Cord Blood Transplantation: State of the Science

By Hal Broxmeyer, PhD, and Filippo Milano, MD
Updated:  March 2018

state of the science


Hematopoietic cell transplantation (HCT) is a life-saving procedure for treatment of malignant and non-malignant disorders, and is usually a last resort for those for whom there is no other available treatment [1,2].

In recent years, umbilical donor cord blood transplantation (CBT) has emerged as a feasible alternative source of hematopoietic progenitors for pediatric and adult patients with hematological malignancies lacking a related or an unrelated donor [3-6]. The increased level of HLA disparity that can be tolerated makes CBT a very attractive alternative source of hematopoietic stem cells. This feature is particularly important for patients from racial and ethnic minorities, as it can be difficult to find an unrelated donor (URD) for such patients [7].

Furthermore, other advantages of Cord Blood (CB) for HCT include the ease of collection of the CB at the birth of the baby, the ability to store CB collections immediately after cryopreservation in either a public CB bank for use by others, or in a family bank for future use by the baby donor or a family member. CB has been used to transplant more than 40,000 recipients with success rates equivalent to those done with bone marrow (BM) or mobilized peripheral blood (mPB) [1,2]. One outstanding advantage of single CBT, besides the almost immediate availability of the cells for transplant, is the documented lower graft-versus-host disease (GVHD) in comparison to that of BM or mPB [1,2]. With double CBT, acute GVHD is comparable to that of other types of unrelated HCT [8].

However, there are disadvantages to using CB compared to BM and mPB, including the more limited numbers of cells collected at the birth of the baby, and the slower time to engraftment for neutrophils, platelets, and immune cell reconstitution [1,2]. Being able to successfully address these two concerns would make CB an even more desirable source of transplantable hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC), and would likely greatly enhance the clinical use of these cells for HCT.

Ongoing Experimental Laboratory and Clinical Efforts to Enhance CB HCT

Clinical efforts for, and the status of, CB HCT have been described in detail in several review articles [1,2,9]. Present efforts to enhance the efficacy of CB HCT include:

a) more effective means to manage high quality and quantity collections of CB that maximize numbers of functional HSC

b) efforts to increase the homing capacity of HSC, since only a small portion of the HSC infused intravenously (i.v.) during HCT actually reach and/or engraft in the BM, a necessary site of eventual lodgement for HSC

c) the capacity to expand numbers of collected HSC and HPC outside the body (ex-vivo)

d) determining how best to enhance the production of the cells that eventually reach (home to) the BM, as part of the actual engraftment procedure

Enhancing Cell Collections

Numbers of HSC/HPC and other cells collected by the best and most efficient means are still sub-par with respect to optimal collections. The BM environment needed to nurture, maintain and expand HSC is extremely hypoxic compared to air. The involvement of hypoxia signaling pathways in stem cell regulation have recently been reviewed [10]. Upon collection of CB cells, the immediate exposure of the cells to the high O2 content of ambient air grossly alters numbers and function of HSC and HPC – a phenomenon termed “extra physiologic oxygen shock/stress” (EPHOSS) [11,12]. By collecting and processing CB cells in hypoxia, there is a 3-5 fold increase in phenotypically defined and functional engrafting HSCs. While it is logistically possible to do CB collections and processing in hypoxia, this would be a complicated procedure, and would have to be done in very selected CB collection centers that maintain good manufacturing procedures.

Thus, the immediate collection and processing of human CB cells in ambient air but in the presence of Cyclosporine A (CsA) mimics the effects of hypoxia with collection of increased numbers of phenotypically and functionally defined HSC [11,12]. However, more work is necessary in this area as CsA is not an easy compound to work with. It is difficult to get into solution, and the exact concentration to use for best advantage may need to be determined for different collection scenarios. Other means to counteract the effects of EPHOSS with mouse BM cells were successful when these cells were collected in ambient air but in the presence of specific combinations of anti-oxidants and/or inhibitors of specific epigenetic enzymes. Use of single anti-oxidants or single inhibitors of epigenetic enzymes did not enhance collection of the mouse BM HSC [13]. It remains to be determined if such procedures will work for human CB HSC collections.

