Taking part in a clinical trial may be the best option for some chronic myeloid leukemia (CML) patients. Clinical trials are designed to be accurate and very safe. There are clinical trials for newly diagnosed patients, for patients with advanced disease, and for patients who are either intolerant to or resistant to their current medications. The Leukemia & Lymphoma Society continues to invest funds in CML research.

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Current CML Research and