Single-unit Unrelated Cord Blood Research Articles

The Clinical Influence of Complete Remission With Incomplete Count Recovery (CRi) on Single-Unit Unrelated Cord Blood Transplantation in Patients With Acute Leukemia

Recent evidence has indicated that measurable residual disease (MRD) markedly affects the prognosis of patients with acute leukemia post-transplantation. However, the prognostic relevance of complete remission with incomplete count recovery (CRi) before transplantation has not been extensively explored. In this single-center, longitudinal study, we assessed the outcomes of 466 MRD-negative acute leukemia patients who underwent single-unit unrelated cord blood transplantation (sUCBT), including 117 patients with CRi. We observed that acute myeloid leukemia (AML) patients with CRi had a significantly lower cumulative incidence of both neutrophil (90.8% versus 96.5%) and platelet engraftment (67.2% versus 85.3%) and experienced increased transplant-related mortality (TRM) (100-day TRM: 14.2% versus 5.3%; 1-year TRM: 20.6% versus 11.3%; P = .024 and .063, respectively), mainly due to infection-related deaths, compared to those in complete remission (CR). Multivariate analysis revealed that CRi was an independent adverse predictor of both neutrophil and platelet engraftment and increased 100-day TRM in AML patients. However, CRi status did not affect relapse or reduce 5-year overall survival (OS), leukemia-free survival (LFS), or GVHD-free relapse-free survival (GRFS) in the AML cohort. Conversely, for patients with acute lymphoblastic leukemia (ALL), CRi did not impact engraftment, TRM, relapse or survival after sUCBT. Our findings underscore that CRi status before sUCBT portends poorer engraftment outcomes and a greater TRM in AML patients, although it does not significantly affect the prognosis of ALL patients.

Feasibility and safety of the discontinuation of systemic immunosuppressive treatment after single-unit cord blood transplantation in adults

We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.

Association of individual comorbidities with outcomes in allogeneic hematopoietic cell transplantation from unrelated adult donors versus unrelated cord blood: A study on behalf of the Donor/Source and Transplant Complications Working Groups of the Japanese Society for Transplantation and Cellular Therapy.

We retrospectively evaluated the effect of 17 individual comorbidities, defined by the hematopoietic cell transplantation (HCT)-specific comorbidity index, on non-relapse mortality (NRM) and overall survival (OS) in 9531 patients aged between 16 and 70 years who underwent their first allogeneic HCT from 8/8 and 7/8 allele-matched unrelated donors (8/8 and 7/8 MUDs) or single-unit unrelated cord blood (UCB) between 2011 and 2020 using data from a Japanese registry database. In the multivariate analysis, infection (adjusted hazard ratio [HR], 1.62, 95% confidence interval [CI], 1.33-1.99 for 8/8 and 7/8 MUDs; adjusted HR, 1.33, 95%CI, 1.12-1.58 for UCB) and moderate/severe hepatic comorbidity (adjusted HR, 1.57, 95%CI, 1.04-2.38 for 8/8 and 7/8 MUDs; adjusted HR, 1.53, 95%CI, 1.09-2.15 for UCB) had a significant impact on NRM in both donor groups. Cardiac comorbidity (adjusted HR, 1.40, 95%CI, 1.08-1.80), mild hepatic comorbidity (adjusted HR, 1.22, 95%CI, 1.01-1.48), rheumatologic comorbidity (adjusted HR, 1.67, 95%CI, 1.11-2.51), renal comorbidity (adjusted HR, 2.44, 95%CI, 1.46-4.09), and severe pulmonary comorbidity (adjusted HR, 1.40, 95%CI, 1.11-1.77) were significantly associated with an increased risk of NRM but only in UCB recipients. Renal comorbidity had the strongest impact on poor OS in both donor groups (adjusted HR, 1.73, 95%CI, 1.10-2.72 for 8/8 and 7/8 MUDs; adjusted HR, 2.24, 95%CI, 1.54-3.24 for UCB). Therefore, unrelated donor selection should be taken into consideration along with the presence of specific comorbidities, such as cardiac, rheumatologic, renal, mild hepatic, and severe pulmonary comorbidities.