Enhancing the Homing Capabilities of HSC for More Efficient Engraftment

There have been a number of attempts to enhance the capacity of HSC to home to the BM after i.v. injection/infusion for enhanced engrafting capability. Some current efforts include: inhibition of the enzymatic activities of Dipeptidylpeptidase (DPP)4 [14-19], use of prostaglandin E (PGE) [20-22], short-term treatment of cells with hyperthermia [23], enforced fucosylation of the cells [24,25], short pulse glycocorticoid hormone stimulation [26], or inhibition of the negative epigenetic regulation by histone deacetylase (HCAC) 5 (Huang, X., Guo, B., Liu, S., Wan, J., and Broxmeyer, H.E., revised paper submitted). Both glycocorticoids (e.g. dexamethasone, cortisol, Flonase, Medrol) or HDAC5 inhibition enhanced expression of a homing receptor CXCR4 on the HSC and increased chemotaxis to SDF-1/CXCL12 in vitro and the in vivo homing and engraftment, of the 16 hour in vitro pulsed cells, into NSG mice.

Combined treatments, such as already demonstrated with DPP4 inhibition plus PGE [27], may be advantageous.

Ex-vivo Expansion of HSC and HPC to Increase the Numbers of these Cells, and Enhance CB HCT

To make up for the relative paucity of cells in a single CB collection, investigators went to use of double CB HCT [1,2]. This did help move the field of CB HCT forward, but at this time there is no definitive proof that double CB HCT is any more effective than single CB HCT [1,2], although most centers still use two CB units for HCT. As a means to find a way to increase the numbers of CB HSC/HPC for CB HCT, different groups have experimented with means to expand the numbers of these cells outside the body (ex-vivo) [1,2,9].

The first successful attempt at clinical use of ex-vivo expanded CB cells involved Notch-mediated culture of CD34+ CB cells [28]. The infusion of these cultured cells resulted in an apparent shortening of the time to neutrophil engraftment. CB cells were also cultured by others in the presence of nicotinamide and a non-cultured T-cell fraction which resulted in encouraging results [29].

More recently, a third group took advantage of background studies that demonstrated that a small molecule, SR1 [30], in combination with a cytokine cocktail could expand HSC numbers, in order to bring this procedure to the clinic [31]. This effort also resulted in quite impressive results. However, all these clinical studies were done in context of a double CB HCT in which the recipients were provided with donor cells from a manipulated and also unmanipulated CB collection. Thus, although the results noted above are impressive, it remains to be seen if in fact the ex-vivo cultured cells can by themselves, without the added presence of a second unmanipulated CB unit, actually engraft.  And if so, can it accelerate the time to neutrophil, platelet and immune cell recovery compared to that noted by either single or even double unmanipulated CB HCT.

There are a number of small molecule experimental procedures that have been evaluated in a laboratory setting, all of which enhance the ex-vivo expansion of CB CD34+ cells and the HSC and HPC population within this phenotyped population of CD34+ cells beyond that of a cocktail of cytokines. This includes SR1 [30,31], an aryl hydrocarbon receptor antagonist, and also pyrimidoindole derivatives [32], which acted as agonists of human HSC self-renewal events. Other small molecules include those involved in antagonism of peroxisome proliferation-activated receptor (PPAR)-g [33], and a structural analog of SB20358 (p38-map kinase inhibitor) [34] have been used to enhance cytokine stimulated ex-vivo expansion of CB HSC, and a search for additional small molecule agonists and antagonists to enhance CB HSC expansion are ongoing.

The above and other efforts to ex-vivo expand CB cells for use in CB HCT [35-38] appear encouraging, but it is not yet clear which ex-vivo expansion procedure(s) will eventually be found to be most efficacious.

However, until the clinical studies are done in context of a single transplantable CB unit, it is not clear how this may change how CB HCT is done.

