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Advances in Stem Cell Transplantation in Children

From The Child's Doctor, Spring 2012

Jennifer Schneiderman, MD, MS
Attending physician, Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant professor of Pediatrics, Northwestern University Feinberg School of Medicine
Disclosure: Dr. Schneiderman has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.

Other Disclosure Information

Educational objectives

At the conclusion of this activity, participants will be able to:

  • Discuss stem cell sources for hematopoietic stem cell transplantation (HSCT)
  • Describe new approaches to reduce complications of HSCT
  • Identify HSCT indications for malignant and non-malignant diseases

CME credit

Credit statement

Hematopoietic stem cell transplantation (HSCT) refers to a procedure in which pluripotent hematopoietic progenitor cells (HPC) are infused to restore bone marrow function in patients with either malignant or nonmalignant diseases. HPCs give rise to all the cell types found circulating in the peripheral blood. This review will familiarize pediatricians with potential stem cell sources and emerging approaches meant to reduce short-term and long-term complications associated with transplantation. In addition, current indications for HSCT will be reviewed. 

Types of transplants and stem cell sources

Depending on the disease, patients might undergo autologous or allogeneic transplantation. Autologous transplants involve harvesting and cryopreserving the patient’s own HPCs and returning them after a cycle of high-dose chemotherapy from which marrow function would not be restored without stem cell support. Use of autologous transplants is reserved for patients with cancers, generally solid tumors, in whom the goal is to intensify the chemotherapy regimen. The effectiveness of autologous HSCT is based entirely on the high doses of chemotherapy administered prior to stem cell infusion. Patients may also undergo tandem cycles of autologous HSCT, which refers to 2 cycles of myeloablative therapy, each followed by infusion of the patient’s HPCs. 

Allogeneic transplants are utilized in patients who might benefit from replacement of bone marrow function using HPCs from healthy related or unrelated donors. The search for a suitable donor is initiated once the patient is referred for consideration of a transplant. The donor HPCs need to be closely matched to the patient; typing of human leukocyte antigen (HLA) is utilized to determine the appropriate donor for each patient. Siblings and parents are typed first, as there are lower rates of complications from graft-versus-host disease (GVHD) with matched related donor transplants. If, however, a healthy related donor cannot be identified, we then look to the National Marrow Donor Program (NMDP, “Be the Match”) to broaden the search. 

Matched or minimally mismatched allogeneic HPCs from an unrelated donor may be obtained from a healthy adult or a previously donated umbilical cord blood unit. One of the main limitations in the use of cord blood units is the finite number of cells in the product and the inability to go back to the donor for more cells. As such, novel approaches including the use of double cord transplants and methods of expanding the number of stem cells in a cord blood unit prior to infusion are currently under investigation. 

Healthy adult donors might donate stem cells in the form of either bone marrow aspirated from the iliac crests or from the peripheral blood following a course of granulocyte colony stimulating factor (GCSF). The decision to use bone marrow versus peripheral blood stem cells is complex and depends on a multitude of factors, including donor preference, transplant center preference, and specific study requirements. 

New approaches to reduce potential risks in HSCT

Regardless of the type of transplant performed (autologous or allogeneic), there are a number of adverse events that might occur. HSCTs of either type carry the risks of acute, overwhelming infections (bacterial, viral, fungal), mucositis requiring administration of narcotic medications, hemorrhage, veno-occlusive disease of the liver, and pulmonary, renal, or cardiac complications. Long-term complications that might follow HSCT also include infertility, impaired growth and neurocognitive development, and secondary malignancies. Outcomes from HSCT overall have improved in the last several years, mainly due to improvements in supportive care, pre-emptive treatment of infections, and the evolution of less toxic conditioning regimens. 

Allo-HSCT may involve the administration of high, myeloablative doses of chemotherapy or novel non-myeloablative regimens, also referred to as reduced intensity transplants. In the setting of a reduced intensity transplant for malignancies, the potential disease control is derived from the donor’s immune system surveying for and destroying any residual disease, termed the graft-versus-malignancy effect. Reduced intensity transplants are largely reserved for patients who have co-morbidities, such as poor cardiac, renal, liver, or lung function, that preclude them from receiving myeloablative therapy. 

Researchers also are investigating novel protocols in which patients undergo myeloablative conditioning with non-conventional chemotherapy agents that may reduce toxicities in the short term (less severe and shorter course of mucositis and neutropenia) and long term (potentially less risk for secondary malignancies and infertility). The goal of these studies is to reduce risks and toxicities related to transplantation while preserving excellent rates of engraftment of the donor cells and disease control. This is an especially important approach when transplanting pediatric patients, as their potential for long-term survival and the development of late toxicities is greater than in adults. Reduced intensity and reduced toxicity transplants might revolutionize the way in which we perform transplantation in pediatric patients. 