Complete Remission with Incomplete Count Recovery (CRi) Prior to sUCBT Is Associated with High Graft Failure in Acute Leukaemia Patients over 14 Years of Age

Recent studies have shown that measurable residual disease (MRD) has a definite impact on transplantation outcomes for acute leukaemia patients. However, the influence of complete remission with incomplete count recovery (CRi) prior to transplantation is rarely reported. Therefore, we retrospectively analysed 364 MRD-negative acute leukaemia patients who received single-unit unrelated cord blood transplantation (sUCBT). Among them, 90 patients were diagnosed with CRi. The cumulative incidence of neutrophil engraftment was lower for the CRi patients than for the CR patients. The cumulative incidences of platelet engraftment, 100-d non-relapse mortality (NRM), acute graft-versus-host disease(GVHD), chronic GVHD and the probabilities of 5-year overall survival, leukaemia-free survival and GVHD-free relapse-free survival were comparable. Among the patients older than 14 years (≥ 14), the CRi group was associated with decreased neutrophil and platelet engraftment compared to the CR patients (92.0% vs. 96.8%, 58.0% vs. 76.0%, P = 0.019, 0.018, respectively). Multivariate analysis of neutrophil engraftment in the patients ≥ 14 revealed that CRi,especially incomplete platelet recovery (CRp) prior to transplantation, were independent risk factors. Our study suggests that CRi is associated with an increased risk of graft failure for patients ≥ 14 after sUCBT, even after controlling for other risk factors.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n=331) or single-unit unrelated cord blood (UCB) (n=668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P=0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P=0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P=0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P=0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P<0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P<0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P<0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P<0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Unrelated Cord Blood Transplantation in Children, Adolescents, and Young Adults with Acute Leukemia or Myelodysplastic Syndrome: A Retrospective Comparative Study from the French Society for Bone Marrow Transplantation and Cellular Therapy Between Real-World Data and Previously Reported Results of a Randomized Clinical Trial

We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality [TRM], engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We compared the characteristics and outcomes of RCT participants (n=137) to a Francophone population-based registry of patients (real-world [RW] group) fulfilling the eligibility criteria used in our RCT and transplanted with 1 or 2 UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n=141). The primary endpoint was the 2-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. The 2 groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, P< .001) and to receive a radiation-free regimen (39.0% versus 60.6%, P< .001). The 2-year CI of transplantation strategy failure, TRM, and the 2-year probability of OS were similar between the 2 groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% versus 20.4% ± 6.8%, P= .01), resulting in a significantly lower disease-free survival (DFS) (59.2% ± 8.4% versus 69.3% ± 8.0%, P= .047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used.

Reducing Mortality of Single-Unit Unrelated Cord Blood Transplantation for Relapsed Acute Myeloid Leukemia after a Previous Allogeneic Transplantation: A Real-World Retrospective Study Over the Past 19 Years in Japan

Relapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Second or subsequent allogeneic HCT using unrelated cord blood has been performed for adult patients with AML who have relapsed after a previous allogeneic HCT. Although outcomes after unrelated cord blood transplantation (CBT) as the first allogeneic HCT have significantly improved in recent years, it is unclear whether survival and engraftment improve after CBT as the second or subsequent allogeneic HCT for adult AML patients relapsing after a previous allogeneic HCT. The objective of this retrospective study was to evaluate trends of survival and other transplantation outcomes after single-unit unrelated CBT as a second or subsequent allogeneic HCT in adult patients with relapsed AML after a previous allogeneic HCT over the past 19 years in Japan. We retrospectively assessed survival trends and other outcomes of single-unit unrelated CBT as a second or subsequent allogeneic HCT in adult patients with relapsed AML after a previous allogeneic HCT according to the time period of CBT (2001-2007, 2008-2013, or 2014-2019) using a nationwide Japanese database. The median age was 45 years among 1109 CBTs, and 844 (78.6%) patients were not in complete remission at the time of CBT. Over the 3 time periods, there was a progressive increase in higher cryopreserved cord blood total nucleated cell dose and myeloablative conditioning regimens. The 2-year overall survival was 14.0% in 2001-2007, 19.9% in 2008-2013, and 24.4% in 2014-2019 (P <.001 by log-rank trend test). The 2-year relapse-related mortality was 54.0% in 2001-2007, 44.4% in 2008-2013, and 39.1% in 2014-2019 (P < 0.001 by Gray's test), but nonrelapse mortality was not significantly different across the time periods (P=0.557 by Gray's test). The 42-day neutrophil engraftment also significantly improved (62.9% in 2001-2007, 69.7% in 2008-2013, and 79.9% in 2014-2019; P < 0.001 by Gray's test). Our data demonstrate significant improvements in overall and relapse-related mortality, as well as neutrophil engraftment, after single-unit unrelated CBT as a second or subsequent allogeneic HCT for adult patients with AML relapsed after previous allogeneic HCT over the past 19 years.

