Matched Unrelated Donor Recipients Research Articles

Allogeneic hematopoietic stem cell transplantation: A single-center experience, 2017 to 2021

IntroductionHematopoietic stem cell transplantation (HSCT) remains a critical treatment for advanced or high-risk hematological malignancies, posing challenges such as finding suitable donors and managing of graft-versus-host disease (GvHD). This study estimates 3-year overall survival in patients who underwent HSCT at our referral service in the state of Minas Gerais, Brazil. Material and methodsThis retrospective observational cohort study involved 41 patients who received HSCT between 2017 and 2021 at the Felício Rocho Hospital. Recipients received HSCT from either haploidentical donor (Haplo), matched unrelated donor (MUD), or HLA-matched sibling donor (MSD). The study evaluated parameters that included 3-year overall survival (OS), treatment-related mortality (TRM), GvHD incidence, post-transplant relapse rate, and engraftment. ANOVA, Kruskal-Wallis, and chi-square tests were used for statistical analysis. Survival curves were calculated using the Kaplan-Meier method and the Log-rank test compared the curves. ResultsOur study found that the engraftment time differed among groups: Haplo recipients engrafted earlier within a median of 16 days (ranging between 10 and 20 days) than MSD recipients with 18 days (ranging between 11 and 28 days), and MUD recipients with 19 days (ranging between 11 and 24 days; p = 0.019). Mild acute GvHD (grade I-II) was observed in 13 patients, progressing to chronic GvHD in 5 patients. Three-year OS rates were as follows: MSD group - 67.7%, Haplo group - 42.2%, and MUD group - 44.4% (MSD vs Haplo, p = 0.039). Three-year cumulative treatment-related mortality (TRM) rates were 17.8% for MSD group, 22.9% for Haplo group, and 22.1% for MUD group (pairwise comparisons p > 0.05). Infection-related mortality was reported in eight patients, while relapse rates at 3 years were similar across MSD, Haplo, and MUD groups (p = 0.891). Donor age influenced OS rates, showing better outcomes with donors under 45 years old, and significant differences were found in pairwise comparisons (p = 0.015). ConclusionDonor type and donor age significantly impacted HSCT outcomes in our analysis, thus emphasizing the importance of rigorous donor selection in risk stratification and suggesting potential benefits for younger donors.

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

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

Risk-Adapted Donor Lymphocyte Infusion after Hematopoietic Cell Transplant in Pediatric and Young Adult Patients Is Associated with Low Risk of Graft Versus Host Disease

Introduction: Donor lymphocyte infusion (DLI) is a form of adoptive immunotherapy administered to enhance the graft-versus-leukemia (GVL) effect after an allogeneic hematopoietic cell transplantation (HCT). DLI is frequently chosen for its ease of administration and low risk of graft ablation as compared with other chemotherapeutic options in patients experiencing mixed chimerism (MC) or disease relapse. But in patients with acute leukemia experiencing relapse, clinical responses are seen in fewer than 20-30%. Success is also limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). We had previously described our risk-adapted strategy of administering DLIs based on chimerism and donor source (Rujkijyanont P, et al. Blood Cancer J 2013). To determine the efficacy and toxicity of DLIs and to identify potential factors influencing the outcomes, we conducted a retrospective single center study including patients who received DLIs after HCT. Methods: We collected data on all HCTs and conventional DLIs that had been administered to patients from 1993 to 2022 for any indication at our center. Each HCT was considered as an independent event. Numeric variables were represented by median and range and compared using the Wilcoxon-Mann-Whitney test. Categorical variables were compared using the Fisher exact test. Competing-risk regression models using the Fine-Gray method were developed to evaluate risk factors for acute GVHD and chronic GVHD. Death and relapse were considered as competing risk events for these GVHD outcomes. Follow-up data were censored at subsequent HCT, 2 years after the first DLI, 5 years after transplant, or the last follow-up. Logistic regression analysis was performed to assess factors associated with the response to DLI within 180 days after the first DLI. Results: During the study period, 236 patients received 252 HCTs followed by DLIs (median age at HCT 9.2 [range 0.2-25.1] years). An additional 743 patients received 806 HCTs with no subsequent DLI (median age at HCT 10.3 [range 0.1-27.2] years). Dosing most frequently used was 1 × 10 5, 1 × 10 6 and 1 × 10 7 CD3+ cells/kg, for haploidentical donor (HAPLO), matched unrelated donor (MUD) and matched sibling donor (MSD) recipients, respectively. Initial doses were occasionally lower based on risk of GVHD and were escalated as tolerated and based on response. After receiving DLI, 19.4% developed acute GVHD, and 9.2% developed chronic GVHD with no significant differences observed between MSD, MUD and HAPLO recipients. After adjusting for donor source, longer duration between HCT and DLI was associated with a significantly decreased risk of both acute (HR 0.97 P&amp;lt;0.001) and chronic GVHD (HR 0.98 P=0.04). A higher CD3+ cell dose was also significantly associated with an increased risk of acute GVHD (HR 1.03 P&amp;lt;0.001) but not chronic GVHD (HR 0.96 P=0.12). The overall response rate after DLI for treating MC or graft failure was 45.2% for MSD, 32.6% for MUD and 41.4% for HAPLO recipients. Logistic regression analysis revealed leukemia patients had a higher response rate after receiving a DLI for mixed chimerism from MSD (OR=19.5 P=0.002) and HAPLO (OR=9.03 P=0.042), but not from MUD HCT (OR=0.65 P= 0.57), compared to patients with non-malignant disorders. We also evaluated the response to DLI for frank disease relapse in 15 patients. The response rate after DLI for disease relapse was 50% (1/2) for MSD, 44.4% (4/9) for HAPLO, but 0% (0/4) for MUD recipients. Conclusions: In our analysis, the incidence of GVHD was not higher in pediatric and young adult HCT recipients who received DLI as compared to those who did not. Overall, the risk of developing acute and chronic GVHD after DLI was low and comparable between different donor sources. The risk of GVHD decreased further away from HCT and increased with higher DLI dose. The response rate for treating MC and disease relapse remains less than 50%. Thus, DLIs may be safely administered to pediatric and young adult patients after HCT. The therapeutic effect may be modulated by adjusting the dose, timing and frequency of DLI administration.