Additional strategies under investigation for reducing the potential morbidities and mortality from HSCT involve further improvements in supportive care. Certainly much of the improved survival in the setting of HSCT over the last 20 years can be attributed to the development of supportive care protocols. For example, fewer patients suffer from invasive viral infections from CMV and adenovirus when preemptive therapy with anti-viral agents is used at the first sign of positivity in the blood. Several new medications for nausea and the prevention of severe mucositis are under investigation in the setting of HSCT with the goals of improving quality of life (less nausea and pain) and reducing the frequency of invasive bacterial infections that result from mucosal interruption following high doses of chemotherapy and radiation. 

A serious risk specific to allogeneic transplant is GVHD, which occurs with increasing frequency when the patient’s donor is unrelated and/or mismatched. Acute GVHD generally occurs within the initial 2 to 3 months after transplantation and can affect 3 main organ systems: the skin, liver, and gastrointestinal tract. Skin manifestations vary from mild itching and localized rash to blister formation and desquamation that may involve the entire body surface. Liver changes are heralded by an elevation in bilirubin due to damage to bile ducts. Manifestations of GVHD in the gastrointestinal tract include nausea, vomiting, abdominal pain, and profuse diarrhea. 

Chronic GVHD generally develops several months following the transplant and is a multi-system disease involving primarily the skin, eyes, gastrointestinal tract, lungs, and liver. While many patients may experience resolution of chronic GVHD, up to 40% of patients may still require immune suppressive therapy 5 to 7 years after initial diagnosis. Given the potential for long-term immunosuppression and morbidities in patients with chronic GVHD, it is imperative that we continue to search for better, more effective prevention and therapy for these children. Prospective, randomized clinical trials are challenging to perform in this group of pediatric patients due to the relatively low number of those affected, and difficulty in assessing disease activity and response to treatment. 

Novel therapies such as extracorporeal photopheresis (ECP) have become more widely available for use in patients with chronic GVHD.  ECP involves the treatment of a patient’s white blood cells in the peripheral blood that are temporarily removed from the body by centrifugation with a medication called 8-methoxypsoralen (8-MOP) and exposure of the cells to ultraviolet light. The cells are then returned to the patient. Over the following 36 – 48 hours, the cells undergo apoptosis (programmed cell death), which triggers a certain subset of lymphocytes in the blood (T-regulatory cells) to become more active, thereby reducing the production of inflammatory cytokines and increasing the production of anti-inflammatory cytokines. When utilized early in the course of GVHD, ECP can be successful in the treatment of skin, lung, and liver GVHD. The optimal frequency and course of ECP is currently under investigation. 

Transplant indications for malignancies

Given the vast improvement in overall survival rates in the field of pediatric oncology, along with potential risks associated with any HSCT, there are fluid disease specific guidelines in place to help the clinician determine which patients need to be referred for transplant. Ultimately, the decision to take a patient to HSCT is always based on individual factors with regards to the disease being treated and the clinical status of the patient at the time. 

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy diagnosed in children, and is one of the more common malignancy indications for HSCT. Approximately 6,500 children and young adults are diagnosed with acute leukemia in the United States annually; ALL accounts for about 80%. Most patients with ALL can be successfully treated and cured from their disease without the need for HSCT. However, there are certain high-risk features that may bring a child to the transplant team even in first remission, including cytogenetic abnormalities such as the 9;22 translocation (known as the Philadelphia chromosome) or evidence of residual disease at the end of the first 4 – 6 weeks of induction therapy. Most patients with ALL are treated initially with chemotherapy and only require transplantation if they experience an early relapse of their disease (within 18 months from the time of diagnosis). Patients who relapse later may be successfully cured of their disease with chemotherapy alone, and may not be referred to the transplant team. 

Patients with acute myelogenous leukemia (AML) can be more difficult to treat than ALL. Some patients with healthy HLA-identical siblings are referred to transplant in first remission, while others are treated aggressively with chemotherapy and only referred if relapse occurs. Again, factors including cytogenetic abnormalities, mutations of signal transduction pathways, and response to therapy go into deciding about earlier referral for transplantation, even if a mismatched unrelated donor is the best donor choice. 

Chronic myelogenous leukemia (CML) is a disorder in which all hematopoietic cell lineages are involved. The Philadelphia chromosome is usually present, which allows for directed therapy with tyrosine kinase inhibitors (TKIs) that can control but not ultimately cure the disease (as evidenced by the disease return when TKIs are stopped). The long-term effects of chronic TKI use in children are unknown. As such, the debate about which patients should undergo curative therapy with HSCT remains active. In general, patients with evidence of the Philadelphia chromosome despite TKI therapy or those who develop TKI resistance are referred for consideration of HSCT. 

