incidence of disease relapse, and the incidence of post-transplant lymphoproliferative disease. Moreover, the study will determine nonrelapse mortality at 100 days and one year past hematopoietic stem cell transplantation (HSCT), as well as overall and disease-free survival at one year post-HSC transplant.
In general, most of the clinical trials going on in the United States for the treatment of hematological cancers are stem cell based, particularly the use of hematopoietic stem cells. Current clinical trials on hematological cancer treatments are directed toward extending the benefits of stem cell to more categories of patients. These approaches include the use of stem cell transplant with less intensity of chemotherapy regimens, which will allow use in patients that may be too sick or old. The use of haploidentical or partially matched cord blood will allow patients who do not have an available matched sibling to utilize transplantation. These trials are exploring pharmacological manipulation and selection of donor stem cells, which will help increase better outcomes and reduce complications. These trials are especially important in adult bone marrow transplant, since fewer than 25% of adult patients have access to matched donors.
Chinedu Anthony Anene
Bradford University School of Management
See Also: Bone Marrow Transplants; Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease; Hematopoietic Transplantation: Cancer.
Further Readings
Ema, H., H. Takano, K. Sudo, et al. “In Vitro Self-Renewal Division of Hematopoietic Stem Cells.” Journal of Experimental Medicine, v.192 (2000).
Gallacher, L., B. Murdoch, D. Wu, et al. “Identification of Novel Circulating Human Embryonic Blood Stem Cells.” Blood, v.96 (2000).
Glimm, H., I. H. Oh, and C. J. Eaves. “Human Hematopoietic Stem Cells Stimulated to Proliferate In Vitro Lose Engraftment Potential During Their S/G (2)/M Transit and Do Not Reenter G(0).” Blood, v.96 (2000).
Clinical Trials, U.S.: Immunologic/Histiocytic Disorders
Clinical Trials, U.S.: Immunologic/Histiocytic Disorders
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Clinical Trials, U.S.: Immunologic/Histiocytic Disorders
The immune system has been the focus of rapid and exciting research over the last decade. An overactive and misguided immune system stimulates the development of autoimmune disorders, whereas primary/acquired immunodeficiency disorders result from a sluggish functioning of the system. The system is also known to mount abnormal and sometimes severe allergic responses to harmless antigens in the environment.
Histiocytic disorders, on the other hand, are a category of rare and therefore poorly understood and difficult to diagnose and treat diseases of cells of the innate immune system known as histiocytes. Histiocytes may either comprise the specialized macrophages stationed in connective tissues or may be dendritic in nature and derived from the Langerhans cells of the skin. Both the cell lineages evolve from the CD34 cells of the bone marrow. The function of histiocytes depends on their location; macrophages are compulsive phagocytes that remove extraneous organic and inorganic material from the system, while the Langerhans and dendritic cells effectively present new antigens to the T4 lymphocytes to initiate the adaptive immune response. Histiocytes also participate in wound and tissue repair and play an important role in the initiation as well as regulation of inflammatory responses of the body.
Proliferation and infiltration of histiocytes in tissues leading to organ damage and tumor formation are the hallmarks of a histiocytic disorder. The etiology is unknown and the clinical presentation is unpredictable and variable, with the symptoms regressing spontaneously at times. However, an aggressive involvement of multiple organs may make it a debilitating, life-threatening disorder. It was therefore imperative that guidelines be established for early diagnosis and effective treatment of the disorder. The Histiocyte Society, established in 1985, has not only issued the guidelines, but also has undertaken the conceptual planning and successful implementation of several clinical trials evaluating treatment regimens.
Because the incidence of histiocytic disorders is rare (that of Langerhans cell histiocytosis is 4–5.4 per million population) and the highest incidence is observed in children aged 1–3 years, recruitment in clinical trials is low and the effort has to compulsorily involve multiple centers internationally. The aim of the earlier trials was to investigate the effectiveness of chemotherapy agents that suppress the proliferation of histiocytes and follow up over a specific period of time. The first trial, LCH-1, compared the efficacy of vinblastine versus etoposide in treating patients with Langerhans cell histiocytosis (LCH) over a six-month period. Both were found equivalent in new cases, but because etoposide was linked to the development of secondary leukemia, vinblastine has remained the treatment of choice. However, etoposide was found to be effective in recurrent cases where use of vinblastine had failed.
The following trial, LCH-2, took this further by devising an intensive treatment plan with multiple drugs, which achieved a faster response and increased survival rates in both single and multisystem LCH. Patients with single system LCH, particularly of the skin, skeleton, and the lymph nodes have an excellent prognosis and may need minimal treatment. The involvement of multiple organs such as the liver and spleen indicate a poor prognosis but the response to timely, initial treatment with vinblastine and steroids may improve outcome. LCH-3 confirmed the use of vinblastine and steroids as the first line of treatment for multisystem LCH. Its prolonged use (12 months) also led to reduced recurrence of the disease. The administration of 6-mercaptopurine along with vinblastine and prednisone has been recommended for patients with multifocal bone or CNS-risk lesions.
The current clinical trials are exploring stem cell transplantation under different regimens. An ongoing study at the Masonic Cancer Center, University of Minnesota is attempting to evaluate the clinical outcomes of a preparative regimen of fludarabine (FLU), anti-thymocyte globulin (ATG)/or campath, and melphalan, followed by hematopoietic stem cell transplant and a post-transplant regimen of Cyclosporin A (CsA) in patients with histiocytic disorders. The researchers hypothesize that this regimen will have a positive effect on post-transplant engraftment and the incidence of graft-versus-host disease (GVHD). Melphalan, fludarabine, and anti-thymocyte globulin (ATG) or campath administered prior to transplantation help the stem cells grow.
The stem cells are transfused via an intravenous (IV) catheter, following which cyclosporin A (CsA) and mycophenolate mofetil (MMF) are given to reduce the risk of graft-versus-host disease. Patients will be randomized biologically into one of three arms based upon donor availability: (1) human leukocyte antigen (HLA) genotypic matched sibling donor, (2) HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor, (3) two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) before administration of the preparative regimen.
A second study by the same group at the University of Minnesota, involving “In-vivo T-cell Depletion and Hematopoietic Stem Cell Transplantation for Life-Threatening Immune Deficiencies and Histiocytic Disorders,” has recently posted preliminary results. The hypothesis was to determine if a preparative regimen of busulfan, cyclophosphamide, and antithymocyte globulin (ATG) followed by allogeneic stem cell transplantation will be effective in the treatment of immune deficiencies and histiocytic disorders. Patients need to have a suitable donor identified prior to starting the conditioning regimen. The chemotherapy is intended to completely eliminate their defective immune system and bone marrow before the transplantation procedure. Medication is given for prevention of graft-versus-host disease (GVHD).
The ATG will help to deplete the donor stem cells of the type of cells that can cause GVHD and will also help to promote engraftment of the new stem cells. The recovery phase usually takes two to four weeks and constitutes the second phase of treatment when the bone marrow function is restored.
Subjects are given a blood cell growth factor, G-CSF, to help speed recovery of the white blood cells, potentially decrease the risk of infection, as well as reduce the time until the