Comparative Study for Haplo, MSD and MUD Allo-Hcts for Core-Binding Factor AML Patients in CR2: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Although core-binding factor acute myeloid leukemia (CBF-AML) generally has a favorable prognosis, relapse occurs in ~40% of cases. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended when patients achieve second complete remission (CR2). However, transplant outcomes and donor preference for these patients remain unclear. We compared in an EBMT global multi-center registry-based analysis the outcomes following allo-HCT using either haploidentical donors (HAPLO), matched siblings donors (MSD), or 10/10 matched unrelated donors (MUD). Methods Data from 865 de novo adult CBF AML patients in CR2 receiving allo-HCT in 227 EBMT centers from 2010-2022 were analyzed. Transplants from mismatched UD (&amp;lt;10/10), umbilical cord blood or grafts with ex-vivo manipulation were excluded. Univariate analyses and Cox regression models were used. Results Results from 329 MSD, 374 MUD, and 162 HAPLO HCTs were analyzed. For the entire cohort, median age was 43y (range: 18-76). Inv(16)/CBFBMYH11 was detected in 503 patients (58%) and t(8;21)/RUNX1-RUNX1T1 was detected in 362 patients (42%). Peripheral blood was the major graft source (86.1%), and myeloablative conditioning was used for the majority (60.1%) of all allo-HCTs. Female-to-male transplants were more common in the MSD group (25.5%) than in the HAPLO (19.8%) or MUD (14.2%) group, respectively (p&amp;lt;0.01). 83% of patients in the HAPLO group received post transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. Engraftment rates were higher in the MSD (98.8%) and MUD (98.9%) than in the HAPLO (94.9%) group (p&amp;lt;0.01). Original disease was the major cause of death for the MSD and MUD cohorts, while in the HAPLO group, it was infection. On univariate analysis, HAPLO HCT was associated with a higher 2-year non-relapse mortality (NRM) (MSD 17.1%, MUD 15.3%, HAPLO 25.7%). The 180-day cumulative incidence of grade II-IV acute GVHD was higher in HAPLOs (14.8%) than in MSD (6.8%) or MUD (7.9%) recipients, respectively . No significant difference was observed among the three cohorts for 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS). CBF-AML with inv(16) was associated with lower relapse incidence RI (18.1%) than with t(8;21) (28.3%), which contributed to better OS (75.7% vs 59.8% at 2 years), LFS (65.8% vs 51.2%) and GRFS (50.8% vs 38.5%) . Older patient age i.e., above the median age, was associated with a higher NRM (22.4% vs 13.3%) and a lower OS (63.8% vs 74.8%) than younger age i.e., below the median age. Peripheral blood grafts were associated with higher incidences of chronic GVHD (41.5% vs 25.8%) and extensive cGVHD (21.6% vs 9.7%) than bone marrow grafts. On multivariate analysis, no significant difference was observed among HAPLO, MSD and MUD allo-HCTs on NRM. HAPLO HCT was associated with lower RI compared to MSD (hazard ratio [HR]=0.56, 95% CI 0.32-0.97; p&amp;lt;0.05) and MUD (HR=0.57, 95% CI: 0.33-0.99, p&amp;lt;0.05) while there was no significant differences between the 3 types of donors on LFS, OS and GRFS. CBF-AML with t(8;21) was associated with both higher RI (HR=1.79, 95% CI 1.3-2.47; p&amp;lt;0.01) and higher NRM (HR=1.58, 95% CI 1.1-2.27; p&amp;lt;0.01) than CBF-AML with inv(16), which led to worse LFS, OS and GRFS. Higher age (per 10 year) was associated with higher risk of NRM (HR=1.29, 95% CI 1.11-1.5; p&amp;lt;0.01) and worse OS (HR=1.13, 95% CI 1.01-1.27; p=0.03). Conclusions For CBF-AML patients in CR2, haploidentical HCTs were associated with a lower RI compared to MSD and MUD allo-HCTs. HAPLO achieved similar LFS, OS and GRFS to MSD or MUD, respectively. In addition, CBF AML with inv(16) had better outcomes than with t(8;21) after allo-HCT.

A Real-World Evidence Comparison of 1-Year Overall Survival and Relapse-Free Survival between Patients Treated with Abatacept in Combination with a Calcineurin Inhibitor and Methotrexate Versus Antithymocyte Globulin or Post-Transplant Cyclophosphamide Following Allogeneic Hematopoietic Cell Transplantation

Introduction: Matched sibling or matched unrelated donor (MUD) availability remains a clinical challenge for hematopoietic cell transplant (HCT) recipients. Though HCTs with a mismatched unrelated donor (MMUD) may be an option, graft-versus-host disease (GVHD)-related mortality risk is elevated with MMUD HCTs. Abatacept (ABA), a selective T-cell costimulation modulator, when administered with calcineurin inhibitor/methotrexate (CNI/MTX), improved survival outcomes in 7/8 MMUD and 8/8 MUD recipients (Watkins B, et al. J Clin Oncol 2021) compared with CNI/MTX prophylaxis alone and was approved in the United States for acute GVHD prophylaxis (US FDA 2021). Alternative prophylactics, such as antithymocyte globulin (ATG) + CNI/MTX or post-transplant cyclophosphamide (PT-Cy) + tacrolimus (Tac) + mycophenolate mofetil (MMF) also show promise for improving post-HCT survival outcomes (Walker I, et al. Lancet Haematol 2020; Shaw B, et al. J Clin Oncol 2021; Luznik L, et al. J Clin Oncol 2022). This real-world analysis compared survival outcomes in 7/8 MMUD and 8/8 MUD recipients treated with ABA + CNI/MTX versus ATG + CNI/MTX and versus PT-Cy + Tac + MMF from the Center for International Blood and Marrow Transplant Research (CIBMTR) database of all allogeneic HCTs performed in the United States. Methods: This retrospective cohort study included CIBMTR database allogenic HCT recipients treated with ABA + CNI/MTX, ATG + CNI/MTX, and PT-Cy + Tac + MMF (PT-Cy). Recipients were aged ≥ 6 years; weighed ≥ 20 kg; had a Karnofsky/Lansky performance score ≥ 80%; were diagnosed with leukemia, lymphoma, or myelodysplastic syndrome; and underwent first allogeneic HCT from a 7/8 MMUD or 8/8 MUD in the United States between 2011 and 2018. Overall survival (OS; time between HCT date and documented date of death) and relapse-free survival (RFS; time between HCT date and date of death or relapse, whichever occurred first) were evaluated over 1 year post-HCT. A weighted log-rank test was used to compare outcomes using inverse probability of treatment weighting (IPTW), based on propensity score calculation to control for treatment bias. Marginal hazard ratios (HRs) and 95% CIs were estimated by a weighted Cox proportional hazards model with treatment as a covariate. Results: The 7/8 MMUD cohort included 378 recipients: 54 ABA + CNI/MTX, 162 ATG + CNI/MTX, and 162 PT-Cy. The 8/8 MUD cohort included 781 recipients: 71 ABA + CNI/MTX, 355 ATG + CNI/MTX, and 355 PT-Cy. For 7/8 MMUD recipients, OS (95% CI) was significantly higher with ABA + CNI/MTX (87% [67-95%]) versus ATG + CNI/MTX (58% [49-66%]); P = 0.0026; HR (95% CI): 0.24 (0.10-0.55). The OS comparison between ABA + CNI/MTX versus PT-Cy was 86% (66-94%) and 79% (70-85%), respectively; P = 0.3376; HR (95% CI): 0.61 (0.25-1.51). In 8/8 MUD recipients, OS (95% CI) was significantly higher with ABA + CNI/MTX versus ATG + CNI/MTX (86% [72-93%] versus 70% [65-75%], respectively); P = 0.0209; HR (95% CI): 0.43 (0.21-0.88). The OS comparison for ABA + CNI/MTX versus PT-Cy was 84% (66-93%) versus 78% (73-82%), respectively; P = 0.3616; HR (95% CI): 0.69 (0.30-1.54). In 7/8 MMUD recipients, the ABA + CNI/MTX subgroup had significantly higher RFS versus ATG + CNI/MTX (81% [60-92%] versus 48% [39-56%], respectively); P = 0.0015; HR (95% CI): 0.27 (0.13-0.55). The RFS comparison between ABA + CNI/MTX versus PT-Cy was 75% (56-87%) versus 62% (52-70%), respectively; P = 0.1636; HR (95% CI): 0.60 (0.26-1.39). For 8/8 MUD recipients, Figure 1 shows ABA + CNI/MTX had significantly higher RFS versus ATG + CNI/MTX (82% [69-90%] versus 61% [55-66%], respectively); P = 0.0032; HR (95% CI): 0.39 (0.21-0.73). Figure 2 shows the RFS comparison between ABA + CNI/MTX and PT-Cy (79% [61-90%] versus 65% [60-70%], respectively); P = 0.0944; HR (95% CI): 0.54 (0.26-1.11). Conclusions: ABA + CNI/MTX significantly improved OS and RFS over 1-year post-HCT compared with ATG + CNI/MTX prophylaxis. There was a trend toward improved OS and RFS 1-year post-HCT on ABA + CNI/MTX compared with PT-Cy, although this did not reach statistical significance. OS and RFS in 7/8 MMUD recipients receiving ABA + CNI/MTX was similar to those in 8/8 MUD recipients, suggesting that this treatment improved the risk/benefit ratio for MMUD HCTs. Study support: This study was sponsored by Bristol Myers Squibb. Medical writing: Efrah Yousuf and Ryan Miller (Caudex), funded by Bristol Myers Squibb. We acknowledge Brian Gavin, PhD, for his contributions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Factors Predicting Efficacy and Toxicity of Post Transplantation Cyclophosphamide for Graft Versus Host Disease Prevention in Hematopoietic Cell Transplantation Recipients: Interim Data of an Ongoing Study

