GVHD-free/relapse-free Survival Research Articles

Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP

AbstractThis retrospective study evaluated 35 children (median age 5.2 years; range 0.4–18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II–IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3–41.1) vs 58.8% (31–78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1–32.8), relapse incidence was 15.9% (5.6–30.9), progression-free survival (PFS) was 66.1% (47–79.7), GvHD-free relapse-free survival was 50% (30.6–66.7), and overall survival (OS) was 71.1% (51.4–84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3–96.1) vs 50.8% (26.3–71), p = 0.03, and 90.9% (50.8–98.7) vs 54% (28.1–74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3–53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Donor matters: Donor selection impact on hematopoietic stem cell transplantation outcomes in Hispanic patients with B-cell acute lymphocytic leukemia: Insights from a myeloablative HSCT study

BackgroundHematopoietic stem cell transplantation (HSCT) is a pivotal treatment for high-risk acute lymphocytic leukemia (ALL), although limited by suitable human leukocyte antigen (HLA)-matched sibling donors (MSD). This study evaluates the impact of donor selection on outcomes in post-HSCT Hispanic B-cell ALL patients. MethodologyThis single-center retrospective study evaluates outcomes in 88 adult Hispanic B-cell ALL patients who underwent haploidentical, MSD, or MUD myeloablative HSCT between 2013 and 2023. ResultsCompared to Haploidentical transplants, MSD exhibited worse cumulative incidence of relapse (CIR) (HR = 3.39; P = 0.014) and disease-free survival (DFS) (HR = 2.44; P = 0.048) whereas MUD outcomes did not differ. This effect persisted even when controlling for pre-HSCT stage and Minimal residual disease (MRD) status. In addition, Ph-like was a significant predictor of worse DFS (HR = 3.60; P=0.014) and CIR (HR = 2.97; P=0.035) on multivariate analysis. Older donor age correlated with worse GVHD-free, relapse-free survival (GRFS) in haploidentical transplants (HR = 1.05; P=0.036). ConclusionOur data highlights improved outcomes with younger, haploidentical donors among Hispanic B-cell ALL patients undergoing myeloablative HSCT. This underscores the importance of donor selection in optimizing outcomes for ALL patients.

Treosulfan- Versus Busulfan-based Conditioning in Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome: A Single-center Retrospective Propensity Score-matched Cohort Study

Treosulfan has shown promise in allogeneic hematopoietic cell transplantation (HCT) for its myeloablative properties and low toxicity. In this single-center retrospective propensity score-matched cohort study we compared treosulfan- and busulfan-based conditioning in allogeneic HCT for patients with myelodysplastic syndrome (MDS). This study included 138 adults who underwent allogeneic HCT for MDS or chronic myelomonocytic leukemia (CMML) at Princess Margaret Hospital, Toronto 2015-2022. Using propensity score matching, we compared transplant outcomes between two well-matched cohorts who received conditioning with either fludarabine-treosulfan (FT) (n=46) or fludarabine-busulfan with total body irradiation (FBT200) (n=92). A scoring system based on patient age, Karnofsky performance score and hematopoietic cell transplant comorbidity index was used to assign patients based on fitness to low-dose (30 g/m2) or high-dose (42 g/m2) treosulfan: 32 (69.6%) received high-dose treosulfan. The racial composition of the two groups was similar, with 27.2% and 21.7% of FBT200 and FT recipients, respectively, identifying as non-Caucasian (P=0.61). Primary outcomes were analyzed at a median follow-up of 747 days. Of all participants, 116 (84.0%) received graft-vs-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) and anti-thymocyte globulin (ATG) . Patients who received FT had a superior 2-y overall survival (OS) compared to those who received FBT200: 66.9% (95% confidence interval (CI): 46.1-81.2) vs. 44.5% (95% CI: 34-54.4), hazards ratio (HR): 0.43, 95% CI: 0.22-0.84 (P=0.013). In multivariate analysis (MVA), only the use of fresh grafts (P=0.02) and FT (P=0.01) were associated with improved OS. FT was associated with superior 2-y relapse-free survival (RFS) compared to FBT200: 63.1% (95% CI: 42.6-77.9) vs. 39.1% (95% CI: 29.1-49.1), HR: 0.44 (95% CI: 0.24-0.81), P=0.008. In MVA, the use of fresh grafts (P=0.03) and FT (P=0.009) were associated with improved RFS. Recipients of FT demonstrated superior 2-y graft versus host disease relapse-free survival (GRFS) compared to those who received FBT200: 57.4% (95% CI: 37.8-72.8) vs. 35.1% (95% CI: 25.5-45). In MVA, only FT was associated with superior GRFS (P=0.02). FT recipients exhibited markedly superior 1-y event-free survival (EFS) compared to recipients of FBT200 in univariate analysis (40.3% (95% CI: 25.9-54.2) vs. 9.2% (95% CI: 4.4-16.3), HR: 0.47 (95%CI: 0.30-0.72), P<0.001) and MVA (P=0.004). FT was associated with lower 1-y non-relapse mortality (NRM) compared to FBT200 in univariate analysis (9.9% (95% CI: 3.0-21.8) vs. 29.7% (95% CI: 20.6-39.3), HR: 0.41 (95% CI: 0.17-0.96), P=0.04) and MVA (P=0.04). Our study utilized propensity score matching to demonstrate superiority of treosulfan- over busulfan-based conditioning in stem cell transplantation of patients with MDS and is the first to evaluate the performance of treosulfan-based conditioning in combination with ATG and PTCY. As such, it contributes to the increasing body of evidence supporting the safety of treosulfan, even at the dose of 42 g/m2.

