Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Aug 15.
Published in final edited form as: Br J Haematol. 2014 Oct 1;168(3):405–412. doi: 10.1111/bjh.13136

Results of a Prospective Multicentre Myeloablative Double-Unit Cord Blood Transplantation Trial in Adult Patients with Acute Leukaemia and Myelodysplasia

Juliet N Barker 1, Mingwei Fei 2, Chatchada Karanes 3, Mitchell Horwitz 4, Steven Devine 5, Tamila L Kindwall-Keller 6, Jennifer Holter 7, Alexia Adams 2, Brent Logan 2, Willis H Navarro 8, Marcie Riches 9, on behalf of the RCI BMT 05-DCB Protocol Team
PMCID: PMC5557396  NIHMSID: NIHMS886811  PMID: 25272241

Summary

Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the one-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2.62 (larger unit) and 2.02 (smaller unit) × 107/kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80–96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51–76) and 36% (95%CI: 24–49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26–52), and the 3-year relapse incidence was 11% (95%CI: 4–21). With a median 37-month (range 23–71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37–63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

Keywords: acute leukaemia, adult cord blood transplantation, double cord, relapse, transplant-related mortality

Introduction

Unrelated donor cord blood (CB) is an alternative haematopoietic stem cell source with the advantages of rapid availability and a reduced stringency of required human leucocyte antigen (HLA)-match (Eapen, et al 2011, Eapen, et al 2010, Eapen, et al 2007, Gluckman and Rocha 2006, Laughlin, et al 2004, Wagner, et al 2002). The latter characteristic permits extension of transplant access to patients without matched unrelated volunteer donors, an attribute that is especially important for patients of racial and ethnic minorities (Barker, et al 2010a). However, CB transplantation (CBT) is limited by the low available total nucleated cell (TNC) dose per unit, restricting single unit CBT predominantly to pediatric patients (Barker, et al 2010b). Retrospective studies have suggested that the combined transplantation of two unrelated donor CB units as a double-unit graft may improve neutrophil engraftment and reduce transplant-related mortality (TRM) as compared with that observed after single-unit CBT in adult patients (Barker, et al 2005, Barker, et al 2003). Subsequent studies suggested there may be an additional advantage of enhanced protection against relapse after double-unit CBT, possibly from graft-versus-graft effects (Brunstein, et al 2007, Rodrigues, et al 2009, Verneris, et al 2009). These observations have led to the widespread investigation of double-unit CBT. However, whether the promising disease-free survival (DFS) reported in single centre series (Barker, et al 2005) can be replicated in a multi-centre setting has not been established. Therefore, we conducted a Phase II open-label multi-centre prospective trial of adult myeloablative double-unit CBT for the treatment of acute leukaemia or myelodysplastic syndrome (MDS). The primary aim of this study was to establish the one-year overall survival (OS) after high-dose myeloablative double-unit CBT in a multi-centre setting.

Patients and Methods

Study Population

Patients (n = 56) were transplanted at 10 United States (US) centres between November 2007 and September 2011. Eligible patients were 22–50 years [or 18–21 years if not a candidate for the paediatric Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0501 randomized trial of single versus double-unit CBT]. Diagnoses included high-risk acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in first or second morphological complete remission (CR) or MDS with < 10% bone marrow blasts in pre-transplant analysis. Persistent cytogenetic or molecular abnormalities were permitted.

High risk features in patients with AML included second CR (CR2) or first remission at a high risk of relapse due to a known prior diagnosis of MDS, therapy-related AML, white cell count at presentation > 100 × 109/l, presence of extramedullary leukaemia at diagnosis, unfavorable FAB type (M0, M5-7), high-risk cytogenetics (such as those associated with MDS, abnormalities of 5, 7, 8, 11q23 translocations, Philadelphia chromosome, or complex karyotype) or high-risk molecular abnormalities such as FLT3 mutation. High risk features in patients with ALL included CR2 or CR1 patients at high risk of relapse due to white cell count at presentation > 50 × 109/l, presence of high-risk cytogenetic abnormalities [such as t(9;22), t(1;19), t(4;11) or other KMT2A (MLL) rearrangements (11q23), t(8;14)], or failure to achieve complete morphological remission after four weeks of induction therapy. High-risk features in MDS patients included intermediate-2 or high International Prognostic Scoring System (IPSS) score, or therapy-related disease. Patients with low or intermediate-1 IPSS score with life-threatening cytopenias were also eligible.

