1 Introduction

Umbilical cord blood transplantation (UCBT) from unrelated donors is a suitable option of HSCT for patients in whom it is indicated, and a suitable related or unrelated BM or PB donor is not available in due time.

Since the 1990s, the majority of UCBT have been performed in children, but the number in adults was growing steadily. In fact, since 2004 the number of UCBT in adults registered in Eurocord was higher than in children. However, a certain decline in the UCBT activity has been observed over the last few years, which is mainly due to an increasing activity of partially matched related (haploidentical) HSCT. It should be noted that, although both options compete in the same niche, their comparative data are very limited and randomized studies are not yet available. As far as we know, two phase III randomized studies are currently ongoing to compare UCBT and haplo-HSCT in the RIC and MAC setting (NCT0159778 and NCT02386332, respectively).

2 Potential Advantages and Disadvantages of UCBT

UCBT versus BMT/PBSCT

Advantages

Disadvantages

• Expanded access to transplanta

 – Higher availability of donora

 – Faster search and shorter time to transplanta

 – Greater HLA disparity allowed with low incidence of GVHDa

• Lower risk of transmission of viral infections

• More versatile transplant planninga

• No risk of donor refusal

• No risk to the donor

• Slower engraftment

• Higher risk of non-immunological rejection (graft failure)

• Remote possibility of transmission of a genetic diseaseb

• Greater delay in immune reconstitution

• No possibility of donor lymphocyte infusionb

  1. aAdvantages shared with haplo-HSCT
  2. bDisadvantages not shared with haplo-HSCT

Similar to UCBT, haplo-HSCT can also be used on an urgent basis and extends donor availability to the vast majority of patients. In addition, haplo-HSCT allows a DLI if necessary. Unfortunately, comparative data of these two approaches are limited and inconclusive (Brunstein et al. 2011; Ruggeri et al. 2015), and randomized studies are still lacking.

3 Indications

Except for some patients with severe BMF, such as aplastic anemia and paroxysmal nocturnal hemoglobinuria, UCBT in adults is performed almost exclusively in patients with malignant hematological diseases. However, UCBT in children has been used for many other nonmalignant diseases, including primary immunodeficiency diseases and inherited metabolic disorders (see Eurocord experience in Table 64.1).

Table 64.1 Distribution by diseases of UCBT registered in Eurocord (1994–2017)
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The American Society for Blood and Marrow Transplantation (ASBMT), EBMT, and British Society of Blood and Marrow Transplantation (BSBMT) have recently published their respective guidelines that include recommendations for transplant indications in children and adults. It should be noted that the ASBMT did not differentiate recommendations for transplant indications based on donor source (i.e., MRD, URD, UCB, or haploidentical donor) or graft source (i.e., BM, PBSC, or UCB). This is in contrast to guidelines published by the EBMT and BSBMT.

4 Approaches to Improve Outcomes After UCBT

Apart from refining criteria for UCB unit selection and optimization of conditioning regimens, several strategies have been developed aiming to shorten the time to engraftment and decrease NRM.

Approaches to improve outcomes of UCBT

Expert point of view

(a) Refining criteria for UCB unit selection

See Chap. 18 of banking, processing, and procurement of cord blood cells

(b) Optimization of conditioning regimens

Specific conditioning regimen can influence transplant outcomes. See Sect. 64.5

(c) Strategies aiming to shorten the time to engraftment

To date none of these strategies have consistently shown to improve outcomes over single unmanipulated UCBT

 1. Double UCBT

– In children, two randomized trials have demonstrated no benefit and increased risk of GVHD (Wagner et al. 2014; Michel et al. 2016)

– In adults, retrospective studies showed no advantage when single-unit with TNC dose >2.5 × 107/kg available (Scaradavou et al. 2013)

 2. Co-infusion with third-party cells

Has consistently demonstrated benefit to accelerate hematopoietic recovery. No proved benefit on NRM or survival (Sanz et al. 2017)

 3. Ex vivo expansion of UCB cells

Promising early studies showing fast engraftment with different expansion techniques. No comparative studies or long-term data (Mehta et al. 2017)

(d) Improvement of supportive measures

Supportive care to prevent or treat opportunistic infections until neutrophil and immune recovery has occurred which is critical in UCBT. See Sect. 64.7

5 Conditioning Regimens

The selection of conditioning regimen for HSCT, including UCBT, should take into account the risk of toxicity and the risk of graft failure and relapse in malignant diseases. In UCBT, given the relatively lower cell dose (T-cells and CD34+ cells) and the use of HLA-mismatched grafts, graft failure is of particular concern, especially in adults. The choice of the conditioning regimen is as important as the graft characteristics and can influence transplant outcomes (Ruggeri et al. 2014).

