Cord Blood Transplantation: State of the Science

By Hal Broxmeyer, PhD, and Filippo Milano, MD
Updated:  March 2020

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.

Umbilical donor cord blood transplantation (CBT) emerged as a feasible alternative source of hematopoietic stem cells (HSC) and progenitors for pediatric and adult patients with hematological malignancies lacking a related or an unrelated donor [1-4]. Increased levels of human leukocyte antigen (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 [5].

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) [6-8].  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 [6-8]. With double unit CBT, acute GVHD was comparable to that of other types of unrelated HCT [9].

Recent Clinical Studies

Cohen and colleagues recently investigated the use of UM171, a haematopoietic stem cell self-renewal agonist, in a Phase I/II study in 27 patients undergoing single CBT. The authors successfully expanded 26 (96%) of 27 CB units with UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment was 18 days, and no graft failure occurred. Median time to platelet recovery was 42 days. Despite the high-risk characteristics of the patients enrolled, only three (14%) of 22 patients had died, two from progressive disease and one from diffuse alveolar haemorrhage. At 1 year, the incidence of transplant-related mortality was 5% and the incidence of relapse was 21%. Overall survival, progression-free survival, GVHD-free and relapse-free survival, and chronic GVHD-free relapse-free survival at 12 months were 90%, 74%, 64%, and 74%, respectively [10]

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 [11]. Similar to a previous report, [9] they confirmed positive outcomes in patients with minimal residual disease (overall survival of 71% at 3 years). Similarly, a recent prospective study investigated the significance of HCT from HLA-matched unrelated donors and CB on outcomes in adults with acute leukemia and myelodysplastic syndrome. In total there were 119 CBT and 91 matched unrelated transplants. In multivariate analyses, graft source was not a significant risk factor for overall survival, cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival [12]. In adjusted analyses, matched unrelated and CBT showed similar overall survival (OS), NRM, and relapse, therefore, CB can be a comparable alternative source to matched unrelated [12].

It is well known that different graft sources yield varying immune system reconstitution profiles after HCT. In a single-center retrospective analysis of immune reconstitution kinetics after HCT was analyzed in BM (n=119), mPB (n=55), CBT (n=136) adult patients, mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT [13]. Multivariate analysis showed that higher CD16(+) CD57(-) NK cell counts correlated with lower disease relapse, whereas higher CD20(+) B-cells and CD8(+) CD11b(-) T-cells lead to lower NRM [13]. Therefore, the cumulative effect of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT. Similar results were observed in another recent study analyzing the immune recovery in 106 adults undergoing CBT. Differently than what we knew before, immune recovery after CBT was associated with robust thymus-independent CD4(+) T-cell recovery, and CD4(+) recovery reduced mortality risk [14]. Additionally, increased cell dose improved T-cell recovery, whereas HLA mismatch was not detrimental [14].

The use of CBT has been associated with less chronic GVHD. 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 haploidentical related donor (n=88) [15]. 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. In another recent report, grade II-IV acute GVHD was not associated with overall mortality, relapse, or NRM in pediatric patients aged 0-15 who received a single CBT [16]. However, the effect of grade II-IV acute GVHD on patients aged 11-15 was similar to what was observed in the adult cohort [16].

The impact of HLA-allele mismatch at HLA-A, -B, -C, and DRB1 was described for single CB HCT [17]. This suggested that allele-level HLA-mismatch affects the outcome of CB HCT, a finding that would have been anticipated and is not surprising. Moreover, HLA haplotype matching was considered as a means to improve engraftment [18]; two-haplotype matches were to be avoided, especially if the risk of relapse is considered high, as the haplotype might impinge on risks of graft vs. host disease and relapse. A validation of an algorithm was proposed to predict the likelihood of an 8/8 HLA-matched unrelated donor search [19]. This was proposed in order to identify searches that were considered poor, very poor, or indeed futile, which would then facilitate quicker efforts to find alternative donor CB units.

A report proposed single CB unit HCT to be a promising source for improving survival in patients with multiple comorbidities [20]. Single unit CB HCT demonstrated good overall survival with a low incidence of non-relapse mortality, even with patients manifesting a high HCT-specific morbidity index.

It was reported that a thiotepa-based intensified reduced intensity conditioning regimen for adults using double-unit CB HCT demonstrated decreases in relapse rates and improved survival of recipients that followed a standard reduced intensity conditioning regimen [21]. Early and late outcomes were noted for pediatric patients with inherited leukodystrophies undergoing CB HCT [22]. It was recommended that early identification of these heterogeneous groups of rare diseases that affect the development and maintenance of brain myelination, and fast referral to a specialized HCT center could lead to earlier clinical treatments, thus improving outcomes.

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 [6-8]. 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 [6-8, 23-26].  There are, however, challenges to improving the efficacy of CB HCT [6-8, 25, 26]. 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 lodgment 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 [27], 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 [28]. 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) [29, 30]. 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 [29, 30]. 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 [31]. Use of single anti-oxidants or single inhibitors of epigenetic enzymes did not enhance collection of the mouse BM HSC [31]. It remains to be determined if such procedures will work for human CB HSC unit collections. In the meantime, other means to mimic the hypoxia effects are being evaluated (Broxmeyer, et. al., 2020, unpublished work).

