- Email: [email protected]
Topping it up: methods to improve cord blood transplantation outcomes by increasing the number of CD34+ cells
Cytotherapy, 2015; 0: 1e7
Topping it up: methods to improve cord blood transplantation outcomes by increasing the number of CD34D cells
CAROLINE A. LINDEMANS1 & KOEN VAN BESIEN2 1
Pediatric Blood and Bone Marrow Transplantation Program, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands, and 2Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA Abstract Cord blood is increasingly recognized for its excellent stem cell potential, lenient matching criteria, instant availability and clinical behavior in transplants when cell dose criteria can be met. However with 1e2 log fewer total (stem cell) numbers in the graft compared with other cell sources, the infused cell dose per kilogram is critical for engraftment and outcome, creating the need for development of stem cell support platforms. The co-transplant platforms of haplo cord and double unit cord blood (DUCB) transplantation are aimed toward increasing stem cell dose. Together with the optimization of reducedintensity protocols, long-term sustained engraftment using cord blood has become available to most patients, including elderly patients. Haplo cord has a low incidence of both acute and chronic graft-versus-host disease but may require antithymocyte globulin ATG for effective neutrophil recovery. DUCB can be performed without anti-thymocyte globulin with excellent immune reconstitution and disease-free survival, but engraftment is considerably slower, and graft-versus-host disease incidence significant. Both haplo-cord and DUCB transplantation appear to both be valid alternatives to matched unrelated donors in adults.
Introduction Unrelated cord blood (UCB) has been established as an important source of hematopoietic stem cells (HSCs) for allogeneic hematopoietic stem cell transplantation (HSCT) when human leukocyte antigen (HLA)-matched sibling and unrelated donors (MUD) are unavailable. Less stringent matching and instant availability are important advantages over conventional grafts. However, UCB transplantation (UCBT) has been associated with delayed engraftment, contributing to prolonged susceptibility to infectious complications [1]. Despite this delay in count recovery, a recent study shows comparable long-term outcome of UCBT and conventional grafts [2,3]. In some studies, an increased rate of treatment-related mortality is offset by lower rates of leukemia recurrence [2,4]. The mechanism of the enhanced graft-versus-leukemia (GVL) effect with UCBT is unknown. One hypothesis relates to GVL effects caused by maternal cells contaminating the UCB graft [5]. Others have
speculated that in double UCB (DUCB) transplant, graft versus graft effects contribute to GVL effects [6]. UCB has a high percentage of stem cells that are functionally highly proliferative and have increased migratory capacity [7,8]. As such, UCB has the intrinsic capacity to be an excellent cell source for cell recovery. This is illustrated clinically by excellent single UCB transplantation outcomes in pediatric cohorts where cell dose is high and engraftment can be as fast as 17 days with graft failure rates <5% [9]. However, with 1e2 log fewer CD34þ HSC available in a cord blood (CB) graft than in an unrelated bone marrow or peripheral blood stem cell (PBSC) graft, the infused total nucleated cell (TNC) dose/kg and/or CD34þ cell dose/kg has been proven to be critical for UCBT outcomes [10,11] with overall significantly better outcomes if the TNC is >3.0 10 e7/kg [12]. With lower cell doses, the risk for delayed neutrophil recovery and for early complications is increased. When complying with guidelines for CB selection, the incidence of infectious complications after CBT is
Correspondence: Caroline A. Lindemans, MD, PhD, KE04.133.1, Wilhelmina Children’s Hospital, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: [email protected] (Received 28 November 2014; accepted 5 February 2015) ISSN 1465-3249 Copyright Ó 2015, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2015.02.005
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comparable to other donor sources both for children and adults [13e15]. However, finding both a large cell dose and a well-matched cord blood unit is challenging, particularly for ethnic minority patients. Consequently, transplantation centers have been attempting various approaches to the CB transplant protocol to maximize the CD34þ HSC dose infused to patients receiving CB. Here we discuss DUCB and third-party donor (TPD) cell confusion. As an alternative, ex vivo CB expansion techniques are discussed elsewhere in this issue. DUCB transplantation The first DUCB transplantation was performed in 2001 in Minnesota with the aim of doubling cell dose and optimizing engraftment; it has since become widely used. In 2009, Eurocord published criteria for cell dose, advising to infuse two units if cell dose can otherwise not be met. Some studies of DUCB show engraftment as early as 12 days [16] with also reports as late as 36 days [17]. Within cohorts, there is considerable variability among subjects, and it is impossible to exactly predict engraftment in an individual patient. After initial combined engraftment, over time one cord usually outcompetes the other, leading to durable CB engraftment of only one of the two donors. The better the units match among each other, the slower the observed switch to full single cord chimerism [18]. Further fine-tuning of CB choice toward HLA or killer cell immunoglobulin-like receptor (KIR) type to potentially improve outcomes is impossible because as of yet, no pre-transplant graft characteristics have been identified to predict which of the two grafts wins [19]. DUCB transplantation has been widely used as an alternative to unrelated donor marrow or PBSC transplantation. Malard et al. show a benefit of DUCB over 9 of 10 mismatched MUD in 152 reducedintensity (RIC) allo-SCTs, with comparable survival but significantly lower incidence of chronic graftversus-host disease (GVHD) in DUCB [20]. In addition, Brunstein et al. showed DUCB to be a valid alternative compared with matched related and unrelated donors with similar 5-year disease-free survival of DUCB transplants in their two-center analysis of 536 transplantations. They observed a decrease in relapse in DUCB, which was compensated for by a slight increase in transplant-related mortality with DUCB [2]. The role of these graft-versus-graft effects giving DUCB transplants an additional graft versus leukemia advantage is focus of widespread investigation, with conflicting results in some other cell source comparison studies. Chen et al. described the DUCB and unrelated (bone marrow/PBSC) donor transplants at Dana-Farber and Massachusetts General Hospital between 2004 and 2008 and found DUCB
