Cord Blood Transplantation: State of the Science

By Hal Broxmeyer, PhD, and Filippo Milano, MD
Updated:  March 2019

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].

Umbilical donor cord blood transplantation (CBT) emerged as a feasible alternative source of hematopoietic stem (HSC) and progenitors for pediatric and adult patients with hematological malignancies lacking a related or an unrelated donor [3-6]. Increased levels of HLA disparity that can be tolerated makes CBT an attractive alternative source of HSC. 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].

Other advantages of Cord Blood (CB) for HCT include 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 unit 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 unit CBT, acute GVHD is comparable to that of other types of unrelated HCT [8].

Recent Clinical Studies

A retrospective study recently reported on 824 pediatric patients who underwent CBT in 3 periods: 1995 to 2001, 2002 to 2007, and 2008 to 2014. The authors provided a detailed overview of changes in CBT over 2 decades and identified future areas of focus for the CBT community. The indications for CBT have changed over time, with decreased use in patients with hematologic malignancies and increased use in patients with nonmalignant disorders [9]. The shift to increased use of CBT in patients with nonmalignant disorders has occurred concomitantly with other practice changes, including more frequent use of double-unit CBT, use of reduced-intensity conditioning regimens, improvements in supportive care, and use of a calcineurin inhibitor plus mycophenolate for GVHD prophylaxis.

In a retrospective study, the role of HHV-6 reactivation and risk of relapse in 152 CBT recipients with hematological malignancies was assessed. Lack of HHV-6 reactivation at day+28 was associated with a lower risk of relapse [10]. This correlation might be an indirect measure of graft-versus-tumor effects played by the CB graft, and might help to stratify patients based on their risk of relapse.

In a phase II study, the efficacy and safety of CBT in young adult patient with refractory severe aplastic anemia (SAA) was tested [11]. Twenty-six patient were enrolled with an overall survival of 88% at 1 year. Cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively, showing that CBT is a valuable curative option for young adults with refractory SAA and no other available donors.

In another retrospective study, the outcomes of 118 children with familial hemophagocytic lymphohistiocytosis (FHLH) undergoing single‐unit CBT performed from 1996 to 2014 were analyzed [12]. Historically this disease has been associated with poor outcomes. In this study, the 6‐year probability of overall survival was 55% with a very low cumulative incidence of chronic GvHD of 17%. Like patients with severe aplastic anemia, CBT may represent a very valuable therapeutic option for patients with FHLH who lack an HLA-matched or an Haploidentical donor.

Clinical investigators compared the incidence of disability related to chronic GVHD in 396 patients who underwent an allogeneic transplantation using: cord blood (n=163), mismatched unrelated (n=145) and haplodentical related donor (n=88) [13]. They found that cumulative incidence of chronic GVHD was significantly lower in recipients of a CB and Haploidentical transplants when compared to transplants using mismatched URD. This correlated with the observation that recipients of CB and haplorelated grafts less often developed disability related to chronic GVHD, and thus were more likely to resume work/school.

A randomized study that compared outcomes among pediatric and young adult patients who received either a single or a double CBT found that transplantation of 2 CB units instead of 1 unit was associated with a lower risk of relapse likely due to increased alloreactivity related to the graft vs graft effect [14]. Similar to a previous report, [8] they confirmed positive outcomes in patients with minimal residual disease (overall survival of 71% at 3 years).

Usually, after double CBT, only 1 of the transplanted units persists in the long term. The characteristics of the winning CB unit that determine unit dominance and how they influence the outcomes of double CBT remain unclear. Based on these observations, efforts have been made to predict the winning CB unit in a double CBT. While some reports have offered results suggesting the prediction of the winning CB unit, a recent study was unable to predict unit dominance, but it did demonstrate that outcomes (347 patients with acute leukemia transplanted with a double CBT (694 CBU) from 2005 to 2013) were strongly influenced by the degree of HLA mismatch between the winning CB unit and recipient [15]. Therefore, selection of both units with the lower number of HLA mismatches with the recipient was indicated.

Ongoing Experimental Laboratory and Clinical Efforts to Enhance CB HCT

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 HSC and hematopoietic progenitor cells, and would likely greatly enhance the clinical use of these cells for HCT. Clinical efforts for, and the status of, CB HCT have been described in detail in several review articles [1,2,16].  There are, however, challenges to improving the efficacy of CB HCT [17]. Present efforts to enhance the efficacy of CB HCT include:

a) more effective means to manage and obtain 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 the survival, proliferation, self-renewal and differentiation of 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

There are automated means to increase recovery of hematopoietic progenitor cells for banked CB unit grafts [18], but numbers of HSC/hematopoietic progenitors 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 (low oxygen levels of 1-5% compared to ambient air oxygen levels of ~21%). The involvement of hypoxia signaling pathways in stem cell regulation have been reviewed [19]. 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, with decreased collection of HSC and increased collection of progenitors, – a phenomenon termed “extra physiologic oxygen shock/stress” (EPHOSS) [20,21]. By collecting and processing CB cells in hypoxia so that the cells are never exposed to ambient air, 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 [20,21]. 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 [22]. Use of single anti-oxidants or single inhibitors of epigenetic enzymes did not enhance collection of the mouse BM HSC [22]. It remains to be determined if such procedures will work for human CB HSC unit 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 [23-28], use of prostaglandin E (PGE) [29-31], short-term treatment of cells with hyperthermia [32], enforced fucosylation of the cells [33,34], short pulse glycocorticoid hormone stimulation [35], or inhibition of the negative epigenetic regulation by histone deacetylase (HCAC) 5 [36]. 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, the ligand for CXCR4, in vitro and the in vivo homing and engraftment, of the 16 hour in vitro pulsed cells, into NSG mice [35,36]. Combined treatments, such as already demonstrated in mouse studies with DPP4 inhibition plus PGE [37], may be advantageous.

