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Alternative Donor Allogeneic Transplants: Introduction
Seminars in Hematology ] (2016) ]]]–]]]
Contents lists available at ScienceDirect
Seminars in Hematology journal homepage: www.elsevier.com/locate/enganabound
Alternative Donor Allogeneic Transplants: Introduction
Allogeneic hematopoietic stem cell transplantation is now a 60-year-old lady, who has aged with grace, becoming more refined and sophisticated, ever evolving to better fit with the needs of a growing cancer population. Since its inception, one of the defining major limitations of this approach has been a lack of donor availability. In the last 15 years, we observed a remarkable number of advances in the procedure, chief amongst which include new possibilities for the use of alternative donors, which have dramatically broadened the application of this life-saving procedure. The discovery and characterization of the human leukocyte antigen (HLA) system first allowed for the successful application of stem cell transplantation into the clinical arena. Very rapidly it was defined that HLA matching between patient and their familial donor was necessary for a successful transplant outcome. However, such a requirement severely limited the broader application of transplantation, which within the constraints defined through Mendelian genetic law, results in only 25% of sibling doors being HLA-identical. Thus, by the end of the 1980s, numerous investigations were launched aimed at expanding the pool of potential stem cell donors. In fact, two divergent investigational strategies were pursued: (1) research efforts aimed at optimizing transplants from non-familial HLA matched donors, and (2) research aimed at avoiding complications associated with HLA mismatches between the donor and recipient. Advances that have occurred over three decades in these radically different approaches to overcoming the shortage of HLA-matched related donors are highlighted in this issue of Seminars in Hematology.
1. HLA match rather than familial transplant Initial efforts exploring HLA-mismatched transplants using graft-versus-host disease (GVHD) prophylaxis similar to those receiving transplants from HLA-identical siblings was met with abysmal failure, quickly bringing this strategy to a dead-end. Concomitantly, transplants from closely HLA matched unrelated donors were initially attempted in patients with non-malignant hematologic diseases before subsequent utilization in patients with leukemia. The limited availability of closely HLA-matched unrelated volunteer donors led to the rapid establishment and growth of many local, national, and international donor registries. Through considerable effort and expense, more than 29 million unrelated donors have been recruited into volunteer donor registries worldwide, with the ensuing increase in unrelated donor transplants accounting for a major increase in overall transplant activity. However, although the potential pool of transplant donors grew greatly as a consequence of this strategy, problems related to http://dx.doi.org/10.1053/j.seminhematol.2016.08.003 0037-1963/$/Published by Elsevier Inc.
donor unavailability and other limitations associated with the use of unrelated donors persist for the following reasons: First, not all patients have the same likelihood of finding a potential donor. Under recruitment of donor populations into registries that have the same genetic background as the patient may in part account for this failure. Whereas for Caucasian and Japanese populations the possibility of finding a perfectly HLA-matched donor is quite high, substantial genetic diversity amongst patients of African, Arabic, or other Asian origins makes the odds for finding a well matched unrelated donor much lower. Second, the protracted time-interval to identify a suitably matched unrelated donor and to ultimately collect the allograft is inherently problematic, with some patients relapsing before the transplant can be performed. Third, administrative expenses to recruit and maintain a large registry of unrelated donors are significant, leading to substantial costs for unrelated allografts. In addition to these practical issues, when unrelated transplants were are performed using conventional post-transplant immunosuppression, they were associated with a higher incidence of severe GVHD compared with familial HLA-matched transplants, although other transplant outcomes with conventional unrelated transplant cohorts appear similar between matched related and unrelated donors. To address this last hitch, strategies utilizing either ex vivo or in vivo T-cell depletion of the allograft, albeit not representing a definitive breakthrough in technology, have been shown to reduce the risk of GVHD. Conglomerate retrospective studies have provided enormous insights that have advanced our understanding and knowledge of the HLA system as it relates to transplant outcome, leading to the development of the field of immuno-genomics. Importantly, molecular techniques have improved the sensitivity of HLA typing, substantially increasing the probability that the selected unrelated donor will truly be HLA-identical to the patient, with a concomitant reduction in GVHD. Further, retrospective studies have shed important insights into the biological relevance and clinical risks that are associated with mismatching at specific HLA loci.
