Hematopoietic Stem Cell Transplantation

Michael J. Joyce, M.D., Director, Pediatric Bone Marrow Transplant Program, Division of Hematology/Oncology, Nemours Children's Clinic

 
Introduction

Stem cell transplantation can offer a chance for cure of a variety of disorders in the pediatric population. Malignant diseases treated with allogeneic stem cell transplantation include Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myelogenous Leukemia (CML) and Myelodysplastic Syndromes. Autologous stem cell transplantation is effective in treating solid tumors such as, neuroblastoma, Wilm's tumor, lymphoma (Hodgkin's and non-Hodgkin's) and brain tumors. This article will briefly review the use of stem cell transplantation in the treatment of children with malignant and non-malignant diseases.

Sources of Stem Cells For Autologous Transplantation

The unique properties of the pluripotent hematopoietic stem cell are the biologic basis for stem cell transplantation. The pluripotent stem cell has the ability to regenerate itself and generate all the mature cellular elements of the blood.

Maintenance of hematopoiesis is entirely dependent on the number of multi-potential stem cells present in the bone marrow of an individual as seen in table 1. Successful stem cell transplantation depends upon (1) engraftment of an adequate number of stem cells and (2) maintenance of sustained hematopoietic cell production by these cells.

When a patient's own hematopoietic cells are used as the source of stem cells, it is termed an autologous stem cell transplant. Traditionally, bone marrow (BM) has been used as the source of autologous stem cells. A bone marrow harvest is performed by performing multiple bone marrow aspirates from the posterior iliac crest until an adequate number of stem cells are obtained. A minimum of 2x106 CD34 cells/kg is usually required to perform an autologous stem cell transplant.

Stem cells can also be harvested from the peripheral blood. Under normal conditions, hematopoietic stem cells and progenitor cells reside in the bone marrow compartment and are rarely found in the circulation. The frequency of stem cells or progenitor cells in the circulation is 2 per 100,000 blood mononuclear cells. In order to obtain sufficient numbers of these cells from peripheral blood for clinical use, the stem cells and progenitor cells must be mobilized from the marrow compartment to the peripheral blood. This process is known as Peripheral Blood Stem Cell mobilization (PBSC). Three methods are commonly used to mobilize PBSC: a) myelosuppressive chemotherapy, b) administration of hematopoietic growth factors (i.e. G-CSF or GM-CSF), c) or the combined use of chemotherapy and hematopoietic growth factor.

The combination of myelosuppressive therapy and hematopoietic growth factors can enhance the mobilization of CD34+ PBSC up to 1000 fold when compared to the use of growth factors alone. Cyclophosphamide has been most frequently used in combination with G-CSF for PBSC mobilization.

PBSC collection in children requires the use of an apheresis catheter and the use of a continuous flow cell separation device (i.e. Baxter CS3000, or Colbe). In children, the apheresis catheter is usually placed in a subclavian or femoral vein. In adults, the antecubital veins may be used with an 18-gauge needle or angiocath. The mononuclear cell fraction, which is enriched in stem cells, is collected while the remainder of the blood elements is re-infused into the patient.

One or more collections may be required to achieve an adequate number of stem cells for transplantation. A total of 2x106 CD34 cells/kg is desired for transplantation. PBSC are then cryoprocessed in liquid nitrogen until needed for transplantation.

Stem Cell Sources For Allogeneic Transplantation

Allogeneic stem cell transplantation (Allo SCT) refers to transplantation of stem cells from a donor into a patient (recipient). Human Leukocyte Antigen (HLA) typing can identify donors who may be a perfect match. The human major histocompatability complex (MHC) is located on the short arm of chromosome 6. The MHC contains genes that encode two distinct types of cell surface glycoproteins termed Human Leukocyte Antigens (HLA). HLA Class I antigens are HLA-A, HLA-B, and HLA-C. HLA Class II antigens are HLA-DR, HLA-DQ and HLA-DP. HLA Class I and Class II antigens were identified by serological methods initially. Newer technologies have now allowed for "molecular typing" of Class I and Class II HLA antigens, which results in more accurate HLA typing and better donor selection.

