Version May 2024
INTRODUCTION — Allogeneic hematopoietic cell transplantation (HCT) is an important and potentially curative treatment option for a wide variety of malignant and nonmalignant diseases. The pluripotent hematopoietic stem cells required for this procedure are usually obtained from the bone marrow or peripheral blood of a related or unrelated donor. Umbilical cord blood (UCB), the blood remaining in the umbilical cord and placenta following the birth of an infant, has emerged as an established alternative source of hematopoietic stem cells in allogeneic HCT.
Engraftment and survival rates following HCT are optimized when the donor and recipient are genetically compatible. Human leukocyte antigen (HLA)-matched sibling donors are generally the preferred donor source for an allogeneic HCT. Unfortunately, finding an HLA-matched sibling is not always possible. Each full sibling potential donor has only a 25 percent chance of being fully HLA-matched with a sibling requiring a transplant. Therefore, most patients do not have an HLA-identical relative. (See "Donor selection for hematopoietic cell transplantation", section on 'Matched sibling donors'.)
When a suitable related donor is not available, a search is conducted to identify a potential unrelated HLA-matched donor. Finding an appropriate donor through a national registry is a lengthy process that is not always successful, especially for individuals who are not of Northern European descent. (See "Donor selection for hematopoietic cell transplantation", section on 'Unrelated donors'.)
In comparison, the relative ease of procurement and the lower than anticipated risk of severe acute graft versus host disease has made unrelated UCB transplantation a possible alternative to unrelated donor bone marrow or mobilized peripheral blood progenitor cell transplant. The increased representation of ethnic underrepresented groups and the ability to use partially HLA-matched UCB units significantly expands the donor pool. In addition, the use of reduced-intensity or non-myeloablative preparative regimens to allow engraftment of UCB broadens the scope of patients who may benefit from allogeneic HCT, including older adult and medically infirm patients without an HLA-matched sibling donor. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Features of UCB grafts'.)
The use of UCB transplantation in adults using myeloablative and non-myeloablative preparative regimens will be discussed here. Other issues related to UCB are discussed separately, including the advantages and limitations of using UCB as a graft, the collection, storage, and ethical issues regarding the use of UCB for HCT, and the selection of an UCB graft for a particular recipient. (See "Collection and storage of umbilical cord blood for hematopoietic cell transplantation".)
CORD BLOOD AS A RESOURCE — Unrelated UCB offers many practical advantages over unrelated donor bone marrow or mobilized peripheral blood progenitor cells as a source of hematopoietic stem cells, including an expanded donor pool, ease of procurement and lack of donor attrition, and decreased graft-versus-host disease. Limitations to UCB included an increased risk of graft failure, delayed immune reconstitution, and unavailability of the donor for additional donations (ie, donor lymphocyte infusions). This is discussed in more detail separately. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Features of UCB grafts'.)
CORD BLOOD UNIT SELECTION — The main criteria for selecting UCB unit(s) for transplantation are the human leukocyte antigen (HLA) haplotype and the cryopreserved total nucleated cell dose per kilogram recipient body weight. This is discussed in more detail separately. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'UCB unit selection'.)
PREPARATIVE REGIMEN
Choice of preparative regimen — UCB transplantation (UCBT) has been performed in adults using both myeloablative and non-myeloablative preparative regimens. These approaches have not been compared directly in a prospective trial. As such, the ideal preparative regimen prior to UCB infusion is unknown and clinical practice varies by institution. Options include:
●Myeloablative regimens – A myeloablative conditioning regimen consists of a single agent or combination of agents expected to destroy the hematopoietic cells in the bone marrow and produce profound pancytopenia within one to three weeks from the time of administration. The resulting pancytopenia is long-lasting, usually irreversible, and in most instances fatal, unless hematopoiesis is restored by infusion of hematopoietic stem cells. An example of a myeloablative regimen commonly used for UCBT is fludarabine 75 mg/m2, cyclophosphamide 120 mg/kg, and total body irradiation 13.2 Gy [1]. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Myeloablative regimens'.)
