A Review of Autologous Stem Cell Transplantation

Robert A. Joyce, M.D.
 

Introduction

For more than forty years, high doses of chemotherapy and extensive radiation therapy have been used to treat certain cancers in patients who have had resistant or relapsed disease. The limiting factor to using high-dose chemotherapy and radiation therapy is the toxic effect of these treatments on bone marrow cells. It was this recognition that lead to the development of technology involved in autologous stem cell transplantation where cells were stored prior to treatment and infused into the patient following treatment to restore bone marrow function. The prime target is to overcome drug resistance in cancer cells by increasing the amount of drug or radiation used. While this may not be the case in all cancers, studies in vitro and clinical studies have demonstrated the effectiveness of this approach.

Over the past four decades, important developments have been made to identify: (1) drugs that can be used safely in high concentrations; (2) safer administration of total body irradiation; (3) technology in the collection and purification of stem cells from the bone marrow and peripheral blood; (4) newer and safer antibiotic and antiviral agents; and (5) the appropriate use of marrow growth stimulating factors to promote early maturation of stem cells into functioning mature cells. Just over ten years ago, stem cells collected from the blood were identified as being safe and effective cells to reconstitute the blood system and to do so at a faster rate than stem cells harvested from the bone marrow.1 These advances have resulted in the use of autologous stem cell transplant in an increasing frequency in patients with cancer. World-wide use of autologous stem cell transplantation has recently been updated by M. M. Horowitz in 1999, with more than 200,000 patients treated world-wide with this technique.2

Autologous Stem Cell Transplant Process

Autologous cells for bone marrow transplant are initially obtained from multiple collections of cells from the bone marrow of patients who are under general anesthesia for purposes of collection. This required hospitalization and often resulted in insufficient cells collected for transplantation because of prior radiation and chemotherapy. Now, stem cells are collected from the peripheral blood after administration of growth factor (granulocyte colony stimulating factor) with or without chemotherapy. The benefit of this technique is that cells can be collected more easily, the process is less painful to the patient and engraftment and recovery of peripheral blood mature cells occurs earlier. These factors have re-written the restriction of the use of this procedure and have allowed for its application in patients almost regardless of age or prior treatment history as long as sufficient cells are available for collection. A prospective randomized clinical trial demonstrated that mobilized blood stem cells were superior to unstimulated bone marrow cells in terms of time to engraftment, requirement for blood product transfusions and especially for the number of days patients spend in the hospital.3,4 In our institution, the average hospital stay for patients undergoing transplantation was reduced from 29 days to 2.5 days.

This reduction in need for hospitalization changed the venue of autologous stem cell transplantation from the hospital to the outpatient stem cell unit. Importantly, this has reduced the cost of the procedure by at least 66%. The process of autologous stem cell transplant begins with releasing stem cells into the peripheral blood, collection and storage of stem cells 10/14 days later, the administration of high-dose chemotherapy, transplantation of stem cells and recovery from the toxicity of high dose chemotherapy usually within 30 days. Recovery of blood counts sufficient for discontinuation of antibiotics and release to the home usually occurs 14 days following transplantation and most patients are back to work part-time 30 days after transplantation. This allows the patient to be more mobile, more active and back to usual routines of work and home management sooner.

Use of Auto-Transplantation For Selective Disorders

Acute and Chronic Leukemias

Autologous transplantation in patients with acute myelogenous leukemia during remission has caused an increased 5-year disease free survival rate over standard dose chemotherapy.5,6 It is not as good as allogeneic transplant because of the absence of graft versus leukemia effect; but, the immediate mortality rates following transplant are better with autologous transplantation. Transplantation of adult patients with acute lymphoblastic leukemia remains investigational. Single institution trials do show improvement over standard treatment.7,8 Because of new developments of chronic myeloid leukemia, treatments including the use of Interferon have allowed for the disappearance of the marker chromosome called the Philadelphia chromosome from the bone marrow of some patients so treated. Although allogeneic transplantation is curative in patients with chronic myeloid leukemia, not all patients have suitable donors for transplantation. This allows for the use of autologous transplantation without the risk of transplant rejection or graft versus host disease. If a patient has no detectable cells with abnormal chromosomes, autologous transplantation may be used. The issue remains whether abnormal clonal cells are transplanted in the process.9 Recent studies have used autologous transplantation in the treatment of chronic lymphocytic leukemia. Data are insufficient to justify the use of this treatment outside of the format of clinical research studies.

Hodgkin's Disease

It is clear that autologous stem cell transplantation is a superior means of treatment for patients who have failed standard chemotherapy or have relapsed early following the treatment of Hodgkin's Disease.10 High-dose chemotherapy or high-dose chemotherapy with radiation therapy followed by autologous stem cell transplantation remains the treatment of choice with patients with sufficient stem cells to harvest prior to treatment.

Non-Hodgkin's Lymphoma

Many studies have demonstrated that the best response to patients with relapsed or persistent lymphoma following initial treatment is with high-dose chemotherapy and stem cell transplantation.11 These patients must be selected carefully as this effect is usually seen only in patients who have chemo-sensitive disease.

Multiple Myeloma

Multiple myeloma is an incurable disease. It has been treated in the palliative setting for many years. A French study that started in the late 1980s randomized between routine chemotherapy and high-dose chemotherapy and showed disease free survival and over-all survival benefit with high-dose chemotherapy and autologous stem cell transplantation.12 This study has lead to the use of high-dose chemotherapy and stem cell transplantation in patients with multiple myeloma. Candidates include patients who are in renal failure from their disease and are on dialysis. With lower morbidity and mortality of autologous transplantation, Medicare has just included autologous transplantation as covered for patients over age 65.

