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Hematopoietic stem cell transplantation (HSCT) is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders (eg, primary immunodeficiency, aplastic anemia, myelodysplasia). HSCT may be autologous or allogeneic; bone marrow, peripheral blood, or umbilical cord stem cells may be used. Peripheral blood has largely replaced bone marrow as a source of stem cells, especially in autologous HSCT, because stem cell harvest is easier and neutrophil and platelet counts recover faster. Umbilical cord HSCT has been mainly restricted to children because the number of stem cells is low.
There are no contraindications to autologous HSCT. Contraindications to allogeneic HSCT are relative and include age > 50, previous HSCT, and significant comorbidities. Allogeneic HSCT is limited mainly by lack of histocompatible donors. An HLA-identical sibling donor is ideal, followed by an HLA-matched sibling donor. Because only ¼ of patients have such a sibling donor, mismatched related or matched unrelated donors (identified through international registries) are often used. However, long-term disease-free survival rates may be lower than those with HLA-identical sibling donors. The technique for umbilical cord HSCT is still being defined, but HLA-matching is probably unimportant.
Procedure
For bone marrow stem cell harvest, 700 to 1500 mL (maximum 15 mL/kg) of marrow is aspirated from the donor's posterior iliac crests; local or general anesthesia is used. For peripheral blood harvest, the donor is treated with recombinant growth factors (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor) to stimulate proliferation and mobilization of stem cells, with standard phlebotomy 4 to 6 days afterward. Fluorescence-activated cell sorting is used to identify and separate stem from other cells.
Stem cells are then infused over 1 to 2 h through a large-bore central venous catheter. In HSCT for cancer, the recipient first is given a conditioning regimen (eg, cyclophosphamide 60 mg/kg/day IV for 2 days with total body irradiation, busulfan 1 mg/kg po qid for 4 days plus cyclophosphamide without total body irradiation) to induce remission and suppress the immune system so that the graft can be accepted. Similar regimens are used for allogeneic HSCT, even when cancer is not the indication, to reduce incidence of rejection and relapse, but not for autologous HSCT. Nonmyeloablative conditioning regimens may reduce morbidity and mortality risks and may be useful for elderly patients, patients with comorbidities, and those susceptible to a graft-vs-tumor effect (eg, those with multiple myeloma).
After transplantation, recipients are given colony-stimulating factors to shorten duration of posttransplantation leukopenia, prophylactic anti-infective drugs (see Transplantation: Infection), and, in allogeneic HSCT, up to 6 mo of prophylactic immunosuppressants (typically methotrexate and cyclosporine ) to prevent donor T cells from reacting against recipient major histocompatibility complex molecules (graft-vs-host disease [GVHD]). Broad-spectrum antibiotics are usually withheld unless fever develops. Engraftment typically occurs 10 to 20 days after HSCT (earlier with peripheral blood stem cells) and is defined by an absolute neutrophil count > 500 × 106/L.
Major early (< 100 days) complications include failure to engraft, rejection, and acute GVHD. Failure to engraft and rejection affect < 5% of patients and manifest as persistent pancytopenia or irreversible decline in blood counts. Treatment is corticosteroids for several weeks.
Acute GVHD occurs in recipients of allogeneic HSCTs, 40% of HLA-matched sibling graft recipients, and 80% of unrelated donor graft recipients. It causes fever, rash, hepatitis with hyperbilirubinemia, vomiting, diarrhea, abdominal pain (which may progress to ileus), and weight loss. Risk factors include HLA and sex mismatching; unrelated donor; older age of recipient, donor, or both; donor presensitization; and inadequate GVHD prophylaxis. Diagnosis is obvious by history and physical examination; treatment is methylprednisolone 2 mg/kg IV once/day, increased to 10 mg/kg if there is no response within 5 days.
Major later complications include chronic GVHD and disease relapse. Chronic GVHD may occur by itself, develop from acute GVHD, or occur after resolution of acute GVHD. It typically occurs 4 to 7 mo after HSCT (range 2 mo to 2 yr). Chronic GVHD occurs in recipients of allogeneic HSCTs, about 35 to 50% of HLA-matched sibling graft recipients, and 60 to 70% of unrelated donor graft recipients. It affects primarily the skin (eg, lichenoid rash, scleroderma) and mucous membranes (eg, keratoconjunctivitis sicca, periodontitis, orogenital lichenoid reactions) but also affects the GI tract and liver. Immunodeficiency is a primary feature; bronchiolitis obliterans similar to that after lung transplantation can also develop. Ultimately, 20 to 40% die of GVHD; mortality rate is higher with more severe reactions. Treatment may not be necessary for skin and mucous membrane disease; treatment of more extensive disease is similar to that of acute GVHD. T-cell depletion of allogeneic donor grafts using monoclonal antibodies or mechanical separation reduces incidence and severity of GVHD but also eliminates a graft-vs-tumor effect that may enhance stem cell proliferation and engraftment and reduce disease relapse rates. Relapse rates with autologous HSCT are higher for this reason and because circulating tumor cells may be transplanted. Ex vivo tumor cell purging before autologous transplantation is under study.
In patients without chronic GVHD, all immunosuppression can be stopped 6 mo after HSCT; thus, late complications are rare in these patients.
Prognosis
Prognosis varies by indication and procedure. Overall, disease relapse occurs in 40 to 75% of recipients of autologous HSCTs and in 10 to 40% of recipients of allogeneic HSCTs. Success (cancer-free bone marrow) rates are 30 to 40% for patients with relapsed, chemotherapy-sensitive lymphoma and 20 to 50% for patients with acute leukemia in remission; compared with chemotherapy alone, HSCT improves survival of patients with multiple myeloma. Success rates are low for patients with more advanced disease or with responsive solid cancers (eg, breast cancer, or germ cell tumors). Relapse rates are reduced in patients with GVHD, but overall mortality rates are increased if GVHD is severe. Intensive preparative regimens, effective GVHD prophylaxis, cyclosporine -based regimens, and improved supportive care (eg, antibiotics, herpesvirus and cytomegalovirus prophylaxis) have increased long-term disease-free survival after HSCT.
Last full review/revision November 2005
Content last modified November 2005
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