In vivo Enhancement of the Engrafted Cells

One potential means to enhance the efficacy of CB HCT is to find a way to accelerate the self-renewal and differentiation capacity of the CB cells that have already homed to and lodged in the BM of the recipients. This could be done by infusing growth factors. Another possibility is to use a DPP4 inhibitor such as sitagliptin [17-19] for more prolonged periods after the engraftment process has started. Another interesting way to enhance engraftment is the use of hyperbaric oxygen for the recipient [39,40].

Comparison of Graft Sources

To date, there are no randomized studies that compare the risks and benefits of CBT relative to those observed with cells from bone marrow or mobilized peripheral blood from unrelated donors (URD). However, several retrospective studies have compared outcomes between CBT and other stem cell sources [3-6]. Recently, outcomes between CBT and matched and mismatched unrelated transplants were compared in the largest retrospective single institution study so far conducted [41]. Survival following transplant from a CBT appeared better than that following transplant from a mismatched URD, largely due to decreased relapse rates. Improved survival with less relapse rate was observed among those transplanted with minimal residual disease in the CBT group when compared both to mismatched and matched URD.

While there are no randomized studies comparing CBT versus URD, a phase III randomized study (BMT CTN 1101) to evaluate potential differences between non-myeloablative haploidentical HCT and CBT is currently ongoing. The randomized study was started in light of the results of two parallel-phase trials of double-unit CBT and haploidentical HCT published by the Bone Marrow Transplant Clinical Trials Network. In the study, patients received a similar conditioning regimen but different GVHD prophylaxis. Disease-free survival at one year was similar between the two groups as a result of higher transplant-related mortality and lower relapse after CBT when compared to patients receiving haploidentical HCT [42].

Concluding Remarks

Many laboratory scientists and clinical investigators continue to work to better understand the biology and the mechanisms involved in the regulation of HSC and HPC. Their objective is a means to enhance CB HCT so that there is more rapid engraftment, without loss of the lesser amounts of GVHD found in CB HCT, and with maintenance of the anti-leukemia, anti-cancer effects of the CB. The newer findings will also have to take into account the economics of the transplant [43]. Without sacrificing the safety and efficiency of the procedure, cost needs to be taken into account.


