According to the American Academy of Pediatrics (2007), cord blood transplantation has been shown to be curative in patients with a variety of serious diseases. Physicians should be familiar with the rationale for cord blood banking and with the types of cord blood banking programs available. Physicians consulted by prospective parents about cord blood banking can provide the following information:

In contrast, cord blood donated to public banks is more commonly used and heavily regulated. Thus, the cost and value of the maintenance of private cord blood banks is not supported by the evidence for use at the present time."

Eapen and colleagues (2010) stated that umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an human leukocyte antigen (HLA)-matched adult unrelated donor is not available. These investigators aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukemia, and to establish whether current graft-selection practices are appropriate. They used Cox regression to retrospectively compare leukemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukemia. Data were available on 1,525 patients transplanted between 2002 and 2006. A total of 165 received UCB, 888 received PBPCs, and 472 received bone marrow. Umbilical-cord blood units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n = 10), or mis-matched at 1 antigen (n = 40) or 2 antigens (n = 115). Peripheral blood progenitor cells and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n = 632 and n = 332, respectively), or mis-matched at 1 locus (n = 256 and n = 140, respectively). Leukemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (hazard ratio [HR] 1.62, 95 % confidence interval [CI]: 1.18 to 2.23; p = 0.003) or bone-marrow transplantation (HR 1.69, 95 % CI: 1.19 to 2.39; p = 0.003). Grades 2 to 4 acute and chronic graft-versus-host disease (GVHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0.57, 95 % CI: 0.42 to 0.77; p = 0.002 and HR 0.38, 95 % CI: 0.27 to 0.53; p = 0.003, respectively), while the incidence of chronic, but not acute GVHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0.63, 95 % CI: 0.44 to 0.90; p = 0.01). These data support the use of UCB for adults with acute leukemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently.

Co-Transplantation of Multipotent Mesenchymal Stromal Cells in Allogeneic Hematopoietic Stem Cell Transplantation

Zhao et al (2015) noted that refractory acute GVHD (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). These researchers evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. A total of 47 patients with refractory aGVHD were enrolled: 28 patients receiving MSC and 19 patients without MSC treatment; MSCs were given at a median dose of 1 × 10(6) cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range of 2 to 8) per patient, overall response rate was 75 % in the MSC group compared with 42.1 % in the non-MSC group (p = 0.023). The incidence of cytomegalovirus, Epstein-Barr virus infections, and tumor relapse was not different between the 2 groups during aGVHD treatment and follow-up. The incidence and severity of chronic GVHD (cGVHD) in the MSC group were lower than those in the non-MSC group (p = 0.045 and p = 0.005). The ratio of CD3(+)CD4(+)/CD3(+)CD8(+) T cells, the frequencies of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), and the levels of signal joint T cell-receptor excision DNA circles (sjTRECs) after MSCs treatment were higher than those pre-treatment; MSC-treated patients exhibited higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks after treatment. The authors concluded that MSCs derived from bone marrow of a third-party donor were effective to refractory aGVHD; it might reduce the incidence and severity of cGVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse. These preliminary findings need to be validated by well-designed studies.

Kallekleiv et al (2016) stated that allo-HSCT is a potentially curative treatment option for patients with hematological malignancies. Co-transplantation of multi-potent MSCs during allo-HSCT has been explored to enhance engraftment and decrease the risk of GVHD. These investigators evaluated and summarized the findings of all relevant controlled clinical studies to determine the potential benefits of MSC infusion during allo-HSCT, with regard to the outcomes engraftment, GVHD, post-transplant relapse and survival. They conducted a systematic search of electronic databases for relevant controlled clinical studies. Studies included patients of all ages with hematological malignancies receiving allo-HSCT with or without infusion of MSCs within a 24-hour time-frame of transplantation. A total of 9 studies met the inclusion criteria, including 3 randomized, 1 non-randomized and 5 historically controlled trials, representing a total of 309 patients. The meta-analyses did not reveal any statistically significant differences in donor engraftment or GVHD. A review of data regarding relapse and overall survival (OS) may result in a positive attitude toward intervention with MSCs, but due to heterogeneous reporting, it is difficult to draw any strict conclusions. None of the studies had overall serious risks of bias, but the quality of the evidence was low. The authors concluded that meta-analysis did not reveal any statistically significant effects of MSC co-transplantation, but the results must be interpreted with caution because of the weak study design and small study populations. They discussed further needs to explore the potential effects of MSCs in a HSCT setting.

