Grade III-IV Acute Graft-versus-host Disease Research Articles

Human leukocyte antigen-haploidentical transplantation for relapsed/refractory acute myeloid leukemia: Better leukemia-free survival with bone marrow than with peripheral blood stem cells in patients ≥55 years of age.

The best stem cell source for T-cell replete human leukocyte antigen (HLA)-haploidentical transplantation with post-transplant cyclophosphamide (PTCy) remains to be determined. In this European Society for Blood and Marrow Transplantation retrospective study, we analyzed the impact of stem cell source on leukemia-free survival (LFS) in adult patients with primary refractory or relapsed acute myeloid leukemia (AML) given grafts from HLA-haploidentical donors with PTCy as graft-versus-host disease (GVHD) prophylaxis. A total of 668 patients (249 bone marrow [BM] and 419 peripheral blood stem cells [PBSC] recipients) met the inclusion criteria. The use of PBSC was associated with a higher incidence of grade II-IV (HR=1.59, p=.029) and grade III-IV (HR=2.08, p=.013) acute GVHD. There was a statistical interaction between patient age and the impact of stem cell source for LFS (p < .01). In multivariate Cox models, among patients <55 years, the use of PBSC versus BM resulted in comparable LFS (HR=0.82, p=.2). In contrast, in patients ≥55 years of age, the use of PBSC versus BM was associated with higher non-relapse mortality (NRM) (HR=1.7, p=.01), lower LFS (HR=1.37, p=.026) and lower overall survival (HR=1.33, p=.044). In conclusions, our data suggest that in patients ≥55 years of age with active AML at HLA-haploidentical transplantation, the use of BM instead of PBSC as stem cell source results in lower NRM and better LFS. In contrast among younger patients, the use of PBSC results in at least a comparable LFS.

P1351: CHARACTERIZING ALLOGENEIC STEM CELL TRANSPLANTATION SAFETY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AFTER PEMBROLIZUMAB THERAPY

Background: Although allogeneic stem cell transplantation (allo-SCT) and programmed cell death 1 (PD-1) blockade have separately shown efficacy in some lymphoid malignancies, the safety of allo-SCT after anti–PD-1 therapy in these patients remains a high clinical interest. Aims: We present data from an analysis from 4 KEYNOTE phase 1-3 studies to describe predetermined complications in patients who received allo-SCT following pembrolizumab therapy. Methods: The analysis included patients from the KEYNOTE-013 (NCT01953692, n=20), KEYNOTE-087 (NCT02453594, n=31), KEYNOTE-170 (NCT02576990, n=5), and KEYNOTE-204 (NCT02684292, n=14) trials who have a known allo-SCT transplantation date received within 2 years of the last dose of study pembrolizumab. Descriptive statistics were used for predefined post–allo-SCT complications of interest. The cumulative incidence of acute grade 2-4 graft-versus-host disease (GVHD), acute grade 3-4 GVHD, and chronic GVHD was estimated. The corresponding competing risk events were death without acute grade 2-4 GVHD, death without acute grade 3-4 GVHD, and death without chronic GVHD, respectively. The cumulative incidence of post–allo-SCT transplant-related mortality (TRM) was estimated with relapse as a competing risk. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Seventy patients were included in the analysis. Median age was 30 y (range, 18-65), 57 (81.4%) had classical Hodgkin lymphoma (cHL), and the rest had non-Hodgkin lymphoma. 69 of 70 (98.6%) patients received pembrolizumab monotherapy; 1 patient received pembrolizumab + lenalidomide. Median duration on study treatment was 5.3 months (range, 0.7-29.6) and median time from last pembrolizumab dose to first allo-SCT was 4.6 months (range, 1-20). Before transplantation, 49 patients (70.0%) had intervening anticancer regimen; 34 (48.6%) had active disease, 31 patients (44.3%) were in remission at time of transplant, and 5 patients (7.1%) had unknown disease status. Overall, 55 patients (78.6%) developed GVHD (acute, 38; chronic, 17). The estimated 6-month post–allo-SCT cumulative incidence was 0.41 (95% CI, 0.30-0.53) for grade II-IV acute GVHD and 0.20 (95% CI, 0.12-0.30) for grade III-IV acute GVHD; 1 year post–allo-SCT was 0.21 (95% CI, 0.12-0.31) for chronic GVHD. Other predetermined complications, including critical illness, immune-mediated adverse events, pulmonary complications, and veno-occlusive liver disease, occurred in 32 patients (45.7%). After a median follow-up (defined as the time from allo-SCT to data cutoff) of 40.1 months (range, 5.1-71.2), the post–allo-SCT median PFS was not reached (NR) (95% CI, 14.5-NR) and the 30-month post–allo-SCT PFS rate was 56.8% (95% CI, 42.9-68.5) (Figure A); median OS was NR (95% CI, NR-NR) and the OS rate at 12 months was 82.2% (Figure B). The estimated post–allo-SCT cumulative incidence for TRM at 6 months was 0.09 (95% CI, 0.03-0.17) and for relapse at 26 months was 0.27 (95% CI, 0.16-0.38). PFS and OS outcomes were comparable in the subgroup of patients with cHL. Image:Summary/Conclusion: The incidence of GVHD in this population is comparable to historical data (40%-80% and 30%-70%, respectively). The incidence of severe acute GVHD may be higher than a typical modern allo-SCT series, although TRM was low. The observed PFS and OS outcomes compare favorably to historical benchmarks (2-year PFS ranging from 45%-48%; 1-year OS >80%). Altogether, this analysis lends confidence that allo-SCT is feasible for patients with lymphoid malignancies after PD-1 blockade.