For a given patient there is a 25% chance that a sibling is an HLA identical match. A sibling who is a Class I and Class II HLA match is termed a matched sibling donor. A patient who has an identical twin is termed a syngeneic match. For patients who do not have a matched sibling donor, a search for someone with an HLA A, B or DR match is initiated through donor banks. In most cases a matched unrelated adult donor or unrelated umbilical cord blood unit can be found by searching the National Marrow Donor Program and Cord Blood Banks. In cases where a matched unrelated donor unit cannot be located, a partially matched family member can be used for the source of stem cells. The term alternate stem cell donors refers to donors who are not a matched sibling donor and includes adult unrelated donors, unrelated umbilical cord blood donor and partially matched family donors.

Transplantation For Malignant Disorders

ALL

ALL is the most common pediatric malignancy. Modern chemotherapy results in an overall disease free survival (DFS) of 70% for newly diagnosed patients with ALL. Despite the advances in treatment of ALL, children who relapse early in the course of their disease have a poor prognosis. Children with the highest risk for relapse include (a) infants who are less than 1 year of age at diagnosis, (b) those who have cytogenetic abnormalities including hyplodiploidy (<45 chromosome), t(4:11), t(9:22) (Philadelphia chromosome), and patients with the MLL gene. Patients who fail to enter remission after induction therapy are in an extremely poor prognostic group. Patients with the cytogenetic abnormalities listed above or who fail induction therapy have a very poor prognosis with conventional chemotherapy. Allogeneic transplantation should be performed in CR1 for these patients. Disease free survival has been reported to be 65% or greater in patients with high risk ALL transplanted with a matched sibling donor in CR1.

Children with relapsed ALL, that have a short first remission (<36 months), should be considered for allogeneic bone marrow transplantation. Disease Free Survival for matched sibling donor transplantation has been reported to be between 40-60%. Transplantation in CR2 with an unrelated adult or umbilical cord blood donor is associated with a DFS of 40%.

For patients with a short, first remission, allogeneic transplantation should be performed when patients have a suitable donor. Patients transplanted in CR3 or greater have a much poorer outcome than patients transplanted in CR2.

AML

Acute myeloid leukemia (AML) is the second most common leukemia in children. For patients who have a matched sibling donor, transplantation is the treatment of choice in CR1. Transplantation results in DFS of 50% or greater (50%-74%). This is superior to the cure rate reported with conventional chemotherapy, which is between 30-40%.

Several studies have also evaluated autologous BMT in first remission for patients with AML. In these studies, BM was purged with 4-hydroxycyclophosphamide (4HC) or mafosfamide in order to reduce leukemia cell contamination in the BM. DFS was 40% that was not significantly different from chemotherapy alone.

Children with AML who relapse require an allogeneic stem cell transplant for cure. Matched sibling donor transplantation in CR2 has a 35% DFS. Unrelated donor transplantation in CR2 is associated with a 20% survival rate.

Up to 20% of patients diagnosed will have refractory AML and will not achieve a first remission. Allogeneic stem cell transplantation has been able to salvage some of these patients with induction failure AML.

CML

Philadelphia chromosome positive chronic myelogenous leukemia (CML) occurs in children and adolescents, as well as adults. Allogeneic transplant with a syngeneic or matched sibling donor is associated with a DFS of 80-85% if the patient is transplanted within one year of diagnosis. In chronic phase, patients who are transplanted >2 years after diagnosis have a DFS of 50-60%. Patients who are in accelerated phase at time of transplant have a DFS of only 35-40% and patients transplanted in blast crisis have a DFS of only 10%.

Patients without a matched sibling donor also require allogeneic transplant in order to be cured. Unrelated donor transplants in children with CML have yielded DFS similar to those reported for matched sibling donor transplants.

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disorder that presents in childhood. This disorder presents in children <5 years old. Patients present with hepatosplenomegaly, monocytosis, leukocytosis, thrombocytopenia, leukoerythromlastosis, absence of the Philadelphia chromosome and increased fetal hemoglobin is currently the only curative therapy for JCMML. Allogeneic bone marrow transplant resulted in only 25-30% DFS. Relapse post transplant is the most common reason for treatment failure. Second allogeneic transplants for patients who relapse has been associated with a very poor outcome.

