An increasing number of agents with variable immunosuppressive, myelosuppressive and anti-malignancy activity have broadened the options for conditioning regimens for haematopoietic stem cell transplantation (HCT). Disease type and remission status, as well as patient age and comorbidities, are important considerations in optimizing HCT regimens. Additional considerations relevant to cord blood transplantation (CBT) include the possibility of delayed time to neutrophil and platelet engraftment, concerns about delayed acquired immune reconstitution, and the increased potential for graft failure. While a variety of factors contribute to the incidence of engraftment following CBT and include cell dose, degree of human leucocyte antigen (HLA) matching, prior treatment and post-grafting immunosuppression, the conditioning regimen is critically important. A summary of reported CBT conditioning regimens is provided in Table I.
Total body irradiation (TBI)-based regimens
High dose total body irradiation (TBI) has been the cornerstone of most myeloablative CBT conditioning regimens used to treat haematological malignancies. In many large series reporting outcomes on patients undergoing CBT in the late 1990s and early 2000s, either all patients (Wagner et al, 2002; Takahashi et al, 2007; Kurtzberg et al, 2008) or the majority of patients (85% and 76%) (Laughlin et al, 2004; Eapen et al, 2007) received conditioning with fractionated TBI, ranging in intensity between 12 Gy and 13·75 Gy. In subsequent series reporting on patients transplanted more recently, many of which involved fewer patients, TBI continued to be the backbone of most myeloablative conditioning regimens (Barker et al, 2005a; Okada et al, 2008; Ooi et al, 2008, 2009; Yamada et al, 2008; Atsuta et al, 2009). Given the heterogeneity of diseases treated in these reports, differences in age of patients, evolving standards for infused cell doses and degree of HLA matching, as well as varying additional therapies used in conjunction with TBI, it is not possible to draw conclusions regarding optimal TBI dose, dose rate, or fractionation schema.
Optimal therapies to accompany TBI have evolved and remain an area of active investigation. In earlier series, 120 mg/kg of cyclophosphamide (CY) and 90 mg/kg of equine anti-thymocyte globulin (ATG) were commonly incorporated into regimens (Wagner et al, 2002; Kurtzberg et al, 2008). More recently, however, the University of Minnesota has replaced ATG with 75 mg/m2 fludarabine (FLU) (Barker et al, 2005a). Though it is uncertain the extent to which this change, along with a change in post-transplantation immunosuppression from ciclosporin (CSA) and methylprednisolone (MP) to CSA and mycophenolate mofetil (MMF), has contributed to improvements in outcomes reported by the University of Minnesota (Barker et al, 2008), the combination of 13·2 Gy TBI, 120 mg/kg CY and 75 mg/m2 FLU has now emerged as a standard myeloablative conditioning regimen at many centres, including ours. Other centres have investigated regimens including 12 Gy TBI, 120 mg/kg CY and high dose (8–12 g/m2) cytosine arabinoside (Ara-C) (Ooi et al, 2008, 2009; Yamada et al, 2008) as well as 12 Gy TBI, 150 mg/m2 FLU and 10 g/m2 Ara-C (Okada et al, 2008) and 12 Gy TBI, 24 g/m2 Ara-C, 90 mg/m2 FLU and G-CSF (Tomonari et al, 2006).
Small patient numbers prevent drawing conclusions regarding the relative efficacy of these conditioning regimens for particular diseases, however they all appear to provide adequate immunosuppression to promote engraftment. As long as cell dose and HLA matching thresholds are met, more recent series consistently report >90% engraftment rates following myeloablative TBI-based conditioning (Barker et al, 2005a; Okada et al, 2008; Ooi et al, 2008, 2009), however, the toxicity of TBI-based regimens limits their widespread use. A recent Japanese report describes comparable outcomes among CBT patients with no marked organ dysfunction aged 50–55 years receiving 12 Gy TBI-based conditioning regimens versus younger patients receiving similar regimens (Konuma et al, 2009), however, the toxicity of TBI increases with age. At our centre, the current upper age limit for our TBI-based CBT conditioning regimen is 45 years. Additionally, younger patients who have received significant prior irradiation during therapy are not eligible.