2. Umbilical cord blood: the first attempt to evade the requirement for strict HLA identity Shortly following the development of transplants utilizing unrelated adult donors, interest and research efforts in the potential use of transplanted umbilical cord blood increased, in part related to the potential advantages of using allografts containing immature newborn hematopoietic progenitor cells. In particular, because hematopoietic progenitors in cord blood are enriched with long-term repopulating stem cells with longer
2
R. Childs, D. Blaise / Seminars in Hematology ] (2016) ]]]–]]]
telomeres, they potentially would have advantages in terms of in vivo proliferation and sustained repopulating potential, which could overcome the disadvantages associated with their containing lower numbers of hematopoietic stem cells compared to a typical bone marrow allograft. The first successful clinical application of cord blood transplantation was achieved by Eliane Gluckman’s team in Paris in 1988 in a young child with Fanconi anemia who received an umbilical cord blood from his HLA-matched newborn sibling. As more cord transplants were performed, it became clear that the relative immaturity of transplanted cord blood immune cells also offered advantages over conventional transplants, decreasing their allo-reactive potential leading to a dramatically reduced incidence and severity of GVHD. This beneficial property of cord blood immune cells overcomes the strict HLA matching requirement of bone marrow and peripheral blood stem cell allografts, therefore substantially increasing the availability of this type of allograft for patients. Based on the early and subsequent success of cord blood transplantation for nonmalignant hematological disorders, indications for this approach gradually expanded to include patients with leukemia, adults, unrelated cords, and to the widespread use of mismatched cord blood products. The creation of numerous cord blood banks globally has further let to the widespread acceptance and use of this source of donor allografts. Further, cord blood transplants offer some practical advantages over unrelated adult donors, as the time to graft acquisition is shorter and grafts are more likely to be available to ethnically diverse and mixed racial populations who are poorly represented in unrelated donor registries. However, exciting new improvements in outcomes associated with the growing use of familial mismatched transplants will likely limit the future broader application of cord transplantation. 3. Familial HLA-mismatched transplants: Back to the future As previously mentioned, transplants from a partially HLAmismatched relative (usually one haplotype fully mismatched explaining the usual denomination of “haplo transplant”) were traditionally associated with poor outcome, initially because of a high-incidence of severe GVHD and subsequently due to high rates of graft rejection, opportunistic infection, and disease relapse associated with the obligatory use of T-cell depletion. However, haplo-identical transplants offer considerable advantages over other alternative donor transplants, not least of which is the considerable advantage of being able to rapidly identify a haplodonor for the vast majority of patients. This permits expedited transplants for patients achieving tenuous disease remissions who historically have a high incidence of disease relapse with the
traditional protracted time-period needed for the identification and collection of an allograft from an unrelated donor. To improve upon the early poor results associated with haplotransplants, the Perugia group has utilized and explored the “mega CD34 þ cells dose” concept. This approach, which combines highly myeloablative conditioning with profound ex vivo and in vivo T-cell depletion, achieved for the first time high rates of engraftment with a surprisingly low incidence of severe acute GVHD. However, the intense T-cell depletion associated with this strategy leads to long lasting profound immunodeficiency, which contributes to high non-relapse mortality rates from infection and disease relapse. Recent refinements of this strategy described in this edition of Seminars have improved upon these limitations, albeit a high degree of sophisticated graft-engineering is currently required that limits its broader diffusion to other transplant centers. More recently, T-cell replete haplo-transplants using in vivo T-depletion through post-transplant cyclophosphamide have been developed and used increasingly worldwide with surprisingly successful outcomes, including recent reports mitigating concerns of high graft-failure rates and disease relapse described with initial studies. The use of a T-replete graft in this setting has the further benefit of avoiding the need for sophisticated and expensive cell processing techniques, which explains its rapid worldwide application. Several platforms using T-cell– replete haplo-grafts are presently under intensive investigation and are summarized in this edition of Seminars. While the results of early studies look remarkably positive, numerous additional clinical trials will need to be conducted to precisely define the exact niche haplo transplants will fill in an arena where the options for alternative donors has expanded substantially. This issue of Seminars is written by a group of international experts who have pioneered in the development of hematopoietic stem cell transplantation. The articles within provide an extensive exploration of the state of the art, pitfalls, advantages and challenges of transplants using allografts from a growing pool of alternative donor sources.