Gene therapy offers new hope for children with metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare, progressive lysosomal storage disease caused by mutations in the gene encoding arylsulfatase A (ARSA), causing disease in the central and peripheral nervous systems. MLD presents in toddlers (late infantile disease) or in children (juvenile disease) with gait disturbances, loss of developmental milestones, and cognitive decline, leading to death in childhood. It is frequently not diagnosed until the later symptomatic phase when it is too late to intervene. Haematopoietic stem-cell transplantation (HSCT) from allogeneic donors has been used with mixed results. Although HSCT can slow progression of disease in the central nervous system, it does not prevent progression in the peripheral nervous system. HSCT is also associated with risks of graft-versus-host disease and treatment-related toxicity. 1 Boucher AA Miller W Shanley R et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015; 10: 94 Crossref PubMed Scopus (66) Google Scholar , 2 Wolf NI Breur M Plug B et al. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020; 7: 169-180 Crossref PubMed Scopus (11) Google Scholar , 3 Beschle J Döring M Kehrer C et al. Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. Mol Cell Pediatr. 2020; 7: 12 Crossref PubMed Google Scholar , 4 Vander Lugt MT Chen X Escolar ML et al. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020; 4: 3041-3052 Crossref PubMed Scopus (3) Google Scholar Additionally, small trials of intrathecal gene therapy in mice or humans did not result in improvement in symptoms of clinical disease. 5 Miyake N Miyake K Sakai A Yamamoto M Suzuki H Shimada T Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A. Sci Rep. 2021; 1120513 Crossref PubMed Scopus (1) Google Scholar Thus, new therapeutic approaches are desperately needed. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded accessTreatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy. Full-Text PDF Open Access

Combined impact of HLA-allele matching and the CD34-positive cell dose on optimal unit selection for single-unit cord blood transplantation in adults

The combined effects of HLA-allele matching at six-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and CD34+ cell dose on clinical outcomes were analyzed in 1,226 adult cases with single-unit unrelated cord blood transplantation. In the six-loci analysis, low HLA-allele matches did not significantly increase the overall mortality compared to higher matches, whereas in the five-loci analysis excluding HLA-DPB1, they caused a higher overall mortality (HR 1.42, p = .002), possibly due to the graft-versus-leukemia effect of HLA-DPB1 mismatches. A lower CD34+ cell dose (<.50 × 105/kg) resulted in higher mortality and lower engraftment; these inferior outcomes were offset by high HLA-allele matches (7-10/10 match), while the inferior outcomes of low HLA-allele matches were improved by increasing the CD34+ cell dose. Consideration of the combined effects of the CD34+ cell dose and HLA matching may expand the options for transplantable units when HLA matching or the CD34+ cell dose is inadequate.

Outcomes of Adolescents and Young Adults Compared with Children with Acute Leukemia after Single-Unit Unrelated Cord Blood Transplantation Using Myeloablative Conditioning without Antithymocyte Globulin

Background: Although the use of cord blood transplantation (CBT) is becoming more frequent in acute leukemia, considering the relationship between the low stem cell dose and graft failure, whether use of CBT for adolescents and young adults (AYAs) is appropriate remains uncertain. Methods: A retrospective registry-based analysis of clinical outcomes and immune reconstitution was conducted for 105 AYAs and 187 children with acute leukemia who underwent single-unit CBT using myeloablative conditioning (MAC) without antithymocyte globulin (ATG). Results: Outcomes were similar between AYAs and children, except for nonrelapse mortality (NRM) and recovery rates of neutrophils and platelets. The 30-day cumulative incidence of neutrophil engraftment was similar between AYAs and children, but children had faster rates of neutrophil and platelet recovery than AYAs. The median time to neutrophil engraftment was earlier in children than in AYAs (AYAs, 19 days, 95% confidence interval [CI] 17.3–21.7; children, 16 days, 95% CI 13.1–19.5, p = 0.00003). The incidence of platelet recovery on day 120 was higher in children than in AYAs (AYAs, 80%, 95% CI 71–81%; children, 88%, 95% CI 82–92%, p = 0.037). CD34⁺ cell dose was the only independent factor influencing both neutrophil and platelet recovery. The cumulative incidence of NRM at 2 years was higher among AYAs than among children (AYAs, 27.5%, 95% CI 20–37%; children, 15%, 95% CI 10–21%, p = 0.008). Conditioning regimen was an independent factor influencing NRM. With respect to immune reconstitution, natural killer cell counts quickly recovered to normal levels 1-month post-CBT in both children and AYAs. CD8⁺ T-cell counts were higher in children than in AYAs at 1 and 3 months post-CBT. CD4⁺ T-cell counts were similar in both children and AYAs after CBT. Conclusion: AYAs with acute leukemia have outcomes of single-unit CBT using MAC without ATG that are as good as those of children. Thus, single-unit CBT using modified MAC without ATG is an acceptable choice for both AYAs and children who do not have a suitable donor.

Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders

AbstractChildren with many inherited nonmalignant disorders can be cured or their condition alleviated by hematopoietic stem cell transplantation (HSCT). Umbilical cord blood (UCB) units are a rapidly available stem cell source and offer great flexibility in HLA matching, allowing nearly uniform access to HSCT. Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections have limited their use in chemotherapy-naive patients. We prospectively evaluated a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa with a single-unit UCB graft in 44 consecutive patients with inborn errors of metabolism, immunity, or hematopoiesis. In addition, 5% of the UCB graft was re-cryopreserved and reserved for cord donor leukocyte infusion (cDLI) posttransplant. All patients engrafted at a median of 15 days posttransplant, and chimerism was >90% donor in the majority of patients at 1-year posttransplant with only 1 secondary graft failure. The incidence of grade II to IV graft-versus-host disease (GVHD) was 27% (95% confidence interval [CI], 17-43) with no extensive chronic GVHD. Overall survival was 95% (95% CI, 83-99) and 85% (95% CI, 64-93) at 1 and 5 years posttransplant, respectively. No significant end-organ toxicities were observed. The use of cDLI did not affect GVHD and showed signals of efficacy for infection control or donor chimerism. This RIC transplant regimen using single-unit UCB graft resulted in outstanding survival and remarkably low rates of graft failure. Implementation of the protocol not requiring pharmacokinetic monitoring would be feasible and applicable worldwide for children with inherited disorders of metabolism, immunity, or hematopoiesis. This trial was registered at www.clinicaltrials.gov as #NCT01962415.

Better Engraftment of Single-Unit Unrelated Cord Blood Transplantation in Patients with Acquired Severe Aplastic Anemia Not Respond to IST Using Conditioning Regimen without ATG

Background: Previous studies show that the use of single-unit unrelated cord blood transplantation (sUCBT) for severe aplastic anemia (SAA) has poor outcome because of high incidence of primary graft failure. Effective measures to completely prevent rejection in SAA remain to be identified, but higher cell dose, less HLA disparities and better conditioning regimen are known to improve the outcome. In this study we compare two conditioning regimens to determine which is better to facilitate engraftment after sUCBT. Patients and methods: We retrospectively analyzed the outcomes of 21 Chinese patients with acquired SAA who do not have HLA-matched siblings and do not respond to first-line immunosuppressive therapy with ciclosporin (CSA) and/or anti-thymocyte globulin (ATG) that received sUCBT were included beteween July 2016 and October 2018. Data collected as of June 2019 were analyzed. 6 patients (ATG group) used a conditioning regimen consisting of ATG (rabbit) 2.5 mg/kg (D-9 to D-7) with fludarabine 30 mg/m2 (D-9 to D-4), cyclophosphamide 60 mg/kg (D-3 to D-2) and total body irradiation (3 Gray) on D-1. Median age at time of sUCBT was 11 (5-20) years, median body weight was 34(18-53)kg. Waiting time from diagnosis to transplantation was 427(277-3407)days. The median total nucleated cell number and CD34-positive cell number at infusion were 3.57(2.77-9.36) × 107/kg and 2.5(1.02-3.99) × 105/kg, respectively. Another group (No-ATG) of 15 patients used a conditioning regimen without ATG consisting of fludarabine 40 mg/m2 (D-8 to D-4), cyclophosphamide 60 mg/kg (D-3 to D-2) and total body irradiation (4 Gray) on D-1. Median age at time of UCBT was 11 (3-42) years, median body weight was 35(13-70)kg. Waiting time from diagnosis to transplantation was 1664(160-2006)days. The median total nucleated cell number and CD34-positive cell number at infusion were 3.63(1.65-9.38)×107/kg and 2.5(0.69-5.61)×105/kg, respectively. CsA and MMF was given to both groups as prophylaxis for graft versus host disease (GVHD). Results: Primary graft failure was observed in 4 out of 6 patients in ATG group. All of these 4 patients received salvage transplantation with haploidentical related donor, 3 patients died after salvage transplantation due to grade IV GVHD in intestinal tract and infection. However, all of 15 patients in the No-ATG group had completely engraftment. The median time to neutrophil engraftment was 18 (13-27) days, platelet engraftment was 32 (17-112) days. 42-day cumulative incidence of engraftment is 100% compared to 33% in ATG group (P=0.008). During follow-up, 2 patients died before 1 year due to renal failure (n=1) and encephalorrhagia (n=1) in the No-ATG group. One-year survival rate is 86.7% in No-ATG group compared to 50% in ATG group (P=0.0598). Conclusion: sUCBT after a FLU-CY-TBI conditioning regimen was an effective and safe option for SAA patients, with better engraftment and survival. Pediatric and adult SAA patients who are younger than 50 years old, lack of HLA-matched sibling donor and refractory to immunosuppressive therapy should consider sUCBT. Table Disclosures No relevant conflicts of interest to declare.