Enzyme-Linked Immunospot Interferon-Gamma Release Assay for Prediction of the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients

Nesher et al (2016) stated that the ability to distinguish allogeneic hematopoietic cell transplant (allo-HCT) recipients at risk for cytomegalovirus (CMV) re-activation from those who are not is central for optimal CMV management strategies. Interferon-gamma (IFN-γ) produced by CMV-challenged T cells may serve as an immune marker differentiating these 2 populations. These researchers prospectively monitored 63 CMV-seropositive allo-HCT recipients with a CMV-specific enzyme-linked immunospot (ELISPOT) assay and for CMV infection from the period before transplantation to day 100 after transplantation. Assay results above certain thresholds (50 spots per 250,000 cells for immediate early 1 or 100 spots per 250,000 cells for phosphoprotein 65) identified patients who were protected against CMV infection as long as they had no GVHD and/or were not receiving systemic corticosteroids. Based on the multi-variable Cox proportional hazards regression model, the only significant factor for preventing CMV reactivation was a CMV-specific ELISPOT response above the determined thresholds (adjusted HR, 0.21; 95 % CI: 0.05 to 0.97; p = 0.046). The authors concluded that the use of this assay as an additional tool for managing allo-HCT recipients at risk for CMV reactivation needs further validation in future studies. They stated that application of this new approach may reduce the duration and intensity of CMV monitoring and the duration of prophylaxis or treatment with anti-viral agents in those who have achieved CMV-specific immune reconstitution.

Mesenchymal Stromal Cells-Derived Extracellular Vesicles for the Prevention or Treatment of Graft-Versus-Host Disease

Dal Collo and associates (2020) stated that GVHD is currently the main complication of allo-HCT. Mortality and morbidity rates are particularly high, especially in steroid-refractory acute GVHD (aGVHD). Immune regulatory human bone marrow MSCs (hMB-MSCs) represent a therapeutic approach to address this issue. Unfortunately, their effect is hardly predictable in-vivo due to several variables, that is, MSC tissue origin, concentration, dose number, administration route and timing, and inflammatory status of the recipient. Interestingly, human bone marrow MSC-derived extracellular vesicles (hBM-MSC-EVs) display many of the hBM-MSC immunoregulatory properties due to their content in paracrine factors that greatly varies according to the collection method. These investigators focused on the immunological characterization of hBM-MSC-EVs on their capability of inducing regulatory T-cells (T-regs) both in-vitro and in a xenograft mouse model of aGVHD. They correlated these data with the aGVHD incidence and degree following hBM-MSC-EV intravenous administration. Therefore, these researchers first quantified the EV immunomodulation in-vitro in terms of EV immunomodulatory functional unit (EV-IFU), that is, the lowest concentration of EVs leading in-vitro to at least 3-fold increase of the T-regs compared with controls. Second, they established the EV therapeutic dose in-vivo (EV-TD) corresponding to 10-fold the in-vitro EV-IFU. According to this approach, these researchers observed a significant improvement of both mouse survival and control of aGVHD onset and progression. The authors concluded that the findings of this study confirmed that EVs may represent an alternative to whole MSCs for aGVHD prevention, once the effective dose is reproducibly identified according to EV-IFU and EV-TD definition.

Batsali and co-workers (2020) stated that MSCs represent a heterogeneous cellular population responsible for the support, maintenance, and regulation of normal hematopoietic stem cells (HSCs). In many hematological malignancies, however, MSCs are deregulated and may create an inhibitory micro-environment able to induce the disease initiation and/or progression. MSCs secrete soluble factors including EVs, which may influence the BM micro-environment via paracrine mechanisms; and MSC-EVs may even mimic the effects of MSCs from which they originate. Thus, MSC-EVs not only contribute to the BM homeostasis but may also display multiple roles in the induction and maintenance of abnormal hematopoiesis. Compared to MSCs, MSC-EVs have been considered a more promising tool for therapeutic purposes including the prevention and treatment of GVHD following allo-HCT. There are, however, still unanswered questions such as the molecular and cellular mechanisms associated with the supportive effect of MSC-EVs, the impact of the isolation, purification, large-scale production, storage conditions, MSC source, and donor characteristics on MSC-EV biological effects as well as the optimal dose and safety for clinical usage. The authors summarized the role of MSC-EVs in normal and malignant hematopoiesis and their potential contribution in the treatment of GVHD.