Organ function/performance status criteria included Karnofsky score ≥ 70%, left ventricular ejection fraction ≥ 50%, spirometry/corrected diffusing capacity ≥ 60% normal, calculated creatinine clearance ≥ 60 ml/min, bilirubin < 42.75 μmol/l, alanine transaminase/aspartate transaminase < 3 × upper limit of normal, and albumin ≥ 25 g/l. All patients provided written informed consent for transplantation, and the study was approved by centre Institutional Review/Privacy Boards. The trial was registered with ClinicalTrials.gov (NCT00514579).

Conditioning, Immunosuppression and CB Grafts

Conditioning consisted of fludarabine 75 mg/m2 (25 mg/m2/day on days -8 to -6), cyclophosphamide 120 mg/kg (60 mg/kg/day on days -7 and -6) and total body irradiation 1320 cGy (2 × 165 cGy fractions/day on days -4 to -1). Immunosuppression included intravenous ciclosporin-A (CSA) and mycophenolate mofetil (MMF) 1 g every 12 h starting on day -3. MMF was continued until day 45 and then stopped without taper. CSA was given until day 100 and then tapered in the absence of graft-versus-host disease (GVHD). Granulocyte-colony-stimulating factor (5 μg/kg/day, rounded to vial size) was given from day +1 post-transplant until absolute neutrophil count (ANC) > 2.5 × 109/l. After transplant, supplemental intravenous immune globulin was administered at the discretion of treating physicians.

Double-unit CB grafts were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient with a cryopreserved TNC dose ≥ 1.5 × 107/kg/unit [or ≥ 2.0 if the units were not red blood cell (RBC)-depleted]. Unit-unit HLA-match was ≥ 3/6 HLA-antigens. HLA-match took priority in unit selection above a cryopreserved TNC of 1.5 × 107/kg. RBC-deplete units were thawed with albumin-dextran dilution (Barker, et al 2009); RBC-replete units were washed.

Study Design, Definitions and Statistical Analysis

At study design, a one-year OS of at least 40% was proposed as promising and warranting further investigation. A sample size of 55 patients was derived such that if at least 30 patients were alive at one year there would be 95% confidence that the true 1-year OS was > 40%. For the purposes of analysis, the time to neutrophil recovery was defined as the first of 3 consecutive days with an ANC ≥ 0.5 × 109/l. Time to platelet recovery was defined as the first of 3 consecutive days at ≥ 20 × 109/l and at least 7 days without platelet transfusion support. Sustained donor engraftment was defined as sustained donor-derived count recovery with donor chimerism of at least 90% (both units combined). GVHD was diagnosed clinically with histological confirmation when appropriate. Consensus criteria were used to grade acute (Przepiorka, et al 1995) and chronic (Filipovich, et al 2005)GVHD, and the algorithm of Copelan et al (2007) was used to assign the primary cause of death. Univariate probabilities of DFS and OS were calculated using the Kaplan-Meier estimator. Values for other endpoints were calculated using cumulative incidence curves to accommodate competing risks. Statistical significance was defined as a p value < 0.05.

Results

Patient and Graft Characteristics

Table I summarizes patient and graft characteristics. This adult cohort included 22 (39%) minority patients and all patients had high-risk disease. Eight (14%) patients received a graft in which one or both units had an infused TNC < 1.5 × 107/kg (range, 1.1–1.4).

Table I.

Patient and graft characteristics (n = 56 patients and 112 units).

Characteristics Value (n = 56)
Median (range) age, years 35 (18–49)
Median (range) weight, kg 78 (50–166)
N (%) recipient CMV+ 37 (66%)
N (%) white non-Hispanic ancestry 34 (61%)
N (%) AML 31 (55%)
CR1* 14
CR2 17
N (%) ALL 19 (34%)
CR1* 11
CR2 8
N (%) other acute leukaemia 4 (7%)
CR1 3
CR2 1
N (%) MDS 2 (4%)
N (%) disease risk: high 56 (100%)
N (%) donor-recipient HLA-A, -B antigen, -DRB1 allele match
6/6 4 (4%)
5/6 40 (36%)
4/6 68 (61%)
Median (range) unit-unit HLA-match 4/6 (3–6)
Median (range) infused TNC (× 107/kg)
Larger unit 2.62 (1.44–5.62)
Smaller unit 2.02 (1.07–5.56)
Median (range) infused CD34+ cells (× 105/kg)
Larger unit 1.09 (0.29–7.06)
Smaller unit 0.82 (0.11–6.89)
Open in a new tab

