Shortened-Duration Tacrolimus after Nonmyeloablative,HLA-Haploidentical Bone Marrow Transplantation

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction.     

Absence of Post-Transplantation Lymphoproliferative Disorder after Allogeneic Blood or Marrow Transplantation Using Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis

Immunosuppressive regimens that effectively prevent graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (allo-BMT) have been associated with an increased incidence of post-transplantation lymphoproliferative disorder (PTLD) in the first year after transplantation. We evaluated the incidence of PTLD associated with the use of high-dose post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Between 2000 and 2011, a total of 785 adult allo-BMT recipients were given PTCy as GVHD prophylaxis at the Johns Hopkins Hospital, including 313 patients who received PTCy as sole GVHD prophylaxis. HLA-haploidentical or unrelated donor graft transplantation was performed in 526 patients (67%). No cases of PTLD occurred during the first year after allo-BMT in this series. PTLD is a rare occurrence after allo-BMT using PTCy, even in high-risk alternative donor transplantations.     

HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose,Posttransplantation Cyclophosphamide

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/μL) and platelet recovery (>20,000/μL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD.     

Outcomes of Related Donor HLA-Identical or HLA-Haploidentical Allogeneic Blood or Marrow Transplantation for Peripheral T Cell Lymphoma

The role of allogeneic blood or marrow transplantation (alloBMT) for peripheral T cell lymphoma (PTCL) remains to be defined. There is growing interest in reduced-intensity conditioning (RIC) regimens and/or utilization of human leukocyte antigen haploidentical (haplo) grafts given concerns about treatment-associated toxicities and donor availability. We reviewed the outcomes of 44 consecutive, related donor alloBMTs for PTCL performed at Johns Hopkins Hospital from 1994 to 2011, including 18 RIC/haplo alloBMTs. Patients receiving RIC (n = 24) were older, with median age of 59 years (range, 24 to 70), than patients receiving myeloablative conditioning (MAC, n = 20), with median age of 46 years (range, 18 to 64), P = .01. The median age at RIC/haplo alloBMT was 60 years. The estimated 2-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 26% to 55%) and overall survival (OS) was 43% (95% CI, 28% to 59%). In older patients (≥60, n = 14), the estimated 2-year PFS and OS were 38% (95% CI, 18% to 79%) and 45% (95% CI, 24% to 86%), respectively. On unadjusted analysis, there was a tendency toward superior outcomes for alloBMT in first remission versus beyond first remission, with an estimated 2-year PFS of 53% (95% CI, 33% to 77%) versus 29% (95% CI, 9% to 45%), P = .08. On competing risk analysis, the 1-year cumulative incidence of relapse was 38% for MAC/HLA-identical alloBMTs and 34% for RIC/haplo alloBMTs. Estimated 1-year nonrelapse mortality was 10% for MAC and 8% for RIC (11% for RIC/haplo alloBMT). On unadjusted landmark analysis, patients with acute grade II-IV or chronic graft-versus-host disease (GVHD) had a 17% probability of relapse (95% CI, 0% to 39%), compared with 66% (95% CI, 48% to 84%) in patients without GVHD, P = .04. Utilization of RIC and alternative donors expands treatment options in PTCL to those who are older and unable to tolerate high-dose conditioning, with outcomes comparable with approaches using myeloablative regimens and HLA-matched donors. AlloBMT may be appropriate in first remission in select high-risk cases.     

HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell–replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor–mobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m², and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell–replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.     