to be associated with higher transplant-related mortality without an advantage for progression-free survival [21]. Others, however, have also shown decreased rates of relapse with single UCB stem cell transplant [4,12], and recent multicenter studies, including a prospective randomized comparison, have not shown any advantage comparing myeloablative single CBT with DUCB [15,22]. Originally, DUCB was performed using a myeloablative approach that was either busulfan-based or total body irradiation (TBI)-based (1000e1200 cGy) and included serotherapy (i.e., usually ATG). More recently, DUCB RIC protocols have been introduced for transplantation of older adults. Commonly used RIC protocols are fludarabine 150 mg/m2 þ cyclophosphamide 200 mg/kg and TBI (400 cGy) [17] or Flu150 mg/m2 þ Cy 200-TBI (200 cGy) [23]. Memorial Sloan Kettering Cancer Center (MSKCC) has performed DUCB with a slightly more intensified RIC conditioning without ATG, adding thiotepa 10 mg/kg to Cy 50/Flu 150/ TBI (400 cGy) conditioning to ensure engraftment and to obtain full donor chimerism with the aim of preventing relapse [24]. There is ongoing debate over the role of ATG in UCBT. Omission of ATG decreases the risk of posttransplant lymphoproliferative disorders (PTLD) [25] and of post-transplant viral infections [26], but it is associated with a considerable risk of GVHD: around 50e55% grade IIeIV for RIC protocols [17,24] and 64% for myeloablative protocols [27] with a high incidence of gut GVHD. Early cytomegalovirus (CMV) infections remained challenging even without ATG [28]. An intensive CMV prophylaxis protocol with pre-transplant ganciclovir and long-term high-dose acyclovir has become standard of care in Weil Cornell Medical Center (WCMC), New York, is well tolerated, appears to significantly reduce CMV reactivations and may find a more widespread implementation in the future [29,30]. Haplo-CB transplantation Supplementing a CB unit with HSCs from adult donors is another approach to augment stem cell dose. The original concept of combined TPD and CB transplants is to provide early myeloid engraftment from the TPD-HSCs until sustainable CB-derived engraftment can be achieved, thereby shortening the neutropenic period to a few days. Following peripheral blood collection from a granulocyte colony-stimulating factor mobilized adult donor, 3e5 10e6 CD34þ cells/kg, positively selected usually using the Miltenyi CliniMACs CD34þ selection column, are infused together with a single UCB unit.
Double cord and haplo cord transplantation platforms The infusion of UCB with CD34þ selected cells from an adult (mostly related haploidentical) donor, was originally performed in 1999 by Fernandez et al. in Spain with the goal of finding a donor solution for more patients with an indication for HSCT but without a conventional donor available. By increasing cell dose in this way, he observed rapid hematopoietic recovery from adult donor cell origin that is replaced over time by complete CB chimerism. They recently reported the outcomes of the 132 haplo-cord transplants performed since that time [31]. Neutrophil engraftment was 95% at 40 days (95% confidence interval, 89e98%) with a median time of 11.5 days. The cumulative incidence of platelet recovery was 78% at 100 days (95% confidence interval, 71e85%) with a median of 36 days. Transplants were performed after a myeloablative conditioning, which consisted of thymoglobulin 4 mg/ kg and fludarabine 120 mg/m2, cyclophosphamide 120 mg/m2 and busulfan 12.8 mg/kg or a regimen that included TBI (1000 cGy) in most cases. GVHD prophylaxis was cyclosporine A from day e5 until engraftment (or day þ50) and steroids 1e2 mg/kg from day e2 until day 14. The lower limit for CB units used in their protocol is 1.5 10e7 nucleated cells/kg recipient. Graft failure rates were 2% for failure of both grafts and 9% specifically for failure of the CB donor with persistence of the haplo donor. In Chicago, we pioneered combined TPD CB transplants with an RIC regimen. In an initial publication, we reported a median time to neutrophil engraftment of 11 days (interquartile range 9e15) and to platelet engraftment of 19 days (interquartile range 15e33) [32]. Similarly to the Spanish group, early TPD engraftment was replaced by durable engraftment of the UCB by 100 days in the majority of patients. In contrast to the Spanish group, we only used related third-party (haplo-) donors. This protocol has been continued with minor adjustments in a collaboration between University of Chicago and WCMC, New York. Currently, patients transplanted with haplo cord receive a commonly used pretransplant conditioning regimen consisting of fludarabine (cumulative dose 125 mg/m2 in 5 days), melphalan (140 mg/m2) and Thymoglobulin (1.5 mg/kg for 4 consecutive doses in patients under age 50 and 3 consecutive doses for patients over 50). Post-transplant GVHD prophylaxis consists of tacrolimus until day 180 and mycophenolate mofetil (MMF) three time daily until day 28 (and then twice daily until day 60). Significantly higher CD34 cell doses >5 106/kg from the haplo donor are avoided because they have been associated with failure of the CB graft. We have studied the lowest threshold for the CB unit in the haplo cord platform in a prospective dose reduction
