**2. Indications for hematopoietic stem cell transplants and the use of umbilical cord blood**

The indications for which allogeneic and autologous HSCTs are most often used have recently been provided as guidelines [28] from the American Society of Blood and Marrow Transplantation (ASBMT). **Table 1** summarizes those for allogeneic HSCT based on the published ASBMT disease categories and recommendations with more specific details discussed in, but without reference to, HSC source. This does not necessarily exclude their use for autologous HSCT and, where this is appropriate, this is also described in Ref. [28].




**Indication and disease status Pediatric <18 years Adult ≥18 years**

Chronic phase Yes Yes Accelerated phase Yes Yes Blast phase Yes Yes

Low risk Yes Yes High risk Yes Yes

Therapy related Yes Yes

Primary, low risk, and intermediate/high risk Yes Secondary Yes Hypereosinophilic syndromes, refractory Yes

Myeloma, sensitive relapse Yes Myeloma, refractory Yes Plasma cell leukemia Yes Relapse after autologous transplant Yes

CR1 Yes Primary refractory, sensitive Yes Primary refractory, resistant Yes First relapse, sensitive Yes First relapse, resistant Yes Second or greater relapse Yes Relapse after autologous transplant Yes

Primary refractory, sensitive Yes Primary refractory, resistant Yes First relapse, sensitive Yes First relapse, resistant Yes Second or greater relapse Yes Relapse after autologous transplant Yes

Myeloma, initial response In development

Juvenile myelomonocytic leukemia Yes

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CR1, high risk Yes CR2 Yes CR3+ Yes Not in remission Yes

**Chronic myeloid leukemia**

**Myelodysplastic syndromes**

**Plasma cell disorders**

**T cell non-Hodgkin lymphoma**

**Diffuse large B cell lymphoma**

**T cell lymphoma**

**Myelofibrosis and myeloproliferative diseases**



SCID, Severe combined immunodeficiency; IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked; MPS, mucopolysaccharidosis.

(Adapted with permission from [28]).

**Indication and disease status Pediatric <18 years Adult ≥18 years**

Primary refractory, resistant Yes First or greater relapse, sensitive Yes First or greater relapse, resistant Yes Relapse after autologous transplant Yes

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Relapse Yes Relapse after autologous transplant Yes

CR1 Yes Relapse Yes

High risk, first, or greater remission Yes T cell prolymphocytic leukaemia Yes B cell, prolymphocytic leukaemia Yes Transformation to high-grade lymphoma Yes

Breast cancer, metastatic In development Renal cancer, metastatic In development

Thalassemia Yes In development

Severe aplastic anemia, new diagnosis Yes Yes Severe aplastic anemia, relapse/refractory Yes Yes Fanconi's anemia Yes Yes Dyskeratosis congenita Yes Yes Diamond-Blackfan anemia Yes Yes Sickle cell disease Yes Yes

Mast cell diseases Yes

Common variable immunodeficiency Yes Wiskott–Aldrich syndrome Yes Yes Hemophagocytic disorders Yes Yes

Congenital amegakaryocytic thrombocytopenia Yes

Severe combined immunodeficiency Yes T cell immunodeficiency, SCID variants Yes

Germ cell tumor, relapse In development Germ cell tumor, refractory In development Ewing's sarcoma, high risk or relapse In development Soft tissue sarcoma, high risk or relapse In development Neuroblastoma, high risk or relapse In development

**Lymphoplasmacytic lymphoma**

**Cutaneous T cell lymphoma**

Plasmablastic lymphoma

**Solid tumors**

**Nonmalignant diseases**

**Chronic lymphocytic leukaemia**

**Table 1.** ASBMT guidelines for indications for allogeneic HSCT in pediatric and adult patients.

Allogeneic UCB HSCT may be used to treat blood disorders, cancers including hematological malignancies, and metabolic and immune disorders. **Table 2** shows a list of 95 diseases in adult and pediatric patients, which Cord:Use defines as being treatable with UCB HSCT [29]. A potential curative option for β-thalassemia is allogeneic HSCT from an HLA-matched sibling donor with reported disease-free survival of 65% in adults and 88% in children (reviewed in reference [30]). For severe sickle cell disease, similar transplants are reported to result in 85– 90% disease-free survival in children [31]. While allografts are usually curative for young patients with an HLA-matched sibling donor, this is not an option for the vast majority of patients with sickle cell disease. HLA-matched sibling directed UCB HSCTs (with or without preimplantation genetic HLA-matching), therefore, can provide curative therapies for children suffering from hemoglobinopathies [32, 33]. Better outcomes have also been reported in children transplanted with UCB HSCs in such metabolic disorders as Hurler syndrome, metachromatic leukodystrophy and Krabbe disease, and for congenital bone marrow failure and immunodeficiencies [4, 34–38].