Clinical Impacts of Using Serum IL-6 Level as an Indicator of Cytokine Release Syndrome after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

HLA-haploidentical allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide (PT/Cy-haplo) is widely used because of such advantages as low procedure cost, high probability of finding a suitable donor, and donor availability at short notice. Cytokine release syndrome (CRS), resulting from bidirectional alloreaction between host and donor, occurs frequently in recipients of PT/Cy-haplo, especially when peripheral blood is used. Severe and life-threatening instances of CRS have been reported. The clinical significance of CRS remains unclear, however. Here we used serum IL-6 level as a surrogate marker of CRS to evaluate the impact of outcomes in 65 consecutive patients receiving PT/Cy-haplo at our institution. Our results indicate that active disease status, high Hematopoietic Cell Transplantation-Specific Comorbidity Index score, and very severe CRS are significantly related to peak serum IL-6 level. In our cohort, high peak serum IL-6 level and severe CRS were significantly associated with the development of grade III or IV acute graft-versus-host disease (GVHD). High peak serum IL-6 level was identified a significant risk factor for poor 3-year overall survival. Our results suggest that even transient CRS following PT/Cy-haplo may contribute to poor survival owing to an increase in severe acute GVHD.     

Donor KIR2DS1-Mediated Decreased Relapse and Improved Survival Depending on Remission Status at HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) is becoming the standard of care for patients without an HLA-matched related or unrelated donor. PT/Cy-haplo can give more patients the opportunity to undergo allo-HCT, because most patients have multiple available HLA-haploidentical related donor candidates. The optimal donor selection algorithm in the PT/Cy-haplo setting has not yet been established, however. To contribute to the establishment of a donor selection formula based on disease status and killer-cell immunoglobulin-like receptor (KIR) genotype, we retrospectively analyzed 91 patients who underwent PT/Cy-haplo at our institution. In both patients and donors, HLA allele genotyping was performed for HLA-A, -B, -C, and -DRB1, and 16 KIR genes were genotyped. Patients in complete remission (CR) who underwent PT/Cy-haplo from a KIR2DS1-positive donor had a significantly lower cumulative incidence of relapse (CIR) than those who underwent PT/Cy-haplo from a KIR2DS1-negative donor (1-year CIR: 0% versus 32.6%, P = .037; 2-year CIR: 9.2% versus 42%, P = .037). Moreover, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved overall survival (OS) (1-year OS: 91.7% versus 58.7%, P = .010; 2-year OS: 83% versus 34%, P = .010). In contrast, in non-CR individuals, PT/Cy-haplo from KIR2DS1-positive donors did not significantly improve CIR or OS (1-year CIR: 56.5% versus 64.7%, P = .973; 2-year CIR: not reached versus 64.7%, Pnot evaluable; 1-year OS: 25.4% versus 20.6%, P = .418; 2-year OS: 5.1% versus 20.6%, P = .418). In addition, lower infused CD34⁺ cell dose, female-to-male transplantation, and acute myelogenous leukemia were significantly associated with increased risk of relapse and mortality. This study demonstrates that graft-versus-leukemia/tumor effects were exerted through donor KIR2DS1 at PT/Cy-haplo when patients have low tumor burdens. It would be worth examining the inclusion of donor KIR genotyping and disease status assessment in establishing optimal donor selection criteria for PT/Cy-haplo.     

Bone Marrow Compared with Peripheral Blood Stem Cells for Haploidentical Transplantation with a Nonmyeloablative Conditioning Regimen and Post-transplantation Cyclophosphamide

Recently, the administration of high-dose cyclophosphamide (Cy) after T cell–replete haploidentical stem cell infusion has been reported to be feasible and effective. In the original study, bone marrow (BM) was used as the source of stem cells. Here, we retrospectively analyzed the use of BM versus peripheral blood stem cells (PBSCs) in a cohort of patients receiving haploidentical T cell–replete transplantation after a nonmyeloablative conditioning regimen with postinfusion Cy. In the PBSC versus BM groups, the incidence of acute graft-versus-host disease (GVHD) was 33% versus 25%, respectively, and the incidence of chronic GVHD was 13% versus 13%, respectively. The median time to achieve a safe and unsupported absolute neutrophil and platelet count was 20 versus 21 days and 27 versus 29 days, respectively. The incidence of engraftment was also similar in the 2 cohorts. The 1-year nonrelapse mortality rate was 12% versus 22%, respectively (P = .96). Finally, nonsignificant differences in survival were observed. In conclusion, the use of PBSCs instead of BM after T cell–replete haploidentical transplantation did not appear to be detrimental in terms of either GVHD or engraftment rate. PBSCs could be a valid alternative to BM after transplantation from a haploidentical donor using postinfusion Cy.     

Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P = .04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P = .02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade III-IV, overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P = .8), 9% versus 9% (P = 1), 66% versus 43% (P = .04), and 41% versus 23% (P = .2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P = .06) and 17% versus 23% (P = .5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P = .2), 35% versus 59% (P = .1), and 17% versus 40% (P = .04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.     

Differences in Graft-versus-Host Disease Characteristics between Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide and Matched Unrelated Donor Transplantation Using Calcineurin Inhibitors

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD.     

Favorable Outcome of Post-Transplantation Cyclophosphamide Haploidentical Peripheral Blood Stem Cell Transplantation with Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring in Pediatric Patients

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PTCy) was performed previously in adults using a nonmyeloablative conditioning regimen and bone marrow as a graft source. In an effort to reduce relapse rates, myeloablative conditioning regimens with higher intensities are now used. We used an intensive daily pharmacokinetic monitoring method for busulfan dosing in children for effective myeloablation and to reduce toxicity. Here, we report the retrospective results of 34 patients (median age 11.1 years) who underwent haplo-HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen and peripheral blood as a stem cell source. The donor-type neutrophil engraftment rate was 97.1%, and the cumulative incidence rates of grade II to IV and grade III to IV acute and extensive chronic graft-versus-host disease were 38.2%, 5.9%, and 9.1%, respectively. The overall survival and event-free survival rates, and treatment-related mortality were 85.0%, 79.4%, and 2.9%, respectively. Based on the subgroup analysis of patients with malignancies (n?=?23), the relapse incidence rate was 21.7%. Haplo-HSCT using PTCy with targeted busulfan-based myeloablative conditioning and peripheral blood as a stem cell source was a safe and promising therapeutic option for children.     

Similar Overall Survival Using Sibling,Unrelated Donor,and Cord Blood Grafts after Reduced-Intensity Conditioning for Older Patients with Acute Myelogenous Leukemia

For older patients with acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT) provides the best chance of long-term survival. A formal comparison between matched sibling (SIB), unrelated donor (URD), or umbilical cord blood (UCB) transplantation has not yet been reported in this setting. We compared reduced-intensity conditioning HCT in 197 consecutive patients 50 years and older with AML in complete remission from SIB (n = 82), URD (n = 35), or UCB (n = 80) transplantation. The 3-year cumulative incidences of transplantation-related mortality were 18%, 14%, and 24% with SIB, URD, and UCB transplantation, respectively (P = .22). The 3-year leukemia-free survival rates were 48%, 57%, and 33% with SIB, URD, and UCB transplantation, respectively (P = .009). In multivariate analysis, poor-risk cytogenetics was associated with relapse (hazard ratio, 1.7 [95% confidence interval, 1.0 to 3.0]; P = .04) and worse leukemia-free survival (hazard ratio, 1.6 [95% confidence interval, 1.0 to 2.5]; P = .03), whereas donor choice had no significant impact on overall survival (P = .73). Adjusted 3-year overall survival rates were 55% with SIB, 45% with URD, and 43% with UCB transplantation (P = .26). Until prospective studies are completed, this study supports the recommendation to consider SIB donor, URD, or UCB for HCT for older patients with AML in complete remission.     