CMV, cytomegalovirus; AML, acute myeloid leukaemia; ALL, acute lymphoblastic leukaemia; MDS, myelodysplastic syndrome; CR, complete remission; HLA, human leucocyte antigen; TNC, total nucleated cells.

*

Reasons for transplant in CR1 for AML patients included high-risk cytogenetics or molecular abnormalities (n = 7), high-risk cytogenetics with preceding MDS (n = 1) or combined with additional high-risk features (n = 3), or preceding MDS (n = 3). Reasons for transplant in CR1 for ALL patients included Philadelphia chromosome positivity ± additional high-risk features (n = 6), or other risk factors, such as other high-risk cytogenetics and/or failure to achieve a morphological remission after initial induction (n = 5).

CB Infusion and Neutrophil and Platelet Engraftment

One-hundred and five (94%) units were RBC-depleted and 7 were RBC-replete. There were no severe infusion reactions. Sustained donor-derived neutrophil engraftment was observed in 89% (95% confidence interval [CI]: 80–96) of patients by 100 days after transplantation with a median time to neutrophil recovery of 22 days (range 13–94) (Figure 1A). In engrafting patients, haematopoiesis was mediated by a single unit in 88% of patients from day 28 and 100% as from 60 days after transplant. The cumulative incidence of day 180 platelet engraftment was 70% (95%CI: 57–81) with recovery to ≥ 20 × 109/l occurring at a median of 49 days (range 31–320) (Figure 1B).

Figure 1.

Figure 1

Figure 1

Open in a new tab

The cumulative incidence of engraftment after myeloablative double-unit cord blood transplantation. (A) Neutrophil engraftment at day 100 (B) platelet engraftment at day 180. 95%CI, 95% confidence interval.

GVHD

The cumulative incidence of day 180 grade II-IV acute GVHD was 64% (95%CI: 51–76) (Figure 2A). While the incidence of grade III-IV disease was 41% (95%CI: 29–54), only one patient had grade IV acute GVHD by Consensus criteria. Of the 36 patients with grade II-IV acute GVHD, 3 had skin involvement alone, 7 had gastrointestinal (GI) involvement alone, 9 had skin and GI, 7 had GI and hepatic disease, 2 had skin and hepatic and 8 had all 3 organs involved. Thus, 31/36 (86%) of acute GVHD patients had GI involvement. Thirty-six percent (95%CI: 24–49) of patients had chronic GVHD by 3-years after CBT (Figure 2B). Of 20 patients with chronic GVHD, 11 patients had mild, 7 had moderate and 2 had severe disease.

Figure 2.

Figure 2

Figure 2

Open in a new tab

The cumulative incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) by day 180 (2A) and chronic GVHD by 3-years (2B) after myeloablative double-unit cord blood transplantation. 95%CI, 95% confidence interval.

TRM and Relapse

Three-year TRM was 39% (95%CI: 26–52) (Figure 3A). Of 22 transplant-related deaths, primary graft failure was the cause in 4 patients. Ten patients died of GVHD including 9 from acute and one from chronic disease. Five patients died of organ failure, all of which were pulmonary deaths due to diffuse alveolar haemorrhage or acute respiratory distress syndrome. Infection was the primary cause of death in 3 patients and included one patient who died of bacterial sepsis, one of C. difficile colitis and multi-organ failure and one from cytomegalovirus (CMV) colitis. The median time to transplant-related death was 3 months (range 1–19) after transplant.

Figure 3.

Figure 3

Figure 3

Open in a new tab

The cumulative incidence of TRM (3A) and relapse (3B) 3-years after myeloablative double-unit cord blood transplantation. 95%CI, 95% confidence interval.

The cumulative incidence of relapse at 3-years after double-unit CBT was 11% (95%CI: 4–21) (Figure 3B). Of the 6 patients who relapsed, one had AML transplanted in CR2 and 5 had ALL (2 in CR1 and 3 in CR2).