●Non-myeloablative (reduced intensity) regimens – A non-myeloablative regimen is one that combines the anti-leukemia effect of more modest doses of chemotherapy with the objective of achieving significant immunosuppression (to allow engraftment), thereby causing less organ and mucosal damage than myeloablative regimens. "Non-myeloablative" is probably not the most appropriate term, since the doses of alkylating agents typically used will result in long period of severe cytopenias prior to marrow recovery. An example of a non-myeloablative regimen commonly used for UCBT is fludarabine 40 mg/m2, cyclophosphamide 50 mg/kg, and total body irradiation 200 cGy (Flu/Cy/TBI 200 cGy) [2]. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)
For younger patients without comorbidities, we suggest a myeloablative preparative regimen such as those used in the initial studies of UCBT. However, many older patients and patients with co-morbidities are not candidates for myeloablative preparative regimens due to high rates of morbidity and mortality with this approach. Because of toxicities from the intensive conditioning regimens to non-marrow organs such as gastrointestinal tract, liver, lung, and heart, UCBT using myeloablative preparative regimen have been restricted to patients younger than 50 to 55 years of age, with none of the series reported thus far including patients older than 60 years of age.
Non-myeloablative conditioning regimens are an acceptable alternative for patients who are not candidates for myeloablative regimens. The ability to achieve stable mixed or full donor chimerism using these regimens, with successful eradication of primary disease in the absence of severe therapy-related toxicity in preliminary clinical studies, signifies an advance in the field of transplantation and immunobiology. However, there are several unresolved issues and remaining questions regarding the utility of this novel strategy, including:
●How does the efficacy of non-myeloablative UCBT differ from that of myeloablative UCBT?
●Is there a difference in the incidence of graft-versus-host disease (GVHD)?
●What is the optimal GVHD prophylaxis for patients undergoing non-myeloablative UCBT?
●How does immune reconstitution differ from that after myeloablative UCBT?
●Does the incidence of infection differ from that seen in myeloablative UCBT?
●What is the optimal non-myeloablative preparative regimen?
●Does non-myeloablative UCBT require a different UCB cell dose?
Future studies should address these questions and carefully define the indications for non-myeloablative versus myeloablative preparative regimens. The benefit of reduced toxicity with non-myeloablative regimens may be offset by the loss of cytoreduction of the tumor cells induced by high dose chemotherapy. The use of non-myeloablative regimens has generally been more successful in patients with indolent lymphoid malignancies or malignancies that are susceptible to graft-versus-leukemia (GVL) effects, such as chronic myeloid leukemia. It is less successful in patients with aggressive malignancies or malignancies that appear relatively insensitive to GVL effect, such as acute lymphoblastic leukemia and high grade lymphoma. The rapid proliferation of these malignancies may outpace the developing immune response. Given the limitation of cell dose of UCB and logistic problem in donor recall, non-myeloablative UCBT does not afford the same advantage as in non-myeloablative transplant using hematopoietic stem cells from an adult donor, in which the transplant provides a platform for repeated delivery of adoptive cellular immunotherapy with donor lymphocyte infusions or other cellular therapies. In the case of an aggressive malignancy where the delayed graft-versus-malignancy effect cannot be relied upon, it may be more beneficial to use a preparative regimen ("reduced toxicity" ablative regimen) that provides some disease control and also facilitates engraftment.
Another important issue is the potential of non-myeloablative UCBT to minimize the in-patient stay and improve quality of life in the peri-transplant period, while reducing cost. The majority of patients at our institution have non-myeloablative transplantation performed largely in the outpatient setting. The median time for hematopoietic recovery is shorter than conventional UCBT. Longer follow-up with larger number of patients will be needed to determine the incidence of chronic GVHD and the quality of life of such recipients.
Myeloablative preparative regimens
Efficacy — Myeloablative preparative regimens have been used to successfully engraft both related and unrelated UCB in adults and children with hematological malignancies, marrow failure syndromes, and immune deficiencies. The results of several large series have been reported in the peer-reviewed literature [3-15]. The myeloablative preparative regimens employed in these studies were either total body irradiation (TBI)-based or chemotherapy-based, with inclusion of antithymocyte globulin in some of the patients. The data from these UCBT registries, in which the majority of the recipients were children, point to significant delay in the time of neutrophil recovery, with the median time to absolute neutrophil count >500/microL ranging between 22 to 30 days. The overall probability of engraftment was between 80 and 90 percent. Despite a higher degree of HLA disparity, grade II to IV GVHD in those unrelated UCB recipients is lower than recipients of unrelated bone marrow or peripheral blood grafts from adult donors. (See 'Graft-versus-host disease (GVHD)' below.)
