Bone marrow transplant (hematopoietic stem cell transplant) (HPSCT) involves the administration of healthy hematopoietic stem cells in patients with dysfunctional or depleted bone marrow. This helps to augment bone marrow function and allows, depending on the disease being treated, to either destroy tumor cells with malignancy or to generate functional cells that can replace the dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases.
History and Evolution
Hematopoietic stem cell transplantation (HSCT) was first explored in humans in the 1950s and 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. These animal-based studies soon found their clinical application into humans when the first successful bone marrow transplant was performed in monozygotic twins in New York in 1957 (syngeneic transplant) in a patient with acute leukemia. As a result, the physician Dr. Thomas who performed the procedure continued his research on the development of bone marrow transplantation and later received the Nobel Prize of physiology and medicine in appreciation of his work. The first successful allogeneic bone marrow transplant was reported in Minnesota in 1968 for a pediatric patient with severe, combined immunodeficiency syndrome. Since then, allogeneic and autologous stem cell transplant has increased in the United States and worldwide. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogenic transplants performed in the United States in 2016 with a higher number of autologous transplants with a steady and higher increase of autologous compared to allogenic.
Major Histocompatibility Complex (MHC)
The group of genes on the short arm of chromosome 6 (p6) that encodes human leukocyte antigens (HLA) which are considered being highly polymorphic leading to a large difference in the resultant expressed proteins on human cells. They are divided into MHC I and MHC II
Human Leukocyte Antigens (HLA)
These are the proteins expressed on the cellular surface and play an important role in alloimmunity. HLA can be divided into (HLA-A, B, and C) which are encoded by class I MHC and are expressed on all cell types and present peptides derived from the cytoplasm and are recognized by CD8+ T cells. The other HLA type is classified as (HLA- DP, DQ, and DR) which are encoded by MHC II and can be found on antigen-presenting cells (APCs) and this class is recognized by CD4+ T cells.
Syngeneic Bone Marrow Transplantation
The donor and the recipient are identical twins. The advantages include no graft versus host disease (GVHD) and no graft failure. However, only a tiny number of transplant patients will have the ability to have an identical twin for transplantation.
Autologous Bone Marrow Transplantation
The bone marrow products are collected from the patient and are reinfused after purification methods. The advantages include no GVHD. The disadvantage is that the 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.
The donor is an HLA matched family member, unrelated matched donor or mismatched family donors (haploidentical).
The process of which infused transplanted hematopoietic stem cells produce mature progeny in the peripheral circulation
This is a regimen that comprises high-dose chemotherapy and/or total body irradiation (TBI) which are administered to the recipient prior to stem cell infusion to eliminate the largest number of malignant cells and to allow for immunosuppression in the recipient so that engraftment can occur.
Autologous stem cell transplant accounts for most hematopoietic stem cell transplants according to CIBMTR in 2016 in the United States. Studies have shown increased overall survival and progression free survival in patients younger than 65 years old when consolidation therapy with melphalan is initiated followed by autologous stem cell transplantation and lenalidomide maintenance therapy. The study showed a favorable outcome of high-dose melphalan plus stem-cell transplantation when compared with consolidation therapy with melphalan, prednisone, lenalidomide (MPR). It also showed a better outcome in patients who received a maintenance therapy with lenalidomide.
Hodgkin and Non-Hodgkin Lymphoma
Studies have shown that chemotherapy followed by autologous stem cell transplantation in cases of recurrent lymphomas (HL and NHL) that do not respond to initial conventional chemotherapy have better outcomes. A randomized controlled trial by Schmitz N et al. showed a better 3-year outcome of high-dose chemotherapy with autologous stem cell transplant compared to aggressive conventional chemotherapy in relapsed chemosensitive Hodgkin lymphoma. However, the overall survival was not significantly different between the two groups. The number of hematopoietic stem cell transplant recipient comes second after multiple myeloma according to CIBMTR.
Acute Myeloid Leukemia
Allogenic stem cell transplant has shown to improve outcome in patients with AML who fail primary induction therapy and do not achieve compete response and may prolong overall survival. The study recommended that early HLA typing for patients with AML can help if they fail induction therapy and are considered for bone marrow transplant.
Acute Lymphocytic Leukemia
Allogenic stem cell transplant is indicated in refractory and resistant cases when induction therapy fails for a second time in inducing remission. Some studies suggest an increased benefit of allogenic hematopoietic stem cell transplant in patients with high risk ALL including patients with Philadelphia chromosome and those with t(4, 11).