Survival

With a median follow-up of 37 months (range 23–71), the OS at 1 and 3 years after CBT was 57% (95%CI: 44–70) and 52% (95%CI: 39–65), respectively. DFS at these time points was 55% (95%CI: 42–68) and 50% (95%CI: 37–63), respectively (Figure 4). There were no differences in 3-year DFS according to age [48% (95%CI: 30–67) in recipients < 35 years old versus 52% (95%CI: 34–69) if ≥ 35 years)], CMV sero-positivity [47% (95%CI: 32–63) in CMV+ recipients versus 56% (95%CI: 33–77) if sero-negative)], or remission status [57% (95%CI: 39–75) in CR1 versus 43% (95%CI: 25–61) in non-CR1 CBT recipients)] (all p values not significant).

Figure 4.

Figure 4

Open in a new tab

The 3-year Kaplan-Meier estimate of overall and disease-free survival after adult myeloablative double-unit cord blood transplantation. 95%CI, 95% confidence interval; OS, overall survival; DFS, disease-free survival.

Immune Recovery

Serial measures of immune recovery are shown in Table II. Progressive immune recovery was observed in long-term survivors. For example, the median CD4+ count was > 0.15 × 109/l by day 180 and > 0.25 × 109/l by 1 year post-CBT. The median CD19+ cell count was 0.189 × 109/l by day 180 and was associated with a median IgG level of 5.01 g/l (range 1.28 – 16.2) at that time-point.

Table II.

Recovery of lymphocyte subsets in long-term survivors of double-unit CBT. Values represent medians with range.

Day 60 Day 100 Day 180 1 year 1.5 years 2 years
N Cells (× 109/l) N Cells (× 109/l) N Cells (× 109/l) N Cells (× 109/l) N Cells (× 109/l) N Cells (× 109/l)
CD4+ 40 0.08
(0–0.573)		 38 0.1
(0–0.434)		 31 0.165
(0–0.581)		 28 0.287
(0.013–0.675)		 16 0.418
(0.215–0.868)		 17 0.573
(0.002–1.024)
CD8+ 39 0.019
(0–0.882)		 38 0.027
(0–0.829)		 31 0.055
(0–2.095)		 28 0.147
(0–1.16)		 16 0.285
(0.046–2.412)		 17 0.207
(0.021–2.187)
CD16/56+ 39 0.162
(0–0.946)		 37 0.207
(0–0.936)		 30 0.24
(0–0.669)		 26 0.228
(0.007–0.761)		 15 0.214
(0.074–0.605)		 16 0.173
(0.018–0.659)
CD19+ 42 0.002
(0–0.747)		 39 0.015
(0–3.26)		 31 0.189
(0–2.670)		 27 0.45
(0–1.996)		 18 0.712
(0.026–3.260)		 20 0.862
(0.041–3.622)
Open in a new tab

Discussion

This study represents the first prospective multi-centre trial of myeloablative double-unit CBT in adults. The 52% OS at 3 years defined the study as successful. Moreover, the 50% DFS at 3 years after transplantation both supports the further investigation of myeloablative double-unit CBT as a viable alternative therapy for adults with high-risk acute leukaemia and MDS, and is comparable to the OS after unrelated donor transplantation as reported in the randomized trial of peripheral blood stem cells (51% at 2-years) versus bone marrow (46% at 2-years) (Anasetti, et al 2012). Importantly, this strategy provides a readily available graft. Furthermore, it extends transplant access to those lacking a suitable related or unrelated donor who may otherwise not be able to receive an allograft. A notable finding was the strikingly low incidence of relapse. In patients with AML, undifferentiated acute leukaemia or MDS, only one patient of 37 relapsed. This suggests robust disease control, which is in contrast to that observed after haplo-identical transplantation (Bashey, et al 2013) and is probably due to a potent graft-versus leukaemia effect from the CB graft as well as the result of high-dose conditioning. Another feature of our results is the demonstration of a plateau on the survival curve, suggesting adequate immune reconstitution in surviving patients. This could serve to both protect against relapse as well as late TRM, and is supported by the serial recovery of the basic measures of immune reconstitution documented in long-term survivors in this study (Table II).

