Clinical Use of Hematopoietic Stem Cells

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The role of hematopoietic stem cells is central to the biological basis of bone marrow transplantation, subsequently referred to as hematopoietic cell transplantation. Hematopoietic cell transplantation (HCT) has developed from a treatment of "last resort" to an effective therapy for patients with a variety of malignant and non-malignant disorders (See Table 2). The field was pioneered by E. Donall Thomas initially in canine model systems in the 1950s and 1960s, with the first patient transplant performed in 1956 (treatment of a patient with total body irradiation followed by an infusion of marrow from an identical twin resulted in complete remission of leukemia). In 1968, the first transplantation from a related, matched donor for a non-malignancy (SCID) was successfully performed, and in 1973, the first transplant was carried using an unrelated donor. In 2002, over 45 000 transplants were performed worldwide for a wide variety of indications.68 It is important to note that while HCT is often termed "stem cell transplantation," clinically these are not purely "stem cell" transplants, as the cells commonly transplanted are not pure HSC but heterogeneous populations of stem, progenitor and mature cell populations contained within unfractionated donor bone marrow, mobilized peripheral blood or cord blood.

Autologous transplantation

There are two primary forms of hematopoietic cell transplantation defined by the donor graft source: autologous and allogeneic. The principle of autologous hematopoietic transplantation allows the use of myeloablative doses of combination chemotherapy and/or radiation to optimize tumor kill, followed by transplantation with the patient's own previously collected and stored bone marrow or mobilized peripheral blood to regenerate or "rescue" the hematopoietic system.69 This treatment modality rapidly evolved in the 1980s and has became the treatment of choice for patients with relapsed or refractory lymphoma, being increasingly used for other chemotherapy-sensitive but infrequently cured cancers, including acute leukemia, multiple myeloma, and selected solid tumors. Generally, autologous transplants have

Table 2. Diseases in which Autologous and/or Allogeneic Hematopoietic Cell Transplants have been used

Malignant

Leukemia/preleukemia

Chronic myeloid leukemia (CML) Chronic lymphocytic leukemia (CLL) Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL)

Myeloproliferative syndromes

Juvenile chronic myeloid leukemia

Myelodysplastic syndromes

Therapy-related myelodysplasia/leukemia Kostmann agranulocytosis

Non-Hodgkin's and Hodgkin's lymphoma

Multiple myeloma

Solid tumors Breast cancer Neuroblastoma Ovarian cancer Renal cancer Brain tumors Testicular cancer

Non-Malignant

Severe aplastic anemia

Paroxysmal nocturnal hemoglobinuria

Hemoglobinopathies Thalassemia major Sickle cell disease

Congenital disorders of hematopoiesis Fanconl's anemia Diamond-Blackfan syndrome Familial erythrophagocytic histiocytosis Dyskeratosis congenital Shwachman-Diamond syndrome

SCID and related disorders

Wiskott-Aldrich syndrome

Inbom errors of metabolism

Storage Diseases

Automimmune disorders

Systemic lupus erythematosis Rheumatoid arthritis lower transplant-related mortality as compared with allogeneic transplantation as engraftment and immune recovery is more rapid and there is no graft versus host disease (GVHD) related morbidity or mortality.

Allogeneic transplantation

Allogeneic hematopoietic cell transplantation by definition involves transplantation of hematopoietic and hematolymphoid cells from a related or unrelated donor. Related donors who share the full HLA type of the recipient are termed "HLA matched" and are preferred donors due to diminished rates of graft rejection and decreased incidence and less severe graft versus host disease (GVHD) (wherein donor mature T cells respond to host transplantation antigens). Full siblings of a prospective transplant patient have a 25% chance of being a full HLA match, and if so are termed matched related donor (MRD), although single HLA mismatch donors are utilized at some transplant centers when no complete match can be identified. If no MRD donor can be identified, unrelated donors are sought, termed matched unrelated donors (MUDs), and are generally identified through marrow donor registries such as the American-based National Marrow Donor Program (NMDP). The first anecdotal reports of successful HCTs using HLA-matched unrelated donor occurred in the early 1970s; however, the polymorphism of human HLA made the feasibility of finding such a donor for an individual low. With the advent of several national and international groups such as the NMDP with organized marrow donor registries, there are now over eight million HLA-typed volunteer donors worldwide.70 More recently, as immunosuppressive techniques have improved, haploidentical parents or sibling donors (which share only a 50% HLA match, or one of the two HLA containing chromosomes) have been utilized as donors when no MRD or MUD donors can be identified. Haploidentical and single HLA mismatched transplants may be most successful if T-cell depleted grafts containing high numbers of CD34+ cells are administered.71

