Claudio G. Brunstein

Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood

Effectiveness of double umbilical cord blood (dUCB) grafts relative to conventional marrow and mobilized peripheral blood from related and unrelated donors has yet to be established. We studied 536 patients at the Fred Hutchinson Cancer Research Center and University of Minnesota with malignant disease who underwent transplantation with an human leukocyte antigen (HLA)-matched related donor (MRD, n = 204), HLA allele-matched unrelated donor (MUD, n = 152) or 1-antigen-mismatched unrelated adult donor (MMUD, n = 52) or 4-6/6 HLA matched dUCB (n = 128) graft after myeloablative conditioning. Leukemia-free survival at 5 years was similar for each donor type (dUCB 51% [95% confidence interval (CI), 41%-59%]; MRD 33% [95% CI, 26%-41%]; MUD 48% [40%-56%]; MMUD 38% [95% CI, 25%-51%]). The risk of relapse was lower in recipients of dUCB (15%, 95% CI, 9%-22%) compared with MRD (43%, 95% CI, 35%-52%), MUD (37%, 95% CI, 29%-46%) and MMUD (35%, 95% CI, 21%-48%), yet nonrelapse mortality was higher for dUCB (34%, 95% CI, 25%-42%), MRD (24% (95% CI, 17%-39%), and MUD (14%, 95% CI, 9%-20%). We conclude that leukemia-free survival after dUCB transplantation is comparable with that observed after MRD and MUD transplantation. For patients without an available HLA matched donor, the use of 2 partially HLA-matched UCB units is a suitable alternative.

Alternative donor transplantation after reduced intensity conditioning: Results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts

The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units

Umbilical cord blood (UCB) transplantation is potentially curative for acute leukemia. This analysis was performed to identify risk factors associated with leukemia relapse following myeloablative UCB transplantation. Acute leukemia patients (n = 177; 88 with acute lymphoblastic leukemia and 89 with acute myeloid leukemia) were treated at a single center. Patients received a UCB graft composed of either 1 (47%) or 2 (53%) partially human leukocyte antigen (HLA)-matched unit(s). Conditioning was with cyclophosphamide and total body irradiation with or without fludarabine. The incidence of relapse was 26% (95% confidence interval [CI], 19%-33%). In multivariate analysis, relapse was higher in advanced disease patients (> or = third complete remission [CR3]; relative risk [RR], 3.6; P < .01), with a trend toward less relapse in recipients of 2 UCB units (RR = 0.6; P = .07). However, relapse was lower for CR1-2 patients who received 2 UCB units (RR 0.5; P < .03). Leukemia-free survival was 40% (95% CI, 30%-51%) and 51% (95% CI, 41%-62%) for single- and double-unit recipients, respectively (P = .35). Although it is known that transplantation in CR1 and CR2 is associated with less relapse risk, this analysis reveals an enhanced graft-versus-leukemia effect in acute leukemia patients after transplantation with 2 partially HLA-matched UCB units. This trial was registered at http://clinicaltrials.gov as NCT00309842.

Analysis of Risk Factors for Outcomes After Unrelated Cord Blood Transplantation in Adults With Lymphoid Malignancies: A Study by the Eurocord-Netcord and Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

PURPOSE To determine risk factors of umbilical cord blood transplantation (UCBT) for patients with lymphoid malignancies. PATIENTS AND METHODS We evaluated 104 adult patients (median age, 41 years) who underwent unrelated donor UCBT for lymphoid malignancies. UCB grafts were two-antigen human leukocyte antigen-mismatched in 68%, and were composed of one (n = 78) or two (n = 26) units. Diagnoses were non-Hodgkins lymphoma (NHL, n = 61), Hodgkins lymphoma (HL, n = 29), and chronic lymphocytic leukemia (CLL, n = 14), with 87% having advanced disease and 60% having experienced failure with a prior autologous transplant. Sixty-four percent of patients received a reduced-intensity conditioning regimen and 46% low-dose total-body irradiation (TBI). Median follow-up was 18 months. RESULTS Cumulative incidence of neutrophil engraftment was 84% by day 60, with greater engraftment in recipients of higher CD34(+) kg/cell dose (P = .0004). CI of non-relapse-related mortality (NRM) was 28% at 1 year, with a lower risk in patients treated with low-dose total-body irradiation (TBI; P = .03). Cumulative incidence of relapse or progression was 31% at 1 year, with a lower risk in recipients of double-unit UCBT (P = .03). The probability of progression-free survival (PFS) was 40% at 1 year, with improved survival in those with chemosensitive disease (49% v 34%; P = .03), who received conditioning regimens containing low-dose TBI (60% v 23%; P = .001), and higher nucleated cell dose (49% v 21%; P = .009). CONCLUSION UCBT is a viable treatment for adults with advanced lymphoid malignancies. Chemosensitive disease, use of low-dose TBI, and higher cell dose were factors associated with significantly better outcome.

Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation : analysis of risk factors

Acute graft-versus-host disease (GVHD) occurs less frequently after umbilical cord blood transplantation (UCBT). More recent investigations include the use of 2 partially human leukocyte antigen (HLA)-matched UCB units, or double UCB graft, to meet the minimum cell-dose requirement. The purpose of this analysis was to assess the relative risk of acute GVHD in 265 consecutive patients receiving transplants with UCB graft composed of 1 (n = 80) or 2 (n = 185) units. The incidence of grade III-IV acute GVHD was similar between cohorts. However, the incidence of grade II-IV acute GVHD was higher among double UCBT recipients (58 vs 39%, P < .01). Three risk factors for grade II-IV acute GVHD were identified in multiple regression analysis: use of 2 UCB units, use of nonmyeloablative conditioning, and absence of antithymocyte globulin in the conditioning regimen. Transplantation-related mortality (TRM) at 1 year, however, was significantly lower after double UCBT (24 vs 39%, P = .02) even if recipients had grade II-IV acute GVHD (20 vs 39%, P = .05). These data suggest that, despite a higher incidence of grade II acute GVHD in recipients of 2 partially HLA-matched UCB units, there is no adverse effect on TRM. This study is registered at (http://www.clinicaltrials.gov) under the identifiers NCT00305682 and NCT00309842.

Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation

The success of allogeneic hematopoietic cell transplantation (HCT) is typically assessed as individual complications, including graft-versus-host disease (GVHD), relapse, or death, yet no one factor can completely characterize cure without ongoing morbidity. We examined a novel composite end point of GVHD-free/relapse-free survival (GRFS) in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. In 907 consecutive University of Minnesota allogeneic HCT recipients (2000-2012), 1-year GRFS was 31% (95% confidence interval [CI] 28-34). Regression analyses showed age, disease risk, and donor type significantly influencing GRFS. Adults age 21+ had 2-fold worse GRFS vs children; GRFS did not differ beyond age 21. Adjusted for conditioning intensity, stem cell source, disease risk, age, and transplant year, HLA-matched sibling donor marrow resulted in the best GRFS (51%, 95% CI 46-66), whereas HLA-matched sibling donor peripheral blood stem cells were significantly worse (25%, 95% CI 20-30, P = .01). GRFS after umbilical cord blood transplants and marrow from matched unrelated donors were similar (31%, 95% CI 27-35 and 32%, 95% CI 22-42, respectively). Because GRFS measures freedom from ongoing morbidity and represents ideal HCT recovery, GRFS has value as a novel end point for benchmarking new therapies.

Expanding the role of umbilical cord blood transplantation.

Umbilical cord blood has become a valuable alternative source of haematopoietic stem cells for allogeneic transplantation. However, largely because of the impact of cell dose on engraftment, risk of transplant‐related mortality and survival, progress in the field has been largely restricted to children. Nevertheless, substantial clinical experience with umbilical cord blood transplantation clearly establishes its safety and effectiveness in young patients with a variety of malignant and non‐malignant diseases. Although less well established in adults, new strategies are now being explored to address the obstacle of cell dose. This article reviews the state of the art and future directions with umbilical cord blood as a source of haematopoietic stem cells for transplantation in both children and adults.

Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia.

