Double unit cord blood (CB) transplantation (CBT) appears to augment engraftment despite only one unit engrafting in most patients. We hypothesized that superior unit quality, as measured by a higher percentage of viable cells post-thaw, would determine the engrafting unit. Therefore, we prospectively analyzed 46 double unit transplants post-thaw using flow cytometry with modified gating that included all dead cells. Using a 75% threshold (mean viability minus 2SD), 20% of units had low CD34+ cell viability, with viability varying according to the bank of origin. Further, in the 44 patients with single unit engraftment, CD34+ cell viability was higher in engrafting units (p=0.0016). While either unit engrafted if both had high CD34+ viability, units with <75% viability were very unlikely to engraft: in 16 patients that received one high and one low CD34+ viability unit, only 1/16 units with viability <75% engrafted (p=0.0006). Further, in the single patient without engraftment of either unit, both had CD34+ viability <75%. Finally, poor CD34+ viability correlated with lower CFUs (p=0.02). Our data suggests one mechanism by which double unit CBT can improve engraftment is by increasing the probability of transplanting at least one unit with adequate viability and the potential to engraft.

Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access due to the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ≥ 4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (p < 0.001). However, the majority of both groups had 5–6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (p < 0.001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (p < 0.001). Their median weight was significantly higher than CB transplant recipients (p < 0.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access.

Factors contributing to infection risk following cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. To potentially reduce the infection risk we have investigated double unit CBT without ATG, and have evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients were transplanted for hematologic malignancies; 52 patients received myeloablative and 20 had non-myeloablative conditioning. The peak incidence of bacterial infections, fungal infections, or bacterial/ fungal pneumonias was in the first 30 days post-transplant and affected 32%, 14%, and 10% of patients, respectively. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days post-transplant affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections prior to day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections after day 120 (n = 5), and all Epstein-Barr virus viremia (EBV, n = 5) and adeno-viral enteritis (n = 2) occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death and 3 contributed to death. Patients exhibited steady immune recovery achieving a median CD3+4+ T-cell count > 200 cells/microL by day 120, and after day 120 there were no infection-related deaths. Our results suggest that double unit CBT without ATG is associated with prompt T-cell recovery, and unlike CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD and serious infections remain a burden, especially in the setting of GVHD. New strategies are required to further reduce infectious complications after CBT and will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T-cell depletion associated with ATG.

Preparation of cord blood (CB) units for infusion by albumin-dextran dilution without centrifugation may be advantageous for adult patients to minimize cell loss and, unlike a bedside thaw, is still conducted in the controlled laboratory environment. Therefore, we studied CB transplantation (CBT) using this technique in 54 consecutive CBT recipients ≥20 kg. Patients [median age 42 years (range 7–66); median weight 71 kg (range 24–109)] were transplanted for high-risk hematological malignancies with ablative (n=35) or non-ablative (n=19) conditioning and 4–6/6 human leukocyte antigen (HLA)-matched double unit grafts. One hundred and seven units were thawed with dilution whereas 1 red blood cell (RBC) replete unit was washed. A 5:1 dextran 40/ 25% albumin solution was used. RBC depleted units (n=104) were diluted ≥5.5 fold [median final volume 200 ml (range 200–500)] whereas RBC replete units (n=3) were diluted ≥4 fold [median final volume 400 ml (range 400–535)]. Total nucleated cell (TNC) recovery was 86%; the median infused TNC dose was 2.17 × 107/kg/unit. While 35 patients (65%) had a total of 45 infusion reactions (6 nausea, 31 hypertension, 3 pain, 1 rigors/fever, 2 transient hypoxia, 2 renal impairment) requiring additional therapy, there were no infusion-related serious adverse events, and reactions were not related to DMSO dose/kg. Cumulative incidence of sustained donor engraftment was 94% (95%CI: 87–100) with neutrophil recovery occurring at a median of 25 days (range 13–43) in ablative and 10 days (range 7–36) in non-myeloablative recipients. CB thaw with albumin-dextran dilution reduces unit manipulation, and minimizes cell loss, speeds time to infusion, is associated with a tolerable infusion reaction profile, and a high rate of sustained engraftment in CBT recipients ≥20 kg.

The pre-engraftment syndrome (PES) after cord blood (CB) transplantation (CBT) is poorly characterized. Therefore, we reviewed 52 consecutive double unit CBT recipients treated for high-risk hematological malignancies. PES was defined as unexplained fever >38.3°C (101F) not associated with infection and unresponsive to antimicrobials, and/or unexplained rash occurring before or at neutrophil recovery. CBT recipients (median 38 years, range 3-66) received either myeloablative (n=36) or non-myeloablative (n=16) conditioning. Sixteen patients (31%) fulfilled PES criteria: 15 with fever [onset median 39°C (102.2F)] with 13 also having rash, and one with rash alone. The median onset was 9 days (range 5-12) post-transplant (a median of 14 days before neutrophil recovery). Sixteen patients received IV methylprednisolone (MP) (14 PES, 2 with infection and possible PES; median dose 1 mg/kg, median duration 3 days) with 15/16 (94%) having fever resolution in ≤24 hours. Recurrent PES (n=3) resolved with retreatment. There was no association between the development of PES and the likelihood of sustained donor engraftment, the speed of neutrophil recovery, grade II-IV acute graft-versus-host disease (aGVHD), day 180 transplant-related mortality, or survival. PES is common after CBT, precedes neutrophil recovery, is distinct from and does not predict for aGVHD, and responds promptly to short course corticosteroids.