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protocol [33]. In successive cohorts with decreasing cell dose, the minimum acceptable UCB nucleated cell dose was studied. Cell doses as low as 0.5 10e7 nucleated cells/kg were followed by durable engraftment of the CB. Limiting cell doses of the UCB unit may provide an opportunity to identify better matching units and thus improve long-term outcomes [34]. Consistent between the myeloablative regimen of the Spanish study and the RIC regimen of Chicago/ WCMC studies are the rapid engraftment and the low rate of acute (<15e25%) and chronic GVHD. For these cohorts of high-risk leukemia patients, nonrelapse mortality was 35% in the Spanish and 28% for the Chicago/WCMC cohort [31,32,35]. Both cohorts have looked at post-transplant immune reconstitution, which is consistent with full in vivo depletion of the CB (ATG) with T-cell recovery dependent on thymic output no earlier than 6 months post-HSCT [29,31]. We compared the 99 patients transplanted in Chicago/WCMC with haplo cord after the Flu/Mel/ ATG conditioning with matched DUCB transplants (1:4) from the Center for International Blood and Marrow Transplant Research registry [36]. In multivariate analysis significant differences were observed for neutrophil (91% versus 72%) and platelet engraftment (53% versus 6%) by day 30 (Figure 1). Survival was superior after haplo cord at all time points, but the survival advantage became more pronounced over time at 4 years post-SCT with 43% versus 21% alive, even though there were slightly higher-risk disease patients in the haplo-cord group (44% versus 34%). Taking advantage of the rapid engraftment characteristics of the haplo-cord platform, patients with ongoing infection, with indications associated with difficult engraftment and or patients with previous graft failure might be particularly likely to benefit. The group at the National Institutes of Health transplanted 16 patients with severe aplastic anemia (SAA), an indication notorious for its high risk of graft failure. They report a median of 10 days for haplo-derived neutrophil engraftment and of 22 days for platelet engraftment [37]. At a median follow-up of 570 days (range 55e1826 days) in 12 of 16 patients, a switch to full CB myeloid chimerism was reported, with persistent mixed chimerism in two and sustained engraftment of the haplo donor in the other two. It was observed that in all those without any CB engraftment (n ¼ 2) and those with only partial CB chimerism by day 400 (n ¼ 3), a haplo versus CB KIR mismatch existed, whereas a KIR mismatch in the haplo-versus CB direction was present in only 27% of the patients who were fully CB engrafted by day 400. It was suggested that haplo
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Figure 1. Engraftment outcomes (A, neutrophils; B, platelets) of a case-control comparison study in which 99 haplo cords from the University of Chicago Medical Center and Weill Cornell Medical Center, New York, were compared with 344 DUCB transplants from the Center for International Blood and Marrow Transplant Research database that were matched for age, sex, race, disease type, disease stage pre-transplant, performance status and year of transplantation. ANC, absolute neutrophil count.
versus CB NK-cell alloreactivity was responsible for failure of the CB graft. KIR mismatch in the opposite direction was not associated with graft failures of any kind. In The Netherlands, we have performed haplocord transplantations in children and adults with an indication for transplant, with the specific aim of rescuing them with expedited engraftment from ongoing infection or previous graft failure [38]. In patients with this substantial comorbidity, a successful myeloid bridge is key for survival. Three important observations were reported in this cohort of 19 difficult-to-transplant patients, who were mostly conditioned with fludarabine (160 mg/m2) and busulfan (target area under the curve 90e95 mg*h/L in four doses) and with/without ATG (Thymoglobulin 10 mg/kg in four doses). First, despite myeloablative conditioning, failure of the haplo-derived myeloid bridge occurred in 11 of 19 patients (58%). None of these patients showed recipient chimerism at any time point post-HCT. Second, post-transplant ATG exposure (area under the curve) was associated with a higher probability of establishing a successful haplo-derived myeloid bridge (P < 0.001). Third, haplo (single)-cord transplantation without ATG failed to establish a haplo-derived myeloid bridge to CB engraftment in 100% of cases (n ¼ 5). On the basis of these observations, we hypothesized that the haplo-derived myeloid bridge can occur only if there is substantial exposure of the CB to serotherapy with Thymoglobulin to prevent CB versus haplo-donor rejection. In this high-risk population, delayed reconstitution was fatal in most cases. Non-relapse mortality in the unsuccessful haplo-bridge group was 80 16% versus 13 11% in the successful haplo-bridge group (P ¼ 0.012). Memorial Sloan Kettering Cancer Center developed a triple-donor strategy with the aim to combine the advantages of both DUCB and haplo cord. In