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 [32-37], use of prostaglandin E (PGE) [38-40], short-term treatment of cells with hyperthermia [41], enforced fucosylation of the cells [42, 43], short pulse glycocorticoid hormone stimulation [44], inhibition of the negative epigenetic regulation by histone deacetylase (HCAC) 5 [45]. 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 [44]. Pharmacological activation of nitric oxide signaling [46] has also been used to enhance homing/engraftment. Combined treatments, such as already demonstrated in mouse studies with DPP4 inhibition plus PGE [47], 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 [6-8]. 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 [6-8], although many clinical 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) and for clinical use [6-8, 10,26,27,48].

The first attempt at clinical use of ex-vivo expanded CB cells involved Notch-mediated culture of CD34+ CB cells [49]. 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 which has led to encouraging results [50, 51].

Another group took advantage of background studies that demonstrated that a small molecule, SR1 [52], in combination with a cytokine cocktail could expand HSC numbers, in order to bring this procedure to the clinic [48]. This effort also resulted in quite impressive results. However, all 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. A more recent clinical study was performed using single CB units expanded with UM171 [10] which shows promise. 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 [53]. These efforts with use of single CB expanded units might be able to accelerate the time to neutrophil, platelet and immune cell recovery compared to that noted by either single or double unmanipulated CB HCT. 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 [53]. 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 [48,52], an aryl hydrocarbon receptor antagonist, and also UM171, a pyrimidoindole derivative [54], 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 [55]. Other small molecules include those involved in antagonism of peroxisome proliferation-activated receptor (PPAR)-gamma [56], and a structural analog of SB20358 (p38-map kinase inhibitor) [57] have been used to enhance cytokine stimulated ex-vivo expansion of CB HSC. DEK, a nuclear protein that can be released from cells when used as a purified recombinant protein enhances the ex-vivo expansion of HSC and HPC from a starting population of human CB cells [58]. A search for additional 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 [59]. 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 [59,60]. 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.

While human CB HSC can be phenotypically-defined, using multiple cell surface markers for their presence and absence, it is very important to understand that phenotype does not always identify or recapitulate the functions, activities, and numbers of human HSC [34, 61]. Thus, when trying to assess the activities and actual numbers of human CB HSC and hematopoietic progenitors it is crucial to perform human cell engrafting studies in sublethally-irradiated immune deficient mice, for HSC and colony assays for hematopoietic progenitors. There have been a few phenotypic markers that purport to identify expanded HSC populations [62, 63]. This, if reproduced, would help to use phenotype to assess functional HSC. This remains to be determined as phenotypic characteristics of CB HSC can change under stress conditions. Using hypoxic collection/processing criteria as noted above [29,30], or means to potentially mimic the effects of such collection/processing procedures [31] and ongoing studies [Broxmeyer, et. al., unpublished] may reduce, at least in part some of the stresses on HSC. Also, a more in-depth study that takes into consideration the HSC/progenitor microenvironmental niche cells [64] in addition to use of low oxygen collections and processing of these microenvironmental niche cells could further allow one to better understand and potentially “ex-vivo” study and expand HSC and hematopoietic progenitors. Hypoxia culture of human HSC and progenitors, already collected first in ambient air influences lymphoid cell development [65]; it would be useful to know how hypoxia collection and processing of such cells would influence the development of lymphoid cells subsequently cultured in hypoxia. Various means are being developed for ex-vivo culture of cells that mimic the effects of hypoxia without need for use of an hypoxic chamber for collection [66,67], but such systems have yet to be adequately tested for how close they are to true hypoxia conditions, and if they do or do not inadvertently change the characteristics of the stem/progenitors from that seen using hypoxia chambers [29,30]. Mitochondria have been intimately linked to the EPHOSS studies [29,30] and need more rigorous evaluations if their modulation is to help in the collection and expansion of CB HSC and their progenitors. Review articles on mitochondria and metabolism offer insights into a role for this in regulation of HSC and progenitors [67-70].

The above and other efforts to ex-vivo expand CB cells for use in CB HCT [70-74] 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 and consistently done in context of a single transplantable CB unit, it is not clear how this may change how clinical 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 [35-37] 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 [75,76].

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 [1-4]. Outcomes between CBT and matched and mismatched unrelated transplants were compared in the largest retrospective single institution study so far conducted [77]. 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 [78].

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 has just been completed and results will be presented soon. 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 [79].

Donor to donor heterogeneity has been detected using mouse xenografts in terms of transplanted human CB CD34+ cells, containing mainly hematopoietic progenitor cells, and a very low frequency of stem cells [80]. The majority of long-term persisting clones showed multilineage output with lymphoid-or myeloid-biased output noted. While this study involved injecting human CB cells into immune-deficient mice, it did uncover substantial interdonor and analysis-induced variability in frequency of CD34+ clones, information of relevance to clinical CB HCT.

CB banking continues to evolve [81]. However, model criteria have now been published for the regulation of CB banks and CB banking [82]. This was put together by an international group of clinical investigators associated with the Cord Blood Association. This a long-overdue set of guidelines for the CB banking community, which was noted in a commentary on the published guidelines [82]. In the commentary [82] 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 [82].

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 transplant [83]. Without sacrificing the safety and efficiency of the procedure, cost needs to be taken into account.

The biggest unmet problem to date is how to institute more clinical trials to evaluate means to enhance the homing and engraftment of CB HSC and progenitors, including those whose HSC collections have been increased. This will not be an easy task, as most clinical trials are funded by companies that only evaluate their own agents. Until the HCT community, especially for CB HCT, leads with this, we are missing out on possibilities to greatly enhance CB HCT.


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