Introduction: Post-transplant cyclophosphamide (PTCy) following allogeneic stem cell transplantation (allo HCT) to decrease the risk of graft vs host disease (GVHD) has transformed the field. Since initially demonstrating safety and efficacy following non-myeloablative (NMA) conditioning in patients (pts) receiving haplo-identical donor (haplo) transplants, PTCy has been implemented in matched related donor (MRD), matched unrelated donor (MUD), and mismatched unrelated donor (mMUD) transplantation. However, PTCy can contribute to toxicity, and some pts still develop GVHD. A personalized approach to PTCy dosing could provide more effective prevention of GVHD and less toxicity without compromising graft versus tumor activity. We present interim results of our study investigating the genetic and metabolic factors that modulate Cy metabolism and the extent to which these drive its immunomodulatory effects. Methods: All adult pts receiving allo HCT with MRD, MUD or haplo donor were eligible. All recipients received NMA preparative regimen which included Cy 14.5 mg/kg on days -6 / -5 and PTCy (50 mg/kg) on days +3 / +4. Pts underwent standard clinical evaluations post-transplant for up to 2 yrs. This study was IRB approved and registered under NCI clinical trial (NCT03555851). Pharmacogenomics (PG): Recipient's germline DNA was extracted from buccal swabs obtained prior to transplant. Candidate genes genotyped using next-generation sequencing included CYP2B6, CYP3A4/5, CYP2C8/9, CYP2C19, ALDH1A1/3A1, GSTP1, GSTM1, and GSTA1. Pharmacokinetics (PK): Blood samples were obtained on day -6 and day +3 within 15 minutes after the end of Cy infusion, and 2, 4, 8, 16, 20, and 24 hours (hrs) after infusion start. Concentrations of Cy and its metabolites hydroxycyclophosphamide (HCY) carboxyethylphosphoramide mustard (CEPM) and phosphoramide mustard (PM) were analyzed using a Waters Quattro Premier triple quadrupole mass spectrometer coupled to an Acquity UPLC system. Immune Profiling (IP): Mononuclear cells were isolated and cryopreserved from haplo donor apheresis products as well as from pts prior to transplant on day -6, day 0, and post-transplant days +3, +5, +14, +30, and 3, 6 and 12 months (mos) post-transplant. Immune effector and memory subsets surveyed by flow cytometry included: CD4, CD8 T cells and regulatory T cells (Treg). Descriptive analysis of recipient PG, cyclophosphamide (and related metabolites) PK, and T cell profiling was performed. Results: Ten pts who underwent allo HCT were evaluated. This included 6 haplo, 2 MRD, and 2 MUD recipients. All pts received NMA conditioning with fludarabine, cyclophosphamide and irradiation. Four pts developed aGVHD, 1 pt grade I (MUD), 2 pts grade II (haplo), and 1 pt grade III (haplo). Two pts died on study from relapsed disease, 1 pt was taken off study after 6 mos with relapsed disease, 7 pts are alive, 5 of whom completed 2 years of follow up. Successful PG analysis was completed in 9 pts. PK assessments were completed in 10 pts with wide interpatient variability, Table 1 summarizes the median and Cmax range for each measured Cy metabolite. Pts with aGVHD had similar mean Cy metabolite Cmax compared to pts who did not develop aGVHD (Table 1). IP profiling in 10 pts showed relative T cell subset distribution (% PBMC) first peaked at day +5 (34.4±9.9%), with mainly T effector subsets and Treg detected, and nadired at 1 mo (10.8±7.5%) with an overrepresentation of central T memory cells followed by a rebound at 2 mo (34.6±16.7%) driven by CD8 effector & effector memory cells. The 4 pts with aGVHD trended towards higher TEff:Treg ratio at day +5 (2±0.6 vs 3.9±1.5); a trend also observed in the transplanted product (20.6±2.4vs 12±1.8). Conclusion: Our results show the feasibility of assessing PK, PG, and IP in pts receiving PTCy. Early IP of both pts and transplanted product may pinpoint immune imbalance associated with aGHVD later masked during immune reconstitution. Study of a large number of additional pts may clarify the association between early IP and Cy metabolites concentrations with immune profile and with risk of aGVHD. Candidate single nucleotide polymorphisms will be used to evaluate the association of pharmacogenetics with Cy PK, IP, and clinical outcomes. We hope these data will help guide individualized dosing of PTCy to improve effectiveness and minimize toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Conditioning Regimen Intensity and Donor Choice Do Not Impact Outcomes of Patients (pts) with Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) in First Complete Remission (CR1): An EBMT Analysis