Patients Lacking a KIR-Ligand of HLA Group C1 or C2 Have a Better Outcome after Umbilical Cord Blood Transplantation.

Donor natural killer (NK) cells can destroy residual leukemic cells after allogeneic hematopoietic stem cell transplantation. This effect is based on the interaction of killer-cell immunoglobulin-like receptors (KIR) of donor NK cells with ligands of the major histocompatibility complex found on the surface of the target cells. HLA-C1 subtypes provide the ligand for KIR2DL2 and KIR2DL3 and the HLA-C2 subtypes for KIR2DL1. We have studied the probability of relapse (PR) after single-unit unrelated cord blood transplantation (UCBT) in relation to the potential graft-vs.-leukemia effect mediated by NK cells present in the umbilical cord blood (UCB) by analyzing KIR-ligand and HLA-C typing of the receptor. Data from 33 consecutive patients given a single unit UCBT were included. We have considered two groups of patients based on the absence or the presence of one of the C-ligands for inhibitory KIR and the incompatibility HLA-C1/2 between UCB and patients. Group 1 (n = 21): the patient lacks a C-ligand for inhibitory KIR present in UCB NK cells, i.e., patients homozygous C1/C1 or C2/C2. Group 2 (n = 12): patients heterozygous C1/C2 in which KIR-mediated graft-vs.-leukemia effect is not expected (presence of both C ligands for inhibitory KIR in the receptor). With a median follow-up post-UCBT of 93 months, patients with absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower actuarial PR than patients with both C-ligands (group 2): 21 ± 10 vs. 68 ± 18% at 2 year and 36 ± 13 vs. 84 ± 14% at 5 years (p = 0.025), respectively. In patients with acute lymphoblastic leukemia, the 2-year PR was 36 ± 21% for group 1 and 66 ± 26% for 2 (p = 0.038). Furthermore, group 1 had a lower incidence of grades II–IV acute graft-vs.-host disease (p = 0.04). In the setting of UCBT, the absence of a C-ligand (C1 or C2) of inhibitory KIR in the patient is associated with lower PR, which is probably due to the graft-vs.-host leukemia effect caused by UCB NK cells that lack a ligand for the inhibitory KIR 2DL1/2DL2/2DL3.