P1326: FACTORS ASSOCIATED WITH THE OUTCOME OF ALLO-HSCT FOR ADVERSE-CYTOGENETIC RISK ACUTE MYELOID LEUKEMIA

Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the unique intention-curative consolidation strategy in patients with Acute Myeloid Leukemia (AML) with unfavorable cytogenetic risk. It is a high-cost procedure with significant transplant-related mortality (TRM), therefore, the correct selection of candidates for allo-HSCT resembles as a crucial issue. Aims: To describe the outcome of this procedure and to identify those patients who could obtain a better benefit. The primary endpoint was Overall Survival (OS) and secondary endpoints were relapse-free survival (RFS), cumulative incidence of Graft-versus-host disease (GVHD), cumulative incidence of relapse and (TRM). Methods: We conducted an observational retrospective study in patients with adverse-risk cytogenetically defined AML (Upon the European LeukemiaNet 2017 criteria and the results of the Next Generation Sequencing) who underwent a first allo-HSCT in two tertiary referral centers between 2010 and 2020. Results: We analyzed 82 patients with a median age at the moment of transplant of 55 (R 22-73) years. The median time from diagnosis to transplant was 5 (IR 4-7) months. Forty-two (51,2%) were women. Twenty-six patients (31,7%) had an identical HLA sibling donor and 37 (45,1%) had an unrelated HLA identical donor. A myeloablative conditioning was performed in 60 (51%) patients and in 48 (59,8%) the source of HSC was bone marrow. The majority (81,7%) had a first complete remission (CR1) at the moment of transplant and 13,4% had a partial response or a refractory disease (PR/RD). The 41,5% patients had a low comorbidity index score (HCT-CI<3). With a median follow up of 36 months, the OS at 1 and 3 years was 67% (95% CI 64-66%) and 48% (95% CI 45-51%) respectively. The RFS at 1 and 3 years was 62% (95% CI 61-63%) and 45% (95% CI 43-47%), the cumulative incidence of relapse at 1 and 3 years was 18% (95% CI 11-28%) and 29% (95% CI 19-40%) and the TRM at 1 and 3 years was 21% (95% CI 13-30 %) and 28% (95% CI 19-39%) respectively. The cumulative incidence of acute GVHD grade III-IV at day +100 was 17% (95% CI 9-26%). The cumulative incidence of moderate-severe chronic GVHD at 1 and 3 years was 21% (95% CI 13-30 %) and 31% (95% CI 21-42%) respectively. There were no differences in OS regarding age (p=0,2), sex (p=0,9), HCT-CI score (p=0,7), type of donor (p=0,4), acute GVHD (p=0,5), HSCT source (p=0,06), conditioning (p=0,04) and subtype of ELN2017 (p=0,9). A worse OS was observed in patients with PR/RD (HR 1,5 95% CI 1,2-1,9) (p<0,01) compared to those in first complete remission. The OS at two years was 28% (95% CI 26-30) and 59% (95% CI 58-60) respectively (Figure 1). Sixty-six patients were analyzed for OS depending on the development of cGVHD. The OS at 2 years of the patients who did not develop cGVHD (n= 32) was 58% (95% CI 56-60) of those with a mild cGVHD (n=10) was 85% (95% CI 83-87) of those with a moderate cGVHD (n=15) was 79% (95% CI 77-81) and of those who develop a severe cGVHD (n=9) was 64% (95% CI 61-67). Therefore, a worse OS was observed in patients who did not develop cGVHD or had a severe grade compared to those who had a mild or moderate cGVHD HR 5 (95% CI 1,8-15) (p<0,01). Image:Summary/Conclusion: In our series, Allo-HSCT in adverse-cytogenetic risk AML are associated with better OS when it is performed in first complete remission and its benefit is unclear performed in partial response or in a refractory disease, where other strategies should be considered. The development of mild or moderate cGVHD was associated with a better overall survival.