However, double-unit CBT can only be considered a promising therapy provided the early post-transplantation TRM can be reduced. While the 3-year TRM of 39% in this study was not higher than what may be expected from myeloablative allografts, especially if performed using a mismatched unrelated donor, our results highlight the need for significant improvement in this therapy. In a similar adult two-centre series of myeloablative double-unit CBT, the TRM was 34% at 2 years (Brunstein, et al 2010). It was notable that the majority of patients in the current study who died of transplant complications succumbed early post-transplant and that the most common cause of death was acute GVHD. However, there was also a significant contribution from delayed or failed engraftment and organ toxicity.

There are multiple potential contributors to the relatively high rate of TRM. As expected, delayed neutrophil and platelet engraftment were demonstrated in this study. The delayed engraftment contributes to morbidity and mortality after CBT and substantially to the cost from prolonged hospitalization and high transfusion requirements and other supportive care measures. Infused TNC and CD34+ cell dose are well established determinants of survival after single unit CBT (Barker, et al 2010b, Wagner, et al 2002) and a recent study of myeloablative CBT found that single unit grafts with a TNC dose < 3.0 × 107/kg were associated with a substantial risk of graft failure and TRM (Eapen, et al 2014). In an effort to avoid single unit CBT with low cell dose units, but also extend transplant access to as many adult patients as possible, the lower limit of the cryopreserved TNC dose in this double unit trial was very low, at 1.5 × 107/kg/unit. This minimum would now be considered too low by most centres even for double-unit CBT. It is likely that this study’s unit selection strategy of prioritizing HLA-match above a TNC threshold of 1.5 × 107/kg was not able to offset an adverse impact of low cell dose even despite the use of double-unit grafts.

Multiple strategies are under investigation to improve engraftment after CBT. Since this trial was designed, the importance of the infused CD34+ cell dose of the engrafting unit in determining the speed and success of neutrophil engraftment after double-unit CBT has been demonstrated (Avery, et al 2011). In the future, CBT will be assisted by a refinement of unit selection criteria. The ability to select units based on the CD34+ cell rather than TNC dose and predict the post-thaw unit quality will be advantageous (Purtill et al, 2014), as would an enlarging CB inventory. Moreover, additional methods to augment engraftment, such as ex vivo expansion, enhanced homing or the addition of haplo-identical progenitors, should be beneficial and are under active investigation (Bautista, et al 2009, Cutler, et al 2013, de Lima, et al 2012, Delaney, et al 2008, Liu, et al 2011, Shpall, et al 2011).

Beyond the challenge of delayed engraftment, it is likely that many adult patients are, in fact, unsuitable for the highest dose chemo-radiation. Toxicity from such conditioning may have been further exacerbated by the eligibility criteria in this trial being too liberal from the standpoint of both performance status and organ function. It is likely that borderline organ function and/or performance status in combination with high dose conditioning and prolonged neutrophil recovery act in combination to greatly increase toxicity risk. Further investigation of better tolerated conditioning is indicated and is already in phase II studies at multiple institutions (Brunstein, et al 2007, Brunstein, et al 2011, Delaney, et al 2009, Ponce, et al 2013a). Of particular interest are preparative regimens of intermediate intensity that are neither high dose nor non-myeloablative. Such regimens are likely to mitigate the risk of graft rejection and relapse as compared with non-myeloablative conditioning, but will also be better tolerated than the highest dose regimens. Consideration of co-morbidity scores could also guide conditioning regimen intensity and potentially ameliorate the risk of organ failure (Sorror, et al 2005).

The rate of chronic GVHD was relatively modest in this study and severe chronic GVHD was rare. However, the incidence of grade III acute GVHD was significant and, in fact, acute GVHD was the most common cause of TRM. The high incidence of acute GVHD involving the GI tract supports the single centre findings reported by Ponce et al (2013b). Augmented acute GVHD prophylaxis is, therefore, a critical requirement for adult double-unit CBT. Selecting units based on the high-resolution donor-recipient match could ameliorate severe acute GVHD and other causes of TRM (Eapen, et al 2014, Ponce, et al 2013b). Increasing MMF dosing to 1 g every 8 h, now the standard in adult donor allografts (Alousi, et al 2013), as well as extending the duration of MMF prophylaxis to approximately day 100 can mitigate GVHD severity (D. Ponce and J. Barker, unpublished data). Whether in vivo T-cell depletion of the CB allograft with anti-thymocyte globulin would result in improved DFS is unknown and a retrospective registry-based CIBMTR analysis addressing this question is currently underway.