Sirolimus,Tacrolimus, and Low-Dose Methotrexate as Graft-versus-Host Disease Prophylaxis in Related and Unrelated Donor Reduced-Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

We assessed the combination of sirolimus, tacrolimus, and low-dose methotrexate as acute graft-versus-host disease (aGVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation from matched related (MRD, n = 46) and unrelated (URD, n = 45) donors. All patients received fludarabine and intravenous busulfan conditioning followed by transplantation of mobilized PBSC. The median time to neutrophil engraftment was 13 days. The cumulative incidence of grade II-IV and III-IV aGVHD were 16% and 7%, respectively. There was no difference in the incidence of aGVHD between MRD and URD cohorts. Two-year cumulative incidence of extensive chronic GVHD (cGVHD) was 40%. Relapse-free survival (RFS) at 2 years was 34%: 21% in MRD and 45% in URD. Overall survival (OS) at 2 years was 59%: 47% in MRD and 67% in URD. High levels (>90%) of donor derived hematopoiesis were achieved in 59% of patients early after transplantation. The addition of sirolimus to tacrolimus and low-dose methotrexate as GVHD prophylaxis following RIC with fludarabine and low-dose intravenous busulfan is associated with rapid engraftment, low rates of aGVHD, and achievement of high levels of donor chimerism.     

Comparable Long-Term Outcome of Unrelated Cord Blood Transplantation with Related Bone Marrow or Peripheral Blood Stem Cell Transplantation in Patients Aged 45 Years or Older with Hematologic Malignancies after Myeloablative Conditioning

We investigated whether bone marrow or peripheral blood stem cells from older sibling donors or cord blood from unrelated donors provided a better outcome in allogeneic hematopoietic stem cell transplantation for relatively older patients who were candidates for myeloablative conditioning. Clinical outcomes of 97 patients aged 45 years or older with hematologic malignancies who received unrelated cord blood transplantation (CBT) (n = 66) or bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) from related donors (n = 31) were compared. The cumulative incidences of grades III to IV acute and extensive chronic graft-versus-host diseases were similar between both groups. Although transplant-related mortality was significantly lower after CBT compared with BMT/PBSCT from related donors (hazard ratio [HR], .29, P = .04), overall mortality (HR, .72, P = .47) and relapse (HR, 2.02, P = .23) were not significantly different after CBT and BMT/PBSCT from related donors. These data suggest that CBT could be as safe and effective as BMT/PBSCT from older related donors for relatively older patients when it is used as a primary unrelated stem cell source.     

Poor Outcome with Nonmyeloablative Conditioning Regimen before Cord Blood Transplantation for Patients with High-Risk Acute Myeloid Leukemia Compared with Matched Related or Unrelated Donor Transplantation

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is recommended for patients with high-risk acute myeloid leukemia (AML). In many situations, a matched related (MRD) or matched unrelated donor (MUD) is lacking, in which case unrelated cord blood units (UCB) provide an alternative. We analyzed the outcome of consecutive high-risk AML patients prepared with reduced-intensity conditioning (RIC) regimens and allografted with UCB (n = 32) and compared their outcome with high-risk AML patients who underwent transplantation with MRD/MUD (n = 49) in the same period of time. Grade III to IV acute graft-versus-host disease (GVHD) occurred slightly more frequently in the UCB group (25%) than in the MRD/MUD group (8%) (P = .069). Conversely, we found a lower incidence of extensive chronic GVHD in the UCB group (6%) than in the MRD/MUD group (20%, P = .085). Nonrelapse mortality at 4 years was 16% and 22% in the UCB and MRD/MUD groups, respectively (P = .529). The cumulative incidence of relapse at 4 years was significantly higher in the UCB group (60%) than in the MRD/MUD group (27%, P = .006). Leukemia-free survival (LFS) and overall survival (OS) at 4 years were 25% and 34%, respectively, in the UCB group and 50% and 56%, respectively, in the MRD/MUD group (LFS, P = .029; OS, P = .072). Multivariate analyses adjusted by cytogenetics and disease status at the time of Allo-HSCT revealed that use of UCB remained an independent predictive factor of shorter LFS (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.6; P = .018), and was associated with a trend for shorter OS (hazard ratio, 1.7; 95% confidence interval, .9 to 3.2; P = .093). Whereas UCB provides an alternative for patients with high-risk AML lacking an MRD/MUD, the high incidence of relapse after RIC-based UCB Allo-HSCT is a concern. Attempts to improve leukemic control with UCB Allo-HSCT are warranted, as well as the evaluation of other alternative donors in this context.