Post-transplant cyclophosphamide pharmacokinetics and haploidentical hematopoietic cell transplantation outcomes: an exploratory study

Pharmacokinetics of cyclophosphamide has been explored to optimize conditioning dosing. We hypothesized that post-transplant cyclophosphamide (PTCy) metabolite carboxy-ethyl phosphoramide mustard (CEPM) pharmacokinetics might impact haploidentical transplantation (haplo-HCT) outcomes. CEPM area under the curve (AUC0–48) was determined by eleven sampling timepoints on day +3/+4 using LC-MS/MS. The median CEPM AUC0–48 in a cohort of 30 patients was 14.2 (14) mg·hr/L. The incidence of severe chronic graft-versus-host disease (GVHD) (73% vs. 11%, p = 0.02), and GVHD-/relapse-free survival (GRFS) was significantly inferior in the CEPM AUC0–48 < 14 mg·hr/L group (54 days vs. 344 days, p = 0.02). There was, however, no difference in grade III-IV acute GVHD (38% vs. 14%, p = 0.12) and overall survival (295 days vs. not reached, p = 0.2). CEPM AUC0–48, is associated with severe chronic GVHD and GRFS post-haplo-HCT in this exploratory study. There is scope for personalizing day + 4 PTCy dose based on day + 3 CEPM AUC0–8.

PTCY and Tacrolimus for GVHD Prevention for Older Adults Undergoing HLA-Matched Sibling and Unrelated Donor AlloHCT

The use of post-transplantation cyclophosphamide (PTCY) for graft-versus-host disease (GHVD) prevention is becoming prevalent in the transplantation community when HLA-identical sibling and 10/10 HLA-matched (MUD) and 9/10 mismatched unrelated donors are selected for alloHSCT. However, reported evidence on outcomes from elderly patients receiving PTCY-containing GVHD prophylaxis remains limited. This study aims to compare the outcomes of PTCY- tacrolimus (TK) prophylaxis and conventional GVHD prophylaxis in patients aged >50 years undergoing peripheral blood alloHSCT from a single institution. A total of 161 consecutive patients aged >50 years undergoing alloHSCT between January 2014 and February 2021 were included. Data were collected retrospectively and updated in December 2021. Patients received grafts from HLA-identical sibling, and from 10/10 and 9/10 HLA matched and mismatched unrelated donors. Overall, median age was 60 years, and 91 (54.8%) received PTCY-TK for GVHD prevention. Time to neutrophil and platelet engraftment was longer in the PTCY-TK group (20 versus 16 days and 19 versus 11 days, P < .001). The cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD) at day 100 and moderate/severe chronic GVHD (cGVHD) at 2 years were 18.2%, 5.7%, and 9.5% for patients receiving PTCY-TK, and 26.0%, 9.6% and 39.5% for those who did not. The multivariate analysis showed that PTCY-TK reduced the probability of grade II-IV aGVHD (hazard ratio [HR] 0.41, P=.035), of cGVHD (any grade: HR 0.43 [P=.014], and of moderate/severe cGVHD [HR 0.15 {P < .001}]). At 2 years, the overall survival (65.4% versus 65.6%, P=.472), non-relapse mortality (17.4% versus 13.7%, P=.967), and cumulative incidence of relapse rates (24.2% versus 27.5%, P=.712) were comparable between both cohorts; GVHD-free/relapse-free survival (GRFS) was higher in the PTCY-TK group (2 years: 50.2% versus 21.8%; HR 0.42, P=.001). In patients aged ≥50 years. PTCY-TK was safe and a more effective drug combination than non-PTCY containing GVHD prophylaxis, even with the use of matched and mismatched unrelated donors, and resulted in comparable relapse rates and better GRFS.

Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation

The effect of single or multiple mismatches at each HLA locus on outcomes after cord blood transplantation (CBT) is controversial. We analyzed the effects of single or multiple HLA locus mismatches on the outcomes after single CBT using Japanese registry data from the Japan Society for Hematopoietic Cell Transplantation. Patients age ≥16 years with acute leukemia and myelodysplastic syndromes who underwent their first CBT between 2003 and 2017 (n=4074) were included. The effect of the number of HLA locus mismatches (0, 1, or 2 for the HLA-A, -B, -C, and -DRB1 loci) on outcomes was analyzed after adjusting for other significant variables. The patient cohort had a median age of 54 years. The median total nucleated and CD34 cell doses were 2.6×107/kg and .8×105/kg, respectively. The number of CBTs with single or double mismatches were 2099 and 292, respectively, for the HLA-A locus, 2699 and 341 for the HLA-B locus, 2555 and 609 for the HLA-C locus, and 2593 and 571 for the HLA-DRB1 locus. Single and double HLA-DRB1 mismatches were associated with a higher risk of grade II-IV acute graft-versus-host disease (GVHD; single: hazard ratio [HR], 1.29, P < .001; double: HR, 1.49, P < .001; P for trend <.001). Single and double mismatches at HLA-DRB1 as well as single mismatches at HLA-A and HLA-B also were associated with grade III-IV acute GVHD. Single and double HLA-B mismatches and double HLA-DRB1 mismatches were associated with a high risk of nonrelapse mortality (NRM). On the other hand, double mismatches at HLA-A or HLA-DRB1 and single mismatches at HLA-B were associated with a lower risk of relapse. HLA-DRB1 double mismatch was associated with high risk of grade II-IV and grade III-IV acute GVHD and NRM but lower risk of relapse. Not only the locus mismatch, but also the number of mismatches, should be considered in cord blood unit selection.