Prognostic Impact of Pre-Transplant Serum C-Reactive Protein in Patients Receiving a Single-Unit Unrelated Cord Blood Transplantation

Background: C-reactive protein (CRP) is an acute-phase protein and its serum level rises in response to inflammation. There have been some reports about the relationship between the serum CRP level before allogeneic hematopoietic stem cell transplantation (HSCT) and transplant outcomes. This study particularly evaluated the impact of pre-transplant CRP on the outcome in patients who received a single-unit unrelated cord blood transplantation (UCBT) for hematologic malignancies.Patients and methods: Adult patients receiving UCBT as first HSCT for hematologic malignancies between April 2009 and April 2016 at Kanagawa Cancer Center were retrospectively analyzed in this study. Serum CRP was measured by a latex agglutination assay (normal range 0.0-0.3 mg /dl). The time of measurement was within a few days before the conditioning procedure. Patients were divided into 2 groups according to the serum CRP levels (normal CRP group [≤0.03 mg/dl] and high CRP group [> 0.03 mg/dl)]). A total of 80 patients (pts) included 36 pts with acute myeloid leukemia (AML), 27 pts with acute lymphoid leukemia (ALL), 13 pts with myelodysplastic syndrome (MDS), and 4 pts with others. The median age was 59 years (range, 20-68 years). There were 45 males and 35 females. A disease risk at transplantation indicated a standard risk in 47 pts and a high risk in 33 pts. Myeloablative conditioning (MAC) was employed for 25 pts and reduced intensity conditioning (RIC) was for 55 pts. Data were analyzed with EZR statistical software.Results: The median level of serum CRP at pre-transplant was 0.17 mg/dl (range: 0.01-12.93). No. of patients in normal and high CRP levels was 56 pts and 24 pts, respectively. Disease high risk was significantly associated with a high level of serum CRP. Other pre-transplant factors such as age, gender, diagnosis, comorbidity index, and serum ferritin levels were not related with serum CRP levels. The high incidence of gradeII-IVacute GVHD was significantly associated with high CRP group compared to normal CRP group (55% vs. 19%, p = 0.001). After a median follow-up of 16 months (range: 1-86 months), 3-year overall survival (OS) was 62%. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 3 years was 26% and 14%, respectively. According to univariate analysis, factors associated with worse 3-year OS included disease high risk at transplantation (vs. low risk; 49% vs. 70%, p = 0.025) and high CRP levels (vs. normal CRP levels; 28% vs. 77%, p < 0.001). Higher 3-year CIR was significantly correlated with high CRP levels (vs. normal CRP levels; 46% vs. 18%, P = 0.009). Adverse factors for NRM was high scores (≥3) of HCT-CI (vs. low scores (≤2) of HCT-CI; 25% vs. 5%, p=0.029). Multivariate analysis showed that high CRP levels (hazard ratio [HR], 4.13; 95% confidence interval [CI], 1.76-9.63; p = 0.001) was an independent determinant of 3-year OS. Prognostic factors related with CIR and NRM was high CRP levels (HR, 2.63; 95%CI, 0.96-7.21; p = 0.059) and high scores of HCT-CI (HR, 4.25; 95%CI, 0.89-20.29; p = 0.069) respectively, but those difference did not reach statistical significance.Conclusions: Pre-transplant serum CRP might be a useful biomarker for predicting the transplant outcome and the development of acute GVHD following UCBT. DisclosuresNo relevant conflicts of interest to declare.

Impacts of ABO incompatibility on early outcome after single unit unrelated cord blood transplantation: a retrospective single center experience

目的研究供受者ABO血型不合对单份非血缘脐血造血干细胞移植（UCBT）患者中性粒细胞、血小板、红细胞植入，急性移植物抗宿主病（aGVHD）累积发生率及180 d移植相关死亡率（TRM）的影响。方法以2008年4月至2014年10月行单份UCBT的208例患者为研究对象，其中供受者ABO血型相合99例，次要不合60例，主要不合38例，主次均不合11例。全部患者均采用强化清髓预处理方案，并予环孢素联合霉酚酸酯方案预防GVHD。结果ABO血型相合与不合的UCBT相比，中性粒细胞、血小板、红细胞累积植入率，Ⅱ~Ⅳ度aGVHD、Ⅲ~Ⅳ度aGVHD及180 d TRM的累积发生率差异均无统计学意义（P值均>0.05），且无一例发生纯红细胞再生障碍。A供O血型不合患者中性粒细胞、血小板、红细胞的中位植入时间分别为+17（+12~+28）、+37（+17~+57）、+25（+13~+52）d，Ⅱ~Ⅳ度aGVHD、Ⅲ~Ⅳ度aGVHD及180 d TRM累积发生率分别为37.50%（95%CI 34.39%~40.61%）、6.25%（95%CI 5.48%~7.02%）及23.53%（95%CI 21.30%~25.76%）。与ABO血型相合、次要不合及主次均不合组比较，差异均无统计学意义（P值均>0.05）。结论接受ABO血型不合UCBT的患者移植后无纯红细胞再生障碍发生。供受者ABO血型不合对UCBT患者的造血重建、aGVHD发生率及TRM均无影响。

Third allogeneic stem cell transplantation (SCT) using unrelated cord blood for relapsed acute leukemia after second allogeneic SCT.