Gupta and colleagues (2021) noted that preventing or treating GVHD following allo-HCT remains a significant challenge. The use of MSC-derived extracellular vesicles (MSC-EVs) appears promising and a systematic review of pre-clinical studies is needed to accelerate the design of translational studies. These researchers identified 4 eligible studies from a systematic review carried out on December 1, 2018. In brief, eligible studies included the prevention or treatment of GVHD in animal models and the use of MSC-EVs. Study design and outcome data were extracted; and reporting was examined using the SYRCLE tool to identify potential bias. Two studies examined the efficacy of MSC-EVs in treatment of GVHD and 2 studies addressed prevention. Mice treated with MSC-EVs showed improved median survival, GVHD clinical scores and histology scores as compared to untreated mice with GVHD. Prophylactic treatment with MSC-EVs attenuated GVHD severity and improved median survival as compared to no treatment or saline. The authors concluded that this systematic review provided important insight regarding the potential of MSC-EVs to prevent or treat GVHD. Although few studies were identified, improved survival and attenuated histologic findings of GVHD were observed in mice following MSC-EV administration for the prevention and treatment of GVHD; however, dosing of EVs and route of administration remain inconsistent, and scalability of EV isolation for clinical studies remains a challenge; standardized outcome reporting is needed to pool results for metanalysis. These researchers stated that MSC-EVs appear promising for the prevention and treatment of GVHD and efforts to accelerate further research are encouraged.

The authors stated that this study’s drawbacks included the possibility of omitting published reports. Conference abstracts were not included as methodological details were often lacking. Given the overall small number of studies and modest number of animals contributing to results in the studies included in this analysis, larger more definitive studies are still needed. Reported outcomes were inconsistent and recorded at variable time points after the intervention. While heterogeneity in studies limited the ability to pool data for a meta-analysis, these researchers were able to identify aspects of pre-clinical study design that could be addressed to reduce potential bias and to allow for pooled estimates of efficacy in the future.

An UpToDate review on “Treatment of acute graft-versus-host disease” (Chao, 2020a) states that “Mesenchymal stromal cells -- The bone marrow contains small numbers of mesenchymal stromal cells (MSCs), which are able to differentiate in vitro and in vivo into cells of mesenchymal origin (e.g., fibroblasts, adipocytes, osteoblasts, chondrocytes) and are pivotal for the supply of growth factors supporting hematopoiesis. The immunosuppressive potential of these cells, including their ability to induce CD4+/CD25+/FOXP3+ regulatory T cells, has set the stage for their testing as cellular immunosuppressants, to promote hematopoietic recovery after autologous and allogeneic HCT, and to treat acute, severe GVHD”. However, this review does not address MSC-derived extracellular vesicles as a therapeutic option.

Furthermore, an UpToDate review on “Treatment of chronic graft-versus-host disease” (Chao, 2020b) does not mention MSC-derived extracellular vesicles as a therapeutic option.