Much of the initial data on UCBT were recorded in patients with very advanced disease with the expected poor results. Given significant improvements in understanding the biology of cord blood cells, importance of cell dose, use of double UCBT, and better patient selection, the outcomes following UCBT have improved. Analyses of registry data have compared the outcomes of UCB with unrelated bone marrow (BM) or peripheral blood progenitor cells (PBPC):
●An analysis of Center for International Blood and Marrow Transplant Research (CIBMTR) database compared outcomes of 503 children with acute leukemia given an unrelated mismatched UCBT with 282 unrelated BM transplant recipients (116 HLA allele matched 8 out of 8) [6]. HLA allele mismatched BM recipients had more acute and chronic GVHD but similar rates of leukemia-free survival (LFS). The data demonstrated that even with an allele-matched BM donor, LFS was not statistically different from one or two HLA disparate UCBT. HLA-matched UCBT recipients had better outcomes compared with HLA allele matched BM recipients. In addition, there was higher transplant-related mortality (TRM) in children receiving a low UCB cell dose (<3 x 107/kg) and 5 of 6 HLA disparate UCB graft or in children given a 4 of 6 HLA disparate UCBT, independently of the cell dose infused. Also of interest was the observation that there was a lower incidence of relapse with the use of two cord blood units. This latter finding has also been observed by the group at the University of Minnesota [13].
●An analysis of the Eurocord database compared the outcome of 442 children who underwent matched unrelated BM (either T depleted or replete) transplant with 99 children who underwent mismatched UCBT [16]. After UCBT, engraftment was delayed and GVHD was reduced similarly to T cell depleted BM transplant. The relapse rate and the disease-free survival were equivalent in this analysis.
●Another Eurocord analysis compared adults with acute leukemia receiving either a matched unrelated BM transplant (584 patients) or a mismatched UCBT (98 patients) [17]. Despite a delay of engraftment, UCBT gave a similar leukemia-free survival to BM transplantation. Similar data were observed in the CIBMTR and New York Cord Blood Bank (NYCBB) where UCBT resulted in similar LFS survival to one antigen mismatched UBMT [18].
●A meta-analysis included 161 children and 316 adults undergoing UCBT along with 316 children and 996 adults undergoing unrelated BM transplantation and excluded T cell depleted unrelated BM transplant [19]. Pooled comparisons in children found that the incidence of chronic GVHD was lower with UCBT, but the incidence of grade III/IV acute GVHD did not differ. There was no difference in two-year overall survival in children. For adults, there was no statistical difference between TRM and LFS.
●A subsequent retrospective analysis included 1525 adults who underwent UCB (165 patients), mobilized PBPCs (888 patients), or BM (472 patients) transplantation with a myeloablative preparative regimen between 2002 and 2006 for acute leukemia [20]. UCB units were 6 of 6 HLA-matched (10 patients), 5 of 6 HLA-matched (40 patients), or 4 of 6 HLA-matched (115 patients) based upon testing for HLA-A and HLA-B at antigen level and HLA-DRB1 at allele level. PBPCs and BM grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (632 and 332 patients, respectively), or mismatched at one locus (256 and 140 patients, respectively). UCBT resulted in the following:
•Similar LFS as that after 8/8 and 7/8 allele-matched PBPC or BM transplantation
•Higher rates of TRM than after 8/8 allele-matched PBPC recipients (HR 1.62, 95% CI 1.18-2.23) or BM transplantation (HR 1.69, 95% CI 1.19-2.39)
•Lower rates of grade II to IV acute (HR 0.57, 95% 0.42-0.77) and chronic (HR 0.38, 0.27-0.53) GVHD than allele-matched PBPC transplantation
•Lower rates of chronic (HR 0.63, 0.44-0.90), but not acute, GVHD than after 8/8 allele-matched BM transplantation
These results support the use of a myeloablative preparative regimen followed by UCBT in adults who do not have an HLA-matched unrelated adult donor available.
Toxicity and transplant-related mortality — Data regarding the toxicity and TRM of myeloablative UCBT are derived from case series and retrospective analyses of highly select, predominantly pediatric, patient populations. These studies have reported TRM between 27 and 39 percent at 100 days post-transplant and between 30 and 44 percent at one year post-transplant [17,18]. A relatively higher incidence of TRM at 100 days post-transplant has been observed in adults, ranging between 43 and 56 percent [21,22]. The high non-relapse mortality in these series is partially attributable to the high risk nature of the patient population. Infection and acute GVHD are the main causes of death within the first 100 days of transplant. Organ toxicity associated with the intensive treatment administered to patients before UCBT is another leading cause of nonrelapse mortality in adult UCB recipients.