Centre experience could have also played a role in these results. CBT requires intensive supportive care, especially early post-transplantation, and the standards for this are not widely established. The National Marrow Donor Program is currently leading an initiative to establish such guidelines in the US. Such guidelines are important as the low rates of relapse and chronic GVHD associated with CBT in this and other series provide a promising platform upon which to build. The goal to reduce TRM is realistic given an increasing global CB inventory and centre experience, and optimized unit selection criteria, new conditioning regimens, strategies to speed engraftment, augmented GVHD prophylaxis and improved supportive care are highly likely to improve outcome and all are under investigation. This should contribute to CBT becoming a routine allograft alternative for patients with high-risk haematological malignancies who lack a readily available matched adult donor.

Acknowledgments

We would like to acknowledge members of the 05-DCB Team including Mary Territo, Mary Laughlin, Mark Juckett, Scott Solomon as well as Mary Horowitz, Dennis Confer, Rebecca Drexler, Amy Foley and the nursing staff and transplant coordinators who greatly contributed to this work.

Research Support: This work was supported by Department of the Navy-Office of Naval Research (Development of Medical Technology for Contingency Response to Marrow Toxic Agents).

Grant Support number: P30 CA008748.

Footnotes

Author role and contributions

Juliet N. Barker conceived of and was Principal Investigator of the trial, Mingwei Fei performed the data analysis, Chatchada Karanes, Mitchell Horwitz, Steven Devine, Tamila L. Kindwall-Keller and Jennifer Holter were co-investigators, Alexia Adams was the CIBMTR Protocol Coordinator, Brent Logan supervised trial data analysis, Willis H. Navarro was the Medical Monitor and the Resource for Clinical Investigation in Blood and Marrow Transplantation (RCI BMT) Scientific Director, and Marcie Riches was the Protocol Officer for the Trial and a co-investigator.

Conflict-of-interest disclosure: The authors have no relevant conflicts of interest to declare.