UNLABELLED Cell dose is a major limitation for umbilical cord blood (UCB) transplantation because units containing a minimum of 2.5 x 10(7) total nucleated cells (TNC)/kilogram patient body weight are frequently not available. The transplantation of 2 partially HLA-matched UCB units has been adopted as a simple approach for increasing the TNC.We sought to determine whether the relative safety and efficacy of this approach was comparable with a single UCB transplantation. Included are adults with acute leukemia who received transplants with 1 (n =106) or 2 (n =303) UCB units. All UCB units for single UCB transplantations contained TNC ≥ 2.5 x 10(7)/kg. For double UCB transplantations, the total TNC for units 1 and 2 were > 2.5 x 10(7)/kg but in approximately half of these transplantations, 1 of the 2 units contained < 2.5 x 10(7) TNC/kg. Adjusting for factors associated with outcomes, risks of neutrophil recovery (odds ratio 0.83, P =.59), transplantation-related mortality (hazard ratio [HR] 0.91, P= .63), relapse (HR 0.90, P= .64), and overall mortality (HR 0.93, P= .62) was similar after double UCB and adequate dose single UCB transplantations. These data support double UCB unit transplantation for acute leukemia when an adequately dosed single UCB unit is not available thereby extending access to nearly all patients. KEY POINTS Efficacy of transplanting adequately dosed 1- or 2-cord blood units.

Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity

We examined the clinical impact of killer-immunoglobulin receptor-ligand (KIR-L) mismatch in 257 recipients of single (n = 91) or double (n = 166) unit umbilical cord blood (UCB) grafts after myeloablative (n = 155) or reduced intensity (n = 102) conditioning regimens. Analyses of double unit grafts considered the KIR-L match status of the dominant engrafting unit. After myeloablative conditioning, KIR-L mismatch had no effect on grade III-IV acute graft-versus-host disease (GVHD), transplantation-related mortality (TRM), relapse, and survival. In contrast, after reduced intensity conditioning, KIR-L mismatch between the engrafted unit and the recipient resulted in significantly higher rates of grade III-IV acute GVHD (42% [CI, 27-59] vs 13% [CI, 5-21], P < .01) and TRM (27% [CI, 12%-42%] vs 12% [CI, 5%-19%], P = .03) with inferior survival (32% [CI, 15%-59%] vs 52% [CI, 47%-67%], P = .03). Multivariate analysis identified KIR-L mismatch as the only predictive factor associated with the development of grade III-IV acute GVHD (RR, 1.8 [CI, 1.1-2.9]; P = .02) and demonstrated a significant association between KIR-L mismatch and increased risk of death (RR, 1.8; 95% CI, 1.0-3.1; P = .05). Our results do not support the selection of UCB units based on KIR-L status and suggest that KIR-L mismatching should be avoided in reduced intensity UCB transplantation.

Reduced-Intensity Allogeneic Transplant in Patients Older Than 55 Years: Unrelated Umbilical Cord Blood Is Safe and Effective for Patients without a Matched Related Donor

The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source to suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients, and compared the treatment-related mortality (TRM) and overall survival (OS) of RIC HCT in patients older than 55 years using either MRD (n = 47) or, in patients with no 5 of 6 or 6 of 6 HLA compatible related donors, UCB (n = 43). RIC regimen consisted of total-body irradiation (TBI; 200 cGy) and either cyclophosphamide and fludarabine (n = 69), or busulfan and fludarabine (n = 16) or busulfan and cladribine (n = 5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received 2 UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median follow-up for survivors was 27 (range: 12-61) months. The 3-year probabilities of progression-free survival (PFS; 30% versus 34%, P = .98) and OS (43% versus 34%, P = .57) were similar for recipients of MRD and UCB. The cumulative incidence of grade II-IV acute graft-versus-host (aGVHD) disease (42% versus 49%, P = .20) and TRM at 180-days (23% versus 28%, P = .36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease (cGVHD) at 1 year (40% versus 17%, P = .02). On multivariate analysis, graft type had no impact on TRM or survival, and the HCT comorbidity index score was the only factor independently predictive for these endpoints. Our study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have an MRD. The use of RIC and UCB extends the availability of transplant therapy to older patients previously excluded on the basis of age and lack of a suitable MRD. A careful review of existing comorbidities is necessary when considering older patients for HCT.