Allogenic stem cell transplant is considered being curative in cases of disease progression and is only indicated in intermediate- or high-risk patients with MDS.
Chronic Myeloid Leukemia/Chronic Lymphocytic Leukemia
Recipients with these two diseases come at the bottom of the list of patients who received allogeneic stem cell transplant in 2016. Hematopoietic stem cell transplantation has shown high cure rates but with available treatments like tyrosine kinase inhibitors and high success rates with low adverse risk profile, HSCT is reserved for patients with the refractory disease to first-line agents in CML.
Myelofibrosis, Essential Thrombocytosis, and Polycythemia Vera
Allogenic stem cell transplant has shown to improve outcomes in patients with myelofibrosis and those who had a diagnosis of myelofibrosis that was preceded by essential thrombocytosis and polycythemia vera.
Autologous stem cell transplant is considered the standard of care in patients with germ cell tumor (testicular tumors) that are refractory to chemotherapy (after the third recurrence with chemotherapy). HSCT has also been studied in medulloblastoma, metastatic breast cancer, and other solid tumors.
Systematic and retrospective studies have suggested an improved outcome with hematopoietic stem cell transplant in acquired aplastic anemia when compared with conventional immunosuppressive therapy. Allogenic stem cell transplant has shown better outcomes when it was collected from bone marrow compared to peripheral blood in a study that involved 1886 patients with acquired aplastic anemia. Patients with aplastic anemia need preparative regimen given they still can develop immune rejection to the graft.
Severe Combined Immune Deficiency Syndrome (SCID)
Large retrospective studies have shown increased overall survival in infants with SCID when they received the transplant early at birth before the onset of infections.
Allogenic stems transplant from a matched sibling donor is considered an option to treat Thalassemia and has shown 15-year survival reaching 80%. However, recent retrospective data showed similar overall survival compared with conventional treatment that consists of multiple transfusions in the case of thalassemia.
Sickle Cell Anemia
Allogenic stem cell transplant is recommended for the treatment of sickle cell disease.
Other Nonmalignant Diseases
Stem cell transplant has been used in the treatment of chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi syndrome, Kostman syndrome, Fanconi anemia, Blackfan-Diamond anemia, and enzymatic disorders. Moreover, the role of stem cell transplant is being explored in autoimmune diseases including systemic sclerosis, systemic lupus erythematosus and has already shown promising results in cases like relapsing-remitting multiple sclerosis.
There are no absolute contraindications for hematopoietic stem cell transplant.
Special equipment exists for the collection, preservation, and administration of stem cell products.
A multidisciplinary team approach is a mainstay of ensuring the high-quality collection and infusion of stem cell products.
Mechanism of Action
The mechanism of action of stem cell transplant against malignancy in leukemia is based on the effect of the graft and donor immunity against malignant cells in recipients. These findings were demonstrated in a study that involved over 2000 patients with different leukemia. These patients received stem cell transplantation and showed that the lowest rate of relapses was in patients who received non-T-cell-depleted bone marrow cells and in those who developed GVHD compared to patients who received T-cell-depleted stem cells, those who did not develop GVHD, and patients who received syngeneic grafts. These findings support the notion that donor cellular immunity plays a central role in the engraftment's efficacy against tumor cells.
The mechanism of action in autoimmune diseases is believed to be secondary to the increase in T-cell regulatory function which promotes immune tolerance. However, more studies are still needed to determine the exact pathophysiology.
In hemoglobinopathies, the transplanted stem cells produce functional cells after engraftment that replaces the diseased cells.
HLA typing is an important step to determine the best donor suitable for stem cell collection. In theory, matched, related donors are the best candidates, followed by matched unrelated donors, cord blood, and then haploidentical donors. HLA typing is analyzed at either an intermediate-resolution level, which entails the detection of a small number of matched alleles between the donor serum and the recipient, or at a high-resolution level to determine the specific number of polymorphic alleles at a higher level. PCR and next-generation sequencing are used for HLA typing, and the results are reported as a score correlating with a match of two alleles for a specific HLA type. Different institutions use a different number of HLA subtypes for eligibility of donors but according to studies that showed matching for HLA-A, B, C, and DRB1 at a high-resolution level were associated with improved survival and outcomes. Recommendations about donor HLA assessment and matching have been proposed by the Blood and Marrow Transplant Clinical Trials Network (BM CTN).
