Cord Blood Transplantation In Patients Research Articles

Lymphocyte Crossmatch Testing or Donor HLA-DP and -DQ Allele Typing Effectiveness in Single Cord Blood Transplantation for Patients With Anti-HLA Antibodies Other Than Against HLA-A, -B, -C, and -DRB1

Anti-human leukocyte antigen (HLA) antibodies other than those against HLA-A, -B, -C, and DRB1 are a risk factor for engraftment delay and failure, especially in cord blood transplantation (CBT). The primary objective of this study was to assess the impact of the presence of anti-HLA antibodies on CBT and to evaluate the utility of lymphocyte crossmatch testing or additional HLA-DP and -DQ typing of CB units in improving transplant outcomes. We retrospectively assessed the engraftment rates and transplant outcomes of 772 patients who underwent their first CBT at our hospital between 2012 and 2021. Donors were routinely typed for HLA-A, -B, -C, and-DRB1 alleles, and the anti-HLA antibodies of recipients were screened before donor selection in all cases. Among patients who had antibodies against other than HLA-A, -B, -C, and DRB1 (n = 58), lymphocyte crossmatch testing (n = 32) or additional HLA-DP/-DQ alleles typing of CB (n = 15) was performed to avoid the use of units with corresponding alleles. The median patient age was 57 years (16 to 77). Overall, 75.7% had a high-risk disease status at transplantation, 83.5% received myeloablative conditioning regimens, and >80% were heavily transfused. Two hundred twenty-nine of the 772 recipients (29.6%) were positive for anti-HLA antibodies. There were no statistical differences in the number of infused CD34-positive cells between the anti-HLA antibody-positive and the anti-HLA antibody-negative patients. Of the 229 patients with anti-HLA antibodies, 168 (73.3%) had antibodies against HLA-A, -B, -C, and-DRB1 (Group A), whereas 58 (25.3%) had antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5 with or without antibodies against HLA-A, -B, -C, and -DRB1 (Group B). No patients in both Groups A and B exhibited donor-specific anti-HLA antibodies against HLA-A, -B, -C, and -DRB1. The neutrophil engraftment rate was lower in patients with anti-HLA antibodies than in those without antibodies (89.9% versus 94.1%), whereas nonrelapse mortality (NRM) before engraftment was higher in antibody-positive patients (9.6% versus 4.9%). In patients who received 2 or more HLA allele-mismatched CB in the host-versus-graft (HVG) direction (n = 685), the neutrophil engraftment rate was lower in the anti-HLA antibody-positive recipients than in the antibody-negative recipients with significant differences (88.8% versus 93.8%) (P = .049). Similarly, transplant outcomes were worse in the antibody-positive patients with respect to 2-year overall survival (OS) (43.1% versus 52.3%) and NRM (44.0% versus 30.7%) than in the antibody-negative patients. In contrast, the results of Group B were comparable to those of the antibodies-negative patients, while the results of Group A were statistically worse than the antibody-negative patients in terms of all engraftment rate (88.6%), OS (34.2%), and NRM (49.0%). The presence of anti-HLA antibodies negatively impacts engraftment, NRM, and OS in CBT. However, HLA-DP/-DQ allele typing of CB units or lymphocyte crossmatch testing could be useful strategies to overcome poor engraftment rates and transplant outcomes, especially in patients with anti-HLA antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5.

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

Impact of Conditioning Intensity and Regimen on Outcomes after Unrelated Cord Blood Transplantation for Patients with Myelodysplastic Syndrome

