Principles of Stem Cell Transplantation

Background

• Hematopoietic stem cell transplantation involves the infusion of either allogeneic or autologous stem cells, which is typically preceded by conditioning chemotherapy and sometimes total-body irradiation to clear residual disease and immunosuppress the recipient.

• Autologous transplantation involves collection, cryopreservation, and reinfusion of a patient's own stem cells. This allows administration of myeloablative doses of chemotherapy with the intent of maximizing the efficacy of chemotherapy while rescuing hematopoiesis using stem cell re-infusion after chemotherapy.

• Allogeneic transplantation refers to the infusion of stem cells collected from either HLA-matched or mismatched donors. In addition to facilitating the administration of high doses of chemotherapy, allogeneic transplantation also allows for an immunologic effect mediated by donor T and natural killer cells on the tumor (graft-versus-tumor effect).

Indications

• Stem cell transplantation can be considered for patients with high-risk or relapsed malignancy that is thought to be chemosensitive or susceptible to graft-versus-tumor effect. MM and lymphoma are the most common indications for autologous transplantation, whereas MDS and acute leukemia are the most common indications for allogeneic transplantation.

• Stem cell transplantations may also be also considered in certain nonmalignant disorders.

Donor Selection

Appropriate donor selection is crucial and is based on the following factors:

• HLA typing: Major histocompatibility class I and II alleles code for HLA proteins that are expressed on the cell surface and play a major role in immune recognition. High-resolution typing of 10 HLA alleles (e.g., HLA-A, HLA-B, HLA-C, HLA-DRBl, and HLA-DQBl) is the current standard.

• The chance of any given sibling being a full HLA match is only 25%. Patients who lack HLA-identical siblings should have a search for HLA-matched unrelated donors through the National Marrow Donation Program (NMDP), although chances of finding an HLA-matched unrelated donor is significantly influenced by the patient's ethnicity due to disparities in NMDP participation.

• Partial HLA-mismatched transplantations, umbilical cord blood, and haploidentical transplantations (3/6 match) are alternate sources of stem cells for patients without matched sibling or matched unrelated donors.

• Cytomegalovirus (CMV)-negative donors are preferred for CMV-negative patients.

• Younger donors are preferred over older donors.

Source of Stem Cells

• Bone marrow can be obtained under general anesthesia via repeated bone marrow aspiration.

• Peripheral blood stem cells can be collected by leukapheresis after mobilization with use of granulocyte colony-stimulating factor (G-CSF) and plerixafor (CXCR4 antagonist), or chemotherapy (e.g., cyclophosphamide). Peripheral blood stem cells are the most common source stem cells for

clinical use currently.

• Umbilical cord blood stem cells can be collected by umbilical cord venipuncture after delivery.

Complications

• Graft-versus-host disease (GVHD): GVHD occurs when the donor T cells react with recipient tissues, leading to acute and/or chronic inflammation in recipient tissues. The most common tissues affected are the skin, liver, and GI tract. Acute and chronic GVHD are associated with significant morbidity and mortality in allogeneic transplantation patients. Chronic GVHD can result in sclerodermatous-type skin changes. The prophylaxis and treatment of GVHD includes the use of posttransplant cyclophosphamide, glucocorticoids, tacrolimus, cyclosporine, ruxolitinib, methotrexate, sirolimus, and mycophenolate.

• Infections: Owing to the conditioning chemotherapy and prolonged immunosuppression, transplant patients are susceptible to a variety of infections in the peritransplant setting. The postengraftment period is complicated by susceptibility to a broad range of bacterial, viral, and fungal infections, such as gram-negative bacilli, CMV, BK virus, Pneumocystis jirovecii pneumonia, Aspergillus, and other opportunistic infections. Given the significantly increased risk of opportunistic infections, prophylactic antimicrobial regimens (acyclovir, trimethoprim/sulfamethoxazole, fluconazole, ciprofloxacin, etc.) are frequently used. The choice of agent and duration of use vary, depending on the type of transplant, the immunosuppression regimen used, and the type of anticancer treatments used.