We analyzed the results of third allogeneic stem cell transplantation (SCT3) using single-unit unrelated cord blood (CB) in seven adult patients with relapsed acute leukemia after second allogeneic stem cell transplantation (SCT2). The median age at SCT 3 was 44years (range 20-58years). The patients had de novo acute myeloid leukemia (AML) (n=4), secondary AML following myelodysplastic syndrome (n=2), and acute lymphoblastic leukemia (n=1). Four patients received myeloablative conditioning, and three received reduced-intensity conditioning. All but one patient had myeloid reconstitution with remission, but five patients relapsed even after SCT3. However, one patient is alive and disease-free 6years after SCT3, which is the longest remission duration among three allogeneic SCTs she received. Furthermore, actual survival after relapse of SCT 2 was significantly better for patients who received SCT3 compared with institutional control patients who never received SCT3 (P<0.001). These results suggest that the use of CB may allow the opportunity to perform SCT3 in patients who have experienced relapsed leukemia without donors, and SCT3 with CB may offer the chance of durable remission for selected patients with relapsed acute leukemia.

The impact of HLA matching on outcome of single unit unrelated cord blood transplantation: a retrospective single center clinical analysis

To retrospectively study the impact of human leukocyte antigen (HLA) mtyping mismatching between donor and recipient on outcome of single unit unrelated cord blood transplantation (sUCBT). 139 patients with hematological malignancies received sUCBT in single center from May 2008 to August 2012 were analyzed. Of 139 patients at enrollment, 22 were 0 mismatched (mm), 69 1 mm, 48 2 mm by low-resolution HLA-A, -B, and high-resolution (HR) DRB1. All patients'conditioning regimen was myeloablative, and a combination of cyclosporine A (CsA) and mycophenolate mofetil (MMF) was given for graft-versus-host disease (GVHD) prophylaxis for all patients. The cohort of patients were followed-up until December 15, 2013. Patients of 0 mm had a statistically significant higher cumulative incidence of neutrophil engraftment by day 42 than those of 1 and 2 mm (P=0.042 and 0.002, respectively), patients of 0 mm with either a higher prefreeze total nucleated cell (TNC) dose (>5 × 10⁷/kg) or lower dose (<5 × 10⁷/kg) had a statistically significant higher cumulative incidence of neutrophil engraftment by day 42 than those of 2 mm (P=0.01 and 0.02, respectively). Patients of 0 mm had a statistically significant lower cumulative incidence of acute GVHD by day 100 than those of 1 and 2 mm (P=0.006 and 0.001, respectively). The difference of 1-year transplant-related mortality (TRM) between 0 and 2 mm patients was statistically significant (P=0.03). Patients of 2 mm received UCB units with a TNC dose less than 5 × 10⁷/kg had a higher 1-year TRM than of 0 mm patients (P=0.03). Patients of 0 mm had a statistically significant higher 3-year disease free survival (DFS) than those of 2 mm (P=0.03), compared with patients of 2 mm given CB units with a TNC dose less than 5 × 10⁷/kg, 0 mm patients and 1mm patients received UCB units with a TNC dose greater than 4 × 10⁷/kg had higher DFS rates (P=0.02 and 0.02, respectively). The HLA typing mismatching between donor and recipient had a great impact on neutrophil engraftment and long term DFS after sUCBT, 2mm cord blood unit with less TNC (<5 × 10⁷/kg) was not an optimum UCB graft.