this protocol, CD34þ selected haplo-derived cells are added to DUCB transplantation [39]. The rationale was to aim for an even shorter neutropenic period and hospital admission duration and a cohort that would be comparable in outcome to the large DUCB cohort. As in the MSKCC DUCB protocols, haplo-DUCB transplants are performed without previous serotherapy for maximum immune reconstitution and GVL. However, similar to the data from the Netherlands, the haplo-bridge is short, and secondary neutropenia after initial haplo-engraftment is common. In the context of a DUCBT, however, this does not lead to an overall failure of both grafts but to a rapid switch to CB chimerism. It may still be questionable, however, how much benefit both from a medical and economic perspective is actually being obtained from adding the haplo-donor in this context. One of the reasons for the scarce number of centers in the United States with experience in haplo cord was the limited accessibility of the CliniMACS CD34þ selection columns (Miltenyi), which have only recently been approved by the U.S. Food and Drug Administration for allo-SCT in certain indications. Discussion Initial outcome analysis showed that DUCB transplants were associated with increased GVL and lower relapse. However, in recent studies in both adults [22] and children [15], survival rates of single-unit UCB and DUCB were similar, with lower risks for GVHD for single-unit UCB. Without a clear benefit of DUCB over single unit CB transplantation, it becomes more attractive to pursue haplo CB transplants. Because cell dose for CB in the setting of haplo cord does not seem to be as limiting, it might allow the use of smaller singleunit CB units that have a more desirable HLA- or KIR-type or non-inherited maternal antigen matching, or a higher likelihood of GVL effect by virtue of T-cell
Double cord and haplo cord transplantation platforms reactivity. One example of such an approach is a computer algorithm developed in Utrecht, The Netherlands, that predicts for a T-cell mediated immune response against a different HLA type [40]. (PIRCHEs or “predicted indirectly recognizable HLA epitopes.”) In retrospective analysis, Otten et al. found that a higher degree of mismatching at class I (higher PIRCHE I) was associated with a lower relapse rate. A higher number for mismatching at class II (higher PIRCHE II) was associated with more chronic GVHD. CB transplantation has previously been shown to be an excellent alternative to transplant with partially matched (7/8) adult unrelated donor transplant [41]. Haplo cord may also emerge as an alternative for patients who have a well-matched unrelated donor. The Spanish group compared their overall haplo cord outcomes to MUD transplant outcome and found similar non-relapse mortality (22e30%) and overall survival (41e47%). GVHD was higher in the MUDs than in haplo-cord transplants [35]. Specifically for elderly patients within our Chicago/ WCMC haplo-cord cohort, we compared with the outcome of matched unrelated donors and found a similar 1-year overall survival of 64% (49e79) versus 57% (44e70) [42]. An important realization is that transplantation outcomes are the combined result of donor source and conditioning regimen used. Both for DUCB and haplo-cord transplantation, platforms now exist that extend transplant access to those lacking a suitable and readily available related or unrelated donor who may otherwise not be able to receive an allograft. For adults in need of a transplantation, it seems haplocord is at least a valid alternative to unrelated donor transplant, even in elderly patients [42]. Although analyzed in a small subset, the data from the Dutch cohort indicate that serotherapy with ATG might be needed for the haplo graft to provide benefit. With the exception of the MSKCC data, all other larger cohorts have used intermediate to high doses of ATG and have an immune reconstitution profile consistent with complete in vivo depletion of the cord. In the Netherlands, graft failures after haplo cord were associated with lower post-HSCT Thymoglobulin exposure and thus occurred most likely because of incomplete depletion of the cord and rapid rejection of the cord. The debate over utility and dose of ATG in CB transplant is likely to continue. Recent reports show excellent immune reconstitution after single CB without any previous serotherapy, although with a high risk of acute GVHD [43]. Thymoglobulin PK studies support aiming for a low post-HSCT exposure for better survival. High (>20 AU*days/L) post-HCT exposure of thymoglobulin is associated with a lower probability of immune reconstitution and a lower overall survival [44]. For further improvement of
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outcome in children, there may not be much benefit of haplo CB over single CB. Children have higher lymphocyte counts pre-transplant and need higher Thymoglobulin exposure for depletion both pre- and post-transplant, leaving them fully depleted with delayed immune reconstitution. In older adults, rapid neutrophil engraftment is nearly universally beneficial and thus some ATG may be required. Mitigating the dose may result in decreased immunosuppression and less PTLD while maintaining the beneficial effects of a low GVHD [45]. Acknowledgments CAL and KvB wrote the manuscript. CAL is supported by a clinical fellowship from the Dutch Cancer Society (2013-5883). Disclosure of interest: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References [1] Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immun 2014;5:1e19. [2] Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, Defor TE, Gooley TA, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 2010;116: 4693e9. [3] Marks DI, Woo KA, Zhong X, Appelbaum FR, Bachanova V, Barker JN, et al. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica 2014; 99:322e8. [4] Zheng C, Zhu X, Tang B, Yao W, Song K, Tong J, et al. Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia. Ann Hematol 2015;94:473e80. [5] van Rood JJ, Scaradavou A, Stevens CE. Indirect evidence that maternal microchimerism in cord blood mediates a graftversus-leukemia effect in cord blood transplantation. Proc Natl Acad Sci USA 2012;109:2509e14. [6] Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH, et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versusleukemia effect in recipients of 2 units. Blood 2009;114: 4293e9. [7] Ueda T, Yoshida M, Yoshino H, Kobayashi K, Kawahata M, Ebihara Y, et al. Hematopoietic capability of CD34þ cord blood cells: a comparison with CD34þ adult bone marrow cells. Int J Hematol 2001;73:457e62. [8] Voermans C, Gerritsen WR, Borne von dem AE, van der Schoot CE. Increased migration of cord blood-derived CD34þ cells, as compared to bone marrow and mobilized peripheral blood CD34þ cells across uncoated or fibronectin-coated filters. Exp Hematol 1999;27:1806e14.
