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 bone marrow recovers. The study had 22 patients enrolled, of whom 14 (63 percent) are disease free. Four (18 percent) patients developed grade II-IV graft-versus-host disease, of whom one showed grade III-IV GVHD symptoms. There were four cases of adverse effects: two patients had graft failure, one patient developed secondary malignancy, and one patient died.
Another trial is currently recruiting patients for “allogeneic hematopoietic stem cell transplant for patients with primary immune deficiencies.” The implementation of four regimens using different combinations of drugs adds to the complexity of this clinical trial. The most appropriate regimen for the patient will be determined based on the diagnosis and clinical history. The regimens comprise Arm A: Fully Myeloablative Preparative Regimen, Arm B: Reduced Toxicity Ablative Preparative Regimen, Arm C: Reduced Intensity Conditioning, and Arm D: No Preparative Regimen.
The registry of clinical trials at the U.S. National Institutes of Health lists 1,428 studies involving stem cells for the treatment of immunologic disorders. They involve a combination of various regimes such as total body irradiation, chemotherapy drugs and bone marrow or peripheral blood stem cell transplantation in patients with autoimmune disorders, systemic lupus erythematosus, human immunodeficiency virus, and severe combined immunodeficiency. The employment of autologous stem cell transplantation for Crohn’s disease and umbilical cord blood stem cells in adults with advanced blood disorders or cancer are also being studied. The efficacy of specific drugs in preventing/controlling GVHD is also being assessed.
The rarity of the disease in combination with a lack of awareness among both physicians and patients are obstacles to the success of clinical research in histiocytic disorders. Patients are unfamiliar with the concept and are reluctant to act as guinea pigs for experimental procedures. Physicians on the other hand may not be willing to put in the time and effort required to plan, conduct, and consolidate the results of a rigorous clinical trial. Some clinical trials are conducted with a small number of patients and the results may not be statistically significant.
However, improved and tested treatment regimes and techniques such as myeloablative chemotherapy (reduced/complete depletion of bone marrow cells) followed by stem cell transplantation have improved the prognosis of patients with immunologic and histiocytic disorders. Future research needs to focus on improving the quality of life and life span of patients with severe and progressive histiocytic disorders involving high-risk organs such as the lungs, the central nervous system, and the liver. Agents to reduce fibrosis and neurodegeneration need to be identified and studied.
Ruby A. Singh
Independent Scholar
See Also: Blood Adult Stem Cell; Current Research on Isolation or Production of Therapeutic Cells; Blood Adult Stem Cell: Development and Regeneration Potential; Bone: Current Research