Stem Cell Boosting for Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

Haen et al (2015) noted that insufficient production of leukocytes, thrombocytes and erythrocytes following allogeneic peripheral blood stem cell transplantation (PBSCT) represents a life-threatening complication. In 20 adult patients with poor graft function (PGF; defined as transfusion-dependent platelet counts of less than 20,000/µl, or leukocytes of less than 1,500/µl, or transfusion-dependent anemia) and variable causes of PGF following allogeneic PBSCT, immunomagnetically selected CD34(+) stem cell boosts (SCB) from matched unrelated (n = 8), mismatched unrelated (n = 11) or haploidentical (n = 1) donors were applied without prior conditioning. Patients received a median of 4.6 × 10(6) CD34(+) cells/kg bodyweight (1.9-9.1 × 10(6)) and low T-cell numbers (median of 0.2 × 10(4), range of 0.04 to 0.6 × 10(4)). All patients showed responses in at least 1 hematopoietic lineage. Engraftment for platelets, leukocytes and hemoglobin was 88 %, 88 % and 100 % after a median of 14, 13 and 18 days, respectively. With regard to the complete cohort, 90 % (n = 18) showed an increase in platelets (median of 76,500/µl, range of -7,000 to 223,000/µl), 95 % (n = 19) had an increase in leukocytes (median of 3,110/µl, range of 150 to 13,740/µl) and 90 % (n = 18) improved with regard to hemoglobin (median of 1.9 g/dL, range of -0.9 to 5.1 g/dL). Due to effective T-cell depletion, only 1 patient developed GVHD (grade-III) after SCB. Patients were followed for a median of 7.5 months (1 to 74 months) with 11 patients being alive and disease free with normalized peripheral blood counts at the end of follow-up. The authors concluded that CD34(+)-selected SCB were safe and effective and could durably improve PGF even in patients receiving grafts from unrelated matched or mismatched donors with low incidence of GVHD.

Mainardi and associates (2018) stated that PGF is a severe complication of HSCT; and administration of donor SCBs represents a therapeutic option. These investigators reported the findings of 50 pediatric patients with PGF who received 61 boosts with CD34+ selected PBSC after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. Within 8 weeks, a significant increase in median neutrophil counts (0.6 versus 1.516 × 10(9)/L, p < 0.05) and a decrease in RBC and platelet transfusion requirement (median frequencies 1 and 7 versus 0, p < 0.0001 and p < 0.001), were observed, and 78.8 % of patients resolved 1 or 2 of their cytopenia. A total of 36.5 % had a hematological CR. Median lymphocyte counts for CD3+ , CD3+ CD4+ , CD19+ and CD56+ increased 8.3-, 14.2-, 22- and 1.6-fold. The rate of de-novo acute GVHD grade I to III was only 6 % and resolved completely. No GVHD grade-IV or chronic GVHD occurred. Patients who responded to SCB displayed a trend toward better OS (p = 0.07). The authors concluded that administration of CD34+ selected SCBs from alternative donors was safe and effective. Moreover, these researchers stated that this study had drawbacks due to its retrospective nature. Nevertheless, it demonstrated that CD34+ positively-selected stem cell boosting is a reasonable and remarkably safe therapeutic option for patients with poor graft function, allowing the avoidance of any immunosuppression.

Shahzad and colleagues (2021) noted that PGF is a life-threatening complication following allo-HSCT characterized by multi-lineage cytopenia in the absence of mixed donor chimerism (less than 95 % donor), relapse, or severe GVHD. In a systemic review and meta-analysis, these researchers examined the outcomes with CD34-selected SCBs for PGF in adult allo-HSCT recipients. They screened a total of 1,753 records identified from 4 databases (PubMed, Embase, Cochrane, and ClinicalTrials.gov) following the PRISMA guidelines, using the search terms "hematological malignancies", "hematopoietic stem cell transplantation", "CD34 antigen(s)", "graft failure", and "poor graft function" from the date of inception to January 2021. After excluding review, duplicate, and non-relevant articles, these researchers included 7 studies reporting outcomes following administration of CD34-selected SCB for PGF after allo-HSCT, including hematologic CR and overall response rate (ORR), GVHD, and OS. Quality evaluation was carried out using the National Institutes of Health (NIH) quality assessment tool. Pooled analysis was performed using the R “meta” package, and proportions with 95 % CIs were computed. The inter-study variance was calculated using the Der Simonian-Laird estimator. These investigators identified 209 patients who received CD34-selected SCB for PGF after allo-HSCT. The median age was 49 years (range of 18 to 69 years), and 61 % were men. Primary graft sources included PBSC (72 %) and bone marrow (28 %). Donor types were matched sibling (37 %), matched unrelated (36 %), mismatched unrelated (22 %), and haploidentical donors (5 %). The median time from allo-HSCT to SCB was 138 days (range of 113 to 450 days). The median SCB dose was 3.45 × 106 CD34 cells/kg (range of 3.1 to 4.9 × 106 cells/kg). CR and ORR were 72 % (95 % CI: 63 % to 79 %; I2 = 26 %) and 80 % (9 5% CI: 74 % to 85 %; I2 = 0 %), respectively. After a median follow-up of 42 months (range of 30 to 77 months), the actuarial survival rate was 54 % (95 % CI: 47 % to 61 %; I2 = 0 %). OS ranged from 80 % at 1 year to 40 % at 9 years. The incidences of acute and chronic GVHD after SCB were 17 % (95 % CI: 13 % to 23 %; I2 = 0 %) and 18 % (95 % CI: 8 % to 34 %; I2 = 76 %), respectively. Non-relapse mortality was reported in 42 patients, with a pooled rate of 27 % (95 % CI: 17 % to 40 %; I2 = 59 %), and death due to relapse was reported in 25 patients, with a pooled rate of 17 % (95 % CI: 11 % to 23 %; I2 = 0 %). The authors concluded that these findings showed that CD34-selected SCB improved outcomes after PGF post allo-HSCT with an acceptable toxicity profile.

