Cord Blood Transplantation: State of the ScienceBy Hal Broxmeyer, PhD, and Filippo Milano, MD, PhD
Introduction 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]. A short history of cord blood banking and transplantation [10], as well as a more recent view on this [11] as has been reported to add to those mentioned above [6-9]. 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 [12]. 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 [13]. 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 [14]. 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 [14]. 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 [15]. 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 [15]. 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 [16]. Additionally, increased cell dose improved T-cell recovery, whereas HLA mismatch was not detrimental [16]. 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) [17]. 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 [18]. However, the effect of grade II-IV acute GVHD on patients aged 11-15 was similar to what was observed in the adult cohort [18]. The impact of HLA-allele mismatch at HLA-A, -B, -C, and DRB1 was described for single CB HCT [19]. 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 [20]; 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 [21]. 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 [22]. 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 [23]. Early and late outcomes were noted for pediatric patients with inherited leukodystrophies undergoing CB HCT [24]. 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. Other More Recent Clinical Studies A number of papers have updated information on CBT. This includes: (1) optimal practices in unrelated donor CBT for hematological malignancies [25], where it was noted that CBT is associated with comparable disease-free survival to unrelated adult donor transplantation; (2) the impact of conditioning on transplant outcomes in children with acute leukemia [26] where survival differences between trial-specified regimens and other regimens indicated the role of the conditioning regimens for CBT; (3) a role for CBT for bone marrow failure syndromes was reported where it was noted that optimization of conditioning regimen and selection of CB units was needed to reduce graft failure and transplantation mortality [27]; (4) the reduction in mortality over a 20 year period (1995-2014) for CBT [28], due to enhanced advances in clinical practice for children with reduced mortality from infections, especially that from invasive aspergillosis, and use of voriconazole for antifungal prophylaxis; (5) the use of less intense condition regimens have been investigated in patients undergoing CBT. In patients with lymphoid malignancies [29] three regimens were used. All three regimens (fludarabine/melphalan/total body irradiation, fludarabine/cyclosphosphamide/total body irradiation, or fludarabine/busulfan/total body irradiation or melphalan) had comparable clinical outcomes in acute lymphoid leukemia while two were found preferable for malignant lymphoma. More recently the group led by Dr. Barker showed an outstanding progression-free survival in adult patients receiving intermediate intensity conditioning regimen undergoing double CBT [30]. Similarly, very positive clinical outcomes were observed in patients undergoing single or double CBT receiving Treosulfan as part of the conditioning regimen [31]. Of note, (6) a report from Eurocord, the Acute Leukemia Working Party, and the CB Committee of the Cellular Therapy and Immunobiology Working Party of the European Bone Marrow Transplant groups assessed transplantation in adults with primary refractory or relapsed acute myeloid leukemia using CBT vs. unrelated donor transplantation [32]. Their results suggested that in patients with acute myeloid leukemia, who had active disease at transplantation, allogeneic HCT with unrelated donors resulted in superior outcomes to that of CBT; (7) splenomegaly had a significant negative impact on recovery of neutrophils after CBT [33], not a totally unexpected observation; (8) cytomegalovirus (CMV)-specific immunity was slower to recover after CBT when compared to matched sibling donor allogeneic transplantation [34], and noting that it was necessary to implement more potent prophylactic strategies to prevent CMV reactivation in CMV seropositive patients undergoing CBT; and (9) evaluation of prophylactic Foscarnet human herpesvirus 6 (HHV-6) after reduced-intensity conditioning for CBT [35]. Although foscarnet prophylaxis did not prevent HHV-6 viremia, there was a delay in time to HHV-6 reactivation. Thus, while advances have been made in clinical CBT, there is much more to be evaluated and learned for enhancement of the efficacy of CBT. Towards this there have been a number of recent papers that have evaluated