research for treatment, many of which are going into clinical trials to test for new approaches for treatment of hematological cancers. The hematopoietic stem cells found in the bone marrow can differentiate into all types of blood cells (white blood cells, platelets, and red blood cells) and have proven useful for the treatment of some blood malignancies such as some forms of leukemias. Hematopoietic stem cells are used by health professionals to rescue the effect of chemotherapy on blood cells. Currently, approaches and methods are being looked at by researchers for ways to improve the use of stem cells in the treatment of cancer and to find new methods for stem cell use in the treatment of cancers. Many clinical trials are currently ongoing around the world, most especially in the United States.
The list of hematological cancers treated with stem cells is extensive and includes acute lymphoblastic leukemia (ALL), acute biphenotypic leukemia, acute undifferentiated leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile chronic myelogenous leukemia (JCML), juvenile myelomocytic leukemia (JMML), and non-Hodgkin’s lymphoma and Hodgkin’s disease. Though several types of stem cells are being utilized or investigated for cancer treatment, hematopoietic stem cells are the preferred choice for the treatment of hematological cancers.
Sources of Hematopoietic Stem Cells
The most important aspects of research relating to the treatment of hematological cancers are characterization, localization, and identification of these hematopoietic stem cells. The main source of these stem cells is the bone marrow; about 1 in every 100,000 cells in the bone marrow is a hematopoietic stem cell. Second, peripheral circulating blood is another good source of hematopoietic stem cells and increasingly is becoming a preferred option in the clinical setting. Finally, human umbilical cord blood and cells from the placenta are also sources of hematopoietic stem cells. Clinical researchers are focused on how to expand the number of cells available in a stem cell culture after isolation from these sources.
Clinical Application of Hematopoietic Stem Cells
The major application of hematopoietic stem cells is the treatment of blood cancers resulting from abnormal proliferation of blood cells. Chemotherapy is typically used to destroy the cancerous blood cells, which are then replenished with the introduction of hematopoietic stem cells. The stem cells differentiate and replace the lost blood cells. Another major application is in rescuing blood cells affected by chemotherapy and cancer drugs that often target all dividing cells. This approach is also applicable to both nonhematological cancers. Graft versus tumor reaction, a process in which transplanted cells destroy tumor cells, is another important mechanism by which transplanted hematopoietic cells help fight cancer.
Problems Affecting the Improvement of Old and Development of New Treatments Using Hematopoietic Stem Cells
Many clinical trials do not make it to actual clinical practice; one of the challenges faced by clinical researchers in the use of human stem cells is the difficulty in expanding the cell number to a usable quantity. Several studies have reported increased survival and efficiency in differentiation when larger numbers of stem cells are introduced to patients. The risk of donor-to-host infection, graft-versus-host diseases, and antigenic rejection occurring before transplanted stem cells initiate and maintain full blood cell production limits their clinical application in serious and fatal cases. On the other hand, the understanding and the knowledge of the conditions facilitating differentiation and plasticity of hematopoietic stem cells remains to be fully characterized. A better knowledge of stem cell biology will ultimately impact the usage of these cells in regular clinical practice.
Stages of Clinical Trials
All new medical procedures or pharmacological substances go through a series of clinical trials, comprising a four-stage process of testing how safe a clinical intervention is and how it is to be used. The stages of clinical trials test different aspects of usability and safety of a drug for patients. The first stage is called a phase I trial, which is used to evaluate the safety of a new clinical method or drug; typically this is conducted in a small group of people. This may include healthy, unhealthy, or a combination of both, used to evaluate any side effects and determine the right dosage. The next stage is a phase II trial, which is aimed at testing the clinical procedure or drug that has passed through stage I on a larger group of people; often ill people are used in this stage of the trial to evaluate how effective the new procedure or drug works in people with the target condition and how well it works in a controlled, short period of time. The middle stage is a phase III trial, designed only for the drugs that are deemed successful in phase I and II trials. Again the procedure or drug is tested on a large number of ill individuals, and the outcome is compared to existing intervention for the target condition or placebo drug in the case of a drug trial. This trial allows researchers to determine whether the new drug or approach works better than the existing ones for the target condition, while evaluating any clinically significant side effects. Finally, in some cases, a last stage is conducted. Phase IV trials are conducted on drugs and procedures that are successful in the first three trial stages and a marketing license is given for the drug. With a marketing license, the drug can be given to patients. This phase allows the further understanding of the safety, side effects, and effectiveness of the drug while it is used in normal clinical practice.
Current Therapies for Hematological Cancer in Clinical Trials
The use of CD4 lymphocyte infusion to improve outcome after stem cell transplantation in treatment of hematological cancer
An ongoing phase II clinical trial aims to evaluate the efficacy of CD4 infusion in improving the ability of transplanted stem cells to replenish blood cells during treatment of leukemia, lymphoma, and myeloma and myelodysplastic syndrome. The use of very low doses of melphalan and fludarabine prior to stem cell transplant in cancer patients helps in stopping cancer growth. In addition, the chances of immune rejection by the host is also reduced by using this low dose of chemotherapy. Ultimately, these stem cells when transplanted have the capability to replace the host immune cells and enhance destruction of cancers cells that are not affected by the chemotherapy regime.
Researchers suggest lymphocyte infusion combined with stem cell transplant may have possible beneficial effects in the stem cell–induced killing of cancer cells and enhanced immune stem. However, it is still unclear whether lymphocyte transplant in this case may elicit immune response against the host cells, since the new immune cells produced by the transplanted stem cells may adjust to the donor cells. Because of this possible risk, the investigators believe that treatment with some cancer drugs like alemtuzumab or cyclosporine before and after transplant may help in stopping any likely immune response induced by the lymphocytes against the normal cells.
To assess the usability of this approach, the trial will investigate the progression of survival following transplant of the stem cells and estimate the ability of patients to achieve a significant or full donor chimerism in the circulating peripheral blood. In addition, the study will check for any occurrence of infections that may require clinical intervention and determine the relative proportion of re-formation and re-constitution T-cell-specific viral-specific immunity. Because of the likelihood of mortality arising from complications, the study will investigate cumulative occurrence of nonrelapse death rates, as well as monitor overall survival, incidence, and pattern of graft-versus-host disease following the combined lymphocytes and stem cell transplantation.
The use of unrelated donor umbilical cord blood in treatment of patients with hematological cancer
There is currently a phase II clinical trial investigating how transplantation of unrelated donor umbilical cord blood combined with reduced intensity of chemotherapy will affect the overall survival of patients with an advanced hematological cancer. The reduced-intensity chemotherapy in this trial will involve a preparative nonmyeloblative regime, which may improve the efficiency of the transplanted stem cells. All forms of transplantation, including cells and stem cells, are often faced with the challenge of host immune response, making the use of preparative regimens very important in suppressing