Allogeneic hematopoietic cell transplantation for older patients with AML with active disease. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted.

Use of Endpoints in Phase III Randomized Controlled Trials for Hematopoietic Stem Cell Transplantation Over the Last 15 Years: A Systematic Review.

This systematic review aimed to evaluate the proportion of primary and secondary endpoints in hematopoietic stem cell transplant (HSCT) phase III randomized clinical trials (RCTs) and analyze their trends in time and study sponsorship status. The Chi-square test and logistic regression analyses were performed using SPSS version 28. A total of 147 HSCT phase III RCTs from 2006 to 2021 reported 197 primary and 600 secondary endpoints. Overall survival (OS, 17 %), progression-free survival (PFS, 15 %), graft versus host disease (GVHD, 8 %), event-free survival (EFS, 8 %), and organ function (8 %) were the most common primary endpoints. GVHD (12.3 %, n = 74), safety/toxicity/adverse events (11.8 %, n = 71), OS (11.5 %, n = 69), PFS (9.3 %, n = 56), and relapse rate (RR; 7.5 %, n = 45) were the most common secondary endpoints during 2006-2021. After 2013, an increase was noted in the use of PFS as a primary endpoint (12 %-18 %, p = 0.196), while the use of OS as a primary endpoint declined (20 %-13 %, p = 0.170). An increase was observed in using the secondary endpoints RR (5 %-10 %, p = 0.047) and NRM (3 %-6 %, p = 0.047). EFS was used more (14 % vs. 4 %, p = 0.012) than ORR (11 % vs. 2 %, p = 0.003) as a primary endpoint in pharmaceutical-compared to non-pharmaceutical-sponsored studies. As secondary endpoints, the use of EFS (4 % vs. 1 %, p = 0.013) and ORR (4 % vs. 1 %, p = 0.028) was higher, whereas that of organ systems/functions (1.5 % vs. 5.5 %, p = 0.022) and GVHD (6.5 % vs. 15 %, p = 0.002) was lower in pharmaceutical-compared to non-pharmaceutical sponsored studies. GVHD-free relapse-free survival was reported as a primary endpoint in 2 % of studies, while only 5 % reported quality of life as a secondary endpoint. We described commonly used endpoints in HSCT phase III RCTs and patterns in their use over time by funding source and study intervention category.

ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?

There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75–0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.

Outcomes of haploidentical peripheral blood stem cell transplantation following myeloablative conditioning using two types of rabbit ATG: a propensity score-matched analysis.

During hematopoietic stem cell transplantation (HSCT), ATG depletes T cells in-vivo to improve engraftment and prevent graft-versus-host disease (GVHD). Here, we compared the clinical efficacy of two different types of ATGs: thymoglobulin and anti-human T-lymphocyte immunoglobulin (Grafalon). A total of 469 patients who received haploidentical transplantation were enrolled in this retrospective study. We applied a propensity score (PS)-matched analysis and 209 patients were assigned to each group. Clinical outcomes were compared between two groups and primary outcome was overall survival (OS). There was no significant difference in OS between two groups. Within the first 180days after HSCT, Grafalon was associated with lower incidences of Epstein-Barr virus (EBV) viremia (31.6 vs. 54.5%, P < 0.0001) and cytomegalovirus viremia (CMV) viremia (54.5 vs. 67.9%, P = 0.005) compared to thymoglobulin. Patients receiving Grafalon had a higher rate of moderate/severe chronic GVHD (26.3 vs. 18.2%, P = 0.046). However, the incidences of engraftment failure, grade II-IV acute GVHD, relapse, non-relapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) did not differ greatly between groups. In the subgroup analysis, Grafalon improved the OS of lymphoid malignancies with young ages (< 40years old) (HR, 0.55; P = 0.04) or with a high/very high disease risk index (HR, 0.36; P = 0.04). In the myeloid cohort, Grafalon reduced NRM in the patients who received non-female for male transplantation grafts (HR, 0.17; P = 0.02). Our results suggest the two types of ATG may differentially influence transplant outcomes and it may optimize ATG selection according to the condition of patients.