Non-TBI based regimens
Development of non-high dose TBI-based conditioning regimens is an area of active investigation, with the goals of retaining potent anti-malignancy potential and reducing the toxicity of high dose TBI while establishing regimens that remain sufficiently immunosuppressive to ensure engraftment.
The literature concerning high intensity non-TBI based regimens is limited. Busulfan (BU) has been a cornerstone of many high dose non-TBI based allogeneic transplant regimens, particularly for the treatment of acute myeloid leukaemia (Santos et al, 1983; Tutschka et al, 1987). In the CBT setting, however, the available data raises concerns about the engraftment potential of BU-based regimens. While BU might be myeloablative and stem cell ablative at higher doses, it has limited toxicity against mature lymphocytes and is not markedly immunosuppressive (Peters et al, 1987). In a recent report from the Duke University School of Medicine group, eight of ten patients experienced primary or secondary graft failure following conditioning with 520 mg/m2 intravenous (IV) BU (median daily area under the curve 4225 μmol-min) and 160 mg/m2 FLU (Horwitz et al, 2008). Similarly, at the MD Anderson Cancer Center, only 6/11 CBT patients conditioned with pharmaco-kinetically guided IV BU/FLU engrafted (Ciurea & Andersson, 2009). In an arm of the Cord Blood Transplantation Study (COBLT) investigating a non-TBI based regimen among infants and young children, BU targeted to 600–900 ng/ml, 135 mg/m2 melphalan (MEL) and equine ATG 90 mg/kg was associated with a cumulative incidence of engraftment of only 59% (Wall et al, 2005). In their initial efforts at developing a reduced intensity conditioning (RIC) CBT regimen, the University of Minnesota group used 8 mg/kg BU, 200 mg/m2 FLU and 2 Gy TBI. In addition to patients experiencing prolonged neutropenia following this conditioning regimen, four of 21 patients experienced graft failure, leading to the replacement of BU with 50 mg/kg of CY (Barker et al, 2003). BU-based regimens have also been described in several large European series, but these reports also included large proportions of patients receiving TBI-based regimens. Because outcomes analyses are not stratified according to conditioning regimens, interpreting the relative efficacy of different conditioning regimens is challenging (Locatelli et al, 1999; Rocha et al, 2000, 2001, 2004; Michel et al, 2003; Kögler et al, 2005; Arcese et al, 2006).
Addition of further immunosuppressive agents to BU-based regimens may facilitate engraftment, but raise concerns about regimen-related toxicities and further delaying immune reconstitution following CBT. Sanz et al (2007) presented encouraging preliminary data regarding the efficacy of 9·6 mg/kg IV BU, 10 mg/kg thiotepa, 150 mg/m2 FLU and 8 mg/kg ATG as a myeloablative regimen capable of promoting engraftment without excessive toxicity. Among 73 consecutive patients with a median follow up of 7 months, the cumulative incidence of engraftment, which occurred at a median of 22 d, was 89%, and day-180 transplant-related mortality (TRM) was 20% (Sanz et al, 2007). At our centre, we have recently initiated an investigation of a treosulfan (TREO)-based conditioning regimen including 42 g/m2 TREO, 150 mg/m2 FLU and 2 Gy TBI. A BU analogue, TREO is a novel agent that in vitro data suggests may have more potent anti-leukaemic and immunosuppressive intensity than BU, and early clinical experience suggests it may be less toxic. Encouraging preliminary data on TREO-based regimens has been reported in the non-CBT allogeneic transplant setting (Casper et al, 2004; Holowiecki et al, 2007; Nemecek et al, 2008).