Garg et al (2021) noted that early mixed chimerism (MC) could lead to secondary graft rejection following allo-HSCT in transfusion-dependent thalassemia (TDT) patients. Reduction of immunosuppression and donor lymphocyte infusions (DLIs) are the mainstays in the treatment of MC. These investigators reported their experience of administering unmanipulated SCB in reversing progressive early MC. There were 70 transplants carried out for 69 TDT patients at the authors’ center between September 2005 and January 2020. Mixed chimerism was defined by greater than 5 % recipient cells and the severity was assigned according to the proportion of recipient cells as level 1 = less than 10 %, level 2 = 10 % to 25 %, level 3 = greater than 25 %. For patients developing MC level 2 and 3, these researchers administered unmanipulated SCB and analyzed its safety and effectiveness. Of 70 transplants, 7 (10 %) had MC level 2 (3/7) and 3 (4/7). These patients received unmanipulated SCB at a median CD34 cell dose of 4.5 × 10(6)/kg (range of 3.5 × 10(6)/kg to 5.5 × 10(6)/kg). Overall response (stable MC and/or transfusion independency) to unmanipulated SCB was observed in 5 patients (71.4 %); 5 patients (71.4 %) developed acute GVHD of which 1 patient expired due to severe GVHD. SCB infusion was well-tolerated by majority of the patients. The 3-year OS and thalassemia-free survival was 85.7 % (6/7) and 57.1 % (4/7), respectively. The authors concluded that timely monitoring of chimerism was important for detecting early MC. These investigators stated that development of acute GVHD is common after administration of unmanipulated SCB and requires vigilance and prompt management. They stated that unmanipulated SCB was a feasible modality for treating progressive MC and salvaging the graft especially in resource-constrained settings.

Liang et al (2021) autologous HSCT (auto-HSCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for SCB for delayed/poor engraftment or for future 2nd auto-HSCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. In a retrospective, single-center study, these researchers examined the use of backup stem cells (BSCs) in patients with MM undergoing auto-HSCT. Patients with MM aged 18 years or older who underwent 1st auto-HSCT at the authors’ institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this trial. This timeframe was selected to allow for adequate follow-up; and a total of 393 patients were included. The median age was 58 years (range of 25 to 73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years; 61 % (n = 240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98 %). The median total CD34+ cells collected was 18.2 × 10(6)/kg (range of 3.4 to 112.4). A median of 5.7 × 10(6) CD34+ cells/kg (range of 1.8 to 41.9) was infused during the 1st auto-HSCT, and a median of 10.1 × 10(6) CD34+ cells/kg (range of 1.5 to 104.5) was cryo-preserved for future use. Of the patients, 6.9 % (n = 27) used BSCs, with 2.3 % (n = 10) using them for SCB, 4.6 % (n = 18) for a 2nd salvage auto-HSCT, including 1 patient for both SCB and 2nd auto-HSCT. Rates of BSC use among patients aged less than 60, 60 to 69, and greater than or equal to 70 years were 7.8 %, 5.7 %, and 5.9 %, respectively. There was a trend toward higher rates of BSC use for 2nd auto-HSCT in patients who were younger, had suboptimal disease control at time of 1st auto-HSCT, and longer PFS. The median dose of SCB given was 5.6 × 10(6) CD34+ cells/kg (range of 1.9 to 20). The median time from SCB to neutrophil, hemoglobin, and platelet engraftment was 4 (range of 2 to 11), 15 (range of 4 to 34), and 12 (range of 0 to 34) days, respectively. Lower CD34+ dose and older age at time of auto-HSCT predicted need for SCB. With new salvage therapies for relapsed MM, the rates of 2nd auto-HSCT were very low. The authors concluded that the low rates of use suggested that institutional policies regarding universal BSC collection and long-term storage should be re-assessed and individualized; however, need for SCB in 2.3 % of patients may present a challenge to that.

