Browse the corpus

Hematopoietic stem cell transplant (HPSCT), sometimes referred to as bone marrow transplant, involves administering healthy hematopoietic stem cells to patients with dysfunctional or depleted bone marrow. There are several types of HPSCT in clinical use, and transplanted cells may be obtained from several sources. This procedure has several benefits and may be used to treat malignant and non-malignant conditions. It helps to augment bone marrow function. In addition, depending on the disease being treated, it may allow for the destruction of malignant tumor cells. It can also generate functional cells that replace dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases. Survival rates after HPSCT are increasing, but morbidity due to complications of the procedure continues. This activity reviews the indications for HPSCT, the different options by which to obtain donor cells, including the advantages and disadvantages of each, and the acute and chronic complications of the procedure. Additionally, it highlights the role of the interprofessional team in managing patients who undergo HPSCT to improve patient outcomes and decrease procedure-associated morbidities. Objectives: Describe the malignant and non-malignant indications for hematopoietic stem cell transplants. Contrast the advantages and disadvantages of different types of hematopoietic stem cells. Outline the potential complications of hematopoietic stem cell transplants and apply strategies to ameliorate these risks. Describe the need for a well-integrated, interprofessional team approach to improve care for patients undergoing hematopoietic stem cell transplants. Access free multiple choice questions on this topic.

Hematopoietic stem cell transplant (HPSCT), sometimes referred to as bone marrow transplant, involves administering healthy hematopoietic stem cells to patients with dysfunctional or depleted bone marrow. This procedure has several benefits. It helps to augment bone marrow function. In addition, depending on the disease being treated, it may allow for the destruction of malignant tumor cells. It can also generate functional cells that replace dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases. History and Evolution Hematopoietic stem cell transplantation (HPSCT) was first explored for use in humans in the 1950s. It was based on observational studies in mice models, which showed that infusion of healthy bone marrow components into a myelosuppressed bone marrow could induce recovery of its function in the recipient.[1] These animal-based studies soon found their clinical application in humans when the first successful bone marrow transplant was performed between monozygotic twins in New York in 1957 to treat acute leukemia.[2] The performing physician, E. Donnell Thomas, continued his research on the development of bone marrow transplantation and later received the Nobel Prize for Physiology and Medicine for his work. The first successful allogeneic bone marrow transplant was reported in Minnesota in 1968 for a pediatric patient with severe combined immunodeficiency syndrome.[3] Since then, allogeneic and autologous stem cell transplants have increased in the United States (US) and worldwide. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogeneic transplants performed in the US in 2016, with an even greater number of autologous transplants; autologous transplants have steadily outpaced allogeneic transplants over time.[4][5] Definitions Major Histocompatibility Complex (MHC) The human MHC genes on the short arm of chromosome 6 (6p) encode for human leukocyte antigens (HLA) and are highly polymorphic. These polymorphisms lead to significant differences in the resultant expressed human cell-surface proteins. They are divided into MHC class I and MHC class II. Human Leukocyte Antigens (HLA)

Major Histocompatibility Complex (MHC) The human MHC genes on the short arm of chromosome 6 (6p) encode for human leukocyte antigens (HLA) and are highly polymorphic. These polymorphisms lead to significant differences in the resultant expressed human cell-surface proteins. They are divided into MHC class I and MHC class II. Human Leukocyte Antigens (HLA) The HLA proteins are expressed on the cellular surface and play an essential role in alloimmunity. HLA class I molecules, encoded by MHC class I, can be divided into HLA-A, HLA-B, and HLA-C. These proteins are expressed on all cell types and present peptides derived from the cytoplasm and recognized by CD8+ T cells. HLA class II molecules are classified as HLA- DP, HLA-DQ, and HLA-DR, are encoded by MHC class II, can be found on antigen-presenting cells (APCs), and are recognized by CD4+ T cells. Syngeneic Bone Marrow Transplantation The donor and the recipient are identical twins. The advantages of this type of transplant include no risk of graft versus host disease (GVHD) or graft failure. Unfortunately, however, only a very few transplant patients will have an identical twin available for transplantation. Autologous Bone Marrow Transplantation The bone marrow products are collected from the patient and are reinfused after purification methods. The advantage of this type of transplant is no risk of GVHD. The disadvantage is that the reinfused bone marrow products may contain abnormal cells that can cause relapse in the case of malignancy; hence, theoretically, this method cannot be used in all cases of abnormal bone marrow diseases. Allogeneic Transplantation The donor is an HLA-matched family member, an unrelated HLA-matched donor, or a mismatched family donor (haploidentical). Engraftment The process by which infused transplanted hematopoietic stem cells produce mature progeny in the peripheral circulation. Preparative Regimen This regimen comprises high-dose chemotherapy or total body irradiation (TBI) or both, which are administered to the recipient before stem cell infusion to eliminate the largest number of malignant cells and induce immunosuppression in the recipient so that engraftment can occur.