Melphalan (MEL), dosed at varying intensities, has also been explored in several smaller studies of non-TBI based regimens. Similar to high dose BU/FLU regimens, high dose MEL/FLU regimens may not be sufficiently immunosuppressive to ensure engraftment. Narimatsu et al (2008) reported only a 60% engraftment rate in 10 recent patients conditioned with 180 mg/m2 MEL and 120 mg/m2 FLU. The addition of either ATG or low dose TBI may, however, be sufficient to promote engraftment in MEL-based regimens; regimens including 180 mg/m2 FLU, 100 mg/m2 melphalan (MEL) and 6 mg/kg rabbit ATG (Ballen et al, 2007) and 125 mg/m2 FLU, 80 mg/m2 MEL and 4 Gy TBI (Miyakoshi et al, 2004) have been associated with engraftment rates >90%. There is insufficient data to determine the relative efficacy of MEL-based regimens versus BU-based regimens with regard to disease-specific relapse or overall TRM.
Beyond establishing non-TBI based regimens with potent anti-leukaemic potential, establishing minimally intensive conditioning regimens suited to older patients or patients with significant comorbidities is an important goal in CBT. While as little as 2 Gy TBI is sufficient to promote engraftment following matched related peripheral blood transplants (McSweeney et al, 2001), the minimum necessary therapy to promote engraftment following CBT is not certain. The University of Minnesota has pioneered a regimen of 200 mg/m2 FLU, 50 mg/kg CY, 2 Gy TBI ± 90 mg/kg equine ATG that has established benchmark outcome expectations for minimally intensive RIC CBT (Brunstein et al, 2007). In a series of 110 patients, median age 51 (range 17–69) years, with heterogeneous haematological diseases, investigators observed a 45% 3-year overall survival, 26% 3-year incidence of TRM and 31% 3-year incidence of relapse. Patients who had received less than two cycles of multiagent chemotherapy within the 3 months before enrollment (and had no history of autologous transplant) were deemed at higher risk for graft failure and received ATG in their conditioning regimen. Primary neutrophil recovery occurred in 92% of patients at a median of 12 d and the cumulative incidence of sustained engraftment (neutrophil recovery with complete chimaerism) was 85% (95% confidence interval, 77–92%). In univariate analysis, ATG was associated with increased TRM, while on multivariate analysis ATG was associated with a lower risk of acute graft versus host disease (GVHD). In a subsequent analysis, the University of Minnesota group confirmed the safety of this regimen in patients older than 55 years (Majhail et al, 2008). Important questions raised by the University of Minnesota experience include whether further dose reductions might be possible to establish a more minimally intensive regimen for heavily pretreated patients and, given concerns about immune reconstitution in the CBT setting, whether ATG might be replaced with alternative dose escalations in patients deemed at higher risk for graft failure. At our centre, we are currently investigating the possibility of replacing ATG with small increases in TBI.
Disease targeted conditioning
Limited data exists regarding conditioning regimens targeted to specific disease types in the CBT setting, but developing such regimens should be an important goal. A growing body of literature supports the efficacy of CBT using minimally intensive regimens to treat low and intermediate grade lymphoid malignancies (Majhail et al, 2006a; Brunstein et al, 2009; Rodrigues et al, 2009). Promising novel therapeutics for lymphoma, including immunotherapeutic and radioimmunotherapeutic agents might be incorporated into novel conditioning regimens targeting specific diseases, and post-transplant maintenance therapy may further improve outcomes. Similarly, for Philadelphia chromosome positive acute leukaemias, tyrosine kinase inhibitors have already shown promise in post-transplant maintenance after conventional transplantations (Carpenter et al, 2007) and require examination in the cord blood setting. As additional molecular aberrations are identified in specific acute leukaemias, the potential benefit of targeted therapies (i.e. FLT3 inhibitors in FLT3 mutated patients), used either in the conditioning regimen or as maintenance therapy, also warrants evaluation.