Comparisons of Modified Post-Transplantation Cyclophosphamide and Granulocyte Colony-Stimulating Factor/Antithymocyte Globulin Regimens for Haploidentical Stem Cell Transplantation in Patients with Aplastic Anemia

Haploidentical stem cell transplantation (HSCT) has become an alternative treatment option for patients with aplastic anemia (AA) without matched sibling donors or matched unrelated donors. Recently, post-transplantation cyclophosphamide (PTCy) and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG) regimens have become the most common protocols used worldwide. In this retrospective study, we retrospectively reviewed and analyzed the clinical data of 130 AA patients who underwent haploidentical HSCT and received the modified PTCy (mPTCy) regimen (n=55) or G-CSF/ATG regimen (n=75) between January 2013 and June 2021 across 7 transplantation centers. Neutrophil engraftment was successful in all patients within 30 days in the G-CSF/ATG group. The cumulative neutrophil engraftment rate in the mPTCy group was 96.36% (95% confidence interval [CI], 94.57 to 97.57; P=.010). The median time to neutrophil engraftment in the G-CSF/ATG group was 10 days (range, 7 to 28 days), which was more rapid than that observed in the mPTCy group (P < .001). There was no significant difference in the incidence of graft-versus-host disease (GVHD) between the 2 groups. The cumulative incidence of grade II-IV acute GVHD was 18.40% (95% CI, 4.27% to 40.31%) in the mPTCy group and 19.32% (95% CI, 5.86% to 38.58%) in the G-CSF/ATG group, whereas the cumulative incidence of grade III-IV acute GVHD was 7.31% (95% CI, .09% to 37.48%) in the mPTCy group and 7.57% (95% CI, .20 to 34.19) in the G-CSF/ATG group. Similarly, there were no significant between-group differences in overall survival (OS), failure-free survival (FFS), and GVHD-free relapse-free survival (GRFS). The 2-year OS, FFS, and GRFS rates were 95.91% (95% CI, 84.59% to 98.96%), 92.25% (95% CI, 80.59% to 97.03%), and 86.68% (95% CI, 73.98% to 93.44%), respectively, in the mPTCy group and 86.67% (95% CI, 76.64% to 92.59%), 81.28% (95% CI, 70.45% to 88.46%), and 77.20% (95% CI, 65.89% to 85.16%), respectively, in the G-CSF/ATG group. Transplantation-related mortality (TRM) was significantly higher in the G-CSG/ATG group than in the mPTCy group (13.33% versus 1.96%; P=.022). In multivariate analysis, the use of a female donor, a higher Hematopoietic Cell Transplantation Comorbidity Index, and grade III-IV acute GVHD were associated with worse survival outcomes. The mPTCy and G-CSF/ATG regimens led to similar outcomes in AA patients, but quicker engraftment was observed with the ATG/G-CSF regimen, and a lower incidence of TRM was observed with the mPTCy regimen.

Combination of Haploidentical Hematopoietic Stem Cell Transplantation with Umbilical Cord-Derived Mesenchymal Stem Cells in Patients with Severe Aplastic Anemia: A Retrospective Controlled Study