Given the heterogeneity of the patient populations, conditioning regimens, GVHD prophylaxis, and supportive care, it is difficult to reliably evaluate the impact of pre-transplant variables on TRM. However, among prognostic variables that have been evaluated, increased cell dose of the UCB graft and improved matching by having more units available has resulted in better outcomes [23]. Future efforts to lower TRM should focus on improving transplant methodology and supportive care. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Cell dose'.)
Infection — When compared with recipients of BM or PBPCs, adults receiving UCB have a higher risk of opportunistic infections for up to two to three years after transplantation. Infection may account for half of all treatment-related-death after UCBT following an ablative regimen. Apart from the prolonged neutropenia associated with myeloablative UCBT, the risk of infection may be an intrinsic property of UCB, because UCB have been shown to be phenotypically naïve [24] and to expand slowly in response to antigen stimulation, demonstrated a higher threshold for cytokine stimulation, and possess a lower effective cytotoxicity relative to adult donor T cell controls. Moreover, thymic production of new T cells is substantially delayed and remains limited in adult recipients of UCB following an ablative preparative regimen.
The increased risk of infection within the first 100 days of UCBT may be related to delayed engraftment, GVHD, and impaired immune recovery. Immune dysfunction is at least partially related to the UCB cell dose. Retrospective studies have noted an association between increasing CD34 cell dose and improved engraftment, fewer infections, lower TRM, and higher survival rates [25]. While some propose that prolonged neutropenia is the main contributory cause of the increased risk of infection, a high incidence of infection after bone marrow recovery suggests the influence of impaired immune recovery and GVHD in causing infections [22]. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Cell dose'.)
The increased risk of infection in adults after UCBT was shown in a study of 27 adult recipients of unrelated UCB that demonstrated a 100 percent incidence of infectious episode, 55 percent incidence of bacteremia, 58 percent incidence of cytomegalovirus antigenemia, and 11 percent incidence of fungal infections [22]. In this study, the reported TRM at day 100 was 37 percent, with 80 percent of deaths related to infections. Importantly, more than half of the infections occurred after myeloid recovery.
The high rate of infection after myeloid recovery has sparked interest in the recovery of lymphocyte populations after UCBT and their impact on infection. A study of lymphocyte subset reconstitution in children after UCBT demonstrated that, when compared with bone marrow transplant, the median time to reach CD8+ T cell recovery was delayed (7.7 versus 2.8 months), while the median time to reach CD19+ B cell recovery was shorter (3.2 months versus 6.4 months), and the median time to CD4+ T cell reconstitution was similar [26]. Another study of immune reconstitution after double UCBT in the setting of high-risk hematologic disease demonstrated decreased T cell and B cell counts with expansion of natural killer cells until nine months post-transplantation [27].
Graft-versus-host disease (GVHD) — Among patients undergoing allogeneic hematopoietic cell transplantation, the incidence and severity of acute and chronic GVHD increases with increasing HLA-mismatch. While the incidence of GVHD does appear to increase with increasing HLA-disparity among recipients of UCB, published data from most of the UCB registries have shown that, despite the infusion of an HLA class I and II disparate graft, the incidence and severity of acute and chronic GVHD has been lower than previously reported in recipients of matched unrelated donor marrow or partially-matched family member marrow allograft. In these series of UCBT recipients, the majority of whom are children, the overall incidence of grade II to IV acute GVHD and grade III to IV acute GVHD were between 30 and 50 percent and 10 and 20 percent, respectively [3-14].
The following studies investigated the relationship between GVHD and HLA-disparity among UCBT recipients:
●A matched-pair analysis demonstrated a similar rate of acute and chronic GVHD between pediatric recipients of zero to 3 HLA-antigen mismatched unrelated donor UCB grafts as compared with those receiving HLA-matched unrelated donor marrow graft [28].
●A multivariate analysis of data from one of the largest series revealed a significant association between the acute GVHD and HLA disparity [29]. The incidence of grade III to IV acute GVHD in patients with no mismatch, one antigen HLA mismatch, and two or more antigen mismatch were 8 percent, 19 percent and 28 percent, respectively.
●Another study analyzed the relative risk of acute GVHD in 265 consecutive patients receiving transplants with UCB graft composed of one unit (80 patients) or two units (185 patients) [30]. There were similar rates of grade III/IV acute GVHD among those receiving one or two units. However, the incidence of grade II to IV acute GVHD was significantly higher among double UCBT recipients (58 versus 39 percent). Three risk factors for grade II to IV acute GVHD were identified in multiple regression analysis: use of two UCB units, use of nonmyeloablative conditioning, and absence of antithymocyte globulin in the conditioning regimen. Despite the increased GVHD, TRM at one year was significantly lower after double UCBT (24 versus 39 percent) even if recipients had grade II to IV acute GVHD (20 versus 39 percent). These data suggest that, despite a higher incidence of grade II acute GVHD in recipients of two partially HLA-matched UCB units, there is no adverse effect on TRM.