#### **Cancers**

Hematological


#### Other


#### **Other blood disorders**


**•** Acute undifferentiated leukemia **•** Juvenile chronic myeloid leukemia **•** Chronic lymphocytic leukemia **•** Chronic myeloid leukemia **•** Juvenile myelomonocytic leukemia **•** Adult T cell leukemia/lymphoma

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**•** Hodgkin's lymphoma **•** Non-Hodgkin's lymphoma

**•** Mantle cell lymphoma **•** Burkitt's lymphoma

**•** Multiple myeloma

**•** Prolymphocytic leukemia **•** Plasma cell leukemia

**•** EBV lymphoproliferative disease

**•** Juvenile chronic myelogenous leukemia

**•** Chronic myelomonocytic leukemia

**•** Waldenstrom's macroglobulinemia

**•** Diamond–Blackfan anemia

**•** Essential thrombocythemia

**•** Congenital dyserythropoietic anemia

**•** Leukocyte adhesion deficiency syndrome **•** Paroxysmal nocturnal hemoglobinuria

**•** Congenital amegakaryocytic thrombocytopenia

**•** Fanconi's anemia **•** Severe aplastic anemia

**•** Polycythemia vera **•** Pure red cell aplasia

**•** Congenital cytopenia **•** Glanzmann's thrombasthenia

**•** Myeloid/natural killer cell precursor acute leukemia

**•** Lymphoma

**•** Thymoma

**•** Ewing sarcoma **•** Neuroblastoma **•** Rhabdomyosarcoma **•** Wilms tumor **Other blood disorders •** β-thalassemia major **•** Sickle cell anemia

Other


#### **Immune and metabolic disorders**


**Table 2.** Disease indications that may be treated with allogeneic cord blood transplantation based on information in [3, 5, 7, 29].

Graft failure and delayed immune reconstitution in UCB HSCT with myeloablative therapy are not without risk, and only 25% of the patients have a matched sibling donor. Lower UCB HSC engraftment rates have been observed where resistance to engraftment occurs (e.g., hemoglobinopathies, chronic myeloid leukemia, and acquired aplastic anemia, see Ref. [4]). Autologous UCB HSCTs have been less common than allogeneic transplants, but the recent development of novel genome editing technologies opens the way to using this new technology to correct certain inherited or acquired gene disorders in autologous HSCs and sourced from UCB at birth or alternatively from mobilized peripheral blood and bone marrow as appropriate, and to then transplant these cells into the affected individual to correct the disease. HLA matching of these grafts and hence GvHD has not, to date, been a problem for these autologous transplants. However, the use of myeloablative conditioning creates a substantial risk. Recently, studies in mice suggest that the risk of myeloablative conditioning can be greatly reduced by using CD45-saporin toxin conjugated antibody treatment to make space in the bone marrow for transplanted cells to treat sickle cell disease in the autologous setting without significant adverse effects on graft recovery [39], but this has not been conducted in the human. However, earlier studies using rat CD45 antibodies produced in Cambridge, UK [40, 41] have demonstrated the safety and efficacy of an 111In-labeled CD45 conjugate in bone marrow transplant patients with acute leukemia [42]. This may then provide a safer approach with gene-modified HSCTs for treating the β-globin-associated severe hemoglobinopathies, as well as congenital immunodeficiencies and HIV AIDS. While α-thalassemia affects the production of the α-globin chain in β-thalassemia and sickle cell disease, mutations in the β-globin gene result in absent or reduced β-globin and abnormal hemoglobin structure, respectively [43– 45]. Importantly, the inherited hemoglobin disorders, the thalassemias, and sickle cell disease constitute the most common monogenic disorders worldwide [43–47]. Around 300,000 children are born with sickle cell disease each year [43–47], and there are around 36.7 million people infected with HIV [48]. These conditions result in a reduced life expectancy and quality of life [48–53].

An analysis of European trends to 2014 [2] suggests a peak of allogeneic UCB HSCTs in 2012 and a slight decline since this time paralleling an increase in haploidentical HSCTs when combined with posttransplant cyclophosphamide prophylaxis. Two parallel Phase II clinical trials using haploidentical versus double UCB HSCTs in a reduced intensity conditioning regime setting indicate that the 1-year disease-free survival is similar (see [4]). A comparative trial of these two approaches is currently recruiting. In a recent review, Kurtzberg [54] cites higher relapse rates with haploidentical HSCTs for hematological malignancies in a limited number of studies.

The UK guidelines for alternative donor selection, dosages, and matching have recently been published [10] for pediatric and adult malignancy and bone marrow failure as well as pediatric immune deficiencies and metabolic disorders. Where UCB HSCTs are done, single UCB units are recommended unless there are insufficient cells when double UCB HSCT are considered, but with each unit having a total nucleated cell count of >1.5 × 107 for each unit per kg recipient body weight or a total CD34 cell dose >1.8 × 105 /kg, as viable cell dose infused is associated with engraftment outcomes [7, 8, 10]. There is no requirement for inter-UCB unit HLAmatching in the double UCB HSCT scenario at this time. Recent studies from Brunstein et al. [55] reviewed in Ref. [54] indicate that greater allele-level HLA mismatching of UCB HSCT between donor and recipient in a significant number of patients with hematological malignancy undergoing double UCB HSCTs could protect against disease relapse without affecting engraftment, GvHD, and nonrelapse mortality. In a further recent survey of UCB HSCT in older patients (50 years) presenting principally with acute myeloid leukemia, myelodysplasia, and non-Hodgkin lymphoma in Europe and North America, Rafii et al. [5] confirmed the efficacy of UCB HSCTs with reduced intensity conditioning in these patients. Further studies on donor selection are warranted. However, leukemic relapse is a major cause of mortality in HSCT recipients, and this must be taken into account in donor selection strategies.

Although there is the potential for autologous UCB HSCTs to rise substantially with new technological developments in the treatment of inherited monogenic diseases and acquired immunodeficiencies such as HIV and AIDS, current indications for autologous UCB use are low or are in development. The main use of autologous UCB grafts (82%) has been for brain injury, and as described in Ref. [4], this includes cerebral palsy, ataxia, apraxia, traumatic brain injury, hypoxic ischemic encephalopathy, and periventricular leukomalacia [56, 57]. Autologous UCB transplants (7%) have been used in clinical trials to treat type 1 diabetes but responses were transient [4, 58, 59].
