCT between April 2017 and December 2020, including 26 who received PTCY-haplo. The WT1 mRNA expression level at day + 30 after allo-HSCT associated with increased risk of 1-year cumulative incidence of relapse (CIR) was ≥ 78 copies/μg RNA in the conventional group (p < 0.01) and ≥ 50 copies/μg RNA in the PTCY-haplo group (p = 0.03). The appropriate cutoff level of WT1 mRNA at day + 30 after allo-HSCT for predicting prognosis in patients treated with PTCY-haplo may be < 50 copies/μg RNA.

Abatacept-based Graft-Versus-Host Disease Prophylaxis in Haplo-identical Hematopoietic Cell Transplant in a High-risk Cohort.

There is insufficient guidance in using posttransplant cyclophosphamide in patients with organ dysfunctions. Abatacept (Aba), a T cell costimulation blockade, has recently been shown to prevent severe acute graft-versus-host disease (GVHD). We report adding Aba as GVHD prophylaxis in 4 pediatrics patients who received haplo-hematopoietic cell transplantation. Two patients had grade 2 acute GVHD and 2 had mild chronic GVHD. All 4 patients are alive with full donor chimerism, and 3 are off immunosuppressants. An Aba-based regimen can result in reliable engraftment and acceptable GVHD when concerns of organ dysfunction prevents the use of posttransplant cyclophosphamide in haplo-hematopoietic cell transplantation.

The impact of donor-specific anti-human leukocyte antigen antibodies in salvage haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide in patients with nonmalignant disorders.

The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) has been recognized as a major risk factor for graft failure (GF) after haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (haplo-PTCy). However, the role of DSAs in salvage haplo-PTCy for rescuing patients with nonmalignant disorders (NMDs) has not yet been reported. The present study retrospectively analyzed 22 patients with NMDs who underwent salvage haplo-PTCy from January 2008 to December 2017. The median age at the time of the rescue haplo-PTCy was 9 years (range, 1-26 years). Median time from the first transplant to second haplo-PTCy was 56 days (range, 37-591 days). Among all patients, six (27.3%) had DSAs, with a median DSA strength (mean fluorescence intensity [MFI]) of 5201 (range, 1412-11,543) in the first DSA testing. In addition, the median DSA MFI was 2672 (range, 832-10,498) before the bone marrow infusion. Overall, GF occurred in 5 (25%) of the 20 assessable patients. Three of four (75%) patients with DSAs experienced GF versus 2 of 16 (12.5%) DSA-negative patients (P=0.032). The median DSA MFI for patients with GF was 6437 (range, 1412-10,498) versus 1845 (range, 832-2672) for those who engrafted or had earlydeath (P=0.030). One-year event-free survival was significantly lower in DSA-positive patients than in those without DSAs (16.7% vs. 62.5%, P=0.002). DSA-negative patients had an acceptable 1-year survival of 62.5%. In conclusion, this study suggests that DSAs may be associated with deleterious outcomes after salvage haplo-PTCy in patients with NMDs.

A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies.

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II–IV and III-IV was seen in 20% (95% CI 8%–37%) and 8% (95% CI 2%–22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%–33%) (moderate-severe 12% (95% CI 3%–27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33–74%), 44% (95%CI 23%–64%), 20% (95% CI 8%–37%), and 36% (95% CI 17%–55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.

Prognostic factors for neutrophil engraftment after haploidentical cell transplantation with PT-Cy in patients with acute myeloid leukemia in complete remission, on behalf of the ALWP-EBMT.

The use of haplo-HCT with posttransplant cyclophosphamide (PT-Cy) is a new standard in the treatment of hematological diseases. A paucity of data exists on risk factors for engraftment failure in haplo-HCT with PT-Cy. We analyzed 1939 adults with acute myeloid leukemia (AML) who received a first haplo-HCT from 2010 to 2019. Status at haplo-HCT was first complete remission (CR1) in 72.5% of patients, secondary AML was reported in 9.9%. Median follow-up was 24.4 months and median age at haplo-HCT was 51 years. Stem cell source was bone marrow (BM) in 42% and peripheral blood stem cell (PBSC) in 58%, and 64% of patients received a myeloablative conditioning (MAC) regimen. Cumulative incidence of primary graft failure (GF) was 6%; GF was reported in 110 patients and 54 died before day +30 with no sign of cell recovery. Overall, 33 patients underwent a second HCT in a median time of 45 days and 13 were alive at last follow-up, the 2-year overall survival (OS) after second HCT being 32.4%. In multivariate analysis, factors independently associated with the risk of nonengraftment were: secondary AML (HR 1.30, p = 0.003), use of RIC (HR 1.22, p < 0.001), and use of BM (HR 1.21, p < 0.001). At 2 years, leukemia-free survival (LFS) and OS for the entire population was 55.2% (95% CI: 52.6-57.6) and 60.9% (95% CI: 58.4-63.3), respectively. Incidence of GF after haplo-HCT with PT-Cy is lower than reported T-cell-depleted haplo-HCT. Optimization of conditioning regimen and graft source should be considered for reducing the risk of GF in haplo-HCT recipients using PT-Cy.

Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients

Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research &amp; Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: &amp;lt;60 years (n=66) versus &amp;gt;60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p&amp;lt;0.001). Baseline characteristics were otherwise similar. Neutrophil engraftment (&amp;gt;500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p&amp;lt;0.001). Platelet engraftment (&amp;gt;20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients &amp;gt;60 years approximate outcomes in patients &amp;lt;60 years. While NRM was inferior in the older patient group, this difference did not result in significant differences in long term OS or DFS. Instead, other variables such as the hematopoietic comorbidity index and the disease risk index were better indicators of survival outcomes. Additionally, these survival outcomes with haplo PBSCT with PTCy appear to be similar to prior published data with haplo BMT with PTCy in older patients (Kasamon, et al. JCO. 2015). Based on this study, haplo PBSCT with PTCy is an appropriate transplant platform for elderly patients. Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Bridging the Gap in Access to Transplant for Underserved Minority Patients Using Mismatched Unrelated Donors and Post-Transplant Cyclophosphamide: A National Marrow Donor Program/be the Match (NMDP/BTM) Initiative

Bridging the Gap in Access to Transplant for Underserved Minority Patients Using Mismatched Unrelated Donors and Post-Transplant Cyclophosphamide: A National Marrow Donor Program/be the Match (NMDP/BTM) Initiative

Haploidentical Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with Myelofibrosis: A Multi-Institutional Experience

Haploidentical Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with Myelofibrosis: A Multi-Institutional Experience

Allogeneic bone marrow transplantation with post-transplant cyclophosphamide for patients with HIV and haematological malignancies: a feasibility study

Allogeneic blood or marrow transplantation (alloBMT) is a potentially life-saving treatment for individuals with HIV and haematological malignancies; challenges include identifying donors and maintaining antiretroviral therapy (ART). The objectives of our study were to investigate interventions to expand donor options and to prevent ART interruptions for patients with HIV in need of alloBMT. This single-arm, interventional trial took place at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD, USA). Individuals with HIV who were at least 18 years of age and referred for alloBMT for a standard clinical indication were eligible. The only exclusion criterion was a history of documented resistance to enfuvirtide. We used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis to expand donor options and an optimised ART strategy of avoiding pharmacoenhancers and adding subcutaneous enfuvirtide during post-transplant cyclophosphamide and during oral medication intolerance. Our primary outcome was the proportion of participants who maintained ART through day 60 after alloBMT. We measured the HIV latent reservoir using a quantitative viral outgrowth assay. This study is registered on ClinicalTrials.gov, NCT01836068. Between June 1, 2013, and August 27, 2015, nine patients who were referred for transplant provided consent. Two patients had relapsed malignancy before donor searches were initiated. Seven patients had suitable donors identified (two matched sibling, two matched unrelated, two haploidentical, and one single-antigen mismatched unrelated) and proceeded to alloBMT. All patients maintained ART through day 60 and required ART changes (median 1, range 1-3) in the first 90 days. One patient stopped ART and developed HIV rebound with grade 4 meningoencephalitis at day 146. Among six patients who underwent alloBMT and had longitudinal measurements available, the HIV latent reservoir was not detected post-alloBMT in four patients with more than 95% donor chimerism, consistent with a 2·06-2·54 log10 reduction in the HIV latent reservoir. In the two patients with less than 95% donor chimerism, the HIV latent reservoir remained stable. By using post-transplant cyclophosphamide as GVHD prophylaxis, we successfully expanded alloBMT donor options for patients with HIV. Continuing ART with a regimen that includes enfuvirtide post-alloBMT was safe, but life-threatening viral rebound can occur with ART interruption. amfAR (the Foundation for AIDS Research), Johns Hopkins University Center for AIDS Research, and National Cancer Institute.