Together, these studies suggest that, while the incidence of GVHD increases with increasing HLA-disparity among patients undergoing UCBT, the incidence is lower than that of patients undergoing a matched unrelated donor marrow transplant with similar HLA-disparity. In addition, although the rate of GVHD is higher among recipients of double UCBT, there does not appear to be an adverse effect on TRM.
Organ toxicity — The use of myeloablative preparative regimens is complicated by toxicity to non-marrow organs such as gastrointestinal tract, liver, lung, and heart. While the specific organ toxicity varies with the preparative regimen used, these toxicities are the major limitation in applying myeloablative preparative regimens to older adults and patients with comorbidities. In one series, 35 percent of deaths after UCBT were related to the preparative regimen [18]. (See "Preparative regimens for hematopoietic cell transplantation", section on 'MAC toxicity'.)
Non-myeloablative preparative regimens — In contrast to UCBT using a myeloablative conditioning regimen, the published series on non-myeloablative UCBT involves smaller cohorts of patients with either refractory hematological malignancies, or patients who were otherwise poor candidates for a conventional transplant approach. Because most non-myeloablative UCBT are performed in situations where standard transplants would not be considered, no comparative studies between myeloablative and non-myeloablative UCBT are likely to be performed in the near future. In general, we reserve non-myeloablative conditioning regimens for patients who are not candidates for myeloablative regimens due to older age or comorbidities.
Efficacy — Initial studies suggest that non-myeloablative preparative regimens followed by UCBT are feasible and result in high levels of engraftment in patients who are not candidates for myeloablative preparative regimens. In addition, there is great interest in applying non-myeloablative UCBT to children since many of them have non-malignant conditions that otherwise would not require intensive cytotoxic therapy to address the underlying disease [31]. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)
The successful engraftment of a single UCB graft following a non-myeloablative conditioning regimen consisting of fludarabine 120 mg/m2, cyclophosphamide 2 g/m2, and antithymocyte globulin (ATG) 90 mg/kg was first demonstrated in two adult patients with non-Hodgkin lymphoma (NHL) and reported in 2001 [32]. Since then, the largest published experience comes from the University of Minnesota using a preparative regimen consisting of fludarabine 40 mg/m2, cyclophosphamide 50 mg/kg, and total body irradiation (TBI) 200 cGy (Flu/Cy/TBI 200 cGy) [28,33,34]. This preparative regimen is generally preferred to busulfan-based regimens because retrospective analyses have demonstrated that Flu/Cy/TBI 200 cGy provided more reliable sustained donor engraftment [35,36], although the addition of thiotepa to busulfan-based regimens may overcome the difficulty with engraftment [37].
Retrospective analyses and one prospective trial have evaluated the use of non-myeloablative UCBT [2,31,33,38-45]:
●A retrospective analysis from the University of Minnesota included 110 patients with a median age of 51 years who were transplanted with a single- (15 percent) or double- (85 percent) UCB graft after Flu/Cy/TBI 200 cGy [33]. Equine ATG 45 mg/kg was given to 35 percent of patients who had received fewer than two cycles of chemotherapy prior to initiation of the transplant conditioning regimen. GVHD prophylaxis was provided with cyclosporine and mycophenolate mofetil. Fifteen patients experienced graft failure. The cumulative incidence of neutrophil and platelet recovery was 92 percent and 65 percent, respectively. TRM was 19 percent at 180 days and 26 percent at three years following transplantation. In this group of patients with a highly diverse spectrum of hematologic malignancies, overall and event-free survival rates at three years were 45 percent and 38 percent, respectively. This report firmly established the concept that a highly immunosuppressive non-myeloablative bone marrow conditioning regimen was capable of providing reliable engraftment from a mismatched unrelated UCB graft.
A subset analysis of the 65 patients with T and B cell lymphoma or Hodgkin lymphoma reported three-year rates of TRM, progression-free survival, and overall survival of 15, 34, and 55 percent, respectively [41]. These results are comparable to those achieved using non-myeloablative conditioning followed by matched sibling or matched unrelated donor grafts [43-45].
