Hematopoietic Stem Cell Transplantation

Continuing Education Activity

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.

Introduction

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)

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.

Indications

Malignant Disease

Multiple Myeloma

Studies have shown increased overall survival and progression-free survival in patients younger than 65 years when consolidation therapy with melphalan is initiated, followed by autologous stem cell transplantation and lenalidomide maintenance therapy.[6] The study showed a favorable outcome of high-dose melphalan plus HPSCT compared to consolidation therapy with melphalan, prednisone, and lenalidomide. It also showed better outcomes in patients who received maintenance therapy with lenalidomide.

Hodgkin and Non-Hodgkin Lymphoma

Studies have shown that in cases of recurrent Hodgkin and Non-Hodgkin lymphomas that do not respond to initial conventional chemotherapy, chemotherapy followed by autologous stem cell transplantation leads to better outcomes. A randomized controlled trial by Schmitz showed a better outcome at three years 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.[7] CIBMTR reports that his group of malignancies accounts for the second highest number of HPSCTs in the US, after multiple myeloma.

Acute Myeloid Leukemia (AML)

Allogeneic stem cell transplant has been shown to improve outcomes. It may prolong overall survival in patients with AML who fail primary induction therapy and do not achieve a complete response.[8] The study recommended that early HLA typing for patients with AML is beneficial if they fail induction therapy and are considered for HPSCT.

Acute Lymphocytic Leukemia (ALL)

Allogeneic stem cell transplant is indicated in refractory and resistant cases of ALL when induction therapy fails for a second time to induce remission. Some studies suggest an increased benefit of allogeneic HPSCT in patients with high-risk ALL, including patients with the Philadelphia chromosome and those with t(4;11).[9]

Myelodysplastic Syndrome (MDS)

Allogeneic stem cell transplant is considered curative in cases of disease progression and is only indicated in intermediate- or high-risk patients with MDS.

Chronic Myeloid Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL)

Patients with CML and CLL received the fewest number of allogeneic transplants in 2020. HPSCT has high cure rates for CML, but because tyrosine kinase inhibitors pair high success rates with a low adverse risk profile, HPSCT is reserved for patients with refractory disease.

Myelofibrosis, Essential Thrombocytosis, and Polycythemia Vera

Allogeneic stem cell transplant has been shown to improve outcomes in patients with myelofibrosis and those diagnosed with myelofibrosis preceded by essential thrombocytosis or polycythemia vera.[10]

Solid Tumors

Autologous stem cell transplant is considered the standard of care in patients with testicular germ cell tumors that are refractory to chemotherapy; in this case, refractory is defined as the third recurrence with chemotherapy.[11] HPSCT has also been studied in medulloblastoma, metastatic breast cancer, and other solid tumors.

Non-Malignant Diseases

Aplastic Anemia

Systematic and retrospective studies have suggested an improved outcome with HPSCT in acquired aplastic anemia compared to conventional immunosuppressive therapy.[12] In a study of 1886 patients with acquired aplastic anemia, transplanted cells collected from the bone marrow produced superior outcomes compared to those collected from the peripheral blood.[13] Patients with aplastic anemia need a preparative regimen, as 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 after birth before the onset of infections.[14]

Thalassemia

Allogeneic stem cell transplant from a matched sibling donor is an option to treat certain types of thalassemia and has shown 15-year survival rates reaching near 80%. However, recent retrospective data showed similar overall survival compared to conventional treatments with multiple blood transfusions.[15]

Sickle Cell Disease

An allogeneic stem cell transplant is recommended to treat sickle cell disease.[16]

Other Non-malignant Diseases

HPSCT has been used to treat chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi syndrome, Kostman syndrome, Fanconi anemia, Blackfan-Diamond anemia, and enzymatic disorders. Moreover, the role of HPSCT is expanding in non-malignant autoimmune diseases, including systemic sclerosis and systemic lupus erythematosus, and has already shown promising results in cases like neuromyelitis optica.[17][18][19][20][21][22][23][24][25] It is also considered best practice for relapsing-remitting multiple sclerosis.[26][27]

Contraindications

There are no absolute contraindications for hematopoietic stem cell transplant.

Equipment

Special equipment exists for collecting, preserving, and administering stem cell products.

Personnel

An interprofessional team approach is a mainstay of ensuring the high-quality collection and infusion of stem cell products.

Preparation

Preparation includes:

• Preparative regimen: high-dose chemotherapy or total body irradiation (TBI) or both
• Collection of hematopoietic stem cells
• Instant infusion or cryopreservation followed by infusion

Technique or Treatment

Mechanism of Action

The mechanism of action of HPSCT 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 leukemias treated with HPSCT. The study showed the lowest relapse rates were in patients who received non-T-cell-depleted bone marrow cells and 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 is central to engraftment efficacy against tumor cells.[28]

The mechanism of action of HPSCT in autoimmune diseases is believed to be secondary to the increase in T-cell regulatory function, which promotes immune tolerance. However, more studies are needed to determine the exact physiology.

In hemoglobinopathies, the transplanted stem cells produce functional cells after engraftment that replace the diseased cells.

Administration

HLA Typing

HLA typing is essential to determine the most suitable donor for stem cell collection. In theory, matched, related donors are the best candidates, followed by matched unrelated donors, cord blood, and haploidentical donors. HLA typing is analyzed at either an intermediate-resolution level, which entails detecting 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. Polymerase chain reaction 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 the eligibility of donors. However, studies that showed high-resolution matching for HLA-A, HLA-B, HLA-C, and HLA-DRB1 were associated with improved survival and outcomes.[29] The Blood and Marrow Transplant Clinical Trials Network (BM CTN) has proposed donor HLA assessment and matching recommendations.[30]

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 HPSCT. For example, the procedure consists of the 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. This is then followed by a preparative regimen and, finally, infusion.