Umbilical Cord Blood Transplantation Using Ex-Vivo Expansion

Cohen et al (2020) noted that benefits of cord blood transplantation include low rates of relapse and chronic GVHD (cGVHD). However, the use of cord blood is rapidly declining because of the high incidence of infections, severe acute GVHD (aGVHD), and transplant-related mortality. UM171, a hematopoietic stem cell self-renewal agonist, has been shown to expand cord blood stem cells and enhance multi-lineage blood cell reconstitution in mice. In an open-label, single-arm, phase-I to phase-II safety and feasibility study, these investigators examined the safety and feasibility of single UM171-expanded cord blood transplantation (CBT) in patients with hematological malignancies who do not have a suitable HLA-matched donor. This trial was carried out at 2 hospitals in Canada; and had 2 parts. In part 1, patients received 2 cord blood units (1 expanded with UM171 and 1 un-manipulated cord blood) until UM171-expanded cord blood demonstrated engraftment. Part 2 of the trial was initiated upon documentation of engraftment. Patients received a single UM171-expanded cord blood unit with a dose de-escalation design to determine the minimal cord blood unit cell dose that achieved prompt engraftment. Eligible patients were aged 3 to 64 years, weighed 12 kg or more, had a hematological malignancy with an indication for allogeneic HSCT and did not have a suitable HLA-matched donor, and a had a Karnofsky performance status (KPS) score of 70 % or more. A total of 5 clinical sites were planned to participate in the study; however, only 2 study sites opened, both of which only treated adult patients; therefore, no pediatric patients (aged less than 18 years) were recruited. Patients aged younger than 50 years without co-morbidities received a myeloablative conditioning regimen (cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and 12 Gy total body irradiation [TBI]) and patients aged older than 50 years and those with co-morbidities received a less myeloablative conditioning regimen (cyclophosphamide 50 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, and 4 Gy TBI). Patients were infused with the 7-day UM171-expanded CD34-positive cells and the lymphocyte-containing CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety of the transplant, kinetics of hematopoietic reconstitution (time to neutrophil and platelet engraftment) of UM171-expanded cord blood, and minimal pre-expansion cord blood unit cell dose that achieved prompt engraftment. These investigators analyzed feasibility in all enrolled patients and all other primary outcomes were analyzed per protocol, in all patients who received single UM171-expanded CBT. Between February 17, 2016, and November 11, 2018, a total of 27 patients were enrolled, 4 of whom received 2 cord blood units for safety purposes in part 1 of the study. A total of 23 patients were subsequently enrolled in part 2 to receive a single UM171-expanded CBT and 22 patients received a single UM171-expanded CBT. At data cut-off (December 31, 2018), median follow-up was 18 months (IQR 12 to 22). The minimal cord blood unit cell dose at thaw that achieved prompt engraftment as a single cord transplant after UM171 expansion was 0·52 × 105 CD34-positive cells. We successfully expanded 26 (96%) of 27 cord blood units with UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment of 100 neutrophils per μL was 9·5 days (inter-quartile range [IQR] 8 to 12), median time to engraftment of 500 neutrophils per μL was 18 days (12.5 to 20.0 days), and no graft failure occurred. Median time to platelet recovery was 42 days (IQR 35 to 47 days). The most common non-hematological adverse events (AEs) were grade-III febrile neutropenia (16 [73 %] of 22 patients) and bacteremia (9 [41 %]). No unexpected AEs were observed; 1 (5 %) of 22 patients died due to treatment-related diffuse alveolar hemorrhage. The authors concluded that these preliminary findings suggested that UM171 cord blood stem cell expansion was feasible, safe, and allowed for the use of small single cords without compromising engraftment. These researchers stated that UM171-expanded CBT might have the potential to overcome the disadvantages of other cord blood transplants while maintaining the benefits of low risk of cGVHD and relapse; and warrants further investigation in randomized trials. They stated that dedicated phase-II clinical trials for niche indications (e.g., high-risk diseases) and randomized phase-III clinical trials are needed to compare UM171-expanded cord blood with standards of care (SOC).