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presented by HLA-DR correlate with the de novo development of donor-specific HLA IgG antibodies after kidney transplantation. Hum Immunol 2013;74:290e6. Atsuta Y, Morishima Y, Suzuki R, Nagamura-Inoue T, Taniguchi S, Takahashi S, et al. Comparison of unrelated cord blood transplantation and HLA-mismatched unrelated bone marrow transplantation for adults with leukemia. Biol Blood Marrow Transplant 2012;18:780e7. Rhodes J, van Besien K, Liu H, Gergis U, Tsai S, Mayer S, et al. Haplocord transplantation vs unrelated donor stem cell transplantation in AML/MDS >50. ASH Annual Meeting Abstract. Blood 2014;124:1235. Chiesa R, Gilmour K, Qasim W, Adams S, Worth AJ, Zhan H, et al. Omission of in vivo T-cell depletion promotes rapid expansion of naïve CD4þ cord blood lymphocytes and restores adaptive immunity within 2 months after unrelated cord blood transplant. Br J Haematol 2012;156:656e66. Admiraal R, Kesteren van C, Jol-van der Zijde CM, Lankester AC, Bierings MB, Egberts TCG, et al. Association between anti-thymocyte globulin (ATG) exposure and CD4þ immune reconstitution predicting overall survival in paediatric haematopoietic cell transplantation: a multicentre retrospective pharmacodynamic cohort analysis. Lancet Haematol 2015; in press. Segovia J, van Besien K. Antithymocyte globulin for graftversus-host disease prophylaxis: mistakenly maligned [published online ahead of print February 6, 2015]. Leuk Lymphoma 2014, http://dx.doi.org/10.3109/10428194.2014.994180
Topping it up: methods to improve cord blood transplantation outcomes by increasing the number of CD34D cells
CAROLINE A. LINDEMANS1 & KOEN VAN BESIEN2 1
Pediatric Blood and Bone Marrow Transplantation Program, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands, and 2Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA Abstract Cord blood is increasingly recognized for its excellent stem cell potential, lenient matching criteria, instant availability and clinical behavior in transplants when cell dose criteria can be met. However with 1e2 log fewer total (stem cell) numbers in the graft compared with other cell sources, the infused cell dose per kilogram is critical for engraftment and outcome, creating the need for development of stem cell support platforms. The co-transplant platforms of haplo cord and double unit cord blood (DUCB) transplantation are aimed toward increasing stem cell dose. Together with the optimization of reducedintensity protocols, long-term sustained engraftment using cord blood has become available to most patients, including elderly patients. Haplo cord has a low incidence of both acute and chronic graft-versus-host disease but may require antithymocyte globulin ATG for effective neutrophil recovery. DUCB can be performed without anti-thymocyte globulin with excellent immune reconstitution and disease-free survival, but engraftment is considerably slower, and graft-versus-host disease incidence significant. Both haplo-cord and DUCB transplantation appear to both be valid alternatives to matched unrelated donors in adults.
Introduction Unrelated cord blood (UCB) has been established as an important source of hematopoietic stem cells (HSCs) for allogeneic hematopoietic stem cell transplantation (HSCT) when human leukocyte antigen (HLA)-matched sibling and unrelated donors (MUD) are unavailable. Less stringent matching and instant availability are important advantages over conventional grafts. However, UCB transplantation (UCBT) has been associated with delayed engraftment, contributing to prolonged susceptibility to infectious complications [1]. Despite this delay in count recovery, a recent study shows comparable long-term outcome of UCBT and conventional grafts [2,3]. In some studies, an increased rate of treatment-related mortality is offset by lower rates of leukemia recurrence [2,4]. The mechanism of the enhanced graft-versus-leukemia (GVL) effect with UCBT is unknown. One hypothesis relates to GVL effects caused by maternal cells contaminating the UCB graft [5]. Others have
speculated that in double UCB (DUCB) transplant, graft versus graft effects contribute to GVL effects [6]. UCB has a high percentage of stem cells that are functionally highly proliferative and have increased migratory capacity [7,8]. As such, UCB has the intrinsic capacity to be an excellent cell source for cell recovery. This is illustrated clinically by excellent single UCB transplantation outcomes in pediatric cohorts where cell dose is high and engraftment can be as fast as 17 days with graft failure rates <5% [9]. However, with 1e2 log fewer CD34þ HSC available in a cord blood (CB) graft than in an unrelated bone marrow or peripheral blood stem cell (PBSC) graft, the infused total nucleated cell (TNC) dose/kg and/or CD34þ cell dose/kg has been proven to be critical for UCBT outcomes [10,11] with overall significantly better outcomes if the TNC is >3.0 10 e7/kg [12]. With lower cell doses, the risk for delayed neutrophil recovery and for early complications is increased. When complying with guidelines for CB selection, the incidence of infectious complications after CBT is
Correspondence: Caroline A. Lindemans, MD, PhD, KE04.133.1, Wilhelmina Children’s Hospital, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: [email protected] (Received 28 November 2014; accepted 5 February 2015) ISSN 1465-3249 Copyright Ó 2015, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2015.02.005