●The French Society for Blood and Marrow Transplantation and Cellular Therapy (SFGM-TC), in collaboration with Eurocord, reported a multicenter retrospective study of UCBT utilizing a regimen similar to the one used by the Minnesota group (cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2 and TBI 2 Gy) in 155 patients with acute and chronic leukemias (myeloid and lymphoid), myelodysplastic syndrome, Hodgkin lymphoma, and NHL with a median age of 47 years [38]. Two UCB units were infused in 59 patients (38 percent). The cumulative incidence of neutrophil engraftment was 80 percent. Autologous recovery occurred in 14 percent of patients. Grade III/IV GVHD and chronic GVHD were observed in 12 percent and 39 percent of patients, respectively. The TRM was 18 percent. These data are comparable to those reported by the Minnesota group and seem to confirm the feasibility of this transplant approach.
●A registry study from the European Blood and Marrow Transplantation (EBMT) group using data from Eurocord–Netcord included 104 patients with lymphoid malignancies who underwent UCBT, 64 of whom were transplanted with non-myeloablative conditioning [42]. The cumulative incidence of neutrophil engraftment was 84 percent by day 60. The cumulative incidence of relapse or progression was 31 percent, and the probability of progression-free survival was 40 percent at one year.
●A registry study from the Center for International Blood and Marrow Transplant Research compared outcomes among 584 patients with acute leukemia who underwent reduced intensity conditioning followed by a 7 or 8 of 8 HLA-matched PBPC transplantation or a 4 to 6 of 6 matched double unrelated UCBT (dUCBT) [34]. Patients who received Flu/Cy/TBI 200 cGy followed by a dUCBT had similar rates of TRM and overall mortality to those who received an 8 of 8 matched PBPC transplant, and lower TRM (but not overall mortality) than those who received a 7 of 8 matched PBPC. The probability of survival at two years after Flu/Cy/TBI cGy followed by a dUCBT was 38 percent. Survival at two years was lower for patients who underwent dUCBT following another conditioning regimen (eg, alkylating agent, fludarabine, with or without TBI).
●The Blood and Marrow Transplant Clinical Trials Network performed two parallel multicenter phase 2 trials using non-myeloablative conditioning followed by either double unrelated UCBT (50 patients) or partially HLA-mismatched (haploidentical) related bone marrow (50 patients) [2]. Patients who underwent Flu/Cy/TBI 200 cGy followed by UCBT had a median time to recovery of neutrophils >500/microL of 15 days (94 percent recovered by day +56) and a median time to recovery of platelets ≥20,000/microL of 38 days (82 percent recovered by day +100). Primary and secondary graft failure occurred in five patients and one patient, respectively, and two patients had autologous bone marrow reconstitution. Grade III/IV acute GVHD was seen in 21 percent and chronic GVHD occurred in 25 percent. One-year rates of non-relapse mortality and relapse/progression were 24 and 31 percent, respectively.
These encouraging observations were a result of selective ablation of the lymphoid cells using lymphotoxic agents, large progenitor cell doses and drugs to prevent host-versus-graft as well as GVHD. While the total numbers of mononuclear cells in UCB are limited, the progenitor content and the proliferative potential of cord blood cells are high. Non-myeloablative preparative regimens allow engraftment of the UCB stem cells, establishing full-donor chimerism with a lower risk of transplantation-related morbidity in older patients and in patients who are deemed unfit to undergo transplantation using conventional myeloablative preparative regimens.
The nature and extent of prior cytotoxic therapy is recognized as an important factor in the likelihood of donor stem cell engraftment following non-myeloablative bone marrow conditioning. It is assumed that patients carrying the diagnosis of acute leukemia or lymphoma will have had significant cytotoxic chemotherapy exposure prior to transplantation. In contrast, many patients with chronic phase chronic myeloid leukemia or myelodysplastic syndrome, and certainly those patients with non-malignant conditions, will enter UCBT with little or no prior cytotoxic therapy. Prior cytotoxic chemotherapy exposure is not specifically addressed in the published non-myeloablative UCBT studies to date. It should be noted that fewer than 5 percent of the patients in the largest of the prospective studies carried the diagnosis of myelodysplastic syndrome or non-malignant disorders [33,39]. Therefore, the likelihood of donor engraftment of the UCB stem cells following non-myeloablative conditioning may be considerably lower in the previously untreated subset of patients compared with what is reported in these studies. (See 'Choice of preparative regimen' above.)