Allo-HCT is a curative treatment for fit pts with intermediate and adverse risk AML who achieve CR1. The presence of minimal residual disease (MRD) before allo-HCT has been shown to increase risk of relapse and decrease survival. Here, we describe outcomes of pts with AML who received allo-HCT in CR1 and the impact of MRD before allo-HCT on outcomes. We identified 1032 pts with AML who received allo-HCT in CR1 between 2015 and 2020 from the EBMT registry. The median age was 53.6 (range, 18.1-82.5) years and 526 (51%) were male. Most (94%) pts had de novo AML. FLT3-ITD and NPM1 mutations were detected in 46% and 44% of pts, respectively and high-risk cytogenetics were present in 20%. >1 course of induction therapy was required by 18% of pts to achieve CR1 and 39% were MRD positive at time of allo-HCT. The median time from diagnosis to allo-HCT was 4.9 months. Of pts with FTL3-wild type (FLT3-wt) disease, 33% were MRD negative and 22% were MRD positive at time of allo-HCT. In pts with FTL3-ITD mutation, 29% were MRD negative and 17% were MRD positive at time of allo-HCT. Donor type was matched sibling donor (MSD) in 29% of pts (n=297), matched unrelated donor (MUD) in 47% (n=481), mismatched unrelated donor (MMUD 9/10) in 8% (n=88), or haploidentical donor (haplo) in 16% (n=166). HCT-specific comorbidity index (HCT-CI) was >3 in 22% of pts (n=190). Myeloablative conditioning (MAC) was administered to 45% of pts (n=470), while reduced intensity conditioning (RIC) was used in 55% (n=562). The most common conditioning regimen was fludarabine/busulfan in MSD (n=148, 50%), MUD (n=272, 57%) and MMUD (n=38, 43%) recipients, while thiotepa/fludarabine/busulfan was the most used in haplo-HCT (n=99, 60%). Total body irradiation (TBI) was given to only 8% of pts (n=84), mainly in haplo-HCT (n=29). Most (n=1002, 98%) pts received calcineurin inhibitors (CNI), tacrolimus or cyclosporine A, for graft-versus-host disease (GVHD) prophylaxis in addition to mycophenolate mofetil (43%) or methotrexate (38%). Post-transplant cyclophosphamide was used in 18% (n=191) of pts, with 71% (n=136) having received haplo-HCT, and anti-thymocyte globulin was given to 67% (n=689). The median follow-up was 24 months. At day 60, the cumulative incidence of neutrophil engraftment was 99%. The cumulative incidence of grade III-IV acute GVHD (aGVHD) was 9% at day 180. At 2 years, the cumulative incidence of extensive chronic GVHD (cGVHD) was 17%. At 2 years, relapse incidence (RI), NRM, overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) were 26%, 13%, 69%, 61%, and 48%, respectively. The main cause of death was primary disease in 55% of pts (n=157). Other causes of NRM were infections in 16% (n=45), and GVHD in 17% (n=47). In the multivariate analysis, compared to MSD, the use of MUD increased NRM (hazard ratio (HR) 1.86, p=0.02), GRFS (HR 1.28, p=0.039), aGVHD (HR 2.17, p<0.0001), and cGVHD (HR 1.36, p=0.044). The use of MMUD was associated with worse OS (HR 1.6, p=0.042) and higher risk of aGVHD (HR 2.11, p=0.003). Haplo-HCT was associated with higher incidence of aGVHD (HR 1.69, p=0.021) but lower risk of cGHVD (HR 0.63, p=0.033). Older age, lower performance status (PS), requiring >1 induction to achieve CR1, and FLT3-MRD positivity before allo-HCT were associated with worse LFS. Factors associated with lower OS were MMUD 9/10, older age, poor PS, >1 induction to achieve CR1, adverse cytogenetics, and FLT3-MRD positivity before transplant. In vivo TCD was associated with improved GRFS and lower risk of acute and cGVHD without increase of relapse. The use of RIC compared with MAC did not affect relapse, NRM or any other outcome. In conclusion, in pts with AML transplanted in CR1, those requiring >1 induction or with persistent FLT3-MRD positivity at time of allo-HCT had lower OS. Strategies to improve induction therapy, possibly through the addition of targeted agents, aiming to improve CR rates and deepening responses could potentially improve OS after allo-HCT. The use of RIC was associated with similar outcomes compared to MAC. This finding is particularly important for older pts or those with high HCT-CI scores unlikely to tolerate MAC. Survival after MSD allo-HCT is comparable to MUD and haplo, a finding that is in accordance with previous results for haplo and MUD as valid alternative donors in the absence of MSD. The use of MMUD was associated with lower OS compared to MSD and should be used as a last resort donor in this setting.

Mucosal-Associated Invariant T (MAIT) Cells Are Functionally Impaired in Pediatric Patients Following HCT and Their Recovery Is Associated with the Onset of GvHD

Delayed quantitative and qualitative immune recovery, in particular of the T-cell lineage, is associated with an increased risk of infections, disease relapse and adverse clinical outcomes in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). This delay is particularly relevant for recipients of T cell-depleted grafts who do not benefit from the adoptive transfer of mature donor T cells and experienced profound and prolonged immunodeficiency which lasts until the T-cell pool is newly generated from donor hematopoietic precursor cells. A better understanding of the reconstitution dynamics of all the components of the immune system after allo-HCT is crucial to optimize the control of infections, leukemia relapse and graft-versus-host disease (GvHD). We performed a longitudinal observational study to explore the kinetics of T-cell recovery in patient peripheral blood by combining multiparameter flow-cytometry and functional ex vivo assays. Ninety-three children with hematological malignancies who received transplantation after myeloablative conditioning regimen were included in the study: 59 patients received T-cell receptor (TCR) alpha-beta/CD19-depleted HLA-haploidentical HCT (alpha/beta-haploHCT), while 34 unmanipulated matched unrelated donor (MUD) HCT (32 MUD recipients received BM and 2 received PBSC). Among the different T-cell populations assessed, we found that mucosal-associated invariant T (MAIT) cells displayed profound alterations in frequency and function across all time points analyzed. MAIT cells are a class of unconventional αβ T cells that recognize microbial proteins presented by non-polymorphic MHC class I related-molecule (MR1) and possess innate-like capacity. While total TCRαβ T cells gradually started to recover approximately from 3 months reaching normal levels between one to two years post transplantation (Figure 1), MAIT cells defined as CD3+ TCRαβ+ MR1-5-OP-RU-tetramer+ showed long-term impaired reconstitution, and their numbers did not reach normal levels up to two-years post-HCT (Figure 1). Compared to MUD HCT, MAIT cell recovery after alpha/beta-haploHCT was significantly delayed, in agreement with the fact that TCRab reconstitution in this clinical setting is primarily driven by de novo T cell formation. Previous studies demonstrated that MAIT cells are characterized by the binding to MR1-Ag tetramers and simultaneous expression of the C-type lectin-like receptor CD161, a marker associated with memory phenotype and trafficking of immune cells. Interestingly, across all time points of the study, we observed that most MAIT cells following were CD161-. We also found increased expression of the activation marker CD38 and the senescence marker CD57, and downregulation of CD28 in MAIT cells following allo-HCT, suggesting a dysfunctional or hyperactivated status. In agreement with these data, ex vivo stimulation of PBMCs at day +360 post allo-HCT with Escherichia Coli or anti-CD3/anti-CD28 showed that MAIT cells had suboptimal upregulation of the activation markers CD25 and CD69, and reduced production of pro-inflammatory cytokines IFNg, TNFa and IL2, when compared to healthy control samples. Previous studies suggested that a low MAIT cell number was associated with an increased risk of acute GvHD, In the MUD cohort of our study, we did not observe significant correlations between the kinetics of MAIT cell recovery and the occurrence of GvHD. On the other hand, we found a significantly higher frequency of CD161+ MAIT cells at day +30 in alpha/beta-haploHCT patients who developed acute GvHD (grade 1 or greater). Trends toward higher frequency of CD161+ MAIT cells in patients developing acute GvHD were also observed at day +60 and +90, although not statistically significant. Our study shows that MAIT cell recovery is delayed in children for up to two years following allo-HCT. MAIT cells exhibited altered functional status as demonstrated by the expression of activation/senescence makers as well as the suboptimal response to TCR stimulation. Interestingly, we found that a large proportion of MAIT cells are CD161- after transplantation, which can be the result of recruitment of CD161+ cells to peripheral tissues or down regulation of CD161 after cell activation. Finally, our data suggested that the evaluation of CD161 expression on MAIT cells after alpha/beta-haploHCT may identify patients at risk of acute GvHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparable Clinical Outcomes between Haploidentical Family Donor and Other Donor Types after Hematopoietic Stem Cell Transplantation for Rare Pediatric Rare non-Malignant Diseases