The authors stated that these findings should be interpreted with caution because of the small sample size of the UM171 cohort and the subsequently wide CIs. Moreover, the retrospective comparison of these findings with the 3 historical cohorts were limited, namely, by the heterogeneity of the patient populations and the absence of matched controls, especially in the context of the small sample sizes. The low T-cell dose and improved HLA-matching did not appear to result in a higher risk of relapse, especially considering that among the 6 patients with acute leukemias not in remission or undergoing a 2nd transplant, none had relapsed by the data cut-off. These researchers stated that although longer follow-up is needed to examine the risk of relapse, they had initiated 2 independent phase-II clinical trials of high-risk leukemia and myelodysplasia to examine treatment-related mortality and the rate of relapse-free survival. If confirmed, this niche indication might, on its own, justify the cost and logistics of expansion since therapeutic options are limited for this patient population. Furthermore, these researchers noted that time to engraftment of 500 neutrophils could likely be improved especially when compared with other expansion techniques. Human herpesvirus-6 (HHV-6) is a well-known risk factor for delayed engraftment and might have affected engraftment in some of the patients included in this trial. Pre-emptive or prophylactic treatment with foscarnet might accelerate platelet and neutrophil recovery in CBT and will be incorporated in future studies.

Saiyin et al (2022) stated that greater use of UCB for hematopoietic cell transplantation (HCT) is limited by the number of cells in banked units. Ex-vivo culture strategies have been increasingly studied in controlled studies; however, their impact on transplantation-related outcomes remains uncertain due to the small patient numbers in these studies. In a systematic review and meta-analysis, these investigators carried out a literature search using the Medline, Embase, and Cochrane databases to March 18, 2022. A total of 9 cohort-controlled phase-I to phase-III clinical trials were identified, and data of 1,146 patients undergoing umbilical CBT (UCBT) were analyzed (308 ex-vivo expanded and 838 un-manipulated controls). Expansion strategies entailed cytokine cocktails plus the addition of small molecules (UM171, nicotinamide [NiCord], copper chelation, Notch ligand, or Stem regenin-1 [SR-1]) and co-culture with mesenchymal stromal cells (MSCs) in a single-unit transplant strategy (5 studies) or a double-unit transplant strategy with 1 un-manipulated unit (4 studies). The included studies reported a median ex-vivo expansion of CD34+ cells from 28-fold to 330-fold; 8 of the 9 studies reported a significantly faster time to initial neutrophil and platelet engraftment using expanded cells compared with controls. Studies using UM171 and NiCord in single-unit UCBT and SR-1 or NiCord double-unit UCBT showed long-term donor chimerism of the expanded unit at 100 days to 36 months post-transplantation in all single-unit recipients and in 35 % to 78 % of double-unit recipients. The meta-analysis showed a lower risk of death at the study endpoint in patients who received ex-vivo expanded grafts (odds ratio [OR], 0.66; 95 % CI: 0.47 to 0.95; p = 0.02), while the risk of grade-II to grade-IV aGVHD was unchanged (OR, 0.79; 95 % CI: 0.58 to 1.08; p = 0.14). The authors concluded that the findings of this review indicated that UCBT following ex-vivo expansion could accelerate initial engraftment. Durable donor chimerism could be achieved following transplanting cord blood units expanded using NiCord, UM171, or SR-1; however, long-term outcomes remain unclear. These researchers stated that larger studies with longer-term outcomes are needed to better understand the merits of specific expansion strategies for improvement of UCB transplantation outcomes.

Scope of Policy

This Clinical Policy Bulletin addresses stem cells for hematopoietic cell transplant.

Medical Necessity

Aetna considers the following indications as medically necessary (unless otherwise stated):

Experimental and Investigational

The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:

Policy Limitations and Exclusions