  1. H.E. Broxmeyer, S.S. Farag, V. Rocha, Cord blood hematopoietic cell transplantation, in: S.J. Forman, R.S. Negrin, J.H. Antin, F.R. Appelbaum (Eds.), Thomas’ Hematopoietic Cell Transplantation, 5th Edition, John Wiley & Sons, Ltd; Oxford, England, 2016, Chapter 39, pp. 437-455.
  2. K.K. Ballen, E. Gluckman, H.E. Broxmeyer, Umbilical cord blood transplantation – the first 25 years and beyond, Blood. 122 (2013) 491-498.
  3. M.J. Laughlin, J. Barker, B. Bambach, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors, N Engl J Med. 344 (2001)  18151822. 
  4. M.J. Laughlin, M. Eapen, P. Rubinstein, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia, N Engl J Med. 351 (2004) 2265-2275. 
  5. V. Rocha, M. Labopin, G. Sanz , et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia, N Engl J Med. 351 (2004) 2276-2285. 
  6. J. Kurtzberg, M. Laughlin, M.L. Graham, et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients, N Engl J Med. 335 (1996) 157-166.
  7. L. Gragert, M. Eapen, E. Williams, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry, N Engl J Med. 371 (2014) 339-348.
  8. F. Milano, C. Delaney, R. Storb. Graft-versus-host-disease after double cord blood transplantation: a new look at its characteristics, Biol Blood Marrow Transplant. 19 (2013) 847-848.
  9. H.E. Broxmeyer. Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation, Transfusion and Apheresis Science. 54 (2016)  364-372.
  10. X. Huang, T. Trinh, A. Aljoufi, H.E. Broxmeyer. Hypoxia Signaling Pathway in Stem Cell Regulation: Good and Evil. Current Stem Cell Reports. (2018) In Press.
  11. C.R. Mantel, H.A. O’Leary, B.R. Chitteti, X. Huang, S. Cooper, G. Hangoc, N. Brustovetsky, E.F. Srour, M.R. Lee, S. Messina-Graham, D.M. Haas, N. Falah, R. Kapur, L.M. Pelus, N. Bardeesy, J. Fitament M. Ivan, K-S. Kim, H.E. Broxmeyer, Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock, Cell. 161 (2015) 1553-1565.
  12. H.E. Broxmeyer, H.A. O’Leary, X. Huang, C. Mantel, The importance of hypoxia and EPHOSS for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex-vivo, Current Opinions in Hematopoiesis.  22 (2015) 273-278.
  13. Q. Cai, M. Capitano, X. Huang, B. Guo, S. Cooper, H.E. Broxmeyer. Combinations of antioxidants and/or of epigenetic enzyme inhibitors allow for enhanced collection of mouse bone marrow hematopoietic stem cells in ambient air. Blood Cells Mol Dis. (2018) pii: S1079-9796(18)30043-3.
  14.  K.W. Christopherson, G. Hangoc, H.E. Broxmeyer, Cell surface peptidase CD26/DPPIV regulates CXCL12/SDF-1a mediated chemotaxis of human CD34progenitor cells,  J. Immunol.  169 (2002) 7000-7008.
  15. K.W. Christopherson II, G. Hangoc, C. Mantel, H.E. Broxmeyer, Modulation of hematopoietic stem cell homing and engraftment by CD26,  Science.  305 (2004) 1000-1003.
  16. H.E. Broxmeyer, J. Hoggatt, H.A. O’Leary, C. Mantel, B.R. Chitteti, S. Cooper, S. Messina-Graham,G. Hangoc, S. Farag, S.L., Rohrabaugh, X. Ou, J. Speth, L.M. Pelus, E.F. Srour, T.B. Campbell, Dipeptidylpeptidase 4 negatively Regulates colony stimulating factor activity and stress hematopoiesis, Nature Medicine. 18 (2012) 1786-1796.
  17. S.S. Farag, S. Srivastava, S. Messina-Graham, J. Schwartz, M.J. Robertson, R. Abonour, K. Cornetta, L. Wood, A. Secrest, R.M. Strother, D.R. Jones, H.E. Broxmeyer, In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies, Stem Cells Dev. 22 (2013) 1007-1015.