References

  1. Alousi A, Bolanos-Meade J, Lee SJ. Graft-versus-host disease: State of the Science. Biol Blood Marrow Transplant. 2013;19:S102–S108. doi: 10.1016/j.bbmt.2012.10.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367:1487–1496. doi: 10.1056/NEJMoa1203517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Avery S, Shi W, Lubin M, Gonzales AM, Heller G, Castro-Malaspina H, Giralt S, Kernan NA, Scaradavou A, Barker JN. Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts. Blood. 2011;117:3277–3285. doi: 10.1182/blood-2010-08-300491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102:1915–1919. doi: 10.1182/blood-2002-11-3337. [DOI] [PubMed] [Google Scholar]
  5. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS, Verfaillie CM, Wagner JE. Transplantation of two partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005;105:1343–1347. doi: 10.1182/blood-2004-07-2717. [DOI] [PubMed] [Google Scholar]
  6. Barker JN, Abboud M, Rice RD, Hawke R, Schaible A, Heller G, La Russa V, Scaradavou A. A “no-wash” albumin-dextran dilution strategy for cord blood unit thaw: high rate of engraftment and a low incidence of serious infusion reactions. Biol Blood Marrow Transplant. 2009;15:1596–1602. doi: 10.1016/j.bbmt.2009.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barker JN, Byam CE, Kernan NA, Lee SS, Hawke RM, Doshi KA, Wells DS, Heller G, Papadopoulos EB, Scaradavou A, Young JW, van den Brink MA. Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow Transplant. 2010a;16:1541–1548. doi: 10.1016/j.bbmt.2010.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Barker JN, Scaradavou A, Stevens CE. Combined effect of total nucleated cell dose and HLA-match on transplant outcome in 1061 cord blood recipients with hematological malignancies. Blood. 2010b;115:1843–1849. doi: 10.1182/blood-2009-07-231068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, Morris LE, Solomon SR. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31:1310–1316. doi: 10.1200/JCO.2012.44.3523. [DOI] [PubMed] [Google Scholar]
  10. Bautista G, Cabrera JR, Regidor C, Fores R, Garcia-Marco JA, Ojeda E, Sanjuan I, Ruiz E, Krsnik I, Navarro B, Gil S, Magro E, de Laiglesia A, Gonzalo-Daganzo R, Martin-Donaire T, Rico M, Millan I, Fernandez MN. Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor. Bone Marrow Transplant. 2009;43:365–373. doi: 10.1038/bmt.2008.329. [DOI] [PubMed] [Google Scholar]
  11. Brunstein C, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, McGlave PB, Wagner JE. Umbilical cord blood transplantation after non-myeloablative conditioning: impact on transplant outcomes in 110 adults with hematological disease. Blood. 2007;110:3064–3070. doi: 10.1182/blood-2007-04-067215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, Defor TE, Gooley TA, Verneris MR, Appelbaum FR, Wagner JE, Delaney C. Allogeneic hematopoietic cell transplantation for hematological malignancy: relative risks and benefits of double umbilical cord blood. Blood. 2010;116:4693–4699. doi: 10.1182/blood-2010-05-285304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O’Donnell PV. 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. Blood. 2011;118:282–288. doi: 10.1182/blood-2011-03-344853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, Wagner JE, Yanovich S, Kernan NA. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007;13:1469–1476. doi: 10.1016/j.bbmt.2007.08.047. [DOI] [PubMed] [Google Scholar]
  15. Cutler C, Multani P, Robbins D, Kim HT, Le T, Hoggatt J, Pelus LM, Desponts C, Chen YB, Rezner B, Armand P, Koreth J, Glotzbecker B, Ho VT, Alyea E, Isom M, Kao G, Armant M, Silberstein L, Hu P, Soiffer RJ, Scadden DT, Ritz J, Goessling W, North TE, Mendlein J, Ballen K, Zon LI, Antin JH, Shoemaker DD. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013;122:3074–3081. doi: 10.1182/blood-2013-05-503177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. de Lima M, McNiece I, Robinson SN, Munsell M, Eapen M, Horowitz M, Alousi A, Saliba R, McMannis JD, Kaur I, Kebriaei P, Parmar S, Popat U, Hosing C, Champlin R, Bollard C, Molldrem JJ, Jones RB, Nieto Y, Andersson BS, Shah N, Oran B, Cooper LJ, Worth L, Qazilbash MH, Korbling M, Rondon G, Ciurea S, Bosque D, Maewal I, Simmons PJ, Shpall EJ. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med. 2012;367:2305–2315. doi: 10.1056/NEJMoa1207285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Delaney C, Brashem-Stein C, Voorhies H, Gutman J, Dallas M, Heimfeld S, Bernstein I. Notch-Mediated Expansion of Human Cord Blood Progenitor Cells Results in Rapid Myeloid Reconstitution in Vivo Following Myeloablative Cord Blood Transplantation. Blood. 2008;112:212. [Google Scholar]
  18. Delaney C, Gutman JA, Appelbaum FR. Cord blood transplantation for haematological malignancies: conditioning regimens, double cord transplant and infectious complications. Br J Haematol. 2009;147:207–216. doi: 10.1111/j.1365-2141.2009.07782.x. [DOI] [PubMed] [Google Scholar]