Mobilization and Collection

Mobilization and collection procedures involve using medication to increase the number of stem cells in the peripheral blood, given that there are insufficient stem cells in the peripheral blood. Medications 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 break vascular adhesion molecules and promote the release of hematopoietic stem cells from the bone marrow. Plerixafor blocks the binding of stromal cell-derived factor-1-alpha (SDF-1) to CXCR, leading to stem cell mobilization to the peripheral blood.[31] 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 sometimes be used to mobilize hematopoietic stem cells; this process is termed chemoembolization.

The usual site of bone marrow collection is the anterior or posterior iliac crest. The aspiration procedure can be performed under local or general anesthesia. Common complications include pain and fever; serious iatrogenic complications occur in less than 1% of cases. Each aspiration contains 15 mL, and multiple aspirations are done. The goal is to collect 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; overall survival and long-term engraftment are strongly influenced by cell dose in allogeneic HPSCT.[32]

Preparative Regimen

The preparative regimen consists of the 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 limited to patients with malignancies. It extends to cases like aplastic anemia and hemoglobinopathies, given that these patients have intact immune systems that could cause graft failure if there is no conditioning.

The administration of the preparative regimen should immediately precede the HPSCT. As a general rule, the effect of the regimen should produce bone marrow suppression within 1 to 3 weeks of administration. The preparative regimen is divided into myeloablative conditioning and reduced-intensity conditioning. Different combination regimens are used in the preparative period, depending on the disease being treated, existing comorbidities, previous radiation exposure, and the source of the harvested hematopoietic stem cells. 

Reduced-intensity conditioning is preferred in patients who are older, have had prior radiotherapy, have comorbidities, and have a history of extensive chemotherapy before HPSCT.[33] The advantages of using reduced-intensity conditioning include less need for transfusion due to transient post-transplant pancytopenia, less chemotherapy-induced liver damage, and less radiation-induced lung damage.[34] However, the relapse rates after reduced-intensity conditioning are higher. Nevertheless, these regimens are better tolerated and have a better safety profile in specific patient populations.

Most chemotherapies used in preparative regimens consist of potent immunosuppressive agents like high doses of cyclophosphamide, alkylating agents like busulfan, nucleoside analogs like fludarabine, and many other agents like melphalan, anti-thymocyte globulin, rituximab, and gemcitabine. Total body irradiation is performed using fractionated doses; there is less pulmonary toxicity than with a one-dose regimen.[35] 

Reinfusion of either fresh or cryopreserved stem cells can occur in an ambulatory setting and takes up to two hours. Before the infusion begins, quality measures are performed to ensure the number of CD34+ cells is sufficient.

In the particular case of SCID, there is no need for a preparative regimen in patients receiving cells from HLA-matched siblings. This is because no abnormal cells need to be eliminated, and the immunosuppression caused by SCID can prevent graft rejection.

Advantages and Disadvantages of Different Hematopoietic Stem Cells

One advantage of peripheral blood stem cell transplant (PBSCT) is a more rapid engraftment rate than the bone marrow-derived stem cells; recovery in the former is two weeks and is delayed for five days more in the latter. Using a post-transplant immunosuppressive regimen to prevent GVHD can prolong the increase in bone marrow products.[36] Moreover, the rate of acute GVHD between PBSCT and bone marrow transplantation appears to be similar in HLA-identical matched related donors.[36] However, chronic GVHD is a more common occurrence after PBSCT, which could lead to more complications. Two-year overall survival rates seem to be similar regardless of stem cell origin.[37] Other studies comparing bone marrow-derived transplant and PSCT concluded that the psychological burden due to chronic GVHD and the 5-year ability to restore normal activities, including returning to work, was better in the bone marrow-derived transplant group.[38]

The advantages of cord blood transplant include the rapid collection and administration times, which facilitate treating urgent conditions, less frequent infections, lower rates of GVHD with the same rate of GVT, and less need for a stringent identical HLA. The disadvantages include delayed engraftment, a higher possibility of graft rejection, and higher rates of disease relapses. The cord blood transplant is most commonly used in patients without matched-related or unrelated donors. One major study demonstrated the utility of cord blood transplants in patients with thalassemia-major and sickle cell disease, indicating similar 6-year overall survival rates compared to the bone marrow-derived transplants.[39] 

The most important factors affecting the success of cord blood transplant are the total nucleated cell dose and HLA matching; the recommended minimum dose of total nucleated cells for successful engraftment is 2 x 10^7 cells/kg. Theoretically, strict HLA matching is not required in the case of cord blood transplant as cord blood 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.[40] Given that a single cord blood unit might not contain the required amount of nucleated cells, a double cord transplant is used. However, only one cord blood transplant product will dominate within three months of infusion. Further, randomized controlled trials failed to show a significant difference in outcome, benefits, or risks between double cord blood and a single cord blood transplant.[41][42]

Haploidentical stem cell transplantation involves administering bone marrow products from a first-degree related haplotype-mismatched donor.[43] This helps underserved patients without broad access to resources as they have fewer chances of having a matched unrelated donor.[44] The advantages of this method include lower cost and rapid availability of hematopoietic cell products. However, the disadvantages include hyperacute GVHD, which increases mortality and graft rejection.[45] This has been overcome by the 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 compared to conventional ex vivo depletion of large T-cell populations.[46]

Complications

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)

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.

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]

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.

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]

Enhancing Healthcare Team Outcomes

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.

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Disclosure: Karam Khaddour declares no relevant financial relationships with ineligible companies.

Disclosure: Caroline Hana declares no relevant financial relationships with ineligible companies.

Disclosure: Prerna Mewawalla declares no relevant financial relationships with ineligible companies.