  18. N. Velez de Mendizabal, R.M. Strother, S.S. Farag, H.E. Broxmeyer, S. Messina-Graham, S.D. Chitnis, R.R. Bies, Modelling the sitagliptin effect on Dipeptidyl Peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation, Clin Pharmacokinet. 53 (2014) 247-259.
  19. S.S. Farag, R. Nelson, M.S. Cairo, H.A. O'Leary, S. Zhang, C. Huntley, D. Delgado, J. Schwartz, M.A. Zaid, R. Abonour, M. Robertson, H. Broxmeyer. High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget. 8 (2017) 110350-110357.
  20. T.E. North, W. Goessling, C.R. Walkley, C. Lengerke, K.R. Kopani, A.M. Lord, G.J. Weber, T.V. Bowman, I.H. Jang, T. Grosser, G.A. Fitzgerald, G.Q. Daley, S.H. Orkin, L.I. Zon, Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis, Nature. 447 (2007):1007-1011.
  21. J. Hoggatt, P. Singh, J. Sampath, L.M. Pelus, Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation, Blood. 113 (2009) 5444-5455.
  22. C. Cutler, P. Multani, D. Robbins, H.T. Kim, T. Le, J. Hoggatt, L.M. Pelus, C. Desponts, Y.B. Chen, B. Rezner, P. Armand, J. Koreth, B. Glotzbecker, V.T. Ho, E. Alyea, M. Isom, G. Kao, M. Armant, L. Silberstein, P. Hu, R.J. Soiffer, D.T. Scadden, J. Ritz, W. Goessling, T.E. North, J. Mendlein, K. Ballen, L.I. Zon, J.H. Antin, D.D. Shoemaker, Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation, Blood. 122 (2013) 3074-3081.
  23. M.L. Capitano, G. Hangoc, S. Cooper, H.E. Broxmeyer, Mild heat treatment primes human CD34+ cord blood cells for migration towards SDF-1a and enhances engraftment in an NSG mouse model, Stem Cells. 33 (2015) 1975-1984.
  24. L. Xia, J.M. McDaniel, T. Yago, A. Doeden, R.P. McEver, Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow, Blood. 104 (2004) 3091-3096.
  25. U. Popat, R.S. Mehta, K. Rezvani, P. Fox, K. Kondo, D. Marin, I. McNiece, B. Oran, C. Hosing, A. Olson, S. Parmar, N. Shah, M. Andreeff, P. Kebriaei, I. Kaur, E. Yvon, M. de Lima, L.J. Cooper, P. Tewari, R.E. Champlin, Y. Nieto, B.S. Andersson, A. Alousi, R.B. Jones, M.H. Qazilbash, Q. Bashir, S. Ciurea, S. Ahmed, P. Anderlini, D. Bosque, C. Bollard,  J.J. Molldrem, J. Chen, G. Rondon, M. Thomas, L. Miller, S. Wolpe, P. Simmons, S. Robinson, P.A. Zweidler-McKay, E. J. Shpall, Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation, Blood. 125 (2015) 2885-2892.
  26. B. Guo, X. Huang, S. Cooper, H.E. Broxmeyer. Glucocorticoid hormone promotes human hematopoietic stem cell homing and engraftment by chromatin remodeling. Nat Med. 23 (2017) 424-428.
  27. H.E. Broxmeyer, L.M. Pelus, Inhibition of DPP4/CD26 and dmPGE2 treatment enhances engraftment of mouse bone marrow hematopoietic stem cells, Blood Cells Mol Dis. 53 (2014) 34-38.
  28. C. Delaney, S. Heimfeld, C. Brashem-Stein, H. Voorhies, R.L. Manger, I.D. Bernstein, Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution, Nat Med. 16 (2010) 232-236.
  29. M.E. Horwitz, N.J. Chao, D.A. Rizzieri, G.D. Long, K.M. Sullivan, C. Gasparetto, J.P. Chute, A. Morris, C. McDonald, B. Waters-Pick, P. Stiff, S. Wease, A. Peled, D. Snyder, E.G. Cohen, H. Shoham, E. Landau, E. Friend, I. Peleg, D. Aschengrau, D. Yackoubov, J. Kurtzberg, T. Peled, Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment, J Clin Invest. 124 (2014) 3121-3128.
  30. A.E. Boitano, J. Wang, R. Romeo, L.C. Bouchez, A.E. Parker, S.E. Sutton, J.R. Walker, C.A. Flaveny, G.H. Perdew, M.S. Denison, P.G. Schultz, and M.P. Cooke, Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells, Science. 329 (2010) 1345-1348.