In fact, specific conditioning regimens seem to tolerate infusion of lower cell doses in the graft (Sanz et al. 2013). A comprehensive and exhaustive review of MAC and non-MAC/RIC regimens in the UCBT setting has recently been published (Ross and Gutman 2017).

The Sorror comorbidity index may be a helpful tool to choose the appropriate conditioning intensity for a given patient. Some conditioning regimens options of varying intensity are to be considered:

Myeloablative conditioning regimens (MAC)

Chemotherapy-based

• Adults: TBF regimen (Sanz et al. 2012)

TT 10 mg/kg + IV BU 9.6 mg/kg + FLU 150 mg/m2 + ATG 6 mg/kg

• Children: FTT regimen (Hough et al. 2016)

• BF regimen (Admiraal et al. 2015)

TREO 30–42 g/m2 + FLU 150 mg/m2 + TT 10 mg/kg

BU (PK guided) + FLU 160 mg/m2 + ATG 19 mg/kg

TBI-based

• TCF regimen (Barker et al. 2005)

TBI 13.2 Gy + CY 120 mg/kg + FLU 75 mg/m2

Medium-intensity conditioning regimens (MIDI)

• MIDI regimen (Barker et al. 2017)

TT 10 mg/kg + CY 50 mg/kg + FLU 150 mg/m2 + TBI 4 Gy

Reduced-intensity conditioning regimens (RIC)

• rTCF regimen (Brunstein et al. 2007)

TBI 2 Gy + CY 50 mg/kg + FLU 200 mg/m2 ± ATG

6 GVHD Prophylaxis

The most important advantage of UCB over unrelated donor grafts is the capability to tolerate HLA disparities and facilitate a low incidence of chronic GVHD. However, acute GVHD is still one of the most important contributors to morbidity and mortality. Different GVHD prophylaxis regimens have been explored with no evidence of benefit of any specific strategy. MTX is generally not recommended to avoid myelotoxicity and delayed neutrophil recovery although it is widely used in Asia. The most frequently used regimen worldwide is the combination of CNI for 6–9 months with MMF for 2–6 months.

The use of in vivo TCD with ATG is controversial. ATG in the conditioning regimen has been used to enhance myeloid engraftment as well as to prevent GVHD. Its use has been associated with reduced rates of GVHD. However, although there is no evidence of a negative impact on NRM (Ponce et al. 2015), there is a concern of impaired immune reconstitution and increased viral infections (Chiesa et al. 2012). Recent data suggest that safety of ATG can be improved by adjusting dose with ATG pharmacokinetics (Admiraal et al. 2016).

7 Supportive Care

The supportive measures described below are not intended to be recommendations but only to be taken into account and to consider their use in the context of each institution’s own experience and epidemiology. The most common measures are described merely as a guide since they have a very variable level of evidence (see Table 64.2).

Table 64.2 Prophylaxis, monitoring, and treatment options to be considered for infections in UCBT
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8 Results (See Table 64.3)

UCBT outcomes have improved in more recent years, probably explained by better patient and CBU selection, improved conditioning, and supported care. Registry data also showed important center effect with superior survival obtained in experienced centers. Eurocord recently updated clinical results.

Table 64.3 Expected results overall survival at 2 years after UCBT
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Multiple retrospective studies have demonstrated that UCBT offers similar long-term outcomes compared with the gold standard of HLA-matched URD transplants in patients with hematologic malignancies, both in children and adults (Eapen et al. 2007; Brunstein et al. 2010; Atsuta et al. 2012). Interestingly, UCBT seems to offer a potent antileukemic efficacy, through yet unknown mechanisms. A recent report that needs to be validated suggested a markedly reduced relapse rate after UCBT as compared to URD transplantation in patients transplanted with MRD (Milano et al. 2016).

Key Points

  • UCB remains a rapidly available and valuable source of stem cells for HSCT.

  • In the absence of a fully matched donor available at an appropriate time, similar outcomes are achieved with CBT, MMURD, and haplo-HSCT approaches in the pediatric and adult setting.

  • CBT may reduce relapse following HSCT for AML.

  • There is a much room for improvement in the field and important progresses are expected in the near future. Decrease in NRM should be the number one goal in future research.

  • Strategies to enhance engraftment and, more importantly, approaches to improve immune reconstitution, such as appropriate ATG dosing, are warranted.