The Role of Molecular or Cytogenetic Response as a Favorable Prognostic Factor Before Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myeloid leukemia (CML) over the last two decades. However, some patients still do not achieve an adequate response to these drugs, and hematopoietic stem cell transplantation (HSCT) is indicated in this scenario. We present the results of a 20-year follow-up study of 70 patients who underwent transplantation after TKI failure. The primary objective of the study was to evaluate overall survival (OS) and the secondary objective was to evaluate the outcomes of relapse-free survival (RFS), GVHD-free, relapse-free survival (GFRS) and the incidences of relapse (RI), non-relapse mortality (NRM), acute and chronic GVHD. Median survival was 11 years, with 1-year OS 70% (57.8 to 79.3) and 5-year OS at 57.7% (45.1 to 68.5). The estimated 5-year OS was not different for CP1 (60%) versus advanced stages (45%); P = .60. The degree of response immediately before transplantation was directly associated with worse outcomes [HR 5.89 (1.19 to 29.16); P = .03] for patients with only a hematological response compared with patients with a cytogenetic or molecular response. This study corroborates the potential of HSCT in the scenario of therapeutic failure and highlights the role of molecular response as a potential target to be achieved before transplantation.

Peripheral blood stem cell transplantation using HLA-haploidentical donor with post-transplant cyclophosphamide versus HLA-matched sibling donor for lymphoma.

Data comparing HLA-haploidentical donors and HLA-matched sibling donors (MSDs) in peripheral blood stem cell transplantation (PBSCT) for lymphoma are scarce. We retrospectively analyzed 465 patients with lymphoma aged 16 years or older who underwent PBSCT using haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo) (n = 166) or MSDs with calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis (n = 299). Two-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) in the PTCy-haplo and MSD groups were 49.2% versus 51.9% (P = 0.64), 38.0% versus 39.9% (P = 0.97), and 27.7% versus 18.5% (P = 0.006), respectively. In multivariable analyses, PTCy-haplo recipients had slower neutrophil recovery (hazard ratio [HR], 0.62; P < 0.001) and platelet recovery (HR, 0.54; P < 0.001), lower risk of chronic GVHD (HR, 0.64; P = 0.038) and extensive chronic GVHD (HR, 0.45; P = 0.008), and better GRFS (HR, 0.66; P = 0.003) than MSD transplant recipients. OS, PFS, relapse or progression, and non-relapse mortality were similar between the groups. The difference might be mainly due to PTCy use rather than donor type; however, the results suggested that PTCy-haplo could be a possible option as an alternative to conventional MSD transplantation for lymphoma in PBSCT.

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

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

Reduced Cytokine Release Syndrome and Improved Outcomes with Earlier Immunosuppressive Therapy in Haploidentical Stem Cell Transplantation

The optimal timing of immunosuppression and post-transplantation cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is unknown. However, cytokine release syndrome (CRS) following haplo-HSCT is associated with worse transplantation outcomes, and the incidence of CRS may be affected by the timing of immunosuppression and PTCy. In this study, we compared CRS and other transplantation outcomes in 2 cohorts receiving different immunosuppression and PTCy schedules following haplo-HSCT. This was a retrospective cohort study of 91 patients who underwent haplo-HSCT at the Intermountain Health Blood and Marrow Transplant Program. The original or standard haplo-HSCT GVHD prophylaxis regimen included PTCy on days +3 and +4, with mycophenolate mofetil (MMF) and tacrolimus starting on day +5. The modified regimen adopted in November 2020 changed PTCy to days +3 and +5, with earlier introduction of tacrolimus and MMF, on day -1 and day 0, respectively. Grade ≥1 CRS occurred in 32% of patients in the modified regimen, in 82% of patients in the standard regimen (P <.0001), and 65% overall. Likewise, grade ≥2 CRS was lower with the modified regimen (16% versus 57%; P = .0002). The mean duration of CRS symptoms was longer with the standard regimen (3.14 days versus 1.44 days; P = .0003). The incidence of acute graft-versus-host disease grade III-IV or extensive chronic GVHD (cGVHD) at 1 year was lower in the modified regimen (6% versus 32%; P = .0068). No differences between the standard and modified regimens were seen in overall survival, relapse, or GVHD-free relapse-free survival (GRFS), although there appeared to be a trend toward improved GRFS with the modified regimen. Post hoc analysis comparing GRFS in patients with CRS and those without CRS found that CRS was associated with lower GRFS at 1 year (36% versus 63%; P = .0138). The duration of broad-spectrum antibiotic therapy was decreased by 7.5 days (P = .0017) and the time to hospital discharge was reduced by 7.1 days (P = .0241) with the modified regimen. This is the first analysis to evaluate and find a difference in CRS with early initiation of immunosuppressive therapy in haplo-HSCT. Our results suggest that this modified GVHD regimen benefits patients by reducing CRS and high-grade GVHD compared to the standard PTCy-based GVHD prophylaxis regimen in haplo-HSCT. Additionally, this novel regimen did not appear to negatively impact outcomes.

Haploidentical Transplant with Post-Transplant Cyclophosphamide for Acute Myeloid Leukaemia and Myelodysplastic Syndromes Patients: The Role of Previous Lines of Therapy.