Objective:We retrospectively compared the outcomes of patients with severe aplastic anemia (SAA) who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) combined or not combined with umbilical cord-derived mesenchymal stem cells (UC-MSCs).Materials and Methods:A total of 101 patients with SAA were enrolled in this study and treated with haplo-HSCT plus UC-MSC infusion (MSC group, n=47) or haplo-HSCT alone (non-MSC group, n=54).Results:The median time to neutrophil engraftment in the MSC and non-MSC group was 11 (range: 8-19) and 12 (range: 8-23) days, respectively (p=0.049), with a respective cumulative incidence (CI) of 97.82% and 97.96% (p=0.101). Compared to the non-MSC group, the MSC group had a lower CI of chronic graft-versus-host disease (GVHD) (8.60±0.25% vs. 24.57±0.48%, p=0.048), but similar rates of grades II-IV acute GVHD (23.40±0.39% vs. 24.49±0.39%, p=0.849), grades III-IV acute GVHD (8.51±0.17% vs. 10.20±0.19%, p=0.765), and moderate-severe chronic GVHD (2.38±0.06% vs. 7.45±0.18%, p=0.352) were observed. The estimated 5-year overall survival (OS) rates were 78.3±6.1% and 70.1±6.3% (p=0.292) while the estimated 5-year GVHD-free, failure-free survival (GFFS) rates were 76.6±6.2% and 56.7±6.9% (p=0.045) in the MSC and non-MSC groups, respectively.Conclusion:In multivariate analysis, graft failure was the only adverse predictor for OS. Meanwhile, graft failure, grades III-IV acute GVHD, and moderate-severe chronic GVHD could predict worse GFFS. Our results indicated that haplo-HSCT combined with UC-MSCs infusion was an effective and safe option for SAA patients.

Targeted Marrow Irradiation Intensification of Reduced-Intensity Fludarabine/Busulfan Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation

Reduced-intensity conditioning (RIC) regimens frequently provide insufficient disease control in patients with high-risk hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated intensification of fludarabine/busulfan (Flu/Bu) RIC with targeted marrow irradiation (TMI) in a dose escalation with expansion phase I clinical trial. TMI doses were delivered at 1.5 Gy in twice daily fractions on days -10 through -7 (dose levels: 3 Gy, 4.5 Gy, and 6 Gy), Flu (30 mg/m2 for 5 days) and Bu (area under the curve, 4800 µM*minute for 2 days). Eligible patients were age ≥18 years with high-risk hematologic malignancy and compromised organ function ineligible for myeloablative transplantation (n=26). The median patient age was 64 years (range, 25 to 76 years). Nineteen patients (73%) had active or measurable residual disease at transplantation. One-year disease-free survival and overall survival were 55% (95% confidence interval [CI], 34% to 76%) and 65% (95% CI, 46% to 85%), respectively. Day +100 and 1 year transplantation-related mortality were 4% (95% CI, 0.6% to 27%) and 8.5% (95% CI, 2% to 32%), respectively. The 1-year cumulative incidence of relapse was 43% (95% CI, 27% to 69%). Rates of grade II-IV and III-IV acute GVHD rates were 57% (95% CI, 39% to 84%) and 22% (95% CI, 9% to 53%), respectively. Whole blood immune profiling demonstrated enrichment of central/transitional memory-like T cells with higher TMI doses, which correlated with improved survival compared with control samples from patients undergoing allogeneic HSCT. Intensification of a Flu/Bu RIC regimen with TMI is feasible with a low incidence of transplantation-related mortality in medically frail patients with advanced malignancies. The recommended phase 2 TMI dose is 6 Gy.

Impact of Donor-to-Recipient ABO Mismatch on Outcomes of Antithymocyte Globulin-Based Peripheral Blood Stem Cell-Derived Myeloablative Conditioning Haploidentical Stem Cell Transplantation

ABO incompatibility is common in hematopoietic stem cell transplantation (HSCT); however, the impact of donor-recipient ABO compatibility on transplantation outcomes in different HSCT settings is controversial. Moreover, haploidentical stem cell transplantation (haplo-SCT) with peripheral blood stem cell (PBSC)-derived grafts has not been well investigated. The present study aimed to investigate the impact of ABO incompatibility on post-transplantation outcomes, engraftment kinetics, blood product requirements, transfusion independence, and the incidence of poor graft function (PGF) in antithymocyte globulin (ATG)-based haplo-SCT with PBSC grafts during long-term follow-up. We prospectively evaluated 510 patients with hematologic malignancies who underwent haplo-SCT after myeloablative conditioning (MAC). The primary endpoint was overall survival (OS), and secondary endpoints were nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, neutrophil and platelet engraftment, blood transfusion requirements, transfusion independence, and the incidence of PGF. There was no significant association between ABO matching and OS, disease-free survival (DFS), relapse, NRM, grade II-IV acute GVHD, grade III-IV acute GVHD, and moderate and severe chronic GVHD. There were also no significant differences in neutrophil and platelet engraftment, blood transfusion independence, and transfusion requirements at 30, 60, 90, 180, and 365 days post-transplantation among patients with ABO matching and those with minor, major, or bidirectional ABO incompatibility. Donor-recipient ABO matching did not differ significantly according to graft function (good versus poor). ABO incompatibility status has no major impact on patient outcomes in patients with hematologic malignancies undergoing ATG-based MAC haplo-SCT with PBSC-derived grafts.