Richard Childs, MD National Heart Lung and Blood Institute National Institutes of Health Bethesda, MD E-mail: [email protected] Didier Blaise, MD Centre de Recherche en Cance´rologie de Marseille Marseille, France Guest Editors
Contents lists available at ScienceDirect
Seminars in Hematology journal homepage: www.elsevier.com/locate/enganabound
Alternative Donor Allogeneic Transplants: Introduction
Allogeneic hematopoietic stem cell transplantation is now a 60-year-old lady, who has aged with grace, becoming more refined and sophisticated, ever evolving to better fit with the needs of a growing cancer population. Since its inception, one of the defining major limitations of this approach has been a lack of donor availability. In the last 15 years, we observed a remarkable number of advances in the procedure, chief amongst which include new possibilities for the use of alternative donors, which have dramatically broadened the application of this life-saving procedure. The discovery and characterization of the human leukocyte antigen (HLA) system first allowed for the successful application of stem cell transplantation into the clinical arena. Very rapidly it was defined that HLA matching between patient and their familial donor was necessary for a successful transplant outcome. However, such a requirement severely limited the broader application of transplantation, which within the constraints defined through Mendelian genetic law, results in only 25% of sibling doors being HLA-identical. Thus, by the end of the 1980s, numerous investigations were launched aimed at expanding the pool of potential stem cell donors. In fact, two divergent investigational strategies were pursued: (1) research efforts aimed at optimizing transplants from non-familial HLA matched donors, and (2) research aimed at avoiding complications associated with HLA mismatches between the donor and recipient. Advances that have occurred over three decades in these radically different approaches to overcoming the shortage of HLA-matched related donors are highlighted in this issue of Seminars in Hematology.
1. HLA match rather than familial transplant Initial efforts exploring HLA-mismatched transplants using graft-versus-host disease (GVHD) prophylaxis similar to those receiving transplants from HLA-identical siblings was met with abysmal failure, quickly bringing this strategy to a dead-end. Concomitantly, transplants from closely HLA matched unrelated donors were initially attempted in patients with non-malignant hematologic diseases before subsequent utilization in patients with leukemia. The limited availability of closely HLA-matched unrelated volunteer donors led to the rapid establishment and growth of many local, national, and international donor registries. Through considerable effort and expense, more than 29 million unrelated donors have been recruited into volunteer donor registries worldwide, with the ensuing increase in unrelated donor transplants accounting for a major increase in overall transplant activity. However, although the potential pool of transplant donors grew greatly as a consequence of this strategy, problems related to http://dx.doi.org/10.1053/j.seminhematol.2016.08.003 0037-1963/$/Published by Elsevier Inc.
donor unavailability and other limitations associated with the use of unrelated donors persist for the following reasons: First, not all patients have the same likelihood of finding a potential donor. Under recruitment of donor populations into registries that have the same genetic background as the patient may in part account for this failure. Whereas for Caucasian and Japanese populations the possibility of finding a perfectly HLA-matched donor is quite high, substantial genetic diversity amongst patients of African, Arabic, or other Asian origins makes the odds for finding a well matched unrelated donor much lower. Second, the protracted time-interval to identify a suitably matched unrelated donor and to ultimately collect the allograft is inherently problematic, with some patients relapsing before the transplant can be performed. Third, administrative expenses to recruit and maintain a large registry of unrelated donors are significant, leading to substantial costs for unrelated allografts. In addition to these practical issues, when unrelated transplants were are performed using conventional post-transplant immunosuppression, they were associated with a higher incidence of severe GVHD compared with familial HLA-matched transplants, although other transplant outcomes with conventional unrelated transplant cohorts appear similar between matched related and unrelated donors. To address this last hitch, strategies utilizing either ex vivo or in vivo T-cell depletion of the allograft, albeit not representing a definitive breakthrough in technology, have been shown to reduce the risk of GVHD. Conglomerate retrospective studies have provided enormous insights that have advanced our understanding and knowledge of the HLA system as it relates to transplant outcome, leading to the development of the field of immuno-genomics. Importantly, molecular techniques have improved the sensitivity of HLA typing, substantially increasing the probability that the selected unrelated donor will truly be HLA-identical to the patient, with a concomitant reduction in GVHD. Further, retrospective studies have shed important insights into the biological relevance and clinical risks that are associated with mismatching at specific HLA loci.