Ex-vivo Expansion of HSC and hematopoietic progenitors 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 unit 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 for time to engraftment [1,2], although many 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 a way to expand numbers of these cells outside the body (ex-vivo) [1,2,, 16,17].

The first successful attempt at clinical use of ex-vivo expanded CB cells involved Notch-mediated culture of CD34+ CB cells [38]. 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 [39].

Another group took advantage of background studies that demonstrated that a small molecule, SR1 [40], in combination with a cytokine cocktail could expand HSC numbers, in order to bring this procedure to the clinic [41]. 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. In a multinational comparative study, on cohort-controlled comparison of CBT using Carlecortemcel-L, a single progenitor-enriched cord blood, to a double CBT, transplanting expanded CD34+ stem cells from a portion of a single CB unit with the remaining unmanipulated fraction, improved 100-day survival compared with double CBT control patients and facilitated myeloid and platelet engraftment [42]. Thus, although the results noted above are impressive, it remains to be seen in additional clinical studies if in fact the ex-vivo cultured cells can by themselves, without the added presence of an unmanipulated CB unit, actually engraft.  If so, can it accelerate the time to neutrophil, platelet and immune cell recovery compared to that noted by either single or double unmanipulated CB HCT. Recently, in a multicenter prospective study, the safety and efficacy of a CB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft was investigated [43]. Thirty-six patients with hematologic malignancies underwent transplantation. The approach was found to be safe and feasible. Patients receiving expanded grafts showed faster recovery of neutrophils (9 days) and platelets (12 days) when compared to an historical cohort of similar patients. Based on this, the same group is leading a larger Phase III randomized study to compare outcomes in patients receiving the expanded product versus patients receiving conventional CBT.

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 hematopoietic progenitor cell population within this phenotyped population of CD34+ cells beyond that of a cocktail of cytokines. This includes SR1 [40,41], an aryl hydrocarbon receptor antagonist, and also UM171, a pyrimidoindole derivative [44], which acted as agonists of human HSC self-renewal events. It is of interest that UM171 has been reported to enhance lentiviral gene transfer and recovery of primitive human HSC [45]. Other small molecules include those involved in antagonism of peroxisome proliferation-activated receptor (PPAR)-gamma [46], and a structural analog of SB20358 (p38-map kinase inhibitor) [47] have been used to enhance cytokine stimulated ex-vivo expansion of CB HSC. A search for additional small molecule agonists and antagonists to enhance CB HSC expansion is ongoing.

Among the more than 100 different chemical modifications on RNA thus far identified, N6-methyladenosine (m6A) is the most abundant epigenetic mark on eukaryocytic messenger RNAs. The m6A modification had been implicated in regulation of a wide range of biological processes [48]. The m6A modification is recognized by its reader YTH domain family members, and most recently it has been reported that knockdown of YTHDF2 results in increased numbers of HSC from CD34+ CB cells [48,49]. This may enhance our understanding of the functions of m6A and YTHDF2 function in the ex-vivo expansion of CB HSCs for clinical utility. This highlights the need to better define intrinsic and extrinsic factors that regulate HSC function.

The above and other efforts to ex-vivo expand CB cells for use in CB HCT [51-53] appear encouraging, but it is not yet clear which ex-vivo expansion procedure(s) will eventually be found to be most efficacious and which one or ones will eventually be adapted for more routine clinical use and in which clinical situations and conditions. However, until the clinical studies are routinely 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 [26-28] for more prolonged periods prior to and after the engraftment process has started. Another reported way to enhance engraftment is the potential use of hyperbaric oxygen for the recipient [54,55].

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 BM or mPB from URD, or for haploidentical HCT. 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 [56]. 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 patients 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 receive 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 [57].

The CB banking industry continues to evolve [58]. However, model criteria have now been published for the regulation of CB banks and CB banking [59]. This was put together by an international group of clinical investigators associated with the CB Association. This a long-overdue set of guidelines for the CB banking community, which was noted in a commentary on the published guidelines [60]. In the commentary [60] a number of interrelated means to potentially enhance the efficiency of CB HCT were discussed and diagrammed. This included means to collect more CB HSC, to ex-vivo expand these CB HSCs and to increase their homing efficiency, along with in vivo efforts to enhance the functional activities of the engrafted HSCs after CB HCT. It is possible that future efforts may encompass one or more of these combination efforts, perhaps in different sequential forms, as noted in the commentary [60].

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 hematopoietic progenitors. Their objective is to find 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 [61]. Without sacrificing the safety and efficiency of the procedure, cost needs to be taken into account.


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