Post-Transplantation Cyclophosphamide After HLA Identical Compared to Haploidentical Donor Transplant in Acute Myeloid Leukemia: A Study on Behalf of GETH-TC

Post-transplantation cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA-identical transplantation. To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy. Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% versus 20%, P = .001), high/very high disease risk index (DRI) (32% versus 67%, P = .000) and prior auto-HSCT (2% versus 11%, P = .010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% versus 62%, P = .07), event-free survival (EFS) (70% versus 54%, P = .055), cumulative incidence of relapse (19% versus 25%, P = .13), non-relapse mortality (14% versus 19%, P = .145), and the composite endpoint of GVHD and relapse-free survival (49% versus 42%, P = .249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced-intensity conditioning, high/very high DRI, and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% versus 47%, P = .000). Cumulative incidences of grade III-IV acute GVHD (4% versus 9%, P = .14) and moderate-severe chronic GVHD (22% versus 19%, P = .28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. The use of an HLA-identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample sizes should be performed to establish a possible benefit of HLA-identical donor on survival.© 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n=30; LTV group) and those receiving preemptive therapy (n=31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P=.434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P=.232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P=.024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P=.124) and a higher rate of acute GVHD grade III-IV (P=.103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis.

The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56months (range 22-108months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging.

Post-Transplantation Cyclophosphamide-Based Haploidentical versus Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplantation cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin using similar busulfan-based myeloablative conditioning regimens in pediatric acute leukemia. Here we compared the outcomes in children and adolescents with high-risk acute leukemia who underwent HRD HSCT with PTCy (n=35) or MUD HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median duration of follow-up was 3.7 years in the HRD group and 4.6 years in the MUD group. No engraftment failure was observed in either group. There were no significant between-group differences in the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) (34.3% versus 48.9%; P=.142), grade III-IV acute GVHD (2.9% versus 8.9%; P=.272), moderate to severe chronic GVHD (11.4% versus 18.3%; P=.417), relapse (25.6% versus 28.0%; P=.832), and nonrelapse mortality (0% versus 2.2%; P=.420). The 3-year severe chronic GVHD-free/relapse-free survival (GRFS), leukemia-free survival (LFS), and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence interval [CI], 45.8% to 80.0%) versus 49.8% (95% CI, 34.9% to 64.7%; P=.318), 74.4% (95% CI, 58.7% to 90.1%) versus 67.5% (95% CI, 53.4% to 81.6%; P=.585), and 88.6% (95% CI, 78.0% to 99.2%) versus 83.7% (95% CI, 72.5% to 94.9%; P=.968), respectively. In a subgroup analysis of patients with acute lymphoblastic leukemia (HRD, n=17; MUD, n=26), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 49.4% (95% CI, 24.3% to 74.5%) versus 39.5% (95% CI, 19.7% to 59.3%; P=.601), 61.8% (95% CI, 37.5% to 86.1%) versus 63.6% (95% CI, 44.4% to 82.8%; P=.872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1% to 98.3%; P=.445), respectively. In patients with acute myelogenous leukemia (AML) (HRD, n=16; MUD, n=16), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 80.8% (95% CI, 61.2% to 100%) versus 61.9% (95% CI, 37.8% to 86.0%; P=.326), 87.1% (95% CI, 70.2% to 100%) versus 73.9% (95% CI, 51.8% to 96.0%; P=.478), and 93.8% (95% CI, 81.8% to 100%) versus 85.6% (95% CI, 67.0% to 100%; P=.628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrate that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen has outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.

Donor lymphocyte infusion after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia

Although haploidentical donor lymphocyte infusion (DLI) is a valid treatment option for relapsed acute myeloid leukemia (AML), the incidence and risk factors for graft-versus-host disease (GVHD) and the efficacy of haploidentical DLI have not been fully evaluated. We retrospectively analyzed the outcomes after haploidentical DLI for 84 patients with AML using a nationwide database and additional questionnaires. The median number of DLI cycles and infused CD3+ cell dose was 1 and 1.0 × 106/kg, respectively. The infused CD3+ cell count of 5.0 × 105/kg or higher was associated with acute GVHD (grade II-IV, 32.1% vs. 10.5%, p = 0.03; grade III-IV, 21.4% vs. 5.3%, p = 0.10). Patients who developed grade III-IV acute GVHD more frequently succumbed to treatment-related mortality (46.7% vs. 15.8% at 1 year, p = 0.002), although the relapse-related mortality was significantly low (40.0% vs. 72.2% at 1 year, p = 0.025). The overall response to DLI was significantly higher in the preemptive DLI group (47.4%) than in the therapeutic group (13.9%, p = 0.002). In the multivariate analysis, preemptive DLI was the predictive factor for overall response (odds ratio, 5.58; p = 0.003). Our results indicated the substantial risk of acute GVHD after haploidentical DLI with CD3+ cell count of 5.0×105/kg or higher and the favorable outcomes after preemptive DLI.

