Hematopoietic stem cell transplantation: procedure, prognosis

Hematopoietic stem cell transplantation (HSCT) is a rapidly developing technology that has the potential to cure malignant blood diseases (leukemia, lymphoma, myeloma) and other hematologic diseases (e.g. primary immunodeficiency, aplastic anemia, myelodysplasia). Hematopoietic stem cell transplantation can be autologous or allogeneic; stem cells isolated from peripheral or cord blood can be used. Peripheral blood is more commonly used as a source of HSC than bone marrow, especially in autologous hematopoietic stem cell transplantation. Since stem cells are easier to isolate from peripheral blood, the number of neutrophils and platelets is restored more quickly. HSCT from umbilical cord blood is approved only for children, since the number of HSCs is small.

There are no contraindications for autologous hematopoietic stem cell transplantation. Contraindications to allogeneic hematopoietic stem cell transplantation for the recipient include severe diseases or a condition that does not allow preoperative conditioning (chemical drugs and radiotherapy aimed at complete suppression of one's own hematopoiesis and immune system function). The ideal donor is an HLA-identical sibling, the probability of which is 25% of the recipient's brothers and sisters. Transplantation of HSCs from completely HLA-identical unrelated donors gives similar results in terms of efficiency. The probability of HLA identity of two randomly selected individuals varies within 1:1,000,000-3,000,000 (depending on the ethnicity of the recipient). The solution to this problem is to create multi-million international registries of unrelated volunteer donors. In 2009, there were approximately 15,000,000 unrelated volunteer donors registered worldwide who were ready to donate HSCT. The use of related HLA-incompatible HSCT has no significant advantages over unrelated ones with a similar level of incompatibility. The technology of using transplantation of hematopoietic stem cells isolated from umbilical cord blood is effectively used in pediatric oncohematology.

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Hematopoietic stem cell transplant procedure

To isolate bone marrow stem cells, 700-1500 ml (maximum 15 ml/kg) of bone marrow is aspirated from the donor's posterior iliac crest under local or general anesthesia. To isolate stem cells from peripheral blood, the donor is injected with recombinant growth factors (granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor) to stimulate proliferation and mobilization of stem cells, followed by standard phlebotomy after 4-6 days. Fluorescence-based cell sorting is then performed to identify and isolate stem cells.

Stem cells are infused over 1 to 2 hours through a large-bore central venous catheter. In hematopoietic stem cell transplantation for hematopoietic malignancies, the recipient is given immunosuppressive drugs [eg, cyclophosphamide 60 mg/(kg x day) intravenously for 2 days with total body irradiation, busulfan 1 mg/kg orally 4 times a day for 4 days, and cyclophosphamide without total body irradiation] to induce remission and suppress the immune system to prevent graft rejection. Similar regimens are used in allogeneic hematopoietic stem cell transplantation, even when not indicated for the malignancy, to reduce the incidence of rejection and relapse; such a regimen is not indicated in autologous hematopoietic stem cell transplantation. Nonmyeloablative immunosuppressive regimens may reduce the risk of morbidity and mortality and are useful in older patients, those with comorbidities, and those susceptible to graft-versus-tumor effects (eg, multiple myeloma).

After transplantation, the recipient receives colony-stimulating factors to reduce the duration of post-transplant leukopenia, a prophylactic course of drugs to protect against infections, and, in the case of allogeneic hematopoietic stem cell transplantation, a prophylactic course of immunosuppressants for up to 6 months (usually methotrexate and cyclosporine) to prevent a reaction of donor T lymphocytes to the recipient's MHC molecules (graft versus host disease - GVHD). Broad-spectrum antibiotics are usually withheld unless the patient has a fever. Graft engraftment usually occurs 10-20 days after hematopoietic stem cell transplantation (earlier in the case of stem cell transplantation from peripheral blood) and is determined by an absolute neutrophil count greater than 500 x 10 ⁶ /L.

Serious early (< 100 days) complications include failure to engraft, rejection, and acute GVHD. Failure to engraft and rejection occur in < 5% of patients and are characterized by persistent pancytopenia or irreversible decrease in blood cell counts. Treatment is with glucocorticoids for several weeks.

Acute GVHD occurs in recipients of allogeneic hematopoietic stem cell transplantation, in 40% of patients receiving cells from incompatible siblings, and in 80% of patients receiving cells from unrelated donors. It is characterized by fever, rash, hepatitis with hyperbilirubinemia, vomiting, diarrhea, abdominal pain (with possible development of intestinal obstruction), and weight loss. Risk factors include HLA and gender incompatibility; unrelated donor; advanced age of recipient, donor, or both; previous donor sensitization; and inadequate GVHD prophylaxis. Diagnosis is obvious from history and physical examination; treatment is with methylprednisolone 2 mg/kg intravenously once daily, increased to 10 mg/kg if there is no improvement within 5 days.

Serious late complications include chronic GVHD and disease relapse. Chronic GVHD may occur independently, develop from acute GVHD, or appear after resolution of acute GVHD. Chronic GVHD usually begins 4-7 months after hematopoietic stem cell transplantation (the period may vary from 2 months to 2 years). Chronic GVHD is observed in recipients of allogeneic hematopoietic stem cell transplantation, in 35-50% of recipients who received cells from HLA-compatible siblings, 60-70% from unrelated donors. The disease primarily affects the skin (eg, lichenoid rash, scleroderma) and mucous membranes (eg, keratoconjunctivitis sicca, periodontitis, orogenital lichenoid reactions), as well as the gastrointestinal tract and liver. The main characteristic is immunodeficiency; obliterating bronchiolitis similar to that seen in lung transplantation may also develop. Ultimately, 20 to 40% of patients die of GVHD; mortality is higher with more severe reactions. Treatment is optional in mucocutaneous disease; in more severe conditions, treatment is similar to that for acute GVHD. Using monoclonal antibodies or mechanical separation, T-cell depletion in the allogeneic donor graft reduces the incidence and severity of GVHD, but it also reduces the graft-versus-tumor effect, which may enhance cell proliferation, improve engraftment, and reduce the relapse rate. Relapse rates are higher with allogeneic HSCs for this reason and because circulating tumor cells may be transplanted. Tumor cells isolated before autologous transplantation are being studied ex vivo.

In patients without chronic GVHD, all immunosuppressants can be discontinued 6 months after hematopoietic stem cell transplantation; thus, late complications are rare in this group of patients.

Prognosis of hematopoietic stem cell transplantation

Prognosis varies depending on the indication and procedure performed. Overall, disease relapses in 40% to 75% of recipients of autologous hematopoietic stem cell transplantation and in 10% to 40% of recipients of allogeneic transplantation. Success rates (bone marrow free of malignant cells) are 30% to 40% in patients with relapsed chemotherapy-sensitive lymphoma and 20% to 50% in patients with acute leukemia in remission; compared with chemotherapy alone, hematopoietic stem cell transplantation improves survival in patients with multiple myeloma. Success rates are lower in patients with more advanced disease or with reactive solid cancers (eg, breast cancer, germ cell tumors). Recurrence rates are reduced in patients with GVHD, but overall mortality is increased if GVHD is severe. Intensive drug therapy, effective GVHD prophylaxis, cyclosporine-based treatment, and good supportive care (eg, antibiotics, herpes simplex virus and cytomegalovirus prophylaxis) increase long-term survival after hematopoietic stem cell transplantation without relapse.