Complications after bone marrow transplant may be acute or chronic. Many factors can affect these adverse events, including age, baseline performance status, the source of stem cell transplant, and the type and intensity of the preparative regimen. Acute complications occur in the first 90 days, including myelosuppression with neutropenia, anemia, or thrombocytopenia; sinusoidal obstruction syndrome; mucositis; acute graft versus host disease; bacterial infections with gram-positive and gram-negative organisms; Herpesviridae infections; and fungal infection with Candida and Aspergillus. Chronic complications include chronic GVHD, infection with encapsulated bacteria, and reactivation of the varicella-zoster virus. Antimicrobial Prophylaxis Levofloxacin is usually given orally or intravenously and initiated on the first day post-transplant. It is continued until the absolute neutrophil count is more than 1000 cells/microL or until the discontinuation of prednisone in cases of GVHD.[47] Prophylaxis against Pneumocystis jirovecii (PCP) is warranted, given the immunosuppression following a hematopoietic stem cell transplant.[48] Trimethoprim-sulfamethoxazole (TMP-SMX) is usually used, and several dosing regimens have been proposed. TMP-SMX may be given twice weekly until the patient is off immunosuppression.[49] Antifungal infection prophylaxis with fluconazole is recommended for one month following the transplant as it has been shown to decrease the incidence of fungal infections. No difference was seen when fluconazole was compared to voriconazole.[50][51] However, voriconazole is used in patients with an elevated risk of developing severe antifungal infections. Anti-viral prophylaxis is achieved with acyclovir, continued for one month to prevent herpes-simplex virus and one year to prevent varicella-zoster virus.[52] Prophylaxis against cytomegalovirus is only recommended in patients who test positive by PCR, and the treatment of choice is ganciclovir. One unique syndrome encountered with cord stem cell transplant is cord colitis which involves diarrhea in recipients of cord blood and is believed to be secondary to Bradyrhizobium enterica, which usually responds to a course of metronidazole or levofloxacin.[53] Sinusoidal Obstruction Syndrome (SOS)

Prophylaxis against Pneumocystis jirovecii (PCP) is warranted, given the immunosuppression following a hematopoietic stem cell transplant.[48] Trimethoprim-sulfamethoxazole (TMP-SMX) is usually used, and several dosing regimens have been proposed. TMP-SMX may be given twice weekly until the patient is off immunosuppression.[49] Antifungal infection prophylaxis with fluconazole is recommended for one month following the transplant as it has been shown to decrease the incidence of fungal infections. No difference was seen when fluconazole was compared to voriconazole.[50][51] However, voriconazole is used in patients with an elevated risk of developing severe antifungal infections. Anti-viral prophylaxis is achieved with acyclovir, continued for one month to prevent herpes-simplex virus and one year to prevent varicella-zoster virus.[52] Prophylaxis against cytomegalovirus is only recommended in patients who test positive by PCR, and the treatment of choice is ganciclovir. One unique syndrome encountered with cord stem cell transplant is cord colitis which involves diarrhea in recipients of cord blood and is believed to be secondary to Bradyrhizobium enterica, which usually responds to a course of metronidazole or levofloxacin.[53] Sinusoidal Obstruction Syndrome (SOS) Sinusoidal obstruction syndrome (SOS), or veno-occlusive disease (VOD), results from chemotherapy during a preparative regimen and occurs within six weeks of HPSCT. This syndrome consists of tender hepatomegaly, jaundice due to hyperbilirubinemia, ascites, and weight gain due to fluid retention. The incidence is reported to be 13.6% in an analysis study assessing the existing literature on the incidence of the disease.[54] The pathophysiology consists of endothelial damage to the hepatic sinusoids leading to obstruction and necrosis of the centrilobular liver.[55] The destruction of the sinusoids leads to hepatic failure and hepatorenal syndrome, which are responsible for the related mortality. The agents most commonly implicated in causing this syndrome are oral busulfan and cyclophosphamide. Using intravenous busulfan has been shown to decrease the occurrence of SOS.[56]

Sinusoidal obstruction syndrome (SOS), or veno-occlusive disease (VOD), results from chemotherapy during a preparative regimen and occurs within six weeks of HPSCT. This syndrome consists of tender hepatomegaly, jaundice due to hyperbilirubinemia, ascites, and weight gain due to fluid retention. The incidence is reported to be 13.6% in an analysis study assessing the existing literature on the incidence of the disease.[54] The pathophysiology consists of endothelial damage to the hepatic sinusoids leading to obstruction and necrosis of the centrilobular liver.[55] The destruction of the sinusoids leads to hepatic failure and hepatorenal syndrome, which are responsible for the related mortality. The agents most commonly implicated in causing this syndrome are oral busulfan and cyclophosphamide. Using intravenous busulfan has been shown to decrease the occurrence of SOS.[56] The diagnosis of SOS is clinical and is based on hyperbilirubinemia greater than 2 mg/dL in the presence of the aforementioned clinical findings. Treatment consists of ursodeoxycholic acid, which has been shown to significantly decrease the occurrence of SOS when given pre- and post-transplant.[57] Another medication, defibrotide, has shown efficacy in treating SOS when it occurs.[58][59] Idiopathic Pneumonia Syndrome (IPS) Idiopathic pneumonia syndrome usually occurs in the first 90 days post-transplant. The incidence is low and is related to the direct chemotoxicity of the preparative regimen. Treatment with steroids is standard, although no randomized controlled clinical trials have been done to support their efficacy. Recently, etanercept has been studied; adding soluble TNF-inhibitors to steroids has not shown added efficacy.[60] Graft Rejection or Failure A loss of bone marrow function after reconstitution following infusion of hematopoietic stem cells or no gain of function after infusion is termed graft rejection or failure. The incidence of failure is highest when there is a high HLA disparity; this disparity is highest in cases of cord blood and haploidentical donors and lowest with autologous and matched donor siblings. Factors responsible for graft failure include but are not limited to functional residual host immune response to the donor cells, a low number of infused cells, in vitro damage during collection and cryopreservation, inadequate preparative regimen, and infections.