Allogeneic haematopoietic stem-cell transplant is an option, potentially curative, for high-risk acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients. Post-transplant cyclophosphamide administration allows for the selection of haploidentical donors in patients who are eligible for the procedure but do not have a fully matched donor since it can overcome the HLA barrier. There is still an active debate on whether intensifying the conditioning regimen is necessary with haploidentical donors when peripheral blood stem cells are used as the graft source. Herein, we report our decennial experience of haploidentical stem-cell transplant using peripheral blood stem cells (haplo-PBSC) at King's College Hospital. The primary objective was to evaluate overall survival (OS) following haplo-PBSC. Secondary objectives were total OS for patients with less than two previous lines of therapy, OS according to cytomegalovirus (CMV) reactivation, incidence of transplant-related mortality (TRM), graft-versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS). One-year and three-year total OS were 62% and 43%, respectively, with a median OS of 22 months. One-year and three-year OS for patients with ≤2 and those with >2 previous lines of therapy were 72% and 55%, and 60% and 22%, respectively (p-value=0.04). The median OS in patients with >2 previous and ≤2 lines of therapy was 16 and 49 months, respectively. Cumulative incidence (CI) of relapse was 25% with a median time to relapse of 5 months (range 1 - 38 months). Haploidentical haematopoietic stem-cell transplant is potentially curative in chemosensitive AML and MDS and offers a high rate of prolonged remission. Our cohort further confirms the role of consolidative haploidentical transplant in patients in complete remission and highlights that patients with heavily pre-treated disease may not benefit from this strategy.

Impact of stem cell selection between bone marrow and peripheral blood stem cells for unrelated hematopoietic stem cell transplantation for hematologic malignancies: on behalf of the Donor/Source Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background aimsThis study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. MethodsA retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0–70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. ResultsAmong 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0–24 years, indicating that both sources are viable choices for young patients. ConclusionsThis real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

Chronic GVHD: review advances in prevention, novel endpoints, and targeted strategies.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for many malignant and non-malignant hematologic disorders. Chronic graft-versus-host (cGVHD) disease remains a significant hurdle for long-term survival in patients post allo-HCT, and it remains the leading cause of late non-relapse mortality. The risk factors for development of cGVHD include degree of human leukocyte antigen (HLA) disparity, increasing recipient age, use of peripheral blood stem cells as a source, myeloablative conditioning regimens, prior acute GVHD (aGVHD), and female donor to male recipient. Our biological understanding of cGVHD is mostly derived from transplantation mouse models and patient data. There are three distinct phases in the development of cGVHD. Approaches to prevent GVHD include pharmacologic strategies such as calcineurin inhibitors (cyclosporine, tacrolimus) combined with methotrexate or mTOR inhibitors (sirolimus), and IMP dehydrogenase inhibitors (mycophenolate mofetil). Increasingly, posttransplant cyclophosphamide is emerging as a promising strategy for GVCHD prevention especially in a setting of reduced intensity conditioning. Other approaches include serotherapy (ATG, Campath) and graft manipulation strategies. A significant obstacle to evaluating the response of novel GVHD-directed therapies has been standardized response assessments. This has functioned as a barrier to designing and interpreting clinical trials that are structured around the treatment of cGVHD. Novel endpoints including failure-free survival, Graft-versus-host disease-free, relapse-free survival (GRFS), and current GVHD-free, relapse-free survival (CGRFS) may create a clearer picture for post-HCT outcomes. Targeted therapies including Bruton's tyrosine kinase inhibition, JAK1/2 inhibition, and ROCK2 inhibitors have improved cGVHD therapy, especially in the steroid refractory setting. Continued improvement in prophylactic strategies for cGVHD, identification of accurate cGVHD treatment endpoints, and access to novel therapeutic agents are expected to improve cGVHD outcomes.

How Much Have Post-Transplant Outcomes Improved Since 2000 for Older Patients with Acute Myeloid Leukemia? a Study from the EBMT Acute Leukemia Working Party