Regimen intensity — The optimal intensity of non-myeloablative preparative regimens is uncertain, and several factors must be considered, including the aggressiveness of the underlying disease, the age of the patient and the immunocompetence of the recipients, and the genetic disparity between the donor and recipient. A wide range of non-myeloablative conditioning regimens has been employed. These regimens are designed not to eradicate the underlying malignancy but to provide sufficient immunosuppression to facilitate engraftment. The question posed is how immunosuppressed the patients need to be to overcome the risk of graft rejection. The benefit of reduced toxicity with non-myeloablative regimens may be offset by the loss of cytoreduction induced by high dose chemotherapy.
As noted above, the use of non-myeloablative UCBT has generally been less successful in aggressive malignancies that are likely to recur rapidly and outpace immune reconstitution. Given the increasing indication of applying non-myeloablative UCBT in older patients with refractory malignancies, future efforts may focus on the development of a more tolerable regimen that has broad anti-neoplastic and immunosuppressive activity that not only facilitates engraftment, but also provides some disease control. The challenge becomes greater when mismatched UCBT is used, where HLA disparity and lower cell dose is associated with higher risk of graft rejection. Further studies are necessary to define the best regimen that reduces the risk of rejection without increasing the risk of relapse and regimen-related toxicity. (See 'Choice of preparative regimen' above.)
Toxicity — Non-myeloablative preparative regimens are considered to have a better toxicity profile than myeloablative preparative regimens with less non-hematopoietic organ toxicity, improved immune reconstitution, and possibly less GVHD.
Immune reconstitution — Among patients undergoing bone marrow or mobilized peripheral blood progenitor cell transplantation, non-myeloablative preparative regimens have been associated with a more rapid reconstitution of T cell repertoire complexity than that seen following myeloablative preparative regimens [46]. There is a paucity of data regarding the immune reconstitution of UCB recipients following non-myeloablative preparative regimens. One study compared immune recovery in five recipients of UCBT following a non-myeloablative preparative regimen with recovery in adult recipients of UCB following a myeloablative regimen [47]. When compared with those receiving a myeloablative preparative regimen, patients receiving a non-myeloablative preparative regimen demonstrated the following:
●A shorter time to the recovery of normal absolute lymphocyte count (6 to 12 versus 24 months)
●Higher numbers of phenotypically naïve (CD45RA+) T cells at 12 months after transplantation with this rapidly expanding naïve population outnumbering the memory cells
●A markedly more diverse and robust T cell repertoire at similar time points
●Shorter time to recovery of thymic output and T cell reconstitution, as measured by T cell receptor excision circle (TREC; 12 months versus 18 to 24 months after transplantation)
The above study demonstrated that adults receiving a non-myeloablative preparatory regimen followed by UCBT have a rapid quantitative and qualitative recovery of peripheral T cells with a complex diversity. The ability of patients receiving non-myeloablative transplantation to recover within a few months suggests that the peripheral "niches" in which T cells can proliferate are preserved in these patients compared with those receiving myeloablative regimens. Moreover, the presence of TREC-positive cells within one year suggests that thymic recovery is likewise accelerated in recipients of non-myeloablative regimens compared with recipients of myeloablative regimens. These favorable results of T cell recovery suggest that it may be possible to have an excellent outcome with an unrelated mismatched UCBT in adult patients who are unable to undergo myeloablative conditioning. The primary difference between the recipients of myeloablative and non-myeloablative regimens is the extent of physiologic damage caused by the preparatory regimen. When the damage is relatively mild, as in non-myeloablative regimen, the donor T cells are able to expand effectively in the periphery and the development of new T cells through the thymus is also accelerated compared with the rate of development in those receiving ablative regimens. Alternatively, the lower incidence of GVHD in non-myeloablative UCBT may also play an important role in the preservation of the peripheral and central niches for T cell development.
Infection — Patients receiving UCBT following a non-myeloablative preparative regimen have a shorter period of neutropenia and more rapid immune reconstitution with more diverse T cell repertoire [47]. Whether the more favorable immune recovery can be translated into faster development of effective immune responses against opportunistic infections, and therefore improved transplantation outcome, remains to be determined in clinical trials.
Our clinical observations suggest that recipients of non-myeloablative hematopoietic stem cell transplantation may have different, but not necessarily decreased, risks for invasive bacterial, viral, and fungal infections. One of the main reasons is due to the employment of differing non-myeloablative or reduced-intensity regimens, and each of these regimens varies in its hematological and non-hematological toxicities. The risk of infection in both myeloablative and non-myeloablative allogeneic hematopoietic cell transplant recipients are dependent on the degree of immuno/myeloablation, severity of GVHD and its immunosuppressive therapies, as well as the rate of immune reconstitution. Preliminary results suggest that non-myeloablative conditioning regimens may decrease risks of bacterial infections associated with mucosal damage and persistent neutropenia; however, risks for late viral and fungal infections persist during severe GVHD [48].