  31. J.E. Wagner, Jr., C.G. Brunstein, A.E. Boitano, T.E. DeFor, D. McKenna, D. Sumstad, B.R. Blazar, J. Tolar, C. Le, J. Jones, M.P. Cooke, C.C. Bleul, Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft, Cell Stem Cell. 18 (2016) 144-155.
  32. I. Fares, J. Chagraoui, Y. Gareau, S. Gingras, R. Ruel, N. Mayotte, E. Csaszar, D.J. Knapp, P. Miller, M. Ngom, S. Imren, D.C. Roy, K.L. Watts, H.P. Kiem, R. Herrington, N.N. Iscove, R.K. Humphries, C.J. Eaves, S. Cohen, A. Marinier, P.W. Zandstra, G. Sauvageau, Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal, Science. 345 (2014) 1509-1512.
  33. B. Guo, X. Huang, M.R. Lee, S.A. Lee, H.E. Broxmeyer. Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nature Medicine. (2018) Jan 29. doi: 10.1038/nm.4477. [Epub ahead of print].
  34. S. Bari, Q. Zhong, X. Fan, Z. Poon, A.S.T. Lim, T.H. Lim, N. Dighe, S. Li, G.N.C. Chiu, C.L.L. Chai, W.Y.K. Hwang. Ex Vivo Expansion of CD34+CD90+CD49f+ Hematopoietic Stem and Progenitor Cells from Non-enriched Umbilical Cord Blood with Azole Compounds. Stem Cells Transl Med. (2018) Feb 2. doi: 10.1002/sctm.17-0251. [Epub ahead of print].
  35. M. de Lima, J. McMannis, A. Gee, K. Komanduri, D. Couriel, B.S. Andersson, C. Hosing, I. Khouri, R. Jones, R. Champlin, S. Karandish, T. Sadeghi, T. Peled, F. Grynspan, Y. Daniely, A. Nagler, E.J. Shpall, Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial, Bone Marrow Transplant. 41 (2008) 771-778.
  36. M. de Lima, I. McNiece, S.N. Robinson, M. Munsell, M. Eapen, M. Horowitz, A. Alousi, R. Saliba, J.D. McMannis, I. Kaur, P. Kebriaei, S. Parmar, U. Popat, C. Hosing, R. Champlin, C. Bollard, J.J. Molldrem, R.B. Jones, Y. Nieto, B.S. Andersson, N. Shah, B. Oran, L.J. Cooper, L. Worth, M.H. Qazilbash, M. Korbling, G. Rondon, S. Ciurea, D. Bosque, I. Maewal, P.J. Simmons, E.J. Shpall, Cord-blood engraftment with ex vivo mesenchymal-cell coculture, N Engl J Med. 367 (2012) 2305-2315.
  37. J. Munoz, N. Shah, K. Rezvani, C. Hosing, C.M. Bollard, B. Oran, A. Olson, U. Popat, J. Molldrem, I.K. McNiece, E.J. Shpall, Concise review: umbilical cord blood transplantation: past, present, and future, Stem Cells Transl Med. 3 (2014) 1435-1443.
  38. S. Bari, K.K. Seah, Z. Poon, A.M. Cheung, X. Fan, S.Y. Ong, S. Li, L.P. Koh, W.Y. Hwang, Expansion and homing of umbilical cord blood hematopoietic stem and progenitor cells for clinical transplantation, Biol Blood Marrow Transplant. 21 (2015) 1008-1019.
  39. O.S. Aljitawi, Y. Xiao, J. Eskew, N. Parelkar, M. Swink, J. Radel, T.L. Lin, B. Kimler, J.D. Mahnken, J.P. McGuirk, H.E. Broxmeyer, G. Vielhauer,  Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34+ cells in a murine model of umbilical cord blood transplantation, Blood Cells Mol Dis. 52 (2014) 59-67.
  40. O.S. Aljitawi, S. Paul, A. Ganguly, T.L. Lin, S. Ganguly, G. Vielhawer, M.L. Capitano, A. Cantelina, B. Lipe, J.D. Mahnken, A. Wise, A. Berry, A. Singh, L. Shune, C. Lominska, S. Abhyankar, D. Allin, M. Laughlin, J.P. McGuirk, H.E. Broxmeyer. Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation. Blood. 128 (2016) 3000-3010.
  41. F. Milano, T. Gooley, B. Wood, et al. Cord-Blood Transplantation in Patients with Minimal Residual Disease, N Engl J Med. 375 (2016) 944-953.
  42. C.G. Brunstein, E.J. Fuchs, S.L. Carter, C. Karanes, L.J. Costa, J. Wu , et al. 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. 118 (2011) 282–288.
  43. H.E. Broxmeyer, S.S. Farag, Background and future considerations for human cord blood hematopoietic cell transplantation, including economic concerns, Stem Cells Development. 22(Suppl 1) (2013) 103-110.