Low-Dose Anti-Thymocyte Globulin Plus Low-Dose Posttransplant Cyclophosphamide as an Effective Regimen for Prophylaxis of Graft Versus Host Disease After Haploidentical Peripheral Blood Stem Cell Transplantation With Maternal/Collateral Related Donors

Maternal and collateral donors were associated with a higher incidence of graft-versus-host disease (GvHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). A more effective regimen for GvHD prophylaxis after haplo-HSCT with maternal/collateral donors needed to be explored. A retrospective study was performed on 62 patients after haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with maternal/collateral donors, which included 35 patients with low-dose antithymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide-based (low-dose ATG/PTCy-based) and 27 with ATG-based regimens for GvHD prophylaxis. The 180-day cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD (aGvHD) were 17.7% and 6.8% in low-dose ATG/PTCy-based group, which were significantly lower than that in ATG-based group (55.4% and 31.9%) (P = 0.003 for grade II-IV and P = 0.007 for III-IV aGvHD). In low-dose ATG/PTCy-based group, the 1-year overall survival (OS) and relapse-free survival (RFS) were 80.0%and 80.4%, which were higher than that in ATG-based group with OS of 59.4% and RFS of 62.0%. In multivariate analysis, the low-dose ATG/PTCy-based regimen significantly reduced the risk of grade II-IV (HR = 0.357; P = 0.049) and grade III-IV aGvHD (HR = 0.190; P = 0.046) as an independent risk factor. The results suggested that the low-dose ATG/PTCy-based regimen could effectively prevent the occurrence of aGvHD after haplo-PBSCT with maternal/collateral donors compared with the ATG-based regimen.

The Two-Step Allogeneic Stem Cell Transplantation Approach Results in Rapid Engraftment and Excellent Outcomes in Patients with Lymphoid Malignancies

The 2-step graft engineering approach has been the main platform for allogeneic hematopoietic cell transplantation (allo-HCT) at Thomas Jefferson University since 2005. We have previously described separating donor lymphocyte infusion followed by cyclophosphamide for bidirectional tolerization from CD34-selected hematopoietic grafts in haploidentical and matched related donors. Here we analyzed 60 patients with high-risk lymphoid malignancies who underwent a 2-step allo-HCT between 2008 and 2020. The majority of patients received haploidentical stem cell grafts (82%), and 20% of patients received matched related donor stem cell grafts. The patients underwent allo-HCT for diffuse large C cell lymphoma (n=17; 28%), chronic lymphoblastic leukemia (n=10; 17%), follicular lymphoma (n=8; 13%), and Hodgkin lymphoma (n=7; 12%). Eight patients (13%) had received prior high-dose chemotherapy. Thirty patients (50%) had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, and 20 patients (33%) had a Center for International Blood & Marrow Transplant Research Revised Disease Risk Index of high risk or very high risk. The median patient age was 56 years (range, 24 to 75 years). Neutrophils engrafted at a median of 11 days (range, 9 to 16 days), and platelets engrafted at a median of 16 days (range, 13 to 37 days). With a median follow-up of 6 years, the 3-year probability of overall survival was 62.9% (95% confidence interval [CI], 49.3% to 73.8%), and that of disease-free survival was 60.2% (95% CI, 46.4% to 71.6%). The cumulative incidence of relapse at 3 years was 11.9% (95% CI, 5.2% to 21.6%). The cumulative incidence of nonrelapse mortality at 3 years was 30.1% (95% CI, 1.91% to 42.0%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 1 year was 45% (95% CI, 32.2% to 57.0%), and that of grade III-IV acute GVHD at 1 year was 5% (95% CI, 1.3% to 12.6%). The cumulative incidence of cGVHD at 3 years was 15.2% (95% CI, 7.5% to 25.4%). The 2-step approach achieved excellent outcomes in high-risk lymphoid malignancies, with rapid neutrophil and platelet recovery.

Chimeric Antigen Receptor T Cell Therapy followed by Unrelated Cord Blood Transplantation for the Treatment of Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia in Children and Young Adults: Superior Survival but Relatively High Post-Transplantation Relapse