Introduction : Hematopoietic stem cell transplantation (HSCT) has been applied as the curative treatment for rare pediatric non-malignant diseases. However, these patients are at risk of transplant related morbidity and there are no established conditioning regimens, especially for children without matched sibling donors. We evaluate the outcome of 43 pediatric cases with rare non-malignant diseases treated with HSCT.Method : We performed a retrospective analysis of a total of 43 transplantations performed in 41 patients with rare non-malignant diseases between May 2002 and May 2017. The conditioning regimens were myeloablative (busulfan, cyclophosphamide) until the middle of 2011, and reduce intensity regimens were applied thereafter. Fanconi anemia patients received fludarabine, cyclophosphamide with or without ATG. In haploidentical hematopoietic stem cell transplantation (HHCT) before year 2016 a combination of fludarabine, cyclophosphamide and ATG was mostly used, while uniformed combination of fludarabine, thiotepa, treosulfan and ATG was used since 2016. Grafts for HHSCT were manipulated by ex vivo CD3 or αβ+ T-cell depletion.Results : This study included 14 patients with congenital immunodeficiency, 13 with congenital bone marrow failure syndrome, 5 with degenerative metabolic disease and 7 with familial hemophagocytic lymphohiotiocytosis (Table 1). By donor types, 8 patients received grafts from matched familial donor (MFD), 22 from matched unrelated donor (MUD), and 10 from haploidentical family donor(HFD), respectively.The median age at HSCT was 2.5 years (range, 0.65-13.5 years). Grafts for HHCTs were CD3-depleted in 2 patients and αβ+ T-cell depleted in 8. The median infused dose of CD34+ cells were 9.38 x 106/kg (range, 0.15-44.11). Among 41 patients, 39 patients reached neutrophil engraftment, with a median of 11 days (range, 9-21) with no significant difference in neutrophil engraftment between donor types (P value 0.355).Graft failure (GF) occurred in 4 patients (primary in 3 patients; Omenn syndrome, Kostmann syndrome, Thalassemia and secondary in 1 patient; Wiskott-Aldrich syndrome). One expired due to sepsis, and 1 patient diagnosed with thalassemia is alive with occasional red blood cell transfusion on an outpatient basis. The other two underwent second HHCT; one with secondary GF died due to pneumonia after engraftment, and the other experienced GF but alive with supportive care.Mixed chimerism was detected in 24 patients 1 month after HSCT (range, 1 - 100%) and in 10 patients 1 year after HSCT (range, 1 - 80%). Grade II-IV acute GVHD occurred in 12 patients (29%, 5 with Gr II, 5 with Gr III and 2 with Gr IV), while chronic GVHD occurred in 4 patients (10%, 1 MFD, 3 MUD and all extensive). There were 4 patients who developed cytomegalovirus (CMV) disease, and 2 with sinusoidal obstruction syndrome (SOS), but no post-transplant lymphoproliferative disorder. There was no mortality related to GVHD, CMV or SOS.As for survival results, a total of 6 patients died; one HFD recipient died of pneumonia on day +216 of second HHCT, 3 MUD recipients died of pulmonary hemorrhage and the other 1 MUD recipient died of sepsis. One MUD patient died due to sudden cardiac arrest 3 years after HSCT. The overall transplant-related mortality was 14.6%. At a median follow up 56 months (range, 0.3 - 182 months), the 5-year overall survival (OS) and event free survival (EFS) was 85.4% and 82.9%, respectively. There was no statistical difference in OS and EFS among HSCTs from 3 different donor types (OS - MFD : 100% vs MUD : 72.7% vs HFD : 90.0%, P=0.336, EFS-MFD : 100% vs MUD : 72.7% vs HFD : 80.0%, P=0.367). Patients who received HSCT at younger age (<500 days) had a worse outcome compared to the older age group (OS : 54.5% vs 96.7%, P=0.001, EFS : 63.6% vs 90.0%, P=0.038). Patients in the congenital immunodeficiency group tended to have a lower OS, although this showed no statistically significant difference (P=0.074).Conclusion : In this study, we presented a single center experience of HSCT in pediatric rare non-malignant diseases and showed that HHCT donors were comparable to HSCT from other donor types, with no statistically significant difference in neutrophil engraftment, OS and EFS. Since an HLA haploidentical relative is available in almost every patient, the improvement of this treatment modality will offer a better chance of cure in patients with a variety of pediatric rare non-malignant diseases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Outcomes between HSCT Donor Sources for Pediatric Patients with Hematologic Malignancies

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for pediatric patients with hematologic malignancies. Historically, matched sibling donors (MSD) have been the preferred donor source given ease of availability and lower rates of graft-versus-host-disease (GVHD). However, only 30% of patients have a MSD and relapse rates are high after MSD HSCT, raising the question of best donor choice. As conditioning regimens evolve, GVHD management improves and supportive care advances, it is important to evaluate the role of donor source on short and long-term clinical outcomes to inform donor selection. We performed a single-center retrospective analysis comparing post-HSCT outcomes in a cohort of pediatric patients undergoing MSD, matched unrelated donor (MUD), and umbilical cord blood (CB) transplants from 2006 to 2018. Methods: A retrospective analysis was performed on an IRB-approved protocol through Fred Hutchinson Cancer Research Center. 232 patients were included who received MSD (n=56), MUD (n=89) or CB (n=87) transplants. Of note, 24 CB patients received expanded CB cells in addition to unmanipulated unit(s). GVHD prophylaxis in all patients consisted of a calcineurin inhibitor and MMF or methotrexate. The vast majority received a high-intensity conditioning regimen (86%, 96%, and 82% respectively for MSD, MUD and CB). Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method. Probabilities of non-relapse mortality (NRM), relapse, and acute GVHD were evaluated using cumulative incidence (CI) estimates with appropriate competing risks. The Cox regression model was used for adjusted analysis for age, year of transplant, sex, CMV status, MRD status, disease risk, and conditioning regimen. Results: Patient/treatment/donor demographics are shown in Table 1. Median follow-up was 2.6, 3.7 and 3.1 years for MSD, MUD and CB respectively. Patient diagnosis, disease risk, gender, age, and CMV serology were balanced between groups. CI of engraftment was similar as well, with only one graft failure in the MUD group (Fig 1). Median time to platelet recovery was significantly faster in MUD and MSD groups as compared to the CB group (p&lt;0.0001; p&lt;0.0001). There was no difference in unadjusted 5 year OS (Fig 2) and NRM (Fig 3) between groups. Five-year DFS was significantly higher in CB v. MSD (71% v. 54%, p=0.03) but not between CB v. MUD (71% v. 61%, p=0.18) or between MSD and MUD (p=0.38) (Fig 4). The CI of relapse at 5 years was 20% for CB patients, significantly lower than that of MSD recipients (49%, p=0.003) and not different from MUD (32%, p=0.11) (Fig 5). After adjusted analysis, the risk of DFS failures was higher among recipients of MSD than CB [HR: 1.88 (CI 95%: 1.01-3.47), p=0.04]. When CB versus MUD groups were compared, there was a trend of higher risk of DFS failures in the MUD group [HR: 1.28 (CI 95%: 0.96-1.66), p=0.09]. No difference was observed in risk of DFS failures between MSD versus MUD groups [HR:0.77 (CI 95%: 0.44-1.4), p=0.43]. Incidence of grade II-IV acute GVHD was 90% (95%CI: 82-95%), 75% (95%CI: 61-84%) and 88% (95%CI: 80-94%), for CB, MSD and MUD, respectively (p=0.25). Incidence of grade III-IV acute GVHD was 33% (95%CI: 23-43%) for CB, 9% (95%CI: 3-18%) for MSD, and 11% (95%CI: 5-18%) for MUD. Incidence of grade III-IV was significantly higher for the CB group compared to the other groups (p=0.001); however, nearly 60% of CB recipients with grade III-IV acute GVHD were diagnosed before engraftment had occurred and in retrospect met criteria for pre-engraftment syndrome. Among surviving patients, 23 CB recipients developed chronic GVHD (26% - 15 mild, 4 moderate, 4 severe) as compared to 14 MSD patients (25% - 13 mild, 1 moderate) and 40 MUD patients (45% - 27 mild, 11 moderate, 2 severe). Conclusions: Our data demonstrate no difference in unadjusted OS between MSD, MUD and CB recipients. Importantly, despite this equivalence, 5-year DFS was significantly better in the CB v. MSD group, reflecting the lower relapse rate observed in CB patients and seen previously by us and others. CB continues to be viewed as an "alternative" donor for HSCT due to the low stem cell dose in a CB graft resulting in delayed neutrophil recovery, primary graft failure and increased NRM. However, this was not observed herein, supporting the use of CB for pediatric HSCT perhaps especially in patients at high risk of post-transplant relapse. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Bleakley:HighPass Biotherapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties, Research Funding.