prognostic factors for single CB unit CBT amongst European and Japanese populations [36], where similar prognostic factors affecting outcomes in adult patients with acute leukemia were noted; efforts to expand the possibilities of CBT using single CB unit transplantation in Japan were noted [37], with outstanding issues requiring resolution needed; a Japanese experience with CB unit selection for adults with acute myeloid leukemia for adults with acute myeloid leukemia in complete remission was evaluated [38], where it was noted in this case that less stringent criteria with CB unit selection was acceptable for the Japanese patient population; a suggested framework for prediction in CBT using modeling was suggested [39]; implications of the CD34+ cell content in the US CB bank inventory [40] suggested that the use of double-unit grafts, and a focus on banking high-dose units, with development of ex-vivo expansion technologies was appropriate [41]. The impact of CD34+ cell content was also analyzed based on ancestry. It was observed that while CBT extends transplantation access to most patients, racial disparities exist in cell content, dose, and HLA match [42]. The use of graft vs. host disease (GVHD) prophylaxis after single CB unit reduced intensity conditioning for adults with acute leukemia was reported [43]. It was suggested that mycophenolate mofetil-containing prophylaxis might be a preference to that of reduced intensity conditioning, especially for high risk disease patients. In this context it has recently been reported that use of oral sitagliptin, a dipeptidylpeptidase 4 inhibitor, previously used to accelerate neutrophil engraftment after CBT [44-46] greatly decreased GVHD disease in adult patients receiving allogeneic peripheral blood transplantation [47]. Thus, sitagliptin may be able to reduce GVHD in patients undergoing CBT, and with the increased days of administration used in this study [47] compared to that in the CBT studies [44-46], might also further accelerate engraftment of neutrophils in CBT. Cord Blood Unit Selection Two recent papers have provided guidelines for selection of CB units. One is from Politikos et al [48] on behalf of the American Society for Transplantation and Cellular Therapy CB Special Interest Group, and the other from Dehn et al for the NMDP/CIBMTR [49]. A comparative analysis of both guidelines would be welcome to see what is, and what is not, agreed upon. This is further discussed later in this review. 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, 50-55]. There are, however, challenges to improving the efficacy of CB HCT. 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
There are automated means to increase recovery of hematopoietic progenitor cells for banked CB unit grafts [51], 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 has been reviewed [52]. 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) [56, 57]. 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. Such hypoxia collections/processing of cells in peripheral blood induced by G-CSF and/or AMD3100/Plerixafor [58], or mouse bone marrow cells from mouse models of Fanconi anemia (such as in fancc -/- and fanca -/- mice) [59] has resulted in collection of significantly enhanced numbers of 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 [56, 57]. 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 [60]. Use of single anti-oxidants or single inhibitors of epigenetic enzymes did not enhance collection of the mouse BM HSC [60]. 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. Recent studies have now demonstrated that collection/processing of CB cells at 4˚C also results in increased numbers of HSCs, thus mimicking effects of hypoxia collection/processing of cells [61] although whether the mechanisms for these two methods of collection/processing (hypoxia vs. 4˚C) may necessarily be similar is yet to be determined. Regardless, collection/processing of cells for CB banking may be a more feasible method for such collections. Hypoxia in the above scenario refers to the oxygen tension inherent in bone marrow which ranges from 1-5 percent oxygen and may more accurately be referred to by the term physioxia (the oxygen content noted in vivo in bone marrow). Enhancing the Homing Capabilities of HSC for More Efficient Engraftment There have been several 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 [44-46,62-64], use of prostaglandin E (PGE) [65-67], short-term treatment of cells with hyperthermia [68], enforced fucosylation of the cells [69, 70], short pulse glycocorticoid hormone stimulation [71], inhibition of the negative epigenetic regulation by histone deacetylase (HCAC) 5 [72]. 