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). Unrelated cord blood transplantation (CBT) is an alternative donor option in MDS patients who lack an HLA-matched donor, and the increased availability of CBT expand indications for allo-HSCT in MDS patients. Because concerns have been expressed regarding decreased hematopoietic recovery and increased relapse after CBT, many studies have been conducted to develop the conditioning regimen in CBT. The optimal intensity of conditioning regimen needs to be addressed based on patient- and disease-related factors. However, the optimal intensity of conditioning regimen in CBT for MDS remains unclear. We here conducted a nationwide retrospective study to clarify the optimal conditioning intensity for MDS in CBT. Methods This study included patients diagnosed with de novo MDS according to the WHO classification. The clinical data of 856 de novo MDS patients (i) who were 16-69 years old and (ii) who underwent their initial single-unit CBT between 2001 and 2020 were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In this study, 501 and 355 patients received myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), respectively. The median age at CBT was 53 (range,17-69) and 62 years (range,18-69) in MAC and RIC groups, respectively. The most frequently used MAC regimen consisted of total body irradiation >8 Gy-based regimen (n=209, 41.7%), followed by fludarabine (Flu) with myeloablative doses of busulfan (Bu 9.6 to 12.8 mg/kg)-based regimen (n=93, 18.6%). The most frequently used RIC regimen consisted of Flu with reduced doses (80 to 120 mg/m 2) of melphalan-based regimen (n=245, 96.1%), followed by Flu with reduced doses of Bu (6.4 mg/kg)-based regimen (n=63, 17.7%). The 3-year OS were 44.3 % and 48.8 % in MAC and RIC groups, respectively; the 3-year CRFS were 33.8 and 37.2%; the 3-year GRFS were 19.2 % and 26.9%; the 3-year CIR were 27.1% and 30.0%; and the 3-year NRM were 18.6% and 18.2 %. The univariate analysis revealed that RIC group tended to correlate with higher GRFS than MAC group (Hazard ratio (HR) 0.86 [95% confidential interval 0.74-1.00]; P=0.057), but there was no significant difference of OS (HR 0.95 [0.79-1.13]; P=0.552), CRFS (HR 0.95 [0.80-1.12]; P=0.522), CIR (HR 1.11 [0.87-1.41]; P=0.401) and NRM (HR 0.96 [0.77-1.20]; P=0.735) between MAC and RIC groups. The multivariate analyses confirmed the better GRFS in RIC group than MAC group (HR, 0.73 [0.61-0.89]; P=0.001). Apart from the conditioning intensity, the following six factors were associated with worse overall mortality: patient's age (40-60 years; P=0.039 and >60 years; P<0.001), patient's sex (male; P=0.038), performance status (PS) at CBT (PS 2-4; P=0.033), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (HCT-CI ≥3; P=0.035), high number of platelet transfusion before HSCT (≥20 times; P<0.001) , and cytogenetic risk group (poor risk; P=0.001). We next performed the subgroup analysis stratified by the patient's characteristic affecting OS, such as age, sex, PS, HCT-CI, the number of platelet transfusion, and cytogenetic risks. The subgroup analysis showed the better OS (HR, 0.74 [0.59-0.92]; P<0.007), CRFS (HR 0.74, [0.60-0.94]; P=0.012), and GRFS (HR 0.62, [0.50-0.78]; P<0.001) of RIC group than MAC group among patients with patients aged >60 years, but no significant impact on CIR and NRM. Conclusion This study showed no significant difference of OS, CRFS, CIR and NRM between MAC and RIC groups, but RIC group correlated with better GRFS in the entire population. Furthermore, the subgroup analysis showed that RIC regimen may be preferable for patient aged >60 years. These findings would improve the management for CBT candidates with MDS.