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comparable to other donor sources both for children and adults [13e15]. However, finding both a large cell dose and a well-matched cord blood unit is challenging, particularly for ethnic minority patients. Consequently, transplantation centers have been attempting various approaches to the CB transplant protocol to maximize the CD34þ HSC dose infused to patients receiving CB. Here we discuss DUCB and third-party donor (TPD) cell confusion. As an alternative, ex vivo CB expansion techniques are discussed elsewhere in this issue. DUCB transplantation The first DUCB transplantation was performed in 2001 in Minnesota with the aim of doubling cell dose and optimizing engraftment; it has since become widely used. In 2009, Eurocord published criteria for cell dose, advising to infuse two units if cell dose can otherwise not be met. Some studies of DUCB show engraftment as early as 12 days [16] with also reports as late as 36 days [17]. Within cohorts, there is considerable variability among subjects, and it is impossible to exactly predict engraftment in an individual patient. After initial combined engraftment, over time one cord usually outcompetes the other, leading to durable CB engraftment of only one of the two donors. The better the units match among each other, the slower the observed switch to full single cord chimerism [18]. Further fine-tuning of CB choice toward HLA or killer cell immunoglobulin-like receptor (KIR) type to potentially improve outcomes is impossible because as of yet, no pre-transplant graft characteristics have been identified to predict which of the two grafts wins [19]. DUCB transplantation has been widely used as an alternative to unrelated donor marrow or PBSC transplantation. Malard et al. show a benefit of DUCB over 9 of 10 mismatched MUD in 152 reducedintensity (RIC) allo-SCTs, with comparable survival but significantly lower incidence of chronic graftversus-host disease (GVHD) in DUCB [20]. In addition, Brunstein et al. showed DUCB to be a valid alternative compared with matched related and unrelated donors with similar 5-year disease-free survival of DUCB transplants in their two-center analysis of 536 transplantations. They observed a decrease in relapse in DUCB, which was compensated for by a slight increase in transplant-related mortality with DUCB [2]. The role of these graft-versus-graft effects giving DUCB transplants an additional graft versus leukemia advantage is focus of widespread investigation, with conflicting results in some other cell source comparison studies. Chen et al. described the DUCB and unrelated (bone marrow/PBSC) donor transplants at Dana-Farber and Massachusetts General Hospital between 2004 and 2008 and found DUCB
to be associated with higher transplant-related mortality without an advantage for progression-free survival [21]. Others, however, have also shown decreased rates of relapse with single UCB stem cell transplant [4,12], and recent multicenter studies, including a prospective randomized comparison, have not shown any advantage comparing myeloablative single CBT with DUCB [15,22]. Originally, DUCB was performed using a myeloablative approach that was either busulfan-based or total body irradiation (TBI)-based (1000e1200 cGy) and included serotherapy (i.e., usually ATG). More recently, DUCB RIC protocols have been introduced for transplantation of older adults. Commonly used RIC protocols are fludarabine 150 mg/m2 þ cyclophosphamide 200 mg/kg and TBI (400 cGy) [17] or Flu150 mg/m2 þ Cy 200-TBI (200 cGy) [23]. Memorial Sloan Kettering Cancer Center (MSKCC) has performed DUCB with a slightly more intensified RIC conditioning without ATG, adding thiotepa 10 mg/kg to Cy 50/Flu 150/ TBI (400 cGy) conditioning to ensure engraftment and to obtain full donor chimerism with the aim of preventing relapse [24]. There is ongoing debate over the role of ATG in UCBT. Omission of ATG decreases the risk of posttransplant lymphoproliferative disorders (PTLD) [25] and of post-transplant viral infections [26], but it is associated with a considerable risk of GVHD: around 50e55% grade IIeIV for RIC protocols [17,24] and 64% for myeloablative protocols [27] with a high incidence of gut GVHD. Early cytomegalovirus (CMV) infections remained challenging even without ATG [28]. An intensive CMV prophylaxis protocol with pre-transplant ganciclovir and long-term high-dose acyclovir has become standard of care in Weil Cornell Medical Center (WCMC), New York, is well tolerated, appears to significantly reduce CMV reactivations and may find a more widespread implementation in the future [29,30]. Haplo-CB transplantation Supplementing a CB unit with HSCs from adult donors is another approach to augment stem cell dose. The original concept of combined TPD and CB transplants is to provide early myeloid engraftment from the TPD-HSCs until sustainable CB-derived engraftment can be achieved, thereby shortening the neutropenic period to a few days. Following peripheral blood collection from a granulocyte colony-stimulating factor mobilized adult donor, 3e5 10e6 CD34þ cells/kg, positively selected usually using the Miltenyi CliniMACs CD34þ selection column, are infused together with a single UCB unit.
Double cord and haplo cord transplantation platforms The infusion of UCB with CD34þ selected cells from an adult (mostly related haploidentical) donor, was originally performed in 1999 by Fernandez et al. in Spain with the goal of finding a donor solution for more patients with an indication for HSCT but without a conventional donor available. By increasing cell dose in this way, he observed rapid hematopoietic recovery from adult donor cell origin that is replaced over time by complete CB chimerism. They recently reported the outcomes of the 132 haplo-cord transplants performed since that time [31]. Neutrophil engraftment was 95% at 40 days (95% confidence interval, 89e98%) with a median time of 11.5 days. The cumulative incidence of platelet recovery was 78% at 100 days (95% confidence interval, 71e85%) with a median of 36 days. Transplants were performed after a myeloablative conditioning, which consisted of thymoglobulin 4 mg/ kg and fludarabine 120 mg/m2, cyclophosphamide 120 mg/m2 and busulfan 12.8 mg/kg or a regimen that included TBI (1000 cGy) in most cases. GVHD prophylaxis was cyclosporine A from day e5 until engraftment (or day þ50) and steroids 1e2 mg/kg from day e2 until day 14. The lower limit for CB units used in their protocol is 1.5 10e7 nucleated cells/kg recipient. Graft failure rates were 2% for failure of both grafts and 9% specifically for failure of the CB donor with persistence of the haplo donor. In Chicago, we pioneered combined TPD CB transplants with an RIC regimen. In an initial publication, we reported a median time to neutrophil engraftment of 11 days (interquartile range 9e15) and to platelet engraftment of 19 days (interquartile range 15e33) [32]. Similarly to the Spanish group, early TPD engraftment was replaced by durable engraftment of the UCB by 100 days in the majority of patients. In contrast to the Spanish group, we only used related third-party (haplo-) donors. This protocol has been continued with minor adjustments in a collaboration between University of Chicago and WCMC, New York. Currently, patients transplanted with haplo cord receive a commonly used pretransplant conditioning regimen consisting of fludarabine (cumulative dose 125 mg/m2 in 5 days), melphalan (140 mg/m2) and Thymoglobulin (1.5 mg/kg for 4 consecutive doses in patients under age 50 and 3 consecutive doses for patients over 50). Post-transplant GVHD prophylaxis consists of tacrolimus until day 180 and mycophenolate mofetil (MMF) three time daily until day 28 (and then twice daily until day 60). Significantly higher CD34 cell doses >5 106/kg from the haplo donor are avoided because they have been associated with failure of the CB graft. We have studied the lowest threshold for the CB unit in the haplo cord platform in a prospective dose reduction