Pediatric Solid Tumors

Neuroblastoma is the most common extracranial solid tumor in children. Unfortunately, over half of the cases present with metastatic disease. Conventional chemotherapy is associated with a DFS of only 20% for patients with metastatic disease. Aggressive chemotherapeutic regimens with autologous stem cell transplantation have resulted in a DFS of approximately 35% in most series. A recent study using tandem PBSC transplants has shown a 3-year DFS of 58%. Relapse is the primary cause of treatment failure. Immunotherapy, monoclonal antibodies and radiolabeled antibodies are strategies that are currently being investigated in clinical trials. Allogeneic transplantation with matched sibling donors was compared to autologous BMT for high-risk neuroblastoma. The DFS was the same (28%). The allogeneic group had a lower relapse group, but was associated with an increase in treatment related mortality.

Wilm's Tumor is the most common abdominal tumor in children. Children who relapse are candidates for autologous stem cell transplantation. The French Society of Pediatric Oncology recently reported results for 29 patients with high risk recurrent Wilm's Tumor. Patients had received melphalen, etoposide and carboplatin for conditioning, followed by stem cell re-infusion. DFS was 50% at 3 years and overall survival 60% at 3 years. Twelve of the 29 patients were in CCR at the time of their reports.

Patients with Ewing's Sarcoma and PNET who have metastatic disease at diagnosis have a DFS of only 30%. Several studies have evaluated PBSC transplant in Ewing's Sarcoma. Patients who are in CR at the time of transplant had a much better outcome, 45% DFS versus 19%, for patients with residual disease at time of transplant.

Relapsed Ewing's Sarcoma and PNET has been treated with PBSC treatment and is associated with a DFS of 44% at 5 years. Patients with non-metastatic disease had a survival rate of 53%. Unfortunately, patients with relapsed metastatic Ewing's Sarcoma have a very poor prognosis.

Lymphomas

Pediatric lymphomas are the third most common group of malignancies in children and account for 12% of all newly diagnosed childhood cancer.

Approximately 60% of pediatric lymphomas are non-Hodgkin's lymphoma with the rest being Hodgkin's lymphomas. Pediatric lymphomas are diffuse, aggressive lymphomas with a propensity for wide spread dissemination. The histologic spectrum includes small non-cleaved cell lymphomas (Burkitt's and non-Burkitt's), lymphoblastic lymphomas and large cell lymphomas. DFS with frontline chemotherapy is 80-90%. Patients who relapse with NHL are candidates for autologous stem cell transplantation. ABMT is associated with a DFS of 75%.

For patients with relapsed non-Hodgkin's lymphoma or Hodgkin's lymphoma, auto stem cell transplant is the treatment of choice. In non-Hodgkin's lymphoma, salvage chemotherapy regimens can induce a second CR or partial response. Patient with chemotherapy sensitive relapsed intermediate or high-grade non-Hodgkin's lymphoma has a DFS of approximately 50% with autologous stem cell transplantation. Patients who have relapsed disease who are not chemotherapy sensitive have a DFS of less than 20% with autologous transplantation.

Relapsed Hodgkin's Disease in children and adolescents, as well as adults, has been successfully treated with autologous stem cell transplantation. Patients who have a CR greater than 12 months have an excellent prognosis with ABMT. DFS rate of 50-80% has been reported for these patients. Patients with a CR less than 12 months following combined modality therapy have a survival at 20-30% with autologous stem cell transplant.

Brain Tumors

Autologous stem cell transplant has been studied in children with brain tumors. Medullo-blastoma is a chemotherapy sensitive tumor. For patients with recurrent medulloblastoma that shows response to chemotherapy, ABMT can result in 68% survival for patients with non-metastatic disease compared to 26% survival for patients with leptomeningeal disease.