The influence of stem cell source on transplant outcomes for pediatric patients with acute myeloid leukemia

AbstractWhen hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; P = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; P = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.

PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

AbstractThis study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD−) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)–based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD−, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD−. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD−. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.

Unrelated donor vs HLA-haploidentical α/β T-cell– and B-cell–depleted HSCT in children with acute leukemia

AbstractTraditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients (P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.

Allogeneic Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: a Single-Center Prospective Trial.

The purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center. Forty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs. Thirty-two patients received MUD PBSCs. All patients received a conditioning regimen of busulfan/alemtuzumab (with low-dose total body irradiation for MUD recipients) with sirolimus graft-versus-host disease prophylaxis. Engraftment occured in 38/40 recipients (95%). Acute or chronic GVHD occurred in 18 (45%) and 5 (12.5%), respectively, with 6 episodes of grades III-IV and/or steroid refractory GVHD. Overall survival was 33/40 (82.5%) and event-free survival was 30/40 (80%). Successful engraftment was associated with myeloid and NK cell, but not CD3+ chimerism. Myeloid engraftment was greater than 70% in 30/32 recipients at mean follow-up of 3.4years. Evidence of persistent immunodeficiency was not seen in successful transplants. Attempts to rescue failed or poorly functioning grafts were associated with unacceptable morbidity and mortality. A reduced-intensity allogeneic transplant protocol based on alemtuzumab and busulfan with sirolimus GVHD prophylaxis produced high rates of successful engraftment and minimal regimen-related toxicity. Prolonged clinical follow-up has confirmed its efficacy in ameliorating CGD-related disease. Outcomes were not acceptable with donor cell infusion rescue of cause with poor graft function.

Comparable Survival Outcome with a Faster Engraftment of HSCT from a Haploidentical Donor Compared to Other Donor Types in Pediatric Acquired Aplastic Anemia

Background: Hematopoietic stem cell transplantation (HSCT) remains the preferred frontline curative modality for patients with aplastic anemia in the presence of a matched familial donor (MFD). In the absence of MFD, the general consensus is frontline immunosuppressive therapy followed by HSCT from a matched unrelated donor (MUD) in case of failure or relapse, and recently haploidentical family donor (HFD) is emerging as an alternative donor in aplastic anemia. We evaluated the outcome of HSCT in children and adolescents with acquired severe aplastic anemia (SAA), and compared outcomes of transplantation according to the donor types.Methods:We performed a retrospectively analysis of 61 patients with acquired SAA at a single center between July 1998 and May 2016. Conditioning regimen was a reduced-intensity combination of fludarabine, cyclophosphamide, and rabbit anti-thymocyte globulin in most cases, and low dose total body irradiation was added for haploidentical hematopoietic stem cell transplantation (HHCT). Grafts for HHCT were manipulated by ex vivo T-cell depletion.Results: Of the 61 patients reviewed, total 66 HSCTs were done. The median age at HSCT was 12.5 years (range, 0.7-21.7 years). By donor types, 15 patients received grafts from MFD, 20 from MUD, and 26 from HFD. Grafts for HHCTs were CD3-depleted in 12 patients, CD3/CD19-depleted in 4, and ¥á¥â+ T-cell depleted in 10 patients.Among 61 patients, 59 patients achieved neutrophil engraftment at a median of 11 days (range, 9-18 days). The medians of neutrophil engraftment were 10 days in HFD recipients, 13 days in MFD and 12 days in MUD HSCTs, respectively, and HHCT group had significantly faster neutrophil engraftment than others (Figure 1).There were 9 patients who experienced graft failure (GF) among 61 patients. Of the 35 patients with matched donors, 1 patient failed to achieve primary engraftment, and 3 experienced graft rejection after engraftment. Of the 26 HFD recipients included, neutrophil engraftment was achieved in 25 patients, except 1 patient. Additional 4 HHCT recipients experienced graft rejection within 1 month post-HHCT. Five (1 MUD, 4 HFD) out of 9 patients who experienced GF received a second HSCT and achieved sustained engraftment, another 1 patient was alive without transfusion or further treatment, and the other 3 patients died after GF.A total of 18 patients developed grade II-IV acute GvHD (13 with grade II and 5 with grade III); 9 had received MUD transplant, 7 HFD, and 2 MFD. Seven patients developed chronic GvHD; 4 patients were MUD recipients, and 3 HFD. The cumulative incidence (CI) of grade II-III acute GvHD was 34% (MUD : 45%, HFD : 33.3%, MFD : 16.7%), and 1-year CI of chronic GvHD was 14.4%. There was no statistically significant difference in GvHD occurrence according to the donor types.As for survival results, total four patients died; one HFD recipient died of CMV pneumonia on day +157 of HHCT, and other 3 patients (1 MFD, 1 MUD, 1 HFD) died after GF. Two out of these 3 patients received a second HSCT; one MUD recipient died of acute respiratory distress syndrome and acute renal failure, and another HFD recipient died of pure red cell aplasia. The other MFD recipient died of poor graft function after GF. The overall transplant-related mortality was 7.6%. At a median follow up 45.7 months (range, 1.5-195.2 months), the estimated 5-year overall survival (OS) was 92.7% in 61 patients. There was no statistical difference in OS among HSCTs from three different donor types (MFD : 92.9% vs MUD : 94.4% vs HFD : 91.3% at 5 years, respectively, p value = 0.915) (Figure 2).Conclusions: Our study demonstrated that survival outcomes of HHCT were comparable to HSCT from matched familial or matched unrelated donors in pediatric patients with acquired SAA. HHCT was associated with rapid neutrophil recovery, and tolerable treatment related toxicities in SAA patients. These data suggest that hematopoietic stem cell transplantation from haploidentical family donors is a reasonable therapeutic option for children and adolescents with acquired SAA. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Morbidity and Mortality Experienced By Chronic Myeloid Leukemia (CML) Patients after Allogeneic Hematopoietic Cell Transplantation (HCT) - a Report from BMTSS-2