Acute myeloid leukemia (AML) is a disease of older patients with a median age at diagnosis of 68 years. Patients older than 65 years historically have performed poorly as not being treated with intensive chemotherapy. Biological age is not the only culprit as other factors also play a role in reducing survival, such as performance status, the presence of comorbid conditions, and most importantly the biology of AML that is usually associated with high risk cytogenetic or molecular aberrations. Despite the increasing use of targeted therapies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an important and potentially curative treatment modality for patients with AML. Over time, significant progress in allo-HCT has resulted in decreased non-relapse mortality (NRM) and allowed the delivery of allo-HCT to older patients. However, little information is available about the global impact of the current standard of care for older AML patients after allo-HCT and about the predictive factors for post-transplant outcomes. To address these challenges, we assessed real-world changes over time in transplant characteristics and post-transplant outcomes in older patients with AML (&amp;gt; 65 years), using a large dataset from the European Society for Blood and Marrow Transplantation registry. We identified 7215 adult patients (40% female; median age 68 years, range 65-80) with AML (secondary AML in 25%) allografted between 2000 and 2021 from a matched sibling donor (MSD; 23%), unrelated donor (UD; 63%) or haploidentical donor (Haplo; 14%). Karyotype risk was intermediate in 71% and adverse in 25%. NPM1 mutation and FLT3 ITD were present in 37% and 30% of patients, respectively.At transplant, 64% of patients were in first complete remission (CR1), 14% in CR2+ and 22% had active disease. Comorbidity index was zero in 43% of patients, 1-2 in 26% and &amp;gt;3 in 31%, while the Karnofsky score was &amp;lt;90 in 35%. Conditioning was reduced intensity (RIC) in 82% of patients. In vivo T cell depletion (TCD) and peripheral blood stem cells (PBSCs) were given to 62% and 93% of patients, respectively. Median follow up calculated by reverse Kaplan Meier was 40 months (interquartile range [IQR] 38-42). We compared changes in patient and transplant characteristics over time in 728 (10%) patients transplanted in 2000-2009, 1775 (25%) patients transplanted in 2010-2014, and 4712 (65%) patients transplanted in 2015-2021. Patients transplanted in recent years (65%) were older, were more likely to be in CR1 and to have an adverse-risk karyotype. Patients transplanted more recently were less likely to have had an MSD but more likely to have had a Haplo, PBSCs and TCD. The 3-year cumulative incidence of relapse (CIR) gradually and significantly decreased from 37% to 31%, then to 30% over the 3 time periods (p=0.001) whereas NRM significantly decreased from 31% and 31% to 27% (p=0.003). The 2-year leukemia free survival (LFS) and overall survival (OS) gradually and significantly improved over time from 32% to 38%, and then to 44% (p=0.001) and from 37% to 42%, and then to 49% (p=0.001), respectively, whereas graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) improved from 22% to 29%, and then to 34% (p=0.001). In a Cox regression multivariate analysis (MVA), a significant reduction in CIR and increased LFS, OS and GRFS were noted after 2015. LFS, OS and GRFS were also negatively affected by secondary AML, low Karnofsky score, active disease at transplant, and adverse-risk cytogenetics. GRFS was also negatively affected by older age, and positively affected by TCD. RIC positively affected OS whereas PBSCs positively affected LFS and OS. This improvement of post-transplant outcomes over time was observed for patients in CR1 with LFS and OS increasing from 39% to 44% and then to 47% (p=0.005) and from 43% to 48%, and then to 52% (p=0.006) as well as for patients in CR2 with LFS and OS increasing from 29% to 40% and then to 47% (p=0.001) and from 37% to 44% and then to 52% (p= 0.001), respectively. In conclusion, in older patients with AML, we observed an impressive improvement over time in post-transplant outcomes with decreased CIR and improved LFS, OS and GRFS. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option.

B-Cell Acute Lymphoblastic Leukemia: Donor Matters in Allogeneic Stem Cell Transplant Outcomes of Hispanic Patients

Introduction: Hematopoietic stem cell transplantation (HSCT) improves long term overall survival (OS) and disease-free survival (DFS) in those with intermediate or high-risk B- cell ALL. Historically, matched related donors were the ideal choice, but with improved GVHD prophylactic regimens and supportive care, haploidentical donors are being increasingly used. Due to their increased graft-versus-leukemia (GVL) effect, they may be an option for Hispanic patients, for whom matched donation may be more challenging. Methods: This is a retrospective chart review of B- cell ALL patients that received allogeneic HSCT at Norris Comprehensive Cancer Center (NCCC) from 2012 to 2023. Mismatch-unrelated donors were excluded. For OS, DFS, and cumulative incidence of relapse (CIR), match sibling donors (MSD) and match unrelated donors (MUD) were grouped. However, for GVHD outcomes including graft-versus-host disease (GVHD)-free relapse-free survival (GRFS), incidence of grade 3-4 acute GVHD (aGVHD), and incidence of severe chronic GVHD (cGVHD) requiring immunosuppression MSD and MUD were separated. Incidence outcomes were evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome, while survival outcomes were analyzed using Cox proportional hazards model. Results: One hundred eighteen B- cell ALL patients were included with a median age at transplant of 43 years (range: 21-69). Donor types included 46 (40.0%) MSD, 45 (38.1%) haploidentical, and 27 (22.9%) MUD. Most were Hispanic (N= 92, 78.0%) and our median follow-up time was 23.6 months. The majority of patients achieved CR1 (N=79, 66.9%) and MRD negativity by flow (N=106, 89.8%), pre-transplant. The 3-year OS and DFS for the cohort were 82.1% (95% CI 73.8-91.3%) and 66.2% (95% CI 57.2-76.6%), respectively, while the CR1 subgroup was 90.5% (95% CI 83.3-98.3%) and 77.1% (95% CI 67.8-87.7%) respectively. When compared to haploidentical HSCT, patients who received matched donors had significantly worse CIR (HR = 2.42; 95% CI 1.06-5.51; P = 0.036) and DFS (HR = 2.14; 95% CI 1.03-4.44; P = 0.041), along with a non-significant trend towards worse OS (HR = 2.54; 95% CI 0.83-7.80; P=0.10). Additionally, pretransplant minimal residual disease (MRD) positivity demonstrated worse OS (HR = 5.01; 95% CI 1.73-14.5; P = 0.003), DFS (HR = 3.25; 95% CI 1.48-7.16; P = 0.003), and CIR (HR = 2.05; 95% CI 0.78-5.39; P = 0.15). The 1-year GRFS, 1-year incidence of severe cGVHD, and 100-day incidence of grade 3-4 aGVHD was 52.6% (95% CI 43.5-63.6%), 29.5% (95% CI 20.9-38.6%), and 7.74% (95% CI 3.79-13.5%), respectively. Compared to haploidentical donors, GRFS was worse in the MUD (HR = 2.07; 95% CI 1.08-3.96; P = 0.028) but similar in MSD. This is likely driven by differences in survival and relapse, and there were no differences in the incidence of severe cGVHD or aGVHD between donor types. Multivariate analysis, which included age, MRD status pretransplant, and stage prior to transplant, demonstrated the improved predictive effect of haploidentical donors. Matched donors exhibited worse DFS (HR = 2.25; 95% CI 1.04-4.90; P = 0.04) and CIR (HR = 2.47; 95% CI 1.09-5.60; P = 0.03), with a trend towards worse OS (HR = 2.84; 95% CI 0.92-8.79; P = 0.07). Given the heterogeneity in donor-type outcomes, we conducted a subgroup analysis of the 45 haploidentical HSCT patients on the GRFS and DFS composite outcomes. After controlling for patient age, older donor age analyzed as a continuous variable was a significant predictor of worse GRFS (HR = 1.05; 95% CI 1.00-1.11; P = 0.039) but did not affect DFS. Conclusion: In a predominantly Hispanic population of ALL patients, haploidentical donors demonstrate improved OS and CIR. In those haploidentical patients, younger donor age confers improved GRFS.