Several studies have indicated that chimeric antigen receptor (CAR) T cell therapy followed by allogeneic hematopoietic stem cell transplantation is beneficial for treating patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Whether consolidative unrelated cord blood transplantation (UCBT) is suitable in R/R B-ALL after CAR-T therapy remain uncertain. We aimed to assess the efficacy and safety of CAR-T therapy before UCBT in children and young adults with R/R B-ALL. We retrospectively analyzed 43 patients aged <18 years with R/R B-ALL who underwent single-unit UCBT at the First Affiliated Hospital of the University of Science and Technology of China between February 2012 and November 2020. Among them, 21 patients achieved complete remission (CR) following CAR-T therapy before UCBT (the CAR-T group), and the remaining 22 patients remained in nonremission (NR) without prior CAR-T therapy before UCBT (the NR group). The clinical outcomes in the 2 groups were analyzed. The median time from CAR-T therapy to UCBT was 62 days (range, 42 to 185 days). There were no significant between-group differences in the incidences of grade II-IV acute graft-versus-host disease (GVHD), grade III-IV acute GVHD, and 2-year extensive chronic GVHD. Compared with the NR group, the CAR-T group had a lower 2-year cumulative incidence of transplantation-related mortality and higher probabilities of 2-year overall survival, leukemia-free survival, and GVHD-free relapse-free survival (P=.037, .005, .028, and .017, respectively). However, the 2-year cumulative incidence of relapse (CIR) was comparably high in the 2 groups (26.7% in the CAR-T group and 38.3% in the NR group; P=.41). In the CAR-T group, patients who were minimal residual disease (MRD)-positive before UCBT had a higher CIR compared with those who were MRD-negative before UCBT (66.7% versus 19.2%; P=.006). CAR-T therapy followed by UCBT produces superior survival in R/R B-ALL, but treated patients still have a high post-transplantation relapse rate.

High Failure-Free Survival after Unrelated Donor Peripheral Blood Stem Cell Transplantation in Pediatric Severe Aplastic Anemia

The use of alternative donor peripheral blood stem cell transplantation (PBSCT) has increased in recent years. In this study, we analyzed the effect of stem cell source and HLA disparity on outcomes in pediatric patients with severe aplastic anemia (SAA). A total of 134 patients who underwent HSCT with nonmyeloablative conditioning between 2006 and 2020 were enrolled and classified into 3 groups: HLA-matched bone marrow transplantation (M-BMT; n = 24), HLA-matched PBSCT (M-PBSCT; n = 66), and HLA-mismatched PBSCT (MM-PBSCT; n = 44). Significantly higher stem cell doses were obtained for PBSCT than for BMT. A total of 13 patients experienced secondary graft failure (GF), with a cumulative incidence (CI) of 10.0%. HLA-mismatched PBSCT and a very severe degree of disease significantly decreased the incidence of secondary GF. The CI of grade II-IV acute graft-versus-host disease (GVHD) was significantly higher in PBSCT than in BMT, but the CI of grade III-IV acute GVHD and CI of chronic GVHD requiring systemic treatment did not increase in PBSCT. The estimated 5-year overall survival (OS), failure-free survival (FFS), and GVHD-free failure-free survival (GFFS) of the total cohort were 93.0%, 89.5%, and 77.5%, respectively. The most favorable FFS was observed in the MM-PBSCT group (97.6%; P = .03), whereas OS and GFFS were similar across the 3 groups. In multivariate analysis, HLA mismatch and short time from diagnosis to transplantation were associated with superior FFS. Unrelated donor PBSCT with low-intensity SAA conditioning showed favorable outcomes in terms of low rate of secondary GF, higher FFS, and manageable GVHD regardless of HLA compatibility. Our findings suggest the feasibility of PBSCT from unrelated donors, resulting in the possible expansion of the donor pool in transplantation for pediatric SAA. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens.

Post-transplant cyclophosphamide (PTCy) combined with tacrolimus (TAC) as graft-versus-host disease (GvHD) prophylaxis post-hematopoietic cell transplantation (HCT) is safe and effective. Optimal serum levels of TAC in this combination remain undetermined. We hypothesized that TAC at initial steady state (TISS) of <10 ng/mL could promote optimal transplant outcomes and prevent TAC-associated toxicities. We retrospectively analyzed a consecutive case series of 210 patients who received PTCy/TAC-based prophylaxis post-HCT from 1/2013–6/2018. Patients received HCT from haploidentical (n=172) or mismatched donors (n=38), and flat dose (FD) or weight-based dose (WBD) TAC. Twenty-four-month overall survival (OS), disease free survival (DFS), and relapse rate (RR) were 61%, 56%, and 22%, respectively, in TISS <10 ng/mL cohort (n=176), and 50%, 43%, and 35%, respectively, in TISS ≥10 ng/mL cohort (n=34) (OS, P=0.71; DFS, P=0.097; RR, P=0.031). OS, DFS, RR, non-relapse mortality, acute GvHD grade II-IV, grade III-IV or chronic GvHD by TISS were similar in multivariable analysis. TISS ≥10 ng/mL conferred increased risk of viral infection (P=0.003). More patients receiving FD vs. WBD had TISS <10 ng/mL (P=0.001). Overall, TISS <10 ng/mL early post HCT conferred similar survival outcomes and lowered risk of viral infection and toxicities compared to TISS ≥10 ng/mL.