2. Umbilical cord blood: the first attempt to evade the requirement for strict HLA identity Shortly following the development of transplants utilizing unrelated adult donors, interest and research efforts in the potential use of transplanted umbilical cord blood increased, in part related to the potential advantages of using allografts containing immature newborn hematopoietic progenitor cells. In particular, because hematopoietic progenitors in cord blood are enriched with long-term repopulating stem cells with longer
2
R. Childs, D. Blaise / Seminars in Hematology ] (2016) ]]]–]]]
telomeres, they potentially would have advantages in terms of in vivo proliferation and sustained repopulating potential, which could overcome the disadvantages associated with their containing lower numbers of hematopoietic stem cells compared to a typical bone marrow allograft. The first successful clinical application of cord blood transplantation was achieved by Eliane Gluckman’s team in Paris in 1988 in a young child with Fanconi anemia who received an umbilical cord blood from his HLA-matched newborn sibling. As more cord transplants were performed, it became clear that the relative immaturity of transplanted cord blood immune cells also offered advantages over conventional transplants, decreasing their allo-reactive potential leading to a dramatically reduced incidence and severity of GVHD. This beneficial property of cord blood immune cells overcomes the strict HLA matching requirement of bone marrow and peripheral blood stem cell allografts, therefore substantially increasing the availability of this type of allograft for patients. Based on the early and subsequent success of cord blood transplantation for nonmalignant hematological disorders, indications for this approach gradually expanded to include patients with leukemia, adults, unrelated cords, and to the widespread use of mismatched cord blood products. The creation of numerous cord blood banks globally has further let to the widespread acceptance and use of this source of donor allografts. Further, cord blood transplants offer some practical advantages over unrelated adult donors, as the time to graft acquisition is shorter and grafts are more likely to be available to ethnically diverse and mixed racial populations who are poorly represented in unrelated donor registries. However, exciting new improvements in outcomes associated with the growing use of familial mismatched transplants will likely limit the future broader application of cord transplantation. 3. Familial HLA-mismatched transplants: Back to the future As previously mentioned, transplants from a partially HLAmismatched relative (usually one haplotype fully mismatched explaining the usual denomination of “haplo transplant”) were traditionally associated with poor outcome, initially because of a high-incidence of severe GVHD and subsequently due to high rates of graft rejection, opportunistic infection, and disease relapse associated with the obligatory use of T-cell depletion. However, haplo-identical transplants offer considerable advantages over other alternative donor transplants, not least of which is the considerable advantage of being able to rapidly identify a haplodonor for the vast majority of patients. This permits expedited transplants for patients achieving tenuous disease remissions who historically have a high incidence of disease relapse with the
traditional protracted time-period needed for the identification and collection of an allograft from an unrelated donor. To improve upon the early poor results associated with haplotransplants, the Perugia group has utilized and explored the “mega CD34 þ cells dose” concept. This approach, which combines highly myeloablative conditioning with profound ex vivo and in vivo T-cell depletion, achieved for the first time high rates of engraftment with a surprisingly low incidence of severe acute GVHD. However, the intense T-cell depletion associated with this strategy leads to long lasting profound immunodeficiency, which contributes to high non-relapse mortality rates from infection and disease relapse. Recent refinements of this strategy described in this edition of Seminars have improved upon these limitations, albeit a high degree of sophisticated graft-engineering is currently required that limits its broader diffusion to other transplant centers. More recently, T-cell replete haplo-transplants using in vivo T-depletion through post-transplant cyclophosphamide have been developed and used increasingly worldwide with surprisingly successful outcomes, including recent reports mitigating concerns of high graft-failure rates and disease relapse described with initial studies. The use of a T-replete graft in this setting has the further benefit of avoiding the need for sophisticated and expensive cell processing techniques, which explains its rapid worldwide application. Several platforms using T-cell– replete haplo-grafts are presently under intensive investigation and are summarized in this edition of Seminars. While the results of early studies look remarkably positive, numerous additional clinical trials will need to be conducted to precisely define the exact niche haplo transplants will fill in an arena where the options for alternative donors has expanded substantially. This issue of Seminars is written by a group of international experts who have pioneered in the development of hematopoietic stem cell transplantation. The articles within provide an extensive exploration of the state of the art, pitfalls, advantages and challenges of transplants using allografts from a growing pool of alternative donor sources.
Richard Childs, MD National Heart Lung and Blood Institute National Institutes of Health Bethesda, MD E-mail: [email protected] Didier Blaise, MD Centre de Recherche en Cance´rologie de Marseille Marseille, France Guest Editors