Risk Factors for CMV Infection, Including HLA Disparity and Ptcy Transplant in the Era of Letermovir Prophylaxis

Reports suggest that post-transplant cyclophosphamide (PTCy) for haploidentical and HLA-matched sibling donor allogeneic stem cell transplant (allo-SCT) is associated with a higher incidence of cytomegalovirus (CMV) infection than calcineurin inhibitor (CNI) for HLA-matched sibling donor allo-SCT. Prophylactic letermovir has been shown effective for CMV seropositive patients, based on the data mostly before the FDA approval of letermovir (2017). We reevaluated the risk of CMV infection in PTCy transplants. We retrospectively analyzed 175 patients after allo-SCT between May 2019-May 2022). CMV infection was monitored at least for the first year by serostatus, viral load over 500 IU/mL, and/or evidence of CMV end-organ disease. Univariate and multivariate Cox regression analyses were used for the factors, including CMV serostatus, use of letermovir, GVHD prophylaxis, and HLA disparities, to affect the risk of CMV infection and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS). Cumulative incidence curves were used to visualize the incidence of CMV infection stratified by HLA match and PTCY use. A landmark analysis at Day +100 was used for GRFS, where patients who had CMV infection beyond Day +100 (N=13) were assigned to the no-infection group. Of the 175 patients, 108 received HLA-matched donors with GVHD prophylaxis, either CNI (N=70) or PTCy (N=38), while 67 received HLA mismatched donors with either CNI (n=6) or PTCy (N=66) ( Table). Letermovir was given to 137 patients (CMV IgG positive N=130, negative N=7) but not to 38 patients (CMV IgG positive N=12, negative N=26). CMV infection occurred in 28 patients (CMV IgG positive N= 28, CMV IgG negative N=0) before or after Day +100 (N=15 or N=13, respectively). CMV IgG positive recipients not receiving letermovir demonstrated a higher risk of infection by Day +100 than those receiving letermovir (Hazard ratio (HR) 10.1 (95% confidence interval (CI) 3.6-28.6), p&amp;lt;0.01). All 13 infections after Day +100 occurred after the cessation of letermovir (median: 82.9 days after cessation). On univariate analysis, PTCy and HLA mismatch donors increased the risk of CMV infection. The risk of infection by Day +100 increased with PTCy (p=0.07). The risk of infection after Day +100 increased with HLA mismatch donors (p=0.05). In addition, it was confirmed that HLA mismatch allo-SCT with PTCy increased the risk of CMV infection over matched allo-SCT with CNI ( Figure, HR 4.6 (95% CI 1.6-11.9), p&amp;lt;0.01), while HLA match allo-SCT with PTCy did not (p=0.3) (Figure 1). The trend was similar when analyzed only in the case of CMV infection by Day +100 (p&amp;lt;0.05) and after Day +100 (p=0.1). In the 130 CMV IgG seropositive patients who received letermovir, multivariate analysis showed that HLA mismatch donors with PTCy increased the risk of CMV infection over HLA match allo-SCT with CNI. When analyzed only for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome with letermovir (N=91), HLA mismatch transplant with PTCy increased the risk of CMV infection over HLA match transplant with CNI (p=0.05), but not for HLA match transplant with PTCy. Landmark analysis demonstrated better GRFS in the PTCy group than the CNI group and in patients who received PTCy with CMV infection than those who received CNI without CMV infection (p&amp;lt;0.01). PTCy increased the incidence of CMV infection in HLA mismatch allo-SCT by D+100 but not HLA match allo-SCT in the era of letermovir prophylaxis. Patients with PTCy transplant who overcome CMV infection have improved GRFS, possibly due to the increased graft-versus-leukemia effect. Further analysis is required to confirm the difference in the incidence of CMV infection between HLA match and mismatch transplant with PTCy and to assess the significance of late CMV (after Day +100) infection on GRFS.