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protocol [33]. In successive cohorts with decreasing cell dose, the minimum acceptable UCB nucleated cell dose was studied. Cell doses as low as 0.5 10e7 nucleated cells/kg were followed by durable engraftment of the CB. Limiting cell doses of the UCB unit may provide an opportunity to identify better matching units and thus improve long-term outcomes [34]. Consistent between the myeloablative regimen of the Spanish study and the RIC regimen of Chicago/ WCMC studies are the rapid engraftment and the low rate of acute (<15e25%) and chronic GVHD. For these cohorts of high-risk leukemia patients, nonrelapse mortality was 35% in the Spanish and 28% for the Chicago/WCMC cohort [31,32,35]. Both cohorts have looked at post-transplant immune reconstitution, which is consistent with full in vivo depletion of the CB (ATG) with T-cell recovery dependent on thymic output no earlier than 6 months post-HSCT [29,31]. We compared the 99 patients transplanted in Chicago/WCMC with haplo cord after the Flu/Mel/ ATG conditioning with matched DUCB transplants (1:4) from the Center for International Blood and Marrow Transplant Research registry [36]. In multivariate analysis significant differences were observed for neutrophil (91% versus 72%) and platelet engraftment (53% versus 6%) by day 30 (Figure 1). Survival was superior after haplo cord at all time points, but the survival advantage became more pronounced over time at 4 years post-SCT with 43% versus 21% alive, even though there were slightly higher-risk disease patients in the haplo-cord group (44% versus 34%). Taking advantage of the rapid engraftment characteristics of the haplo-cord platform, patients with ongoing infection, with indications associated with difficult engraftment and or patients with previous graft failure might be particularly likely to benefit. The group at the National Institutes of Health transplanted 16 patients with severe aplastic anemia (SAA), an indication notorious for its high risk of graft failure. They report a median of 10 days for haplo-derived neutrophil engraftment and of 22 days for platelet engraftment [37]. At a median follow-up of 570 days (range 55e1826 days) in 12 of 16 patients, a switch to full CB myeloid chimerism was reported, with persistent mixed chimerism in two and sustained engraftment of the haplo donor in the other two. It was observed that in all those without any CB engraftment (n ¼ 2) and those with only partial CB chimerism by day 400 (n ¼ 3), a haplo versus CB KIR mismatch existed, whereas a KIR mismatch in the haplo-versus CB direction was present in only 27% of the patients who were fully CB engrafted by day 400. It was suggested that haplo
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Figure 1. Engraftment outcomes (A, neutrophils; B, platelets) of a case-control comparison study in which 99 haplo cords from the University of Chicago Medical Center and Weill Cornell Medical Center, New York, were compared with 344 DUCB transplants from the Center for International Blood and Marrow Transplant Research database that were matched for age, sex, race, disease type, disease stage pre-transplant, performance status and year of transplantation. ANC, absolute neutrophil count.
versus CB NK-cell alloreactivity was responsible for failure of the CB graft. KIR mismatch in the opposite direction was not associated with graft failures of any kind. In The Netherlands, we have performed haplocord transplantations in children and adults with an indication for transplant, with the specific aim of rescuing them with expedited engraftment from ongoing infection or previous graft failure [38]. In patients with this substantial comorbidity, a successful myeloid bridge is key for survival. Three important observations were reported in this cohort of 19 difficult-to-transplant patients, who were mostly conditioned with fludarabine (160 mg/m2) and busulfan (target area under the curve 90e95 mg*h/L in four doses) and with/without ATG (Thymoglobulin 10 mg/kg in four doses). First, despite myeloablative conditioning, failure of the haplo-derived myeloid bridge occurred in 11 of 19 patients (58%). None of these patients showed recipient chimerism at any time point post-HCT. Second, post-transplant ATG exposure (area under the curve) was associated with a higher probability of establishing a successful haplo-derived myeloid bridge (P < 0.001). Third, haplo (single)-cord transplantation without ATG failed to establish a haplo-derived myeloid bridge to CB engraftment in 100% of cases (n ¼ 5). On the basis of these observations, we hypothesized that the haplo-derived myeloid bridge can occur only if there is substantial exposure of the CB to serotherapy with Thymoglobulin to prevent CB versus haplo-donor rejection. In this high-risk population, delayed reconstitution was fatal in most cases. Non-relapse mortality in the unsuccessful haplo-bridge group was 80 16% versus 13 11% in the successful haplo-bridge group (P ¼ 0.012). Memorial Sloan Kettering Cancer Center developed a triple-donor strategy with the aim to combine the advantages of both DUCB and haplo cord. In