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 [71, 72]. Pharmacological activation of nitric oxide signaling [73] has also been used to enhance homing/engraftment. Combined treatments, such as already demonstrated in mouse studies with DPP4 inhibition plus PGE [74], 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 [6-8,12,75-77]. The first attempt at clinical use of ex-vivo expanded CB cells involved Notch-mediated culture of CD34+ CB cells [78]. 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 [79, 80]. Another group took advantage of background studies that demonstrated that a small molecule, SR1 [81], in combination with a cytokine cocktail could expand HSC numbers, in order to bring this procedure to the clinic [75]. 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 [12] which shows promise. It is not always clear if the phenotype of the expanded HSCs after ex-vivo culture is similar to that of the HSCs prior to ex-vivo expansion. Fares et al [82] noted that expression of the endothelial protein C receptor (EPCR/CD201/PROCR) was able to mark CD34+ CB HSCs expanded by UM171. However, how reliable this marker is for HSCs ex-vivo expanded by other means remains to be determined. Frequencies of SCID repopulating cells, (SRCs; equal to human HSCs) are greatly decreased in CD34+ HSCs and progenitors after ex-vivo culture [Chen, Fang, Jiang…,Broxmeyer, Guo, manuscript in revision]. Transcriptome analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of the CB HSCs and progenitors increased along with loss of stemness. It was noted that functional CB HSCs were significantly enriched in an adhesion G protein-coupled receptor G1 positive (ADGRG1+) population of CD34+CD133+ cells after ex-vivo expansion stress. Thus, ADGRG1 enriches for functional human CB HSCs under the oxidative stress induced during ex-vivo culture. It is suggested that these cells may be novel targets for drug screening of agonists for expansion of CB HSCs. Future studies may identify other markers of ex-vivo expanded CB HSCs, thus allowing for screening of other agonists for expansion of CB HSCs. 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 [83]. 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 [79, 80]. 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 [75, 84], an aryl hydrocarbon receptor antagonist, and UM171, a pyrimidoindole derivative, 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 [85]. Other small molecules include those involved in antagonism of peroxisome proliferation-activated receptor (PPAR)-gamma [86], and a structural analog of SB20358 (p38-map kinase inhibitor) [87] 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 [88]. 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 [89]. 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 [89, 90]. 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. More recent studies have identified additional means to ex-vivo expand human CB HSCs. This includes: DUSP16 [91], Eupalinilide E and UM171, alone and in combination [92], pharmacological activation of nitric oxide [93], the Bet inhibitor CB1203 [94], Nov/ccN3 [95], natural estrogens [96], and continuous inhibition of the NFkB pathway [97], as well as modulation of the of the neurotransmitter receptor Gabbr1 [98, 99]. It has also been reported that RXR, the retinoid X receptor acts to negatively regulate ex-vivo expansion of human CB HSCs and progenitors [100]. Physioxia has been reported to enhance ex-vivo development of T cells from CB HSCs and progenitors [101], and UM171-expanded CBT have reported the robust reconstitution of T cells with low rates of severe infections [102]. 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 [64, 103, 104]. 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 as mentioned above. Thus, if reproduced, this 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 [56, 57], or other means to potentially mimic the effects of such collection/processing procedures [60, 61]. Also, a more in-depth study that takes into consideration the HSC/progenitor microenvironmental niche cells [105] 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 [101, 106]. 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 [60, 61, 107, 108], 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 [56, 57]. Mitochondria have been intimately linked to the EPHOSS studies [56, 57] 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 [109-111]. The above and other efforts to ex-vivo expand CB cells for use in CB HCT [112-115] 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 [44-46, 116] 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 [117, 118]. Comparison of Graft Sources Several retrospective studies have compared outcomes between CBT and other stem cell sources [1-4, 119]. In a recent retrospective analysis from Kanda et al, no significant differences were found in overall survival, nonrelapse mortality rates and relapse rates. Both 7/8 UBMT and UCBT are appropriate alternative donor procedures. Outcomes between CBT and matched and mismatched unrelated transplants were compared in the largest retrospective single institution study so far conducted [120]. 