Improved Gvhd-Relapse Free Survival of Ex Vivo αβtcr/CD19 Depleted Allo-Sct Combined with In Vivo T Cell Depletion with ATG When Compared to T Cell Replete Transplantations with or without the Addition of ATG

Introduction The aim of allogeneic stem cell transplantation (allo-SCT) is to reach graft-versus-host disease, relapse free survival (GRFS). To reduce the incidence of graft-versus-host disease (GVHD), we have developed an allo-SCT platform combining ex vivo αβTCR/CD19 depletion with in vivo T-cell depletion through administration of antithymoglobulin (ATG). Here we compare GRFS to historical cohorts of T-cell replete allo-SCT. Methods Adults with hematological malignancies and transplanted between 2011 and 2022 were included in this retrospective analysis. Written informed consent was obtained in accordance with the JACIE guidelines. Clinical data was extracted from the EBMT registry. 3 cohorts were identified. Cohort A: Allo-SCT of unmanipulated peripheral blood derived mononuclear cells (PBMCs) of matched related donors (MRD) after non-myeloablative (NMA) or myeloablative (MA) conditioning without ATG. Cohort B: Allo-SCT of unmanipulated PBMCs of 10/10 or 9/10 matched unrelated donors (MUD) after NMA or MA conditioning with ATG. Patients in cohorts A &amp; B received dual immunosuppression with cyclosporin (CsA) and mycophenolic acid (MMF). Cohort C: Allo-SCT of αβTCR/CD19 depleted PBMCs of MRD and MUD (10/10 and 9/10) after ATG and a myeloablative conditioning as previously described[1]. Patients in cohort C received 28 days of MMF. Cumulative incidence (CI) of GVHD was defined as time to onset of GVHD, with relapse and death as competing events. Overall survival (OS) was defined as time to death from any cause. CI of relapse was defined as time to relapse, with death as a competing event. Non-relapse mortality (NRM) was defined as time to death, without relapse or progression. Event free survival (EFS) was defined as the time to relapse, graft failure or death. GRFS was defined as the time to relapse, aGVHD 3-4 or extensive cGVHD, graft failure or death. CI of CMV and EBV reactivations were calculated with relapse and death as competing events. Results 341 patients were included (cohort A: N=63; cohort B: N=150; cohort C: N=128) (table 1). In T cell replete allo-SCT (A&amp;B) ATG was administered to recipients of MUD and MA conditioning was administered to patients &amp;lt; 40 years with acute leukemia. In cohort C, all patients received ATG and an MA conditioning, regardless of age or underlying malignancy. This explains differences donor types and intensity of conditioning between the cohorts (table 1). Other clinical characteristics were comparable. Two year OS (A=66.7%; B=58.7%; C=63.8%) and EFS (A=57.1%; B=52%; C=55.7%) was comparable between the cohorts. Two year CI of relapse was also comparable (A=30%; B=23%; C=28%). Two year NRM appeared higher in B, but this difference did not reach significance (A= 9.8%; B=24%; C=15%). The CI of aGVHD grade 2-4 and 3-4 at day 100 was significantly higher in T cell replete allo-SCT with MUD (2-4; A=23%; B=37%; C=20% (p=0.002); 3-4: A=5%; B=16%; C=4.7% (p=0.043)). The incidence of extensive cGVHD was significantly higher in T cell replete allo-SCT of MRD. (A= 25%; B=13%; C= 2.3% (p=&amp;lt; 0.001)). The low incidence of grade 3-4 aGVHD and extensive cGVHD without an increase in relapse or NRM, translated into a superior 2 year GRFS in patients receiving ATG combined with an αβTCR/CD19 allograft (C=55.6%) as compared to T cell replete allo-HSCT of MRD (A=38.1%) and MUD (B=40.8%) (Figure 1, p=0.04). This difference remained significant in a multivariate analysis. Conclusion We demonstrate that αβTCR/CD19 depletion combined with ATG, with a myeloablative conditioning and a very short course of immunosuppression results in very low incidences of life-threatening GVHD and an improved GRFS as compared to T cell replete allo-SCT for adult patients up to the age of 70. This is likely to positively impact the long term quality of life in survivors of allo-SCT[2]. In addition, this platform provides a window for additional early post allo-interventions to further improve the control of underlying hematological malignancies. 1. de Witte, M.A., et al., alphabeta T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies. Blood Adv, 2021. 5(1): p. 240-249. 2. Oerlemans, S., et al. Relapse and severe Graft-versus-Host Disease have a negative impact on long-term symptoms and quality of life of patients three years after allogeneic haematopoietic stem cell transplantation. Annual meeting EBMT 2022.