Different effects of HLA disparity on transplant outcomes after single-unit cord blood transplantation between pediatric and adult patients with leukemia

Recent advances in unrelated cord blood transplantation have increased chances and options available in allogeneic stem cell transplantation. The effect of HLA disparity on outcomes after cord blood transplantation was studied recently in mainly pediatric populations. Results showed that HLA matching in combination with total nucleated cell dose positively affects survival. The effect of HLA disparity after single-unit cord blood transplantation may be different in adults because their total nucleated cell dose is much lower compared to pediatric patients. We investigated the effect of HLA disparity on the outcome of single-unit unrelated cord blood transplantation separately in 498 children aged 15 years or under (HLA-A, HLA-B low-resolution, and HLA-DRB1 high-resolution matched [6/6], n=82, and one locus- [5/6], n=222, two loci- [4/6], n=158, three loci- [3/6] mismatched, n=36) and 1,880 adults (6/6, n=71; 5/6, n=309; 4/6, n=1,025; 3/6, n=475) with leukemia. With adjusted analyses, in children, 4/6 showed significantly increased risks of overall mortality (relative risk [RR]=1.61, P=0.042) and transplant-related mortality (RR=3.55, P=0.005) compared to 6/6. The risk of grade 2 to 4 acute GVHD was increased in 5/6 (RR=2.13, P=0.004) and 4/6 (RR=2.65, P<0.001). In adults, the risk of mortality did not increase with the number of mismatched loci (RR=0.99, P=0.944 for 5/6; RR=0.88, P=0.436 for 4/6). The risk of relapse was significantly decreased in 4/6 (RR=0.67, P=0.034). The risk of transplant-related mortality (TRM) or acute GVHD was not increased in 5/6 or 4/6. The effect of HLA disparity on transplant outcome differed between children and adults. In children, an increased number of mismatched HLA loci correlated with an increased risk of mortality. In adults, there was no increase in mortality with an increase in the number of mismatched HLA loci.

Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative option for adult T-cell leukemia (ATL), an intractable mature T-cell neoplasm causally linked with human T-cell leukemia virus type I (HTLV-I). We compared outcomes of 386 patients with ATL who underwent allogeneic HSCT using different graft sources: 154 received human leukocyte antigen (HLA)–matched related marrow or peripheral blood; 43 received HLA-mismatched related marrow or peripheral blood; 99 received unrelated marrow; 90 received single unit unrelated cord blood. After a median follow-up of 41 months (range, 1.5-102), 3-year overall survival for entire cohort was 33% (95% confidence interval, 28%-38%). Multivariable analysis revealed 4 recipient factors significantly associated with lower survival rates: older age (> 50 years), male sex, status other than complete remission, and use of unrelated cord blood compared with use of HLA-matched related grafts. Treatment-related mortality rate was higher among patients given cord blood transplants; disease-associated mortality was higher among male recipients or those given transplants not in remission. Among patients who received related transplants, donor HTLV-I seropositivity adversely affected disease-associated mortality. In conclusion, allogeneic HSCT using currently available graft source is an effective treatment in selected patients with ATL, although greater effort is warranted to reduce treatment-related mortality.

KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia

Donor killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility is associated with decreased relapse incidence (RI) and improved leukemia-free survival (LFS) after haploidentical and HLA-mismatched unrelated hematopoietic stem cell transplantation. We assessed outcomes of 218 patients with acute myeloid leukemia (AML n=94) or acute lymphoblastic leukemia (n=124) in complete remission (CR) who had received a single-unit unrelated cord blood transplant (UCBT) from a KIR-ligand-compatible or -incompatible donor. Grafts were HLA-A, -B or -DRB1 matched (n=21) or mismatched (n=197). Patients and donors were categorized according to their degree of KIR-ligand compatibility in the graft-versus-host direction by determining whether or not they expressed HLA-C group 1 or 2, HLA-Bw4 or HLA-A3/-A11. Both HLA-C/-B KIR-ligand- and HLA-A-A3/-A11 KIR-ligand-incompatible UCBT showed a trend to improved LFS (P=0.09 and P=0.13, respectively). Sixty-nine donor–patient pairs were HLA-A, -B or -C KIR-ligand incompatible and 149 compatible. KIR-ligand-incompatible UCBT showed improved LFS (hazards ratio=2.05, P=0.0016) and overall survival (OS) (hazards ratio=2.0, P=0.004) and decreased RI (hazards ratio=0.53, P=0.05). These results were more evident for AML transplant recipients (2-year LFS and RI with or without KIR-ligand incompatibility 73 versus 38% (P=0.012), and 5 versus 36% (P=0.005), respectively). UCBT for acute leukemia in CR from KIR-ligand-incompatible donors is associated with decreased RI and improved LFS and OS.Supplementary informationThe online version of this article (doi:10.1038/leu.2008.365) contains supplementary material, which is available to authorized users.