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

Background : Double-unit cord blood transplantation (dCBT) is standard therapy for patients with acute myelogenous leukemia (AML) who do not have suitable adult donors. We & others have reported low relapse rates & high progression free survival (PFS) in dCBT recipients suggesting robust CB-derived graft-versus-leukemia effects. However, the efficacy of dCBT in high-risk AML as determined by ELN genetic risk & pre-transplant minimal residual disease (MRD) status has not been performed to date. Methods : All consecutive adult patients with AML who received first dCBT with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400) between 2014-2022 were analyzed. GVHD prophylaxis was with either Cyclosporine-A (CSA)/ Mycophenolate Mofetil (MMF) or CSA/MMF/Tocilizumab on an institutional protocol. Results : 63 patients (pts) (median age 49 years, range 23-63) were eligible for analysis (Table); 42 (67%) were CMV seropositive, 31 (49%) had non-European ancestry, & median HCT-CI was 2 (range 0-6). Most (n = 55, 87%) were in CR1, 5 (8%) in CR2, & 3 were relapsed or primary refractory at transplant (5-9% blasts). By ELN2022 genetic risk criteria, 8 pts had favorable, 29 intermediate, & 20 adverse risk AML (6 were missing ELN status). Of the 60 pts in CR, 36 were MRD- & 18 MRD+ by multicolor flow cytometry (6 had unknown/ indeterminate MRD status). Sixty-one of 63 pts engrafted for a 60-day cumulative incidence of 98% (95%CI:81-100). The median follow-up of survivors was 58 months (range 8-104 months). The 1- & 3-yr incidences of transplant-related mortality (TRM) were 13% (95%CI: 5.9-22) & 18% (95%CI: 9.6-29), respectively. The 1- & 3-year relapse incidences were 3.2% (95%CI: 0.6-9.9) & 8.6% (95%CI: 3.1-18), respectively. The 1- & 3-year OS were 87% (95%CI: 79-96) & 82% (95%CI:72-92) respectively, whereas the 1- & 3-year PFS were 84% (95%CI: 76-94) & 73% (95%CI: 63-85), respectively. When stratified by ELN2022 genetic risk, the 3-year relapse incidence was 0% in favorable, 10% (95%CI: 2.5-25) in intermediate & 13% (95%CI: 2-36%) in adverse risk AML patients. Pts with favorable risk AML had a 3-year PFS of 88% (95%CI: 67-100); the 3-year PFS was similar in patients with intermediate [68% (95%CI: 53-88)] or adverse [67% (95%CI: 48-93)] risk AML (Figure 1A). When stratified by MRD status, the 3-year relapse incidence was 8.4% (95%CI:2.1-20) in MRD- & 13% (95%CI: 1.9-34) in MRD+ patients. The 3-year PFS was similar in patients with AML in CR who were MRD- 80% (95%CI: 68-94) or MRD+ 76% (95%CI: 57-100), whereas all 3 relapsed/ refractory patients died of TRM (Figure 1B). Of 4 TP53-mutated AML patients, one relapsed, one died of TRM, & two are alive in remission. Conclusions: While retrospective, our findings highlight the low relapse rates & promising PFS in adult AML patients, including those with high risk features such as adverse-risk ELN genetic risk &/ or MRD positivity supporting robust CB-derived graft-versus-leukemia (GVL) effects. This observation, together with the mitigation of TRM in recent years due to the optimized transplant practices in adult dCBT (see Politikos et al, ASH 2023), makes intermediate intensity dCBT an attractive strategy for AML patients with a suitable dCB graft & high-risk disease. Our findings warrant prospective multi-center investigation with correlative studies to elucidate the biology of CB-derived GVL.

Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Relapse or Refractory Peripheral T-Cell Lymphoma at Toranomon Hospital and Toranomon Hospital Kajigaya