Breast Cancer

Seldom has there been as much controversy about the usefulness of a clinical treatment as has been the case with high-dose chemotherapy and stem cell transplantation in patients with breast cancer. This topic has been source of many lawsuits initiated against insurance carriers when insurance carriers were denying this form of treatment in patients because of insufficient randomized clinical data. It then became a treatment based upon demand and only recently have we seen the completion of some randomized clinical trials aimed at determining whether high-dose chemotherapy with stem cell transplantation is beneficial in patients with advanced breast cancer. This political `hot potato" continues even now. Randomized clinical trials which have been closed because of sufficient patient accumulation still do not have enough time to determine whether or not this treatment is useful in patients with metastatic or advanced local stage breast cancer. The problems of data interpretation include insufficient time for appropriate analysis, numerous studies that were insufficient in patient numbers to reach a conclusion and even the generation of tainted data used for analysis of treatment outcomes. They can best be summarized by saying that after more than 10 years of conflict about the usefulness of high-dose chemotherapy and stem cell transplantation in patients with breast cancer, data do not all show a survival advantage. Many important studies are too early to be analyzed and high-dose chemotherapy with stem cell transplantation should not be used outside of the setting of National Cancer Institute approved clinical trials.

Other Disorders

Studies of high dose chemotherapy and stem cell transplantation have been active in diseases that are not associated with hematologic abnormalities or malignancies. High-dose chemotherapy with autologous transplantation has been used as a means of suppressing the patient's immune system. These studies have principally been generated form Europe and are starting to show improvement in patients with immune diseases such as multiple sclerosis, progressive systemic sclerosis and immunologic disorders such as refractory immune thrombrocytopenia properia.13, 14 It is under study for treatment of amyloidosis.15

The Future

High-dose chemotherapy and autologous transplantation has been beneficial in certain select diseases. The advantage of its use is the reduction in the toxicity associated with treatment and the ability of patients to have longer disease-free survivals and time without the need for additional treatment. In breast cancer, for example, many studies have demonstrated a longer period of time where the patient does not require additional treatment. This has led to studies to incorporate high-dose chemotherapy with additional treatment modalities including immunotherapy in the treatment of patients with such cancers. Clearly this is the case in patients with multiple myeloma. High-dose chemotherapy may only be a part of the treatment necessary to over-come the malignant clone of plasma cells that may exist unperturbed following a variety of different modalities of treatment. Better standard treatment modalities, improved high-dose regiments, better selection techniques for stem cells devoid of contaminating tumor cells and improved immunomodulatory therapies remain on the horizon.

REFERENCES

  1. Walters MC, et al: Impact of bone marrow transplantation for symptomatic sickle cell disease. Blood, 2000;95(6):1918.
  2. Chen KW, Chorosty : Bone marrow transplantation: Perspectives on pediatric patients. Managed Care and Cancer, 1999:22.
  3. Shad A, Magrath I: Non-Hodgkin's Lymphoma. Pediatric Clinics of North America, 1997;44(4):863.
  4. Hudson MM, Donaldson SS: Hodgkin's Disease. Pediatric Clinic of North America, 1997;44(4):891.
  5. Sanders JE: Bone marrow transplantation for pediatric malignancies. Pediatric Clinics of North America, 1997;44(4):1005.
  6. Sanders JE: Bone Marrow Transplantation in Pediatric Oncology in Principles and Practice of Pediatric Oncology. 3rd Edition, edited by Philip A. Pieto and Daniel Poplack. Lippincott-Raven Publishers, Philadelphia, 1997, p 357.
  7. Hite S, Peters C and Krivit W: Correction of Odenfield dysplasia following bone marrow transplantation end engraftment (in Hurler Syndrome MPS IH). Pediatric Radiology, 2000;30:464-470.
  8. Krivit W, et al: Hematopoietic stem cell transplantation in globoid cell leukodystrophy. New England Journal of Medicine, 1998;338:1119-1126.
  9. Krivit W, et al: Long term effect of bone marrow transplantation for childhood onset cerebral X-linked adrenoleukodystrophy. Lancet, 2000;356:13.
  10. Peters C, et al: Hematopoietic stem cell transplantation for metachromatic leukodystrophy prior to onset of clinical signs and symptoms. In O. Ringdon; JR Hobbs, eds. Correction of Genetic Diseases by Transplantation, 1997. London: COGENT 1997, pp 34-48.
  11. Peters C, et al: Hurler Syndrome II: Outcome of HLA genotypically identified sibling and HLA-Haploidentical related donor bone marrow transplantation in fifty-four children. Blood, 1998;91(A):2601-2608.
  12. Yeager AM: Hematopoietic cell transplantation for storage diseases. In Hematopoietic Stem Cell Transplantation, 2nd Edition, edited by E. Donrell thomas, Karl E. Blume and Stephen Forman. 1999, Malden, Massachusetts, Blackwell Science, pp 1182-1194.
  13. Lucarilli G, Clift RA: Marrow transplantation in Thalassemia. In Hematopoietic Stem Cell Transplantation, G. Donnell Thomas, Karl G. Blume and Stephen J. Forman (eds.), Malden, MA, Blackwell Science, 1999, pp1137-1143.
  14. Wagner JE, Davies SM and Auurbach AD: Hematopoietic cell transplantation in the treatment of Fanconi anemia. In: Hematopoietic Stem Cell Transplantation, Thomas, Blume and Forman (eds.), Malden, MA. Blackwell Science 1999, pp 1204-1219.
  15. Kramer RA: Hematopoietic cell transplantation for juvenile myelomonocytic leukemia. In: Hematopoietic Stem Cell Transplantation, Thomas, Blume and Forman (eds.) Blackwell Science, 1999, pp817-822.

November, 2000/ Jacksonville Medicine

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