Nonpharmacologic Therapy

Harvesting, Preparing, and Transplanting Allogeneic Hematopoietic Cells

^^ Bone marrow, PBPCs, and umbilical cord blood can serve as the source of hematopoietic cells. The optimal cell source differs based on the donor and recipient characteristics.

Bone Marrow Harvesting the bone marrow from an allogeneic donor is conducted via the same process as for an autologous HSCT. The harvest occurs on day 0 of the HSCT such that it is infused into the recipient immediately after processing. The marrow may need additional processing if the donor and recipient are ABO-incompatible, which occurs in up to 30% of HSCTs. Red blood cells (RBCs) may need to be removed before infusion into the recipient to prevent immune-mediated hemolytic anemia and thrombotic microangiopathic syndromes.

Peripheral Blood Progenitor Cells The allogeneic donor first undergoes mobilization therapy with an HGF to increase the number of hematopoietic cells circulating in the peripheral blood. The most commonly used regimen to mobilize allogeneic donors is a 4- to 5-day course of filgrastim, 10 to 16 mcg/kg/day, administered subcu-taneously, followed by leukopheresis on the fourth or fifth days when peripheral blood levels of CD34+ cells peak. An adequate number of hematopoietic cells usually are obtained with one to two apheresis collections, with the optimal number of CD34+ collected being a minimum of 5 x 106 cells/kg of recipient body weight. Higher numbers of CD34+ cells are associated with more rapid neutrophil and platelet engraft-ment; patients who receive less than 2 x 106/kg CD34+ cells experience a higher mortality rate and a decreased overall survival compared to patients who receive at least 2 x 106/kg CD34+ cells.8 Hematopoietic stem cells obtained from the peripheral blood are processed like bone marrow-derived stem cells and may be infused immediately into the recipient or frozen for future use. In comparison with bone marrow donation, allogeneic PBPC donation leads to quicker hematopoietic recovery. Neutrophil engraftment occurs 2 to 6 days earlier and platelet engraftment occurs approximately 6 days earlier with PBPC grafts compared to bone marrow grafts.9 The donor may experience musculoskeletal pain, headache, mild increases in hepatic enzyme or lactate dehydrogenase levels related to filgrastim administration. Hypocalcemia may also occur owing to citrate accumulation, which decreases ionized calcium concentrations during apheresis.

Allogeneic PBPC grafts contain approximately 10 times more T and B cells than bone marrow grafts. Historically, there has been significant concern that the greater T- and B-cell content of PBPCs could increase the risk of acute and/or chronic GVHD. In patients with a hematologic malignancy who have an HLA-matched sibling donor, a PBPC graft is optimal relative to bone marrow graft because the PBPC graft is associated with quicker neutrophil and platelet engraftment and potentially improved disease-free survival rates.10 Grafts from PBPCs are associated with a similar incidence of acute GVHD but an approximately 20% increase in the incidence of extensive-stage and overall chronic GVHD.10 Similar trends for engraftment and GVHD have been found with unrelated donors.11

Umbilical Cord Blood Transplant with umbilical cord blood offers an alternative stem cell source to patients who do not have an acceptable matched related or unrelated donor. When allogeneic hematopoietic cells are obtained from umbilical cord blood, the cord blood is obtained from a consenting donor in the delivery room after birth and delivery of the placenta. The cord blood is processed, a sample is sent for HLA typing, and the cord blood is frozen and stored for future use. Numerous umbilical cord blood registries exist, with the goal of providing alternative sources of allogeneic stem cells. One potential limitation to the use of umbilical cord blood transplants is the inability to employ donor-lymphocyte infusions in the event of relapse.

Engraftment is slower in umbilical cord blood transplants, with a potential lower risk

of GVHD and similar survival rates relative to BMT. In children receiving an umbilical cord blood graft from an unrelated donor, cell dose (e.g., nucleated cells) is re-

lated to engraftment, transplant-related morbidity, and survival. Although there were initial concerns regarding whether a umbilical cord blood transplant could provide enough nucleated cells to engraft adequately within an adult, there is growing experience to indicate that a umbilical cord blood transplant is feasible when at least 1 x

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10 nucleated cells per kilogram of recipient body weight are administered. The prospective use of dual umbilical cord units and ex vivo expansion of umbilical cord units to obtain adequate engraftment are methods currently under exploration.

T-Cell Depletion Immunocompetent T lymphocytes may be depleted from the donor bone marrow ex vivo before infusion (referred to as T-cell-depleted hematopoietic cells) into the recipient as a means of preventing GVHD. Depletion of T lymphocytes in donor hematopoietic cells is completed ex vivo using physical (e.g., density-gradient fractionation) and/or immunologic (e.g., antithymocyte globulin [ATG] and CAMPATH-1 antibodies) methods. Functional recovery of T cells in the recipient is delayed, and the risk of Epstein-Barr virus-associated lymphoproliferative disorders is higher with the use of T-cell-depleted bone marrow. The use of T-cell-depleted grafts reduces the incidence of GVHD, but graft failure and relapse are more common. The use of donor lymphocyte infusion in patients who relapse after receiving a T-cell-depleted HSCT is being investigated.

Engraftment After chemotherapy and radiation, pancytopenia lasts until the infused stem cells reestablish functional hematopoiesis. The median time to engraftment is a function of several factors, including the source of stem cells such as PBPCs, which can result in earlier engraftment than bone marrow.9 Myeloablative preparative regimens have significant regimen-related toxicity and morbidity and thus usually are limited to healthy, younger (i.e., usually younger than 50 years) patients. Alternatively, nonmyeloablative transplants are being performed with the hope of curing more patients with cancer by increasing the availability of HSCT with less regimen-related toxicity and by using the graft-versus-tumor effect.1

A delicate balance exists between host and donor effector cells in the bone marrow environment. Residual host-versus-graft effects may lead to graft failure, which is also known as graft rejection. Graft failure is defined as the lack of functional hem-atopoiesis after HSCT and can occur early (i.e., lack of initial hematopoietic recovery) or late (i.e., in association with recurrence of the disease or reappearance of host cells after initial donor cell engraftment). Engraftment usually is evident within the first 30 days in patients undergoing an HSCT; however, rejection can occur after initial engraftment. Therapeutic options for the treatment of graft rejection are limited; a second HSCT is the most definitive therapy, although the toxicities are formidable.14

Graft-Versus-Tumor Effect

A graft-versus-tumor effect occurs owing to the donor lymphocytes, as supported by three observations after myeloablative allogeneic HSCT; namely, (a) lower relapse rates in patients with GVHD relative to those who did not have GVHD; (b) a higher rate of leukemia relapse after T-cell-depleted, autologous, or syngeneic HSCT, and (c) the effectiveness of donor lymphocyte infusions in reinducing a remission in patients who relapsed after allogeneic HSCT. Rapid taper of immunosuppression in patients with residual disease may induce a graft-versus tumor effect. In donor lymphocyte infusion, lymphocytes are collected from the peripheral blood of the donor and administered to the recipient. Eradication of the recurrent malignancy is due to either specific targeting of the tumor antigens or to GVHD, which may affect cancer cells preferentially. Patients with hematologic malignancies (e.g., CML and AML) and certain solid tumors (e.g., renal cell carcinoma) appear to benefit from a graft-versus-tumor effect. These data gave rise to the use of nonmyeloablative preparative regimens.

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