[Background] Relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) is known to have a poor prognosis. Although new medications have been introduced in recent years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for R/R PTCL. We review the results of allo-HSCT for PTCL at our institution. [Methods] We performed a retrospective analysis of R/R PTCL patients who underwent first allo-HSCT at our hospital from February 2011 and April 2023. The primary endpoint was OS, which was defined as the time from allo-HSCT to death from any cause or the last follow-up. The secondary endpoints included progression-free survival (PFS), relapse/progression incidence (RI) and non- relapse mortality (NRM). PFS was defined as the time from allo-HSCT to relapse/progression, death, or the last follow-up. OS and PFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. [Results] During the study period, a total of 44 patients received first allo-HSCT for PTCL (ALK positive ALCL: 2, ALK negative ALCL: 2, AITL: 10, PTCL-NOS: 21, CTCL: 7, HSTL: 2). The median follow-up months of survivors was 51.6 (range, 2.6-141.6). The median age of patients at transplantation was 50 years (range, 17-70). Clinical stage I/II at diagnosis was 10 cases, and clinical stage III/IV was 34 cases. Prognostic Index for PTCL(PIT) was score 1 in 20 cases, score 2 in 20 cases and score 3 in 3 cases. Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≧ 2 was 21 cases. Performance Status (PS) 0-1 was 32 cases and PS 2-4 was 12 cases. Primary induction failure (PIF) was 28 cases and relapse after first remission (REL) was 16 cases, including 5 cases of relapse after autologous stem cell transplantation. Median number of chemotherapy regimens received before allo-HSCT was 3 (range, 1-8). Clinical stage at transplantation was CR/PR in 23 patients and SD/PD in 21 patients.The majority, thirty-two had received unrelated cord blood transplantation (CBT), six did unrelated bone marrow transplantation (uBMT), and 6 did related peripheral blood stem cell transplantation (rPBSCT). Thirty-two patients received myeloablative conditioning (MAC), eighteen of which included total body irradiation (TBI) and 15 of which included busulfan (BU). Twelve patients received reduced-intensity conditioning (RIC) . Regarding the primary endpoint, the 4-year OS after allo-HSCT was 53.3%. The 4-year PFS, RI and NRM were 50.4%, 20.7% and 28.8%, respectively. The 4-year OS of CBT, uBMT and rPBSCT patients was 55.2%, 66.7% and 33.3%, respectively. The 4-year OS of REL and PIF patients was 79.1% and 39.5%, respectively (p<0.01). The 4-year OS of MAC and RIC was 49.5% and 64.3%, respectively (p=0.58). The 4-year OS of patients with TBI was superior to patients without TBI (71.1% vs 40.3%, p=0.05). The 4-year OS of CR/PR patients at transplant was superior to SD/PD patients (67.1% vs. 42.9%, p=0.05). In the univariate analysis, PS 0-1, HCT-CI 0-1, REL, CR/PR patients at transplant, patients with TBI and patients without BU were favorable prognostic factors. In the multivariable analysis, REL was associated with better OS (p=0.01, HR 0.16; 95% CI: 0.04-0.65). Except for 3 patients who died from transplant complications before engraftment, 41 patients achieved neutrophil engraftment, with a median engraftment date of 19 days (range, 11-31 days) after transplantation. Twenty-seven patients had acute GVHD (Grade I: 3, Grade II: 13, Grade III: 8, Grade IV: 3), and 11 patients had chronic GVHD. Eleven patients relapsed after transplant, and the median time from transplant to relapse was 26.3 months (range, 0.6-87.1 months). Three patients survived at the last follow up, and the median follow-up time of survivors from relapse was 430 days (range, 12-1301). [Conclusion] Our data indicated good results of allo-HSCT for R/R PTCL, and significantly better in relapse after first remission patients.

377 - Favorable Outcomes of Acute Leukemia in Cord Blood Transplant Patients with Graft Failure: A Report of Three Cases 5 Years Follow up

377 - Favorable Outcomes of Acute Leukemia in Cord Blood Transplant Patients with Graft Failure: A Report of Three Cases 5 Years Follow up

Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real World Evidence

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources. CBT has low rates of chronic graft-versus-host disease (GVHD) and allows for several human leukocyte antigen (HLA) mismatches, thus expanding donor availability. However, CBT has fallen into disfavor because of its low cell dose and associated prolonged cytopenias, which result in prolonged hospitalization and higher risk of non-relapse mortality (NRM). Furthermore, the need for large CBs leads to selection of poorly HLA matched CBs, further increasing NRM. UM171 is a small molecule that expands hematopoietic stem cells. From 2016 to 2018, 22 patients with high-risk malignancies who lacked a donor were transplanted on a phase I-II clinical trial with a single UM171-expanded CB (Cohen S et al. Lancet Haematol 2019) after a myeloablative conditioning. The goal was to accelerate engraftment while selecting smaller, better HLA matched CBs to decrease NRM while preserving the benefits of CBT. Results demonstrated that indeed UM171-expanded CB has the potential to overcome slow neutrophil engraftment and diminish NRM. The aim of the current analysis was to examine outcomes after conventional single/double ≥ 4/6 HLA-matched CB and 8/8-matched unrelated donor (MUD) peripheral blood stem cell (PBSC) transplantation with UM171-expanded CBT. Methods: Data on UM171-expanded adult CBT recipients were drawn from the phase I-II trial. Data for adult recipients of myeloablative CB and PBSC transplants for hematologic malignancies (acute myeloid and lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin and Hodgkin lymphoma) in the United States and Canada during 2014-2019 with a Karnofsky performance status (KPS) score ≥70 were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. CB recipients who received anti-thymocyte globulin or alemtuzumab in the conditioning were excluded from the CIBMTR population. Patients were directly matched for the number of prior allogeneic transplants (alloHCT), refined disease risk index (for 1st alloHCT), disease status (for 2nd alloHCT), and acute myeloid leukemia cytogenetic risk. Patients were matched by propensity score for age, comorbidity index and KPS. CIBMTR attempted to identify 4 controls per UM171 patient. Clinical outcomes included engraftment, NRM, progression-free survival (PFS), overall survival (OS), relapse, GVHD-free, relapse-free survival (GRFS), acute GVHD grade III-IV, and chronic GVHD. PFS, OS, and GRFS were estimated by Kaplan-Meir method; other outcomes were calculated using cumulative incidence estimates; marginal Cox regression models were used for analyzing NRM and GRFS. Results: Overall, 137 CIBMTR (67 CB, 70 PBSC) and 22 UM171-expanded CBT patients participated. Univariate analysis and marginal Cox regression analysis results are shown in Tables 1 and 2, respectively. Median time to neutrophil engraftment was 18 days (range 10-30) for UM171-expanded CB recipients compared to 21 days (range 8-53) for CIBMTR CB recipients (p<0.01) (data not shown). Univariate analysis revealed less 1- and 2-year NRM, improved 2-year PFS, improved 1-year OS, and 1- and 2-year GRFS for UM171-expanded CBT compared to CIBMTR CB controls. The UM171 cases had less 1- and 2-year NRM, improved 2-year PFS, and improved 1- and 2-year GRFS compared to CIBMTR PBSC controls. Furthermore, UM171-expanded CB patients experienced less acute GVHD III-IV and chronic GVHD compared to PBSC recipients. In marginal Cox regression analysis, UM171-expanded CBT recipients were 87% and 63% less likely than CIBMTR CB controls to experience NRM and GRFS events, respectively, and 73% less likely to experience GRFS events than CIBMTR PBSC recipients. Conclusions: This real-word evidence suggests that UM171-expanded CB recipients have select improved outcomes compared to conventional CB and MUD PBSC recipients. While this study was limited by the small number of UM171 CB trial participants and inability to identify the planned number of controls for each case, UM171 expansion of CB appeared to achieve the desired outcome of maintaining CB's benefits while removing its disadvantages. Thus, prospective randomized studies of UM171-expanded CBT compared to MUD PBSC alloHCT are warranted to confirm these results. Study Support: This study was funded by ExCellThera. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Decision Analysis for Unrelated Bone Marrow Transplantation or Immediate Cord Blood Transplantation for Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission

An HLA-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is an alternative option. Higher rates of engraftment failure and nonrelapse mortality (NRM) are significant problems, but the ready availability of cord blood can be an advantage, because patients can immediately undergo transplantation before progression. This study was conducted to identify an appropriate alternative donor in patients with Ph-negative ALL in CR1 who do not have an HLA-matched related donor (MRD). Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from an 8/8 MUD (8/8 uBMT) or uBMT from a 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients age 16 to 55 years with Ph-negative ALL in CR1 who did not have an MRD. We constructed a decision tree. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, resulting in evaluation of the 5-year life expectancy after both decisions. Transition probabilities (TPs) and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan. Subgroup analyses were performed according to risk stratification based on WBC count and cytogenetics at diagnosis and according to age stratification, with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were performed as well. The baseline analyses showed that 8/8 uBMT or 7/8 uBMT had superior results to CBT, with quality-adjusted life years (QALYs) of 2.86 in 8/8 uBMT, 2.84 in 7/8 uBMT, and 2.75 in CBT. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probability of NRM in CBT improved. Subgroup analyses showed similar results in younger, older, and high-risk patients. However, QALY was worse in 8/8 uBMT compared with CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in younger and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the one-way sensitivity analyses. For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either an 8/8 MUD or a 7/8 MUD is expected to yield a better outcome than immediate CBT. Nonetheless, CBT is a viable option, and improvements to reduce the risk of NRM in CBT may change these results.

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Poor survival and prediction of prolonged isolated thrombocytopenia post umbilical cord blood transplantationin patients with hematological malignancies.