▪Background: Tyrosine kinase inhibitors have become the treatment of choice for CML. However, the high cost and need for life-long treatment contribute to non-adherence and represent a major challenge in their use. Allogeneic HCT is potentially curative, but the very long-term health of the survivors is not known. It is also not clear whether a subgroup of CML patients carries a relatively low risk of long-term morbidity.Methods: We addressed these gaps by studying long-term outcomes in 637 CML patients treated with allogeneic HCT between 1981 and 2010 at City of Hope or Univ MN, and surviving for at least 2y after HCT (median follow-up: 16.7y from HCT); 80% of the cohort was <45y at HCT; 68% received HCT in 1st chronic phase (CP); 63% received matched related [MRD], 34% matched unrelated donor (MUD) and 3% non-myeloablative HCTs; 79% received TBI; 65.8% developed chronic GvHD. Vital status information was collected as of May, 2016, using medical records, National Death Index and Lexis Nexis. US mortality rates were obtained from CDC’s National Center for Health Statistics. Thirty percent (n=192) died after having survived at least 2 years after HCT; median time between HCT and death was 8.3y. Of the 445 patients alive at study, 288 (65%) completed the BMTSS health questionnaire used to examine the risk of CTCAE grade 3 (severe) or 4 (life-threatening) chronic health conditions. A sibling comparison group (n=404) also completed the BMTSS questionnaire.Results: Late Mortality: Overall survival was 72.1% at 20y and 69.9% at 30y from HCT. The 20y cumulative incidence of relapse-related mortality was 3.9% (95% CI, 2.6-5.8%) and of non-relapse-related mortality was 18.2% (95% CI, 19.8-28.1%) (Figure 1). 20y cumulative incidence of mortality by cause of death was as follows: infection (7%), chronic GvHD (6%), subsequent malignant neoplasms (SMNs: 3%). HCT recipients were at 4.4-fold increased risk of death (95% CI, 3.8-5.1, p<0.0001) than age-, race-, and sex-adjusted normal populations. For patients transplanted in 1st CP and surviving 15y, mortality rates became comparable with the general population (SMR, 1.5, 95% CI, 0.9-2.3, p=0.1). Among CML patients receiving HCT at <45y with Bu/Cy (n=70), overall survival was 81.5% at 20y from HCT; the 20y cumulative incidence of relapse-related mortality was 2.9% and of non-relapse-related mortality was 14%. This cohort was at 3.3-fold higher risk of death when compared with the general population (95% CI=1.7-5.7, p<0.0001). Late Morbidity: The 20y cumulative incidence of a severe/life-threatening chronic health condition among HCT survivors was 47.2% (95% CI, 39.0-54.9%); the incidence was higher (p=0.0006) for MUD vs. MRD recipients (Figure 2). After adjusting for age, sex, race and SES, HCT survivors were at 2.7-fold higher risk for severe/life-threatening chronic health conditions as compared with siblings (95% CI, 1.8-3.9, p<0.0001). The 20y cumulative incidence of specific conditions experienced by survivors and siblings were: SMNs (10.1% vs. 1.7%, p<0.001); diabetes (11.1% vs. 1.5%, p<0.001) and coronary artery disease (6.9% vs. 3.2%, p<0.001). CML patients receiving MRD HCT at <45y with Bu/Cy were not at increased risk of severe/life-threatening chronic health conditions when compared with the sibling comparison group (HR=0.81, 95% CI, 0.26-2.54, p=0.7).Conclusions: Conditional on surviving the first 2y after HCT, the overall survival exceeds 70% at 20y and remains stable at 70% at 30y after HCT. Non-relapse related mortality (infections, chronic GvHD, SMNs) is by far the major contributor to the late mortality. Conditional on surviving the first 15y, mortality rates are similar to those observed in the general population. HCT survivors are at a 2.7-fold higher risk of severe/life-threatening morbidity when compared with siblings. The more common morbidities include SMNs, diabetes and coronary artery disease. However, CML patients receiving HCT at <45y with Bu/Cy conditioning enjoy survival rates exceeding 81% at 20y from HCT, and their burden of long-term morbidity is comparable to that experienced by siblings. These findings could help inform decisions regarding therapeutic options for management of CML. [Display omitted] [Display omitted] DisclosuresSnyder:BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.

Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation

Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m2 and treosulfan 42 g/m2 (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m2 to 180 mg/m2, busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation–specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

Evolving Criteria of Donor Selection for Allogeneic Transplant in Acute Myeloid Leukemia

Background. Similar probabilities of survival have been reported for patients transplanted from Matched Unrelated Donor (MUD), Umbilical Cord Blood (UCB) or Haploidentical (Haplo) donors as alternative hematopoietic stem cell sources. However, few studies have compared these results with those obtained in patients transplanted from HLA Id-siblings (Id-sib). Moreover, all reported studies are retrospective and the criteria of donor selection were not predefined. We report the intention to treat (ITT) analysis results on 238 patients with high-risk acute myeloid leukemia (AML) prospectively transplanted according to the policy of the Rome Transplant Network (RTN), a metropolitan transplant program established in Rome in 2006.Patients and Methods. For AML patients eligible to an allogeneic transplant, the RTN policy consists of an algorithm of donor choice based on a hierarchy according to the following criteria: 1) HLA identical sibling; 2) MUD ≥8/10 HLA 3) UCB as single unit selected on the base of cell dose and number of HLA disparities (0-1/6 HLA: TNC ≥2.5x107/kg and CD34 ≥1x105/kg; 2/6 HLA: TNC ≥3.5x107/kg and CD34 ≥2x105/kg); 4) G-CSF primed, unmanipulated bone marrow Haplo donor. Myeloablative (MAC) or reduced intensity (RIC) TBF (Tiothepa, Busulfan, Fludarabine) conditioning regimen was identical for all patients, GVHD prophylaxis was uniform for each categories. of transplantResults. From January 2006 to December 2014, 238(89%) out of 303 adult patients candidates to an allogeneic transplant for high-risk AML were considered eligible. Overall, a donor was available for 205 (86%) of 238 eligible patients. At time of the analysis, 17 of these 205 patients (8%) had lost the transplant eligibility and 4 (2%) were still scheduled for transplant, therefore 184/205 (90%) patients with an available donor were finally transplanted from Id-sib (n=76), MUD (n=38), UCB (n=17) or Haplo (n=53) donors. The 8-yrs overall survival (OS) of the 238 eligible patients from time of HLA typing and of the 184 transplanted patients from time of the graft was 40±4%and 43±4%, respectively. By excluding the low number of UCB recipients (n=17), the OS was particularly dismal for the 34 patients transplanted in advanced disease phase (7±4% at 4 yrs), whereas for the 132 patients transplanted in early (CR1+ CR2) phase the 8-yr OS was 56±5%: 58±7% for 61 HLA Id-sib, 50±8% for 40 Haplo and 63±10% for 27 MUD recipients (P=NS). The OS of patients transplanted in early phase was 63±5% for 97 patients receiving MAC and 33±9% for RIC recipients. For these 97 patients, the survival by type of donor was 62±10% either for 47 Id-sib or 28 Haplo and 70±10% for 22 MUD recipients (P=NS). The results were analyzed by various donor/recipient (D/R) combinations such as age, sex and CMV status. The median donor age was 39 years (range, 18-70) and the median patient age was 43 years (range, 16-59): the 8-yr OS of patients (n=30) with younger D/R combination (D<39y-R<43y) was79±9%, significantly higher than 55±7% observed for the other D/R combinations (P=0.04). The 4 D/R sex combinations were homogeneously distributed among Id-sib, MUD and Haplo recipients: for 51 sex mismatched (DM/RF; DF/RM) patients the 8-yr OS was 73±7%, significantly higher than the 53±8% rate observed for 46 sex matched patients (P=0.03). Finally, the 8-yr OS by D/R CMV status was 68±6% for 74 D/R CMV matched and 46±12% for D/R CMV mismatched patients (P=NS). In multivariate analysis, the factors influencing survival were D/R age (P=0.059), D/R sex (P=0.03) and D/R CMV status (P=0.04). The donor source (Id-sib vs MUD vs Haplo) did not affect survival (P=NS).Conclusions. RTN policy allowed donor identification in 86% of all eligible AML patients and allowed an allogeneic transplant to be carried out in 90% of them with no substantial differences in terms of long-term survival between initially eligible (ITT analysis) and definitively transplanted patients. Only the definition of a specific transplant policy and the ITT analysis allow to evaluate the real impact of a transplant program. As the probability of survival is not substantially different comparing different donor stem cell sources, the final conclusion which can be drawn from our study is that for patients with AML undergoing an allogeneic transplant, the HLA matching is unlikely to remain the first criterion for donor identification. Other factors such as D/R age, sex and CMV status should drive the search for the best donor. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lower Use of DLI Post Relapse of Malignancy May Result in Shorter Post-Relapse Survival (PRS) in Patients Undergoing T Cell Replete Haploidentical Donor Transplantation (HIDT) Versus Matched Related (MRD) or Matched Unrelated Donor (MUD) Hematopoietic Cell Transplantation (HCT)