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 [121]. Comparison of CBT to that of Haploidentical Donor Transplantation. Haploidentical (Halpo) transplantation is becoming a choice for HCT, and it is only recently that Haplo-HCT and CBT have begun to be compared. Kosuri et al [122] did a prospective evaluation of Halpo and unrelated CB donor access and noted that graft availability varied by ancestry of patient with regards to selection of donors. It was suggested that there were barriers to the availability of both types of grafts in adult patients, especially in those with African ancestry. Kanate et al [123] evaluated direct changes of Haplo vs. CB availability and suggested that Haplo-HCT might result in early cost savings over double unit CB-HCT, and thus might be preferred for patients with more limited resources. A comparative study from Eurocord and the ALWP EBMT regarding unrelated CB or Haplo donor grafts in adult patients with secondary acute myeloid leukemia [124] indicated that Haplo was associated with better GVHD-free-relapse-free survival and lowered acute GVHD, but that CBT can be a valid alternative for these patients who lack a matched sibling or proper Haplo or unrelated donor. A meta-analysis and systemic review of unrelated CBT compared to Haplo HCT in adult and pediatric patients with hematological malignancies [125] concluded that both forms of HCT can be considered as an equally effective option for adult patients who do not have an HLA-matched donor. Very recently, on behalf of the Blood and Marrow Transplant Clinical Trials Network, Fuchs et al [126] evaluated the use of unrelated CB vs. bone marrow from HLA-haplo relatives in a randomized clinical trial (www.clinicaltrials.gov, NCT01597778). The primary endpoint of the study was progression free survival, which was similar between the 2 approaches; however they noted that at this time, while both extend the access to reduced-intensity HCT, haplo bone marrow HCT was favored after analysis of secondary end points, including overall survival. This paper [126] was commented on by Mohty [127]. Konuma et al [128] found after comparing results of 1313 adult patients with intermediate- or poor-risk acute myeloid leukemia in complete remission in Japan between 2007 and 2018, that the cumulative incidence of recovery of neutrophils and platelets were lower in single unit CBT compared to that of Haplo-HCT with similar survival outcomes, and higher grade 2 to 4 acute GVHD in single CB HCT and higher CMV antigenemia in recipients of Haplo-HCT. The final assessments of Haplo-HCT vs. CB-HCT for short- and long-term engraftment, GVHD, survival, etc. is not in yet, and more analyses with wider ranging comparative trials of Haplo-HCT vs. CB-HCT are warranted, especially for longer term survival. Other end product analysis is needed to fully understand the pros and cons of Haplo vs. CB HCT. Such analyses are ongoing. Cord Blood Banking Different factors influence the CB banking industry [129]. 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 [130]. 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 [129]. However, model criteria have now been published for the regulation of CB banks and CB banking [48, 49, 131]. As noted above, the different guidelines need to be checked to see what are similar and what are different between these guidelines. A long-overdue set of guidelines for the CB banking community, was noted in a commentary [132] on published guidelines. In the commentary [132] 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 [132]. Involvement of SARS-CoV-2/COVID-19 in CB Banking and Transplantation The SARS-CoV-2 induced COVID-19 pandemic has highlighted the need to clearly demonstrate that this virus has not infected CB units banked and to be used [133]. While there is no evidence that this yet presents a problem, human CB HSCs and progenitors, as well as more mature immune cells respond ex-vivo to SARS-CoV-2 Spike protein [134] hence precautions are warranted for collection and banking of CB units to make sure that they are free of the SARS-CoV-2 virus. Concluding Remarks and What Remains To Be Done to Enhance CB 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 [135], especially with maneuvers to increase CB HSC numbers and engrafting capability. Without sacrificing the safety and efficiency of the procedure, cost needs to be taken into account. The biggest and still 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. There are so many potential means to enhance CB HCT, but their lack of translation to clinical utility, and which may be most effective, is a detriment to the still evolving field of CB-HCT. References
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