Graft-versus-host disease (GVHD) — UCBT has been associated with a reduced risk of developing severe GVHD in children and adults, even when cells from partially HLA-mismatched donors are used. Non-myeloablative preparative regimens were introduced with the hope that patients would experience less GVHD following reduced intensity conditioning regimens. This was based on the hypothesis that less tissue injury would occur due to lower dose of cytotoxic agents and the induction of mixed chimerism could reduce the incidence of GVHD. However, GVHD remains the significant cause of morbidity and mortality following non-myeloablative conditioning. Previously published reports on non-myeloablative have shown a 38 to 60 percent incidence of grade II to IV of acute GVHD [33]. The early data suggest that the incidence of acute GVHD is somewhat lower compared with myeloablative regimens.
In addition, studies on immune recovery have shed some light of hope that patients undergoing non-myeloablative UCBT may experience less GVHD. These studies on immune reconstitution among patients receiving following UCBT and bone marrow transplantation have demonstrated the potential benefit of minimizing thymic damage through non-myeloablative conditioning. The early restoration of thymic function could allow early dominance of thymus-dependent phase and thus preventing the exclusive expansion of peripheral T cell clones. In addition, the increased level of T cell repertoire complexity observed in patients receiving non-myeloablative regimens may lead to increased numbers of alloreactive immunoregulatory cells such as those marked by CD4+CD25+ expression and thereby suppressing GVHD. Nevertheless, determining whether the incidence and severity of GVHD following non-myeloablative conditioning and UCBT is lower than myeloablative UCBT will require clinical trials in comparable groups of patients.
GVHD remains the leading cause of death among patients receiving non-myeloablative conditioning. Thus, optimizing the GVHD prophylaxis regimen is of paramount importance in improving the transplantation outcome. Although acute GVHD tends to be less severe after a non-myeloablative preparative regimen, it frequently occurs after the early termination of immunosuppressive therapy.
SUMMARY
●Umbilical cord blood (UCB), the blood remaining in the umbilical cord and placenta following the birth of an infant, has emerged as an established alternative source of hematopoietic stem cells in allogeneic hematopoietic cell transplantation.
●UCB transplantation (UCBT) has been performed in adults using both myeloablative and non-myeloablative preparative regimens. These approaches have not been compared directly in a prospective trial. As such, the ideal preparative regimen prior to UCB infusion is unknown and clinical practice varies by institution. For younger patients without comorbidities, we suggest a myeloablative preparative regimen such as those used in the initial studies of UCBT (Grade 2B). However, many older patients and patients with co-morbidities are not candidates for myeloablative preparative regimens due to high rates of morbidity and mortality with this approach. Non-myeloablative conditioning regimens are an acceptable alternative for such patients. (See 'Choice of preparative regimen' above.)
●Myeloablative UCBT is associated with an overall probability of engraftment between 80 and 90 percent. There is a significant delay in the time of neutrophil recovery, with the median time to absolute neutrophil count >500/microL ranging between 22 to 30 days. (See 'Efficacy' above.)
●Myeloablative UCBT can be associated with a transplant-related mortality (TRM) as high as 50 percent in adults, although studies using modern regimens suggest that TRM is decreasing. When compared with recipients of bone marrow or peripheral blood progenitor cells, adults receiving UCB have a higher risk of opportunistic infections for at least two years after transplantation, accounting for up to half of all treatment-related deaths. Despite a higher degree of HLA disparity, grade II to IV graft-versus-host disease (GVHD), especially chronic GVHD, is lower than in recipients of unrelated bone marrow or peripheral blood grafts from adult donors. (See 'Toxicity and transplant-related mortality' above.)
●Non-myeloablative UCBT is associated with an overall probability of engraftment between 80 and 90 percent. When compared with myeloablative regimens, there is a faster time to neutrophil recovery, with a median time to recovery of neutrophils >500/microL of approximately 15 days. (See 'Efficacy' above.)
●Non-myeloablative UCBT is associated with a non-relapse mortality rate of approximately 25 percent. Non-myeloablative preparative regimens are considered to have a better toxicity profile than myeloablative preparative regimens with less non-hematopoietic organ toxicity and improved immune reconstitution. Initial studies also suggest that patients undergoing non-myeloablative UCBT experience less GVHD. (See 'Toxicity' above.)
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