  19. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, Loberiza FR, Champlin RE, Klein JP, Horowitz MM, Wagner JE. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369:1947–1954. doi: 10.1016/S0140-6736(07)60915-5. [DOI] [PubMed] [Google Scholar]
  20. Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, Sirvent A, Champlin RE, Chao N, Gee AP, Isola L, Laughlin MJ, Marks DI, Nabhan S, Ruggeri A, Soiffer R, Horowitz MM, Gluckman E, Wagner JE. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol. 2010;11:653–660. doi: 10.1016/S1470-2045(10)70127-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Eapen M, Klein JP, Sanz GF, Spellman S, Ruggeri A, Anasetti C, Brown M, Champlin RE, Garcia-Lopez J, Hattersely G, Koegler G, Laughlin MJ, Michel G, Nabhan SK, Smith FO, Horowitz MM, Gluckman E, Rocha V. Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis. Lancet Oncol. 2011;12:1214–1221. doi: 10.1016/S1470-2045(11)70260-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Eapen M, Klein JP, Ruggeri A, Spellman S, Lee SJ, Anasetti C, Arcese W, Barker JN, Baxter-Lowe LA, Brown M, Fernandez-Vina MA, Freeman J, He W, Iori AP, Horowitz MM, Locatelli F, Marino S, Maiers M, Michel G, Sanz GF, Gluckman E, Rocha V. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014;123:133–140. doi: 10.1182/blood-2013-05-506253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–956. doi: 10.1016/j.bbmt.2005.09.004. [DOI] [PubMed] [Google Scholar]
  24. Gluckman E, Rocha V. Donor selection for unrelated cord blood transplants. Curr Opin Immunol. 2006;18:565–570. doi: 10.1016/j.coi.2006.07.014. [DOI] [PubMed] [Google Scholar]
  25. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE, Stevens C, Barker JN, Gale RP, Lazarus HM, Marks DI, van Rood JJ, Scaradavou A, Horowitz MM. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351:2265–2275. doi: 10.1056/NEJMoa041276. [DOI] [PubMed] [Google Scholar]
  26. Liu H, Rich ES, Godley L, Odenike O, Joseph L, Marino S, Kline J, Nguyen V, Cunningham J, Larson RA, Del Cerro P, Schroeder L, Pape L, Stock W, Wickrema A, Artz AS, van Besien K. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood. 2011;118:6438–6445. doi: 10.1182/blood-2011-08-372508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ponce DM, Sauter C, Devlin S, Lubin M, Gonzales AM, Kernan NA, Scaradavou A, Giralt S, Goldberg JD, Koehne G, Perales MA, Young JW, Castro-Malaspina H, Jakubowski A, Papadopoulos EB, Barker JN. A novel reduced-intensity conditioning regimen induces a high incidence of sustained donor-derived neutrophil and platelet engraftment after double-unit cord blood transplantation. Biol Blood Marrow Transplant. 2013a;19:799–803. doi: 10.1016/j.bbmt.2013.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ponce DM, Gonzales A, Lubin M, Castro-Malaspina H, Giralt S, Goldberg JD, Hanash AM, Jakubowski A, Jenq R, Papadopoulos EB, Perales MA, van den Brink MR, Young JW, Boulad F, O’Reilly RJ, Prockop S, Small TN, Scaradavou A, Kernan NA, Stevens CE, Barker JN. Graft-versus-Host Disease after Double-Unit Cord Blood Transplantation Has Unique Features and an Association with Engrafting Unit-to-Recipient HLA Match. Biol Blood Marrow Transplant. 2013b;19:904–911. doi: 10.1016/j.bbmt.2013.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828. [PubMed] [Google Scholar]
  30. Purtill D, Smith KA, Devlin S, Meagher R, Tonon J, Lubin M, Ponce DM, Giralt S, Kernan NA, Scaradavou A, Stevens CE, Barker JN. Dominant Unit CD34+ Cell Dose Predicts Engraftment After Double-Unit Cord Blood Transplantation and is Inluenced by Cord Blood Bank Practice. Blood. 2014 doi: 10.1182/blood-2014-03-566216. (in press) [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rodrigues CA, Sanz G, Brunstein CG, Sanz J, Wagner JE, Renaud M, de Lima M, Cairo MS, Furst S, Rio B, Dalley C, Carreras E, Harousseau JL, Mohty M, Taveira D, Dreger P, Sureda A, Gluckman E, Rocha V. 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. J Clin Oncol. 2009;27:256–263. doi: 10.1200/JCO.2007.15.8865. [DOI] [PubMed] [Google Scholar]
  32. Shpall EJ, Bollard CM, Brunstein C. Novel cord blood transplant therapies. Biol Blood Marrow Transplant. 2011;17:S39–45. doi: 10.1016/j.bbmt.2010.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919. doi: 10.1182/blood-2005-05-2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH, Burke MJ, Blazar BR, Miller JS, McGlave PB, Weisdorf DJ, Wagner JE. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood. 2009;114:4293–4299. doi: 10.1182/blood-2009-05-220525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, Goldman A, Kersey J, Krivit W, MacMillan ML, Orchard PJ, Peters C, Weisdorf DJ, Ramsay NK, Davies SM. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611–1618. doi: 10.1182/blood-2002-01-0294. [DOI] [PubMed] [Google Scholar]

RESOURCES