The process may vary depending on the source of the stem cell site collection, whether it is bone marrow, peripheral blood, or cord blood. Moreover, there is a slight difference based on whether it is autologous, allogeneic, or syngeneic. For example, the procedure consists of initial mobilization of stem cells, in which peripheral blood stem cells are collected given the low number and the need for high levels of progeny cells, and then this is followed by preparative regimen and finally, infusion.
Mobilization and collection involved the use of medication to increase the number of stem cells in the peripheral blood given that there are not enough stem cells in the peripheral blood. The agents used include granulocyte colony-stimulating factors (G-CSF) or chemokine receptor 4 (CXCR4) blockers like plerixafor. G-CSF is believed to enhance neutrophils to release serine proteases which lead to a break of vascular adhesion molecules and the release of hematopoietic stem cells from the bone marrow. Plerixafor blocks the binding of stromal cell-derived factor-1-alpha (SDF-1) to (CXCR4) which leads to the mobilization of stem cells to the peripheral blood. CD34+ is considered the marker for progenitor hematopoietic stem cells in the peripheral blood, and usually, a dose of 2 to 10 x 10/kg CD34+ cells/kg is needed for proper engraftment. Chemotherapy can be used in some instances for mobilization of hematopoietic stem cells; this process is termed chemoembolization.
The usual site of bone marrow collection is the anterior or posterior iliac crest. The procedure can be performed under local or general anesthesia. Complications include pain, fever, and serious iatrogenic complications can occur in less than 1% of cases. Multiple aspirations are done with each aspirate containing 15 mL. The goal is to collect up to 1 to 1.5 L of bone marrow product from the aspirations. The dose of nucleated cells from bone marrow should range between 2 to 4 x 10 cells/kg as studies showed that overall survival and long-term engraftment is strongly influenced by cell dose in allogeneic hematopoietic stem cell transplantation.
The preparative regimen consists of administration of chemotherapy with or without total body irradiation for the eradication of malignant cells and induction of immune tolerance for the transfused cells to engraft properly. This process is not only limited to patients with malignancies but also extends to cases like aplastic anemia and hemoglobinopathies given that these patients have an intact immune system that could cause graft failure if there is no conditioning.
The preparative regimen is divided into myeloablative conditioning and reduced intensity conditioning. The preparative regimen depends on the disease being treated, existing comorbidities, and the source of the harvested hematopoietic stem cells. The preparative regimen consists of chemotherapy, total body irradiation, or both. There are different combination regimens used in the preparative period, and the choice of the regimen depends on the disease being treated, existing comorbidities, and previous exposure to radiation.
In the special case of SCID, there is no need for preparative regimen in patients receiving from HLA-matched siblings given that there are no abnormal cells that are needed to be eliminated and because immunosuppression caused by SCID can prevent graft rejection. Reduced-intensity conditioning is preferred in patients with prior radiotherapy, older age, the presence of comorbidities, and history extensive chemotherapy before BMT. The advantages of using reduced-intensity conditioning include less need for transfusion due to the transient post-transplant pancytopenia and less damage to the liver in cases of chemotherapy and lung due to radiation. However, the relapse rates are higher, but these regimens are more tolerated with a better safety profile in a specific patient population. Most of the chemotherapies used in preparative regimens consist of either potent immunosuppressive agents (high doses of cyclophosphamide 60 mg/kg IV), alkylating agents especially busulfan 130 mg/m2 IV, nucleoside analogs (fludrabine 40 mg/m2) and other agents like melphalan, antithymocyte globulin, rituximab, gemcitabine, and many others. Total body irradiation (TBI) is performed using fractionated doses because it has shown less pulmonary toxicity when compared with one dose regimen. The administration of the preparative regimen should immediately precede the bone marrow transplantation, and as a general rule, the effect of the regimen should produce bone marrow suppression within 1 to 3 weeks of administration.
Reinfusion of either fresh or cryopreserved stem cells can occur in an ambulatory setting and takes up to 2 hours. Before the infusion begins, quality measures are performed to ensure the number of CD34+ cells is sufficient.