▪Relapse of hematologic malignancies remains a major cause of treatment failure and mortality among patients receiving allogeneic hematopoietic cell transplantation (HCT). Patients relapsing after a matched related or unrelated donor transplantation may benefit from donor lymphocyte infusion (DLI) as part of their post relapse therapy. DLI post-relapse has less frequently been utilized among recipients of HIDT presumably due to the potential for severe GVHD if high T-cell doss are administered without immunosuppression. However, reluctance to administer DLI may limit the possibility of remission following disease relapse in HIDT. We compared the frequency of use of DLI and survival outcomes for patients relapsing after HIDT using post-transplant cyclophosphamide to those relapsing after MRD or MUD HCT at our institution.195 consecutive HCT recipients with relapse of hematologic malignancy occurring after HIDT (N=35), MUD (N=74) and MRD (N=81) between 1998 and 2014 were included in this analysis. The median age was 50 years (19-77 years) and median time to relapse was 159 days (25-2465 days) post HCT. Patients receiving HIDT had similar median time to relapse (5.1 vs 5.2 vs 5.2 months, p=0.638), Dana-Farber/CIBMTR disease risk index (DRI), comorbidity index (CMI) scores, longer times to neutrophil engraftment (17 vs 14 vs 14 days, p<0.001), and platelet engraftment (28 vs 19 vs 18 days, p<0.001) when compared to MUD and MRD recipients respectively. Post-relapse survival at 1 year was worse among HIDT recipients when compared to MRD (9% versus 41%, p=0.008) and MUD (9% vs 35%, p=0.025). DLI was used in 3 (8%) relapsed HIDT patients, 48 MRD patients (59%) and 28 (38%) MUD recipients. Among patients relapsing post MRD and MUD HCT, use of DLI was associated with a better post relapse survival (p=0.04). In a multivariate analysis, donor type (HIDT), time to relapse (<3 months versus > 3months post-transplant) and comorbidity index (CMI score >= 3) were all predictive of worse post relapse survival.This analysis shows that relapse post HIDT carries a worse prognosis than relapse post MRD and MUD. Efforts such as post-transplant maintenance and haploidentical DLI infusions should be investigated further in the HIDT setting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Haploidentical Allogeneic Transplantation Provides Comparable Outcomes to HLA-Matched or Mismatched Unrelated Donor Grafts in Hematological Malignancies

Haploidentical (HAPLO) and unrelated donors (URD) are established cell sources for patients (pts) who lack HLA-matched siblings. Limited data are available comparing transplant (TP) outcomes using cells from HAPLO vs URD donors. We performed a retrospective analysis of sequential pts (n=54) undergoing HAPLO transplants with post-transplant cyclophosphamide (Cy). A control group of HLA 7/8 or 8/8 matched URD recipients (n=59) matched by diagnosis, transplant date, and cell source (PBSC or marrow) was identified (Table). Most HAPLO pts received cycles of pre-TP fludarabine (Flu) for lymphodepletion to achieve CD4 <0.2x109/l. HAPLO pts received Flu 30 mg/m2 qd x 5 with Cy 14.5 mg/kg qd x 2, followed by TBI, 200-400 cGy in 1 or 2 fractions (physician discretion). PB (n= 30) or BM (n= 24) was infused from 1st or 2nddegree related HAPLO donors. Post-transplant immunosuppression was Cy 50-60 mg/kg on days +3 and +4, followed by tacrolimus (tacro) and mycophenolate (MMF) starting on day +5. Pts received filgrastim daily starting at day +5. URD recipients were conditioned with a variety of standard myeloablative (n=23) or reduced intensity (n=36) regimens, and received PB (n= 40) or BM (n= 19), with daily filgrastim starting on day +9. GvHD prophylaxis was tacro and short-course methotrexate (n= 53) or tacro/MMF (n=6). CD3+ and CD15+ cell chimerisms were assessed at 4 week intervals commencing at day +28. Bone marrow staging and CD34+ cell chimerism were assessed at day +84. GvHD was staged per standard guidelines. Analysis of categorical variables was performed using the Fisher’s exact test. Non-parametric analysis of median values was used for continuous variables. Survival was assessed using the log-rank test. Informed consent for analysis of transplant outcome data was obtained before transplantation for all patients and donors.Engraftment kinetics in the HAPLO cohort was slightly slower compared to the URD cohort, ANC >0.5x109/l at a median of 16 days (range: 13-45) vs 13 days (range: 9-25, p<0.001); PLT >20x109/l median 24 days (range: 13-109) vs 15 days (range: 8-216, p= 0.02). ANC and PLT recoveries were faster for URD PB compared to BM recipients. However, engraftment kinetics did not differ for HAPLO PB or BM recipients, (ANC median days 16.5 vs. 16, p=0.38; PLT median 24 vs 26 days p=0.80). HAPLO donor CD3 engraftment was robust, with 44 of 48 (92%) HAPLO compared to 37 of 52 (71%) URD recipients achieving >95% CD3+ chimerism at day +28 (p=0.01). Engraftment failure defined by failure to achieve ANC recovery and day +28 donor CD3 chimerism >5% was reported in 4 (7.4%) HAPLO and 2 (3%) URD recipients (p=0.42).The cumulative incidence of grade II-IV aGVHD by day 100 was similar for both groups (61% vs 47%, p=0.19). The cumulative incidences of cGVHD in the HAPLO vs URD cohorts were comparable (39% vs 36%, p=0.84) and the incidence of moderate or severe cGVHD was 15% and 22%, respectively (p=0.34). At time of analysis, relapse occurred for 37% HAPLO pts (n=20) compared to 33% (n=20) in the URD group (p=0.84). 23 pts died (43%) in the HAPLO group: 12 from relapse, 5 from infection, 6 from other causes. In the URD group, 23 (39%) died: 13 from relapse, 3 from infection, 7 from other causes. The one-yr survival probabilities were 56% HAPLO and 66% URD, with median OS probabilities 18 mo and 22 mo (p=0.85). OS was lower for recipients of 7/8 vs 8/8 matched URD grafts, but the difference was not significant (not shown).These results show similar outcomes after HAPLO and URD transplant for engraftment, GvHD, relapse and OS. Almost all HAPLO pts achieved full donor CD3+ chimerism by day +28. In conclusion, HAPLO transplant with post transplant Cy is an option for pts lacking HLA matched siblings; prospective studies are needed to validate these findings. [Display omitted] ; [Display omitted] DisclosuresNo relevant conflicts of interest to declare.