this protocol, CD34þ selected haplo-derived cells are added to DUCB transplantation [39]. The rationale was to aim for an even shorter neutropenic period and hospital admission duration and a cohort that would be comparable in outcome to the large DUCB cohort. As in the MSKCC DUCB protocols, haplo-DUCB transplants are performed without previous serotherapy for maximum immune reconstitution and GVL. However, similar to the data from the Netherlands, the haplo-bridge is short, and secondary neutropenia after initial haplo-engraftment is common. In the context of a DUCBT, however, this does not lead to an overall failure of both grafts but to a rapid switch to CB chimerism. It may still be questionable, however, how much benefit both from a medical and economic perspective is actually being obtained from adding the haplo-donor in this context. One of the reasons for the scarce number of centers in the United States with experience in haplo cord was the limited accessibility of the CliniMACS CD34þ selection columns (Miltenyi), which have only recently been approved by the U.S. Food and Drug Administration for allo-SCT in certain indications. Discussion Initial outcome analysis showed that DUCB transplants were associated with increased GVL and lower relapse. However, in recent studies in both adults [22] and children [15], survival rates of single-unit UCB and DUCB were similar, with lower risks for GVHD for single-unit UCB. Without a clear benefit of DUCB over single unit CB transplantation, it becomes more attractive to pursue haplo CB transplants. Because cell dose for CB in the setting of haplo cord does not seem to be as limiting, it might allow the use of smaller singleunit CB units that have a more desirable HLA- or KIR-type or non-inherited maternal antigen matching, or a higher likelihood of GVL effect by virtue of T-cell
Double cord and haplo cord transplantation platforms reactivity. One example of such an approach is a computer algorithm developed in Utrecht, The Netherlands, that predicts for a T-cell mediated immune response against a different HLA type [40]. (PIRCHEs or “predicted indirectly recognizable HLA epitopes.”) In retrospective analysis, Otten et al. found that a higher degree of mismatching at class I (higher PIRCHE I) was associated with a lower relapse rate. A higher number for mismatching at class II (higher PIRCHE II) was associated with more chronic GVHD. CB transplantation has previously been shown to be an excellent alternative to transplant with partially matched (7/8) adult unrelated donor transplant [41]. Haplo cord may also emerge as an alternative for patients who have a well-matched unrelated donor. The Spanish group compared their overall haplo cord outcomes to MUD transplant outcome and found similar non-relapse mortality (22e30%) and overall survival (41e47%). GVHD was higher in the MUDs than in haplo-cord transplants [35]. Specifically for elderly patients within our Chicago/ WCMC haplo-cord cohort, we compared with the outcome of matched unrelated donors and found a similar 1-year overall survival of 64% (49e79) versus 57% (44e70) [42]. An important realization is that transplantation outcomes are the combined result of donor source and conditioning regimen used. Both for DUCB and haplo-cord transplantation, platforms now exist that extend transplant access to those lacking a suitable and readily available related or unrelated donor who may otherwise not be able to receive an allograft. For adults in need of a transplantation, it seems haplocord is at least a valid alternative to unrelated donor transplant, even in elderly patients [42]. Although analyzed in a small subset, the data from the Dutch cohort indicate that serotherapy with ATG might be needed for the haplo graft to provide benefit. With the exception of the MSKCC data, all other larger cohorts have used intermediate to high doses of ATG and have an immune reconstitution profile consistent with complete in vivo depletion of the cord. In the Netherlands, graft failures after haplo cord were associated with lower post-HSCT Thymoglobulin exposure and thus occurred most likely because of incomplete depletion of the cord and rapid rejection of the cord. The debate over utility and dose of ATG in CB transplant is likely to continue. Recent reports show excellent immune reconstitution after single CB without any previous serotherapy, although with a high risk of acute GVHD [43]. Thymoglobulin PK studies support aiming for a low post-HSCT exposure for better survival. High (>20 AU*days/L) post-HCT exposure of thymoglobulin is associated with a lower probability of immune reconstitution and a lower overall survival [44]. For further improvement of
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outcome in children, there may not be much benefit of haplo CB over single CB. Children have higher lymphocyte counts pre-transplant and need higher Thymoglobulin exposure for depletion both pre- and post-transplant, leaving them fully depleted with delayed immune reconstitution. In older adults, rapid neutrophil engraftment is nearly universally beneficial and thus some ATG may be required. Mitigating the dose may result in decreased immunosuppression and less PTLD while maintaining the beneficial effects of a low GVHD [45]. Acknowledgments CAL and KvB wrote the manuscript. CAL is supported by a clinical fellowship from the Dutch Cancer Society (2013-5883). Disclosure of interest: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References [1] Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immun 2014;5:1e19. [2] Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, Defor TE, Gooley TA, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 2010;116: 4693e9. [3] Marks DI, Woo KA, Zhong X, Appelbaum FR, Bachanova V, Barker JN, et al. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica 2014; 99:322e8. [4] Zheng C, Zhu X, Tang B, Yao W, Song K, Tong J, et al. Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia. Ann Hematol 2015;94:473e80. [5] van Rood JJ, Scaradavou A, Stevens CE. Indirect evidence that maternal microchimerism in cord blood mediates a graftversus-leukemia effect in cord blood transplantation. Proc Natl Acad Sci USA 2012;109:2509e14. [6] Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH, et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versusleukemia effect in recipients of 2 units. Blood 2009;114: 4293e9. [7] Ueda T, Yoshida M, Yoshino H, Kobayashi K, Kawahata M, Ebihara Y, et al. Hematopoietic capability of CD34þ cord blood cells: a comparison with CD34þ adult bone marrow cells. Int J Hematol 2001;73:457e62. [8] Voermans C, Gerritsen WR, Borne von dem AE, van der Schoot CE. Increased migration of cord blood-derived CD34þ cells, as compared to bone marrow and mobilized peripheral blood CD34þ cells across uncoated or fibronectin-coated filters. Exp Hematol 1999;27:1806e14.
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