Advantages and Disadvantages of Different Hematopoietic Stem Cells
The advantages of peripheral blood stem cells transplant (PBSCTs) include more rapid engraftment rate compared to bone marrow where it takes about 2 weeks of recovery in the former and is delayed for 5 days more in the latter, but the use of post-transplant immunosuppressive regimen to prevent GVHD can prolong the increase in bone marrow products. Moreover, the rate of acute GVHD appears to be similar when compared with bone marrow transplantation in HLA- identical matched related donors. However, chronic GVHD appears to be encountered more after peripheral blood stem cell transplant which could lead to more complications. In the study by Anasetti et al., the primary endpoint was the difference in the 2-year overall survival seemed to be non-significant in the two groups. However, secondary end points showed more stable grafts with decreased graft failure in the group which received peripheral blood stem cell transplant but also this group had a higher incidence of chronic GVHD. Other similar studies comparing both bone marrow transplant and peripheral blood SCTs concluded that the psychological burden due to chronic GVHD and the 5-year ability to restore normal activities including going back to work were better in the bone marrow transplanted group.
The advantages of cord blood transplant include the rapid collection and administration which serves in treating urgent conditions, less frequency of infections, lower rates of GVHD with the same rate of GVT, less need for a stringent identical HLA. The disadvantages include delayed engraftment with a higher possibility of graft rejection and higher rates of disease relapses. The cord blood transplant is most used in patients without matched related or unrelated donors. A major study by Locatelli et al. demonstrated the utility of cord blood transplant in patients with thalassemia major and sickle cell anemia and showed similar 6-year overall survival in the CBT and BMT groups. The most important factors that affect the outcome of CBT are the total nucleated cell dose and HLA matching with a recommended minimum dose of total nucleated cells of 2 x 10*7 cells/kg for successful engraftment. Theoretically, strict HLA matching is not required in the case of cord blood transplant given it is devoid of mature T cells but studies have shown better outcomes when matching recipients at HLA-A, HLA-B, HLA-C, and HLA-DRB1. Given that a single blood cord unit might not contain the required amount of nucleated cells an approach using double cord transplant is used to overcome this problem. However, only one cord blood transplant product will predominate within 3 months of infusion. Further, randomized controlled trials failed to show a significant difference in terms of outcome benefits or risks between double cord blood and a single cord blood transplant.
Haploidentical stem cell transplantation refers to the administration of bone marrow products from a first degree related haplotype-mismatched donor. This helps in non-white patients like African American, Hispanics, and patients from countries where there is no wide access to resources as they have fewer chances of having a matched unrelated donor. The advantages include lower cost and rapid availability of the hematopoietic cell products. However, the disadvantages include hyperacute GVHD which increases mortality and graft rejection. This has been overcome by depletion of T cells responsible for the reaction mentioned above, but this also leads to delayed immune recovery and decreased graft versus tumor effect. Recently strategies including selective depletion of subsets of T cells including alpha-beta have shown improved outcomes when compared to conventional ex vivo depletion of large T-cell populations.
Complications after bone marrow transplant can be divided into acute and chronic. Many factors can affect the occurrence of these adverse events including the age of the patient, baseline performance status, the source of stem cell transplant the type and intensity of the preparative regimen. Acute complications can occur in the first 90 days and include myelosuppression with neutropenia, anemia, thrombocytopenia, sinusoidal obstruction syndrome (SOS), mucositis, acute graft versus host disease, gram-positive/gram-negative infections, HSV, CMV, Candida, and Aspergillus. Chronic complications include chronic GVHD, infection with encapsulated bacteria and VZV. Levofloxacin is usually given by mouth or intravenously (IV) at day 1 post-transplant and is continued until absolute neutrophil count (ANC) is more than 1000 cells/uL or until the discontinuation of prednisone in cases of GVHD. PCP prophylaxis is warranted given the immunosuppression following hematopoietic stem cell transplant. Trimethoprim-sulfamethoxazole (TMP-SMX) is usually used, and several dosing regimens have been proposed. TMP-SMX is given 2 days per week until the patient is off immunosuppression. Antifungal infection prophylaxis with fluconazole is recommended for 1 month following transplant as it has shown to decrease the incidence of fungal infections and no difference was seen when fluconazole was compared to voriconazole. However, voriconazole is used in patients with a high-risk profile of developing severe forms of antifungal infection. Prevention against HSV and VZV is achieved with acyclovir that is continued for 1 month for the prevention against HSV and for 1 year for preventions against VZV.  Prophylaxis against CMV is only recommended in patients who test positive for CMV 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.