Outcome of Allogeneic Stem Cell Transplantation in FLT3-TKD-Mutated AML - a Study on Behalf of the Acute Leukemia Working Party of the EBMT

Introduction The overall prognostic impact of point mutations in the tyrosine-kinase domain 1 of FLT3 (FLT3-TKD mut) in patients (pts) with acute myelogenous leukemia (AML) remains controversial. Furthermore, co-occurrence of FLT3-TKD mut and mutated nucleophosmin-1 (NPM1 mut) was shown to have a favorable prognostic impact on AML pts receiving conventional chemotherapy. However, little is known about the outcome of AML pts with FLT3-TKD mut with or without co-occurring NPM1 mut treated with allogeneic stem cell transplantation (alloSCT). Patients and Methods This is a retrospective study of the acute leukemia working party (ALWP) of the European Society for Blood and Marrow transplantation (EBMT) investigating the outcome of adult AML pts with FLT3-TKD mut with or without NPM1 mut after first alloSCT using matched sibling (MSD), unrelated (UD) or haploidentical (haplo) donors between 2005 and 2022. All patients were in first or second complete remission (CR1 of CR2). Information on cytogenetic risk was necessary for inclusion. No ex-vivo T-cell depletion (TCD) was allowed. The primary endpoint was leukemia-free survival (LFS) at two years after alloSCT. Secondary endpoints were overall survival (OS), cumulative incidence of relapse (RI), non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) and GVHD-free, relapse free survival (GRFS). One hundred and eighty-two adult AML pts with FLT3-TKD mut were identified, of which 74 (40.7%) had a co-occurring mutation in NPM1. Median age was 55.1 years (range 18.6-79.1) and 46.7% were male. Median follow-up was 21.4 months [IQR 13.6-28.1]. 78% of the pts were in CR1. Cytogentic risk was favorable, intermediate and adverse in 12.6%, 75.3% and 12.1% of pts, respectively. Additional FLT3 internal tandem duplication (FLT3-ITD) was present in 25.8% of pts. Information on measurable residual disease (MRD) was available for 68.7% of pts, being positive in 48% of these. Karnofsky performance score was &amp;lt; 90% in 21.1%, and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was &amp;gt;=3 in 28.1% of pts. 69.6% of pts were cytomegalovirus (CMV) positive. Conditioning was myeloablative in 52.8% and reduced intensity in 47.2% of pts. Stem cell donors were MSD, UD and haplo in 25.8%, 55.5% and 18.7% of cases. Stem cell source was bone marrow in 10.4%, peripheral blood in 87.4% and both in 2.2%. In-vivo TCD was performed in 59.2% of pts. GVHD prophylaxis was calcineurin inhibitor-based in 92.2% of pts. Results Engraftment was achieved in 99.4% of pts with a day-60 absolute neutrophil count (ANC) &amp;gt;0.5 x 10 9/L of 97.7% [95% CI: 93.7-99.2]. Day-180 rates of acute GVHD (aGVHD) grade II-IV and grade III-IV were 26.2% (95% CI:19.9-32.9) and 8.1% (95% CI:4.6-12.8), respectively. At two years, rates of total chronic GVHD (cGVHD) and extensive cGVHD were 30% (95% CI: 22.5-38) and 16.6% (95% CI:10.6-23.7), respectively. Two-year LFS and OS were 66.1% (95% CI: 57.6-73.2) and 74% (95% CI: 65.4-80.8), respectively. Two-year RI, NRM and GRFS were 22.5% (95% CI:16-29.8), 11.4% (95% CI: 7-17), and 51.1% (95% CI: 42.4-59.1), respectively. Cause of death was original disease in 47.5%, infection in 27.5%, GVHD in 22.5% and non-SCT related in 2.5% of cases. In univariate analysis the only factor with significant impact on LFS was donor type (haplo [n=34] vs. others, p=0.006). For GRFS, patient CMV negativity (p=0.014) and in-vivo TCD (p=0.01) were significant. Interestingly, co-occurring mutations in FLT3 (FLT3-ITD) or NPM1 were not identified as having a significant impact on LFS or GRFS. Moreover, MRD status before alloSCT was also not shown to have a significant impact on these outcomes. In multivariate analysis of LFS and GRFS, only donor type (haplo [n=34] vs. others) was shown to be significant for both endpoints, hazard ratio (HR) 2.54; 95% CI: 1.4-4.6; p=0.002, and HR 2.01; 95% CI: 1.18-3.41; p=0.01, respectively. Conclusion Acknowledging the limitations of our retrospective study in this rare entity results are encouraging given the high-risk population (median age 55.1 years, CR2 in 22%, co-occurring FLT3-ITD in 25.8%, positive MRD in 48%, HCT CI &amp;gt;=3 in 28.1%). LFS, OS and GRFS rates were 66.1%, 74% and 51.1%, respectively, and both RI and NRM were comparably low with rates of 22.5% and 11.4%, respectively. No positive prognostic impact of co-occurring mutations in FLT3-TKD and NPM1 was detected, unlike what was found for conventional chemotherapy.

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 &amp; 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 &amp;gt;0.10 unless inclusion affected the hazard ratio (HR) of HLA match by more than 10%. Interactions were tested against a p-value of &amp;lt;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&amp;lt;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.