A loss of bone marrow function after reconstitution following infusion of hematopoietic stem cells or no gain of function after infusion is termed graft rejection or failure. The incidence of failure is highest when there is a high HLA disparity; this disparity is highest in cases of cord blood and haploidentical donors and lowest with autologous and matched donor siblings. Factors responsible for graft failure include but are not limited to functional residual host immune response to the donor cells, a low number of infused cells, in vitro damage during collection and cryopreservation, inadequate preparative regimen, and infections. Chimerism refers to the presence of a cell population from a person in the blood of a different person. Evaluating for chimerism is an important step in ensuring engraftment and success of the transplantation. This evaluation is done by checking the expression of CD33, which indicates the presence of granulocytes, and CD3, which indicates the presence of T cells, and confirming that most of the cells present are from the donor. The importance of effective chimerism has been demonstrated in many studies that showed decreased relapse rates and increased survival in allogeneic transplantation.[61] Graft Versus Host Disease (GVHD) Graft versus host disease (GVHD) is a reaction between T cells from the donor in an allogeneic transplant and the recipient's HLA polymorphic epitopes, leading to a constellation of symptoms and manifestations. GVHD may be acute or chronic; each is sub-categorized into classic and late-onset, classic, and chronic overlap.[62] Acute GVHD usually develops within three months. However, it can develop after three months and is then termed delayed acute GVHD. Prophylaxis is generally achieved with calcineurin inhibitors, methotrexate, and anti-thymocyte globulins. The severity of GVHD is estimated using the Glucksberg scale, which classifies acute GVHD from grade I to VI. Treatment with either high-dose prednisone or methylprednisolone is indicated in higher-grade disease.[63]

Acute GVHD usually develops within three months. However, it can develop after three months and is then termed delayed acute GVHD. Prophylaxis is generally achieved with calcineurin inhibitors, methotrexate, and anti-thymocyte globulins. The severity of GVHD is estimated using the Glucksberg scale, which classifies acute GVHD from grade I to VI. Treatment with either high-dose prednisone or methylprednisolone is indicated in higher-grade disease.[63] Chronic GVHD occurs over three months after transplant and involves multiple organs, similar to collagen vascular diseases. Grading of chronic GVHD assesses the severity of the disease and has been developed by the National Institute of Health; grade determines the treatment modality and predicts survival [64]. Treatment is similar to acute GVHD, but the duration of treatment is usually more than two years.[65] Toxicity Chemotherapy and radiation of the preparative regimen and post-transplant immunosuppression can induce severe pancytopenia in the first week following infusion of hematopoietic stem cells, leading to life-threatening infection. This depends on the type and the dose of chemotherapy administered and factors related to the recipients. Chemotherapy causes the destruction of healthy, normal bone marrow products, including neutrophils, macrophages, monocytes, and lymphocytes. Also, chemotherapy-induced mucosal toxicity disrupts the barriers protecting against infectious agents, and the use of indwelling intravenous catheters provides another means for the entrance of infectious agents. According to the guidelines, vaccination against the following agents is recommended: pneumococcus, tetanus, diphtheria, pertussis, Haemophilus influenzae, meningococcus, polio, Hepatitis B virus, influenza, measles, mumps, and rubella.[47] Several prophylaxis regimens have been proposed to prevent infections depending on the risk stratification of patients.

According to the guidelines, vaccination against the following agents is recommended: pneumococcus, tetanus, diphtheria, pertussis, Haemophilus influenzae, meningococcus, polio, Hepatitis B virus, influenza, measles, mumps, and rubella.[47] Several prophylaxis regimens have been proposed to prevent infections depending on the risk stratification of patients. Many risk-scoring tools exist for evaluating hematopoietic stem cell transplant recipients to stratify risk so that proper preparation and treatment can be established to minimize the risks and toxicities before, during, and after transplantation. The most commonly utilized scoring tools in clinical practice are the European Group for Blood and Marrow Transplantation risk score, the hematopoietic cell transplantation-comorbidity index/age, and the Armand disease risk index.[66][67][68]

The use of HPSCT in clinical practice has expanded in the last decade, and there are many ongoing clinical trials to assess its efficacy in different medical conditions. However, given the lack of knowledge across most medical practices, an interprofessional team approach to care can help improve patient outcomes, where all team members can offer suggestions and guidance based on their knowledge and experience regarding potential stem cell transplant therapy for patients where it can benefit.