Indications for HCT

The most common indications for allogeneic and autologous HCT are malignancy. The diseases treated in 2002 in North America are shown in Fig. 4. 69% of allogeneic HCTs were for leukemia or preleukemia; 28% for AML; 17% for ALL; 11% for CML; 9% for myelodysplastic or myeloprolifer-ative syndromes; and 4% for other leukemias. Twenty percent are for other cancers, including non-Hodgkin's lymphoma (12%); multiple myeloma (3%); Hodgkin's disease (<1%); and other cancers (4%). The remainder are for aplastic anemia (3%; immune deficiencies (2%); and other diverse non-malignant disorders (6%)). The most common indications for autologous transplantation were multiple myeloma (34%); non-Hodgkin's lymphoma (33%); Hodgkin's disease (12%); leukemia (5%); neuroblastoma (3%); and other cancers.72

Allogeneic HCT most often involves high-dose radiation and chemotherapy with the aim to eliminate any residual malignancy. This therapeutic effect is often augmented by the graft versus malignancy or "graft versus

4,500

4,500

Multiple NHL AML Hodgkin MDS / CML CLL Breast Other Non-

Myeloma Disease ALL Other Neuroblastoma Cancer Cancer Malignant

ALL Leukemia Disease

Figure 4. Indications for hematopoietic cell transplantation in North America, 2002. Abbreviations: Non-Hodgkins lymphoma (NHL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic disease (MDS), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL). Courtesy of the Statistical Center the IBMTR and ABMTR.

Multiple NHL AML Hodgkin MDS / CML CLL Breast Other Non-

Myeloma Disease ALL Other Neuroblastoma Cancer Cancer Malignant

ALL Leukemia Disease

Figure 4. Indications for hematopoietic cell transplantation in North America, 2002. Abbreviations: Non-Hodgkins lymphoma (NHL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic disease (MDS), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL). Courtesy of the Statistical Center the IBMTR and ABMTR.

tumor" effect (GVT) mediated by donor T-cells.73 Standard allogeneic bone marrow grafts contains ~107 CD3+ cells per kilogram of recipient weight. GCSF mobilized peripheral blood contains 10-fold greater numbers of T cells per kilogram (approximately 108 CD3+ cells/kg). T cells within the graft can mediate a graft versus tumor effect (targeting, for example, minor histocompatability antigens expressed on residual donor hematolyphoid tissues and any residual malignant cells), but often also mediate graft versus host disease (GVHD).74 GVHD causes significant morbidity and mortality through the action of mature, donor derived T cells which recognize host antigens as foreign and mount an immune attack, primarily manifested clinically on the patient's skin, gut, and liver.75 The degree of HLA disparity between donor and host is a primary predictor for the occurrence of acute GVHD (within 100 days of transplant), and chronic GVHD (greater than 100 days post transplant).76 All allogeneic recipients are therefore placed on immunosuppression during conditioning, and usually for at least 6 months post transplantation. Common immunosuppressive drugs include cyclosporine, methotrexate, anti-thymocyte globulin (ATG) and prednisone. More recently utilized suppressors of donor T-cell activity

Figure 5. Relapse rates following allogeneic and syngeneic marrow transplantation. Allogeneic T cells in marrow grafts mediate both GVHD and graft versus leukemia effect. Relapse rates are least in patients who develop both acute and chronic graft-versus-host disease (AGVHD + CGVHD); higher in those who develop no clinically evident GVHD; and higher still if T cells are depleted from the marrow graft or in recipients of identical twin transplants.

Figure 5. Relapse rates following allogeneic and syngeneic marrow transplantation. Allogeneic T cells in marrow grafts mediate both GVHD and graft versus leukemia effect. Relapse rates are least in patients who develop both acute and chronic graft-versus-host disease (AGVHD + CGVHD); higher in those who develop no clinically evident GVHD; and higher still if T cells are depleted from the marrow graft or in recipients of identical twin transplants.

include mycophenolate mofetil and tacrolimus. Treatment of GVHD flares often requires increasing immunosuppression, leading to increased risk of morbidity and mortality from bacterial and fungal infections.77 Depletion of T cells from hematopoietic grafts significantly reduces GVHD; however, this depletion also results in significantly increased incidences of graft failure,78 as well as loss of the graft-versus-tumor activity. The GVHD and Graft vs Tumor effect is a "double edged sword," in that patients with the lowest relapse rates are those who develop both acute and chronic GVHD, and disease relapse rates are higher in those who develop no clinically evident GVHD, and higher still if T cells are depleted from the marrow graft or in recipients of identical twin transplants79 (see Fig. 5).

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