Hematopoietic Stem-Cell Transplantation Edward A. Copelan, M.D. N Engl J Med 2006; 354: Review Article MEDICAL PROGRESS

Early work 1959, leukemia treated with total-body irradiation, followed by infusion of identical twin’s marrow. in the early 1960s, allogeneic transplantation became feasible after the identification and typing of HLA, the major histocompatibility complex. –The genes for HLA are closely linked on chromosome 6 and are inherited as haplotypes. –Thus, two siblings have about one chance in four of being HLA identical. –BMT from an HLA-matched child to his immunodeficient sibling was successful because the recipient could not reject the allograft. In the 1970s, cured end-stage leukemia by using marrow from their HLA- identical siblings after ablating the host marrow with total-body irradiation combined with cyclophosphamide. The occurrence of GVHD reduced the incidence of leukemic relapse, which suggested that donor lymphocytes can eradicate tumor cells that survive preparative regimens.

Current knowledge and theory Stem cells have the unique capacity to produce some daughter cells that retain stem-cell properties; they do not become specialized and thus are self-renewing —a lifetime source of blood cells. Tumors arise from malignant stem cells that usually originate from normal stem cells and retain the mechanism for self-renewal. Most leukemic cells have a limited capacity for proliferation and are continuously replenished by leukemic stem cells. Chemotherapy acts primarily on proliferating cells. Normal and malignant stem cells are quiescent -> ∴ insensitive to therapy. Thus, although chemotherapy can destroy a tumor almost completely, the stem cells are spared, allowing the cancer to recur. Some malignant stem cells survive even lethal doses of total-body irradiation and chemotherapy given in preparation for HSCT. -> Such cells may be eliminated by immunologically active donor cells.

Current knowledge and theory Allogeneic grafts initiate immune reactions related to histocompatibility. The severity of the reaction depends on the degree of incompatibility. T-cell receptors interact with HLA cell-surface glycoproteins binding with peptides from degraded proteins –Recipient T : recognize foreign donor Ag and can reject grafts –Donor T : recognize recipient Ag and can cause GVHD and graft-versus-tumor effects. Major histocompatibility Ag (HLA) mismatch -> strongest transplant reactions Minor histocompatibility Ag -> provoke graft-versus- leukemia response.

Graft-versus-Leukemia effect from a minor histocompatibility antigen Reduce relapse rates after allogenic transplantation and among patients in whom GVHD develops. Can explain the effectiveness of infusions of donor lymphocytes in treating leukemia relapse after transplantation.

GVHD is an immune response accentuated, and possibly stimulated, by injury resulting from preparative regimen used before transplantation. –injury primarily confined to GI tract, –Peyer’s patches attract donor T cells after the injury -> may contribute to the development of GVHD. Cytokines are critical to GVHD, and their genetic variants influence its development.

Preparative Regimens Total-body irradiation Fractionated total-body irradiation combined with cyclophosphamide Radiation-free regimens –Busulfan combined with high doses of cyclophosphamide –Busulfan + low dose cyclophosphamide Reduced-intensity prep regimens Low-dose total-body irradiation and immunosuppressive drug after transplantation +fludarabine (immunosuppressive agent, before total-body irradiation) +donor lymphocyte infusion (few months after transplant)

Sources of Stem cells 1 st source : BM obtained by repeated aspiration of post. Iliac crests under anesthesia 2 nd source : from peripheral blood –More rapid hematopoietic reconstitution –Increase incidence and prolong the Tx of chronic GVHD –Mobilization of CD34+ with G-CSF+AMD3100 –Leukaphresis

Sources of Stem cells Autologous transplantation –Does not induce GVHD -> used in older pts –Mortality is considerably lower than allo- –Absence of graft-versus-tumor activity Less than 30% of potential recipients of hematopoietic stem cells have HLA-identical siblings Unrelated donor use increased DNA typing to identify HLA alleles and most closely matched donor

Complications -Early Effects Mucositis : m/c short-term cx of myeloablative prepartive regimens and MTX Palifermin (recombinant human keratinocyte GF) reduces incidence of oral mucositis after autologous transplant

Complications -Early Effects Hepatic veno-occlusive disease : 2 nd m/c acute adverse effect Potentially fatal syndrome of painful hepatomegaly, jaundice, and fluid retention “sinusoidal obstruction syndrome” Caused by total body irradiation, busulfan, cyclophosphamide, No effective Tx -> prevention is critical Substitution of fludarabine for cyclophosphamide and the use of reduced-intensity regimens -> decrease risk

Complications -Early Effects Transplantation-related lung injury Occurs within 4 months, mortality > 60% Risk factors: total-body irradiation, allogenic transplantation, and acute GVHD Neutrophil, lymphocyte, TNF -> lung injury Tx : etanercept combined with corticosteroid Transplantation-related infections Prolonged neutropenia, GVHD, and administration of corticosteroid -> predispose to fungal infection CMV pneumonia ; once fatal, became rare

Complications -Early Effects GVHD ; most important Cx Acute GVHD : damages skin, gut, liver Pruritic micropapillary rash : palm,sole,generalized N/V/abd pain/diarrhea/bloody stool/jaundice GVHD and Tx with corticosteroid -> predisposing fatal infection Principal risk factor : HLA mismatch –Prophylaxis ; reduce the risk of GVHD MTX(short-term) + cyclosporine(few months) In vitro T-cell depletion of the graft before transplantation Reduced-intensity regimen of total lymphoid irradiation and antithymocyte globulin

Complications -Delayed Effects Chronic GVHD Risk increases with recipient/donor age, PB grafts or grafts from unrelated donors. Can cause bronchiolitis, keratoconjunctivitis sicca, esophageal stricture, malabsorption, cholestasis, hematocytopenia, generalized immunosuppression Tx with corticosteroid for 2 yrs or longer –Cx : aseptic necrosis of bone and osteoporosis, predispose pt to fatal infections –Severe hypogammaglobinemia : IV immunoglobulin

Complications -Delayed Effects Ovulation failure / Infertility Hormonal suppression of ovaries before preparative regimen administration -> might permit the recovery of ovulation after transplant Cryopreserve embryos or oocytes / semen Growth and developmental impairment Growth hormone therapy in children 2ndary cancers Allogenic : skin, oral mucosa, brain thyroid, bone↑ HD/NHL Autologous : myelodysplasia, acute leukemia

Uses and Results