Recurrent anaplastic astrocytoma treated with high dose chemotherapy and stem cell rescue has shown a survival rate of 20% compared to a DFS rate of 5% with conventional chemotherapy. Autologous stem cell transplantation for brain tumors should only be utilized for histologic diagnosis in which transplantation has been shown to be of benefit, or in a closely monitored experimental clinic trial.

Rates of DFS for several of these hematologic disorders are shown in Table 2. Severe aplastic anemia has >80% survival with MSD transplantation.

Nonmalignant Disorders

A number of nonmalignant disorders are treatable with allogeneic bone marrow transplantation. Inherited hematoPatients with SAA who have a matched sibling donor should undergo transplantation at diagnosis. Immunosuppressive therapy with ATG, cyclosporin, prednisone and G-CSF or GM-CSF has a response rate between 50-70% in most reported series. Patients who do not respond to immunosuppressive therapy should be considered for an unrelated bone marrow transplant.

Fanconi's Anemia is an inherited disorder that can evolve into aplastic anemia. Allogeneic transplantation should be considered in all patients with Fanconi's anemia who develop aplastic anemia.

Diamond Blackfan Syndrome (pure red cell aplasia) will respond to medical (corticosteroids) therapy in most patients. There are a number of patients with Diamond Blackfan Anemia who do not respond to medical therapy. These patients should be evaluated for allogeneic transplantation if a suitable donor can be located.

Thalassemia Major is an inherited disorder. Matched sibling donor transplantation has a >90% DFS in patients who are transplanted early in the course of their disease. Patients transplanted over the age of 16 years old have a lower DFS of only 62%. Unrelated donor transplantation has also been successful in the treatment of Thalassemia Major.

 
Hemoglobinopathies are curable with transplantation. Matched sibling donor transplant is considered only in patients with severe sickle cell disease. Sickle cell patients eligible for transplantation include patients who have had (1) a cerebral vascular accident (CVA), (2) multiple episodes of acute chest syndrome or (3) patients whose disease is so debilitating that they are having frequent hospitalizations and a very poor quality of life. Results of transplantation in sickle cell disease are shown in Table 3.

Unrelated bone marrow transplantation has been reported in a few cases. Currently, alternative donor transplantation with unrelated donors should be considered experimental therapy and only is performed in the context of well-controlled clinical trials with strict eligibility criteria and close monitoring of patient safety.

 

Genetic Disorders

Genetic disorders treatable with stem cell transplantation include: osteopetrosis, Hurler's Disease, Gaucher's Disease, globoid cell leukodystrophy, adrenoleukodystrophy and immunodeficiency syndromes. All of these disorders have been successfully treated with allogeneic stem cell transplantation. Matched sibling donor, unrelated adult umbilical cord blood and partially related adult donors have been used in these patients. Results for transplantation in these disorders are shown in Table 3.

Wolfson Children's Hospital - Nemours Children's Clinic Pediatric Stem Cell Transplantation Program

In 1994, the WCH/NCC Stem Cell Transplant Program was initiated. To date, a total of 67 transplants have been performed in 62 patients. Thirty-four autologous transplants have been performed which includes ten autologous bone marrow transplants and 29 peripheral blood stem cell transplants.

Twenty-eight allogeneic transplants have been performed. Fifteen of the patients had a matched sibling as the donor. Thirteen patients had an unrelated umbilical cord blood unit as the donor. A wide variety of diseases were transplanted with relapsed leukemia or high-risk leukemia being the most common reason for transplant (18 patients including ALL and AML). The second most common reason for transplant was neuroblastoma followed by Ewing's Sarcoma and PNET.

Thirty-five of sixty patients are surviving for an overall survival rate of 58%. The most common reason for failure was relapse of the patient's malignancy.

Conclusion

Stem cell transplantation is a therapy that can offer the potential for cure for a variety of malignant and non-malignant disorders. Improvements in our ability to use unrelated donors have increased the possibility to find a donor or a matched sibling donor.

Improvements in molecular typing, immunosuppression, treatment for GVHD and better methods to detect diseases and immunity will improve the cure rates and the survival rates in stem cell transplantation.

REFERENCES

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Jacksonville Medicine / November, 2000

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