Myelodysplastic syndromes (MDS) include a heterogeneous group of disorders characterized by cytopenias, dysplasia of cells in the bone marrow, and ineffective hematopoiesis. MDS may be primary or secondary from exposure to certain medications and has the potential to transform into AML. Patients with certain cytogenetic abnormalities including loss of chromosome 5 or 7 are at particular risk for malignant transformation. Due to this risk, patients found to have MDS are often referred for transplant. Patients with juvenile myelomonocytic leukemia (JMML) may also be included in this group. HSCT remains the only curative therapy for these disorders. 

Children with solid tumors may also be referred to the stem cell transplant team at varying points during their therapy, most often to undergo autologous HSCT with the goal of intensifying chemotherapy, thus necessitating “rescue” of bone marrow function with their own cells that have been harvested previously. Patients with high-risk neuroblastoma undergo such cycles of high-dose chemotherapy and auto-SCT as up-front therapy for their disease, based on data acquired in a clinical trial from the early 1990s in which children with high-risk neuroblastoma who were randomized to undergo single transplantation had an improvement in survival that was statistically significant. Subsequent clinical trials in this disease have focused on determining if tandem cycles of auto-SCT are more effective than a single cycle. 

Single or tandem transplants have also been used for consolidation therapy in patients with certain CNS tumors and in the setting of relapsed Hodgkin’s and non-Hodgkin’s lymphoma, Wilms tumor, and germ cell tumors. The use of allogeneic HSCT in patients with diseases such as Hodgkin’s lymphoma and neuroblastoma in order to induce a graft-versus tumor effect is currently under investigation in patients who have relapsed following autologous HSCT. 

Novel therapies for patients with neuroblastoma include the use of antibodies directed to a marker (GD2) present on neuroblastoma cells. After the antibody attaches to GD2, the patient’s immune system is directed to treat the cell as foreign to induce killing. Anti-GD2 antibodies are used systemically after transplant in order to “seek and destroy” any remaining tumor cells in the hopes of reducing rates of relapse. In addition, these antibodies are being successfully used in the central nervous system to treat isolated relapses to the brain. 

Transplant indications for non-malignant diseases

HSCT may also be used in the setting of nonmalignant diseases in which the phenotype can be cured by replacing abnormally produced or functioning red cells, white cells, or platelets. Transplant centers are participating in novel clinical trials using reduced intensity regimens and unrelated donors for patients with hemoglobinopathies including sickle cell disease and thalassemia, giving patients without a related donor their first hope for cure of an otherwise lifelong disease. In general, HSCT is being offered for patients with severe phenotypes who require chronic transfusion therapy, which over time adversely affects linear growth, cardiac and liver function, and reproductive potential. Children who successfully undergo transplantation will have freedom from chronic morbidities from their disease that patients before them would not have otherwise enjoyed. 

Children with either congenital (Fanconi anemia or Diamond Blackfan anemia) or acquired (severe aplastic anemia) bone marrow failure syndromes may require transplantation in order to correct abnormal hematopoiesis. Finally, children with primary immunodeficiency diseases including severe combined immune deficiency (SCID), Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, X-linked lymphoproliferative disease, and others undergo allogeneic HSCT in order to replace their non-functioning immune system with one that is healthy. Reduced intensity conditioning regimens are now available for immunodeficiency patients with the hopes of minimizing short- and long-term toxicities in these children who otherwise do not require exposure to chemotherapeutic agents. 


Hematopoietic stem cell transplantation remains an effective treatment for patients with rare, severe disorders. Future advances targeted at reducing the short- and long-term risks associated with HSCT, including further improvement in general supportive care, reduced toxicity and intensity regimens, and better treatments for GVHD will continue to improve overall survival rates. 

For Further Reading 

[1.] Laport GG, Alvarnas JC, Palmer JM, et al. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen. Blood Aug 1 2008;112(3):903-909. 

[2.] Satwani P, Sather H, Ozkaynak F, et al. Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of acute lymphoblastic leukemia: a Children’s Oncology Group study report. Biol Blood Marrow Transplant Feb 2007;13(2):218-227. 

[3.] Neudorf S, Sanders J, Kobrinsky N, et al. Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival. Blood May 15 2004;103(10):3655-3661. 

[4.] Anderlini P, Saliba R, Acholonu S, et al. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin’s lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica Feb 2008;93(2):257-264. 

[5.] George RE, Li S, Medeiros-Nancarrow C, et al. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol Jun 20 2006;24(18):2891-2896. 

[6.] Couriel D, Caldera H, Champlin R, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer Nov 1 2004;101(9):1936-1946. 

[7.] Miano M, Faraci M, Dini G, Bordigoni P. Early complications following haematopoietic SCT in children. Bone Marrow Transplant Jun 2008;41 Suppl 2:S39-42. 

[8.] Nasilowska-Adamska B, Rzepecki P, Manko J, et al. The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant. Bone Marrow Transplant Nov 2007;40(10):983-988. 

[9.] Duncan CN, Buonanno MR, Barry EV, et al. Bronchiolitis obliterans following pediatric allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant Jun 2008;41(11):971-975.


Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this live activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.