Prolonged isolated thrombocytopenia (PIT) is a common complication after umbilical cord blood transplantation (UCBT). However, data on PIT prediction and impacts on transplantation outcomes for UCBT patients are rare. We retrospectively analyzed 244 patients with hematological malignancies who received single-unit UCBT at the First Affiliated Hospital of USTC between August 2018 and December 2019. Among them, PIT occurred in 49 recipients, with a crude incidence of 20.1%. In the PIT patients, the 2-year cumulative incidence of transplant-related mortality (TRM) was significantly higher, and the probabilities of 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were significantly poorer (57.1% vs. 88.6%; 53.1% vs. 81.9%; 22.4% vs. 59.8%; p<0.001), without remarkable increases in the cumulative incidence of relapse or chronic GVHD. Importantly, the multivariate analysis revealed that lower high-resolution HLA compatibility (≤6/10), lower infused CD34+ cell count (≤1.78×105 /kg), grade II-IV acute GVHD preplatelet engraftment, a lower pretransplantation platelet count (≤100×109 /L), and a longer neutrophil engraftment time (≥17 days) were independent risk factors for PIT after UCBT. These results demonstrate that PIT is common after UCBT, predicting inferior survival and the need for more monitoring during the early phase.

Stem cell transplantation for pediatric patients with adrenoleukodystrophy: A nationwide retrospective analysis in Japan.

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms. We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n=39), Regimen B; busulfan/cyclophosphamide±others (n=23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation±anti-T lymphocyte globulin±fludarabine (n=27), and Regimen D: others (n=10). The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p=0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p=0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p=0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p=0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p=0.173). Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.

Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT.

Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P = 0.36) and 84% in UD 9/10 patients (P = 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P < 0.001), male gender (P < 0.001), second complete remission (CR2) versus CR1 (P = 0.05), secondary AML (P = 0.01), antecedent of chronic GVHD (P < 0.001) and poor-risk cytogenetics (P = 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.

Favorable Outcomes after Single Cord Blood Transplantation for Patients with High-Risk Hematologic Diseases: A Single-Institute Retrospective Analysis

The donor selection algorithm for cord blood (CB) with regards to matched related and unrelated donors has not been fully investigated. To assess the potential of CB transplantation (CBT) in patients with hematologic malignancies, especially for high-risk patients, we performed a single-institute retrospective analysis and compared the clinical outcomes of CBT with those of HLA-matched sibling and unrelated donor transplantation. We included 394 patients aged 16 years and older with hematologic diseases who received their first allogeneic hematopoietic cell transplantation between 1990 and 2018 at Kyoto University Hospital. These included 394 recipients of single unrelated cord blood units (UCB, n=108), HLA-matched sibling donors (MSDs, n=143), or HLA-matched unrelated donors (MUDs, n=143). There was no significant difference in relapse-free survival (RFS) between UCB, MSD, and MUD recipients (P=.975). However, we found a significant interaction between transplant year and CBT outcomes (P=.010), with significantly better outcomes observed in the more recent years. Furthermore, we found that CBT showed better RFS than matched donor transplantation (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30 to 0.84). This impact was more prominent in high-risk patients (HR, 0.35; 95% CI, 0.16 to 0.77), with lower relapse rates (HR, 0.25; 95% CI, 0.11 to 0.54), and comparable non-relapse mortality (NRM) compared to matched donor transplantation. Extensive chronic graft-versus-host disease was less frequently observed in CBT (HR, 0.58; 95% CI, 0.26 to 1.28). CBT associated with favorable outcomes, particularly in high-risk patients, with good RFS and low relapse rates without an increase in NRM in the single-institute study. Although the findings should be externally validated, CBT might serve as a reasonable donor choice, particularly in high-risk patients.

307 - Favorable Outcomes of Acute Leukemia in Cord Blood Transplant Patients with Graft Failure: A Report of Three Cases

307 - Favorable Outcomes of Acute Leukemia in Cord Blood Transplant Patients with Graft Failure: A Report of Three Cases

Population pharmacokinetics of tacrolimus in umbilical cord blood transplant patients focusing on the variation in red blood cell counts.

The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count. A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model. Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L)=91.4×(Hb/8.2)(-1.07) . In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation.

IntroductionCord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients.MethodsAll patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived.ResultsMedian age was 27 (range 1–58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).ConclusionsUsing a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.

Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant

AbstractWe compared outcomes among adult matched related donor (MRD) patients undergoing peripheral blood stem cell transplantation and adult patients undergoing double unit cord blood transplantation (CBT) at our center between 2010 and 2017. A total of 190 CBT patients were compared with 123 MRD patients. Median follow-up was 896 days (range, 169-3350) among surviving CBT patients and 1262 days (range, 249-3327) among surviving MRD patients. Comparing all CBT with all MRD patients, overall survival (OS) was comparable (P = .61) and graft-versus-host disease (GVHD) relapse-free survival (GRFS) was significantly improved among CBT patients (P = .0056), primarily because of decreased moderate to severe chronic GVHD following CBT (P < .0001; hazard ratio [HR], 3.99; 95% confidence interval [CI], 2.26-7.04). Among patients undergoing our most commonly used MRD and umbilical cord blood (CB) myeloablative regimens, OS was comparable (P = .136) and GRFS was significantly improved among CBT patients (P = .006). Cumulative incidence of relapse trended toward decreased in the CBT group (P = .075; HR, 1.85; CI 0.94-3.67), whereas transplant-related mortality (TRM) was comparable (P = .55; HR, 0.75; CI, 0.29-1.95). Among patients undergoing our most commonly used nonmyeloablative regimens, OS and GRFS were comparable (P = .158 and P = .697). Cumulative incidence of both relapse and TRM were comparable (P = .32; HR, 1.35; CI, 0.75-2.5 for relapse and P = .14; HR, 0.482; CI, 0.18-1.23 for TRM). Our outcomes support the efficacy of CBT and suggest that among patients able to tolerate more intensive conditioning regimens at high risk for relapse, CB may be the preferred donor source.

Effect of KIR/HLA receptor-ligand mode on prognosis of single unrelated cord blood transplantation in patients with hematological malignancies

目的探讨自然杀伤细胞免疫球蛋白样受体（KIR）与人类白细胞抗原（HLA）受配体模式对血液病患者单份非血缘脐血移植（sUCBT）预后的影响。方法回顾性分析2012年7月至2018年6月270例接受sUCBT的血液病患者。移植前脐血及患者均进行HLA12个位点高分辨配型，选择移植物（脐血）的KIR均同时表达2DL1和2DL2/2DL3抑制性基因，根据患者KIR配体情况分为缺失组（C1/C1或C2/C2）和无缺失组（C1/C2）。结果270例血液病患者中男146例（54.1％），女124例（45.9％），中位年龄13（1～62）岁；缺失组174例（64.4％），无缺失组96例（35.6％）。全部患者均采用不含抗胸腺细胞球蛋白（ATG）清髓性预处理方案。缺失组、无缺失组粒细胞植入率均为98.9％（172/174、95/96），中位植入时间分别为16（10～41）d、17（11～33）d（P＝0.705）；血小板植入率分别为88.5％（154/174）、87.5％（84/96），中位植入时间分别为35（11～113）d、38.5（13～96）d（P＝0.317）；缺失组、无缺失组Ⅱ～Ⅳ级急性GVHD发生率分别为38.7％（95％CI 31.4％～45.9％）、50.0％（95％CI 39.6％～59.6％）（P＝0.075），多因素分析显示KIR配体缺失是影响Ⅱ～Ⅳ度急性GVHD发生的独立保护性因素（P＝0.036）。移植后3年累积复发率分别为17.7％（95％CI 11.7％～24.9％）、22.7％（95％CI14.4％～32.2％）（P＝0.288）。中位随访时间742（335～2 512）d，缺失组、无缺失组3年总生存率分别为72.1％（95％CI 64.1％～78.6％）、60.5％（95％CI 47.9％～69.2％）（χ2＝3.629，P＝0.079），3年无病生存率分别为64.9％（95％CI 56.2％～72.3％）、55.4％（95％CI 44.4％～65.0％）（χ2＝3.027，P＝0.082），移植后180 d 非复发死亡率分别为12.1％（95％CI 7.7％～17.4％）、16.7％（95％CI 10.0％～24.8％）（P＝0.328）。结论在不含ATG清髓性预处理sUCBT血液病治疗体系中，缺失抑制性KIR配体患者移植后急性GVHD发生率更低。

Different Immune Reconstitution between Cord Blood and unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease

Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.