Sinusoidal Obstruction Syndrome (SOS)
Also known as veno occlusive disease (VOD) is the result of chemotherapy during preparative regimen and occurs within 6 weeks of hematopoietic stem cell transplant. 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. The pathophysiology consists of endothelial damage to the hepatic sinusoids leading to obstruction and necrosis of the centrilobular liver. 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. The use of IV busulfan has shown to decrease the occurrence of SOS. The diagnosis is clinical and is based on hyperbilirubinemia greater than 2 mg/dL with the other clinical findings of tender hepatomegaly and fluid retention. Treatment consists of ursodeoxycholic acid (UDCA) which has shown to significantly decrease the occurrence of SOS when given pre and post-transplant. Another medication, defibrotide, has shown efficacy in the treatment of SOS when it occurs.
Idiopathic Pneumonia Syndrome (IPS)
This usually happens in the first 90 days post-transplant. The incidence is low and is related to direct chemotoxicity due to preparative regimen. Treatment with steroids is usually used although no randomized controlled clinical trials have been done to support their efficacy. Recently, etanercept has been studied in a randomized control trial in patients who develop this syndrome. The study assessed the addition of soluble TNF inhibitors to steroids in the treatment and has not shown added efficacy with combination therapy.
The process of which there is a loss of bone marrow function after reconstitution following infusion of hematopoietic stem cells or if there is no gain of function after infusion and is termed graft failure or rejection. The incidence of failure is highest when there is a high HLA disparity that usually occurs in the case of cord blood and haploidentical donors and is 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. Checking for chimerism is an important step in ensuring engraftment and success of the transplantation. The physician does this by checking the expression of CD33 which indicates the presence of granulocytes and CD3 which indicate the presence of T cells and confirming that most of the present cells 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.
Graft Versus Host Disease
The graft versus host disease (GVHD) consists of the reaction between T-cells from the donor in allogeneic transplant and recipient’s HLA polymorphic epitopes that leads to a constellation of symptoms and manifestations. GVHD can be categorized into acute and chronic which are both sub-categorized into classic and late onset, classic, and chronic overlap respectively. Acute GVHD usually develops within three months. However, it can develop after 3 months and is termed delayed acute GVHD. Prophylaxis is usually achieved with calcineurin inhibitors, methotrexate, and anti-thymocyte globulins. Severity is estimated based on Glucksberg scale which classifies acute GVHD from grade I to VI, and treatment with either high dose prednisone or methylprednisolone is indicated in higher grades.
Chronic GVHD occurs after three months and is represented by the involvement of multiple organs in a similar fashion to collagen vascular diseases. Grading has been developed by NIH (Global Grading System) to assess the severity of GVHD which determines the treatment modality and predicts survival . Treatment is similar to that of acute GVHD, but the duration is usually over 2two years.
Chemotherapy and radiation of preparative regimen along with post-transplant immunosuppression can induce severe pancytopenia in the first week following infusion of hematopoietic stem cells which can lead to life-threatening infection. This depends on the type and the dose of chemotherapy administered and factors related to the recipients. Chemotherapy causes a destruction of healthy, normal bone marrow products including neutrophils, macrophages, monocytes, and lymphocytes. Also, mucositis toxicity due to chemotherapy disrupts the barriers protecting against infectious agents, and use of indwelling intravenous catheters provides another mean of the entrance of infectious agents. Vaccination is recommended for the following agents according to the guidelines: pneumococcal conjugate (PCV), TDaP, Haemophilus influenzae, meningococcal conjugate, onactivated polio, recombinant hepatitis B, inactivated influenza, and MMR. Several regimens of prophylaxis have been proposed to prevent infections depending on the risk stratification of patients (low-risk, high-risk, treatment of ongoing GVHD.
Many risk scoring tools exist for the evaluation of recipients of hematopoietic stem cell transplant and stratification of risks so that proper preparation and treatment can be established to minimize the risks and toxicities before, during, and after transplantation. Some of the most commonly utilized scores in clinical practice are the European Group for Blood and Marrow Transplantation (EBMT) risk score, hematopoietic cell transplantation-comorbidity index/age, and Armand disease risk index (DRI).
Hematopoietic stem cell transplant use in clinical practice has been expanding in the last decade, and many clinical trials are still ongoing to assess its efficacy in different medical conditions.
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