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Hematopoietic Transplantation: Past, Present, and Future
Hematopoietic transplantation, commonly termed hematopoietic cell transplantation (HCT), involves engraftment of donor hematopoietic stem cells with subsequent regeneration of the blood and immune system.
Transplants can be from another individual ( allogeneic ), a genetically identical twin ( syngeneic ), or patient's own cells ( autologous ). Cell sources for the transplant can be bone marrow, peripheral blood, or umbilical cord blood. The procedure for HCT is unique. The transplant procedure involves intravenous infusion of the graft and the hematopoietic stem cells home to the bone marrow where they proliferate and differentiate into the mature elements of the blood and immune system. Hematopoiesis posttransplant is derived from donor hematopoietic stem cells in the CD34+, thy-1, c-kit+ fraction and not from the more differentiated cell populations. The only exception is T lymphocytes, which are partially derived from T cells present in the graft in addition to the prodigy of hematopoietic stem cells and processed by the recipient thymus.
Hematopoietic transplantation is used for treatment of severe disorders of the blood and immune system. Following successful allogeneic hematopoietic transplantation, the recipient’s blood and immune system is repopulated with healthy donor derived cells. This can also be used to correct inborn errors of metabolism involving hematopoietic cells. Successful hematopoietic transplantation results in immunologic tolerance, with coexistence of donor and recipient cells, termed chimerism .
The major use of hematopoietic transplantation has been for the treatment of cancer. Hematologic malignancies and selected solid tumors exhibit dose dependent sensitivity to myelosuppressive chemotherapy and/or radiation; higher doses produce more severe myelosuppression, as well as a greater antitumor effect. Improved antitumor responses can be achieved by administering high-dose chemoradiotherapy followed by hematopoietic transplantation to restore hematopoiesis. Allogeneic transplants also confer an immune graft-versus-malignancy (GVM) effect, where malignant cells surviving the preparative regimen may be eradicated by donor immune cells. Hematopoietic transplantation may be curative in many clinical settings where conventional therapies are less effective.
The Past—Determination of the Fundamental Principles of Hematopoietic Cell Transplantation and Initial Clinical Experience
Much of the initial interest in hematopoietic transplantation came with concerns regarding nuclear energy and nuclear weapons. High doses of total body radiation produce lethal marrow aplasia. HCT can reverse radiation-induced bone marrow failure and much of the early research in the field was directed to potential use of HCT to treat victims of nuclear exposure and even nuclear war. Although it is clearly impractical to consider HCT as treatment for massive casualties in a nuclear war, it has been used with limited success to treat victims of radiation accidents at nuclear power plants who have radiation exposure sufficient to produce bone marrow failure, but less than that causing lethal injury to other tissues ( Fig. 1.1 ).
Initial efforts in HCT were largely unsuccessful until the basic principles of histocompatibility were defined and effective immunosuppressive regimens were developed. Allogeneic HCTs are subject to graft rejection (host-versus-graft), and donor immune cells can react against recipient tissues and produce graft-versus-host disease (GVHD). Effective pre- and posttransplant immunosuppressive regimens are necessary to prevent rejection and to prevent and treat GVHD. Recipients are subject to opportunistic infections because of pancytopenia early posttransplant and posttransplant immune deficiency.
The field has grown from its inception by a small number of pioneering physician-scientists and institutions who established the fundamental principles of hematopoietic transplantation, and the initial clinical applications ( Fig. 1.2 ). E. Donnell Thomas was awarded the Nobel Prize in 1990 for his pioneering work in this field. The growth of HCT was related to incremental improvements in every aspect of the transplant procedure and supportive care. This includes optimization of the pretransplant preparative regimen, the composition of the graft including both stem cells and immune cells, posttransplant immunosuppressive therapy and posttransplant therapy to eradicate residual malignant cells ( Fig. 1.3 ).
The initial use of hematopoietic transplantation used super lethal, myeloablative doses of chemotherapy and/or radiation, which was limited by treatment-related mortality (TRM) because of its toxicities and from infections related to pancytopenia and posttransplant immune deficiency. Preparative regimens have slowly been optimized to reduce severe toxicities, but myeloablative regimens must be limited to relatively young, medically fit patients who can tolerate this treatment.
The pioneering studies of allogeneic HCT were conducted in the 1960s and 1970s in an era before development of effective antimicrobial therapies. A large fraction of patients died from bacterial, viral, fungal, and parasitic infections. A major clinical problem was cytomegalovirus (CMV) infections; approximately 25% of patients died from CMV pneumonia before development of effective antiviral therapy. The dramatic improvement in the field of Infectious Diseases and the management of immunocompromised patients greatly facilitated the progress of the field. Important advances included development of effective prophylaxis and treatment for gram-positive and -negative bacteria, particularly pseudomonas and drug resistant bacteria; acyclovir, ganciclovir, and foscarnet for CMV and herpes viruses; azoles and echinocandins for fungal infections; sulfamethoxazole-trimethoprim and other agents for Pneumocystis jirovecii . The success of HCT has also been related to advances in transfusion medicine, particularly in eliminating blood borne pathogens, and providing CMV seronegative or filtered blood products to reduce transmission of CMV infection. These gradual improvements in supportive care led to reduction of TRM by 1% to 2% each year over several decades.
The Present—Current Concepts and Practice of Hematopoietic Cell Transplantation
Autologous Transplantation
Autologous HCT exploits the dose-dependent response of chemotherapy and/or radiation by hematologic malignancies and many solid tumors. High-dose myelosuppressive therapy is given with the goal to eradicate the malignancy, followed by infusion of the autologous hematopoietic cells to restore hematopoiesis. The patient’s own cells are used, so they are not subject to rejection or GVHD, and immune reconstitution is more rapid than after allogeneic HCT. Compared to allogeneic transplants, autologous HCT is relatively safe, with a low rate of nonrelapse mortality (NRM).
Contamination of the autograft by malignant cells may contribute towards relapse after autologous HCT, shown by gene marking studies. However, studies evaluating ex vivo or in vivo purging of the autografts to deplete malignant cells have not been shown to improve outcomes. Since the patient receives their own hematopoietic and immune cells in an autologous transplant, the GVM effect of allogeneic transplantation does not occur.
Compared to allogeneic HCT, autologous transplants generally have a higher risk of relapse of the malignancy, but this is offset by a lower risk of TRM and major complications. Autologous HCT has an established role in the treatment of multiple myeloma (MM), Hodgkin and non-Hodgkin lymphoma, and selected solid tumors including germ cell tumors, neuroblastoma, and other Pediatric malignancies.
Allogeneic Transplantation
Allogeneic HCT combines cytotoxic treatments with the immune-mediated GVM effect. Compared to autologous HCT, allogeneic transplantation is more complex, and graft rejection and GVHD may occur; posttransplant immune deficiency is more severe and prolonged and opportunistic infection is more common.
Patients with cancer have defective immunity against their malignancy, and allogeneic hematopoietic transplantation provides normal donor derived immune cells, which mediate an immune GVM effect, which can eliminate drug-resistant cancer cells surviving the preparative regimen. GVM is likely directed against alloantigens in hematopoietic cells that differ between donor and recipient, as well as potentially malignancy specific antigens. Because of the GVM effect, relapse of the malignancy is less common with allogeneic HCT than with autologous transplant, but this is offset by a higher rate of NRM. An allogeneic HCT is a major undertaking for the patient, requiring intensive therapy and close follow-up and ongoing management of complications for the first year posttransplant. Late infections can occur, particularly with encapsulated bacteria because of splenic dysfunction. Allogeneic transplants are generally used for leukemias and hematologic malignancies involving the blood and bone marrow. They are also used for advanced cases of lymphoma or MM who have a poor prognosis with autologous HCT.
Syngeneic Transplantation
Syngeneic hematopoietic transplants are from a genetically identical twin. These transplants will not be rejected or cause GVHD, and hence are safer than allogeneic transplants. Syngeneic transplants have an advantage to autologous transplants since the donor cells are immunologically normal, and are not contaminated by malignant cells. Since the donor and recipient are genetically identical, there is a less potent GVM effect and higher risk or malignancy relapse than with allogeneic transplants.
Therapeutic Use of Hematopoietic Cell Transplantation for Malignant and Nonmalignant Disorders
The decision to perform syngeneic, autologous, or allogeneic HCT for malignancy depends on patient, disease, and treatment related factors. For each patient, the prognosis with each form of HCT as well as nontransplant therapies needs to be considered to provide the patient the best therapeutic opportunity. The main considerations balance the antitumor efficacy of the treatment with the risks of morbidity and NRM.
For nonmalignant indications, syngeneic or allogeneic transplantation is generally required to replace defective hematopoietic or immune cells. Recently, genetically modified autologous hematopoietic or immune cells have been shown to correct immune deficiency, hemoglobinopathy, and metabolic disorders. Autologous transplants have also been used for treatment of autoimmune diseases, and have been effective in stabilizing patients multiple sclerosis and scleroderma.
Histocompatibility
The major histocompatibility complex (MHC) region, also termed the human leukocyte antigen ( HLA ) complex in humans, is a highly polymorphic gene locus. The Immunogenetic/HLA database currently contains > 26,000 HLA alleles, and hundreds of new alleles are reported every month. The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. The most relevant to allogeneic HCT are class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1, -DPB1) molecules. These are glycoproteins that bind and present self, abnormal self, and foreign peptide antigens on the surface of nucleated cells. T lymphocytes recognize antigens presented on HLA molecules, leading to an immune response.
The HLA molecules were initially detected by serologic typing. However, deoxyribonucleic acid–based HLA typing techniques are more comprehensive and precise and can identify single alleles as defined in the World Health Organization HLA nomenclature ( http://hla.alleles.org/nomenclature/index.html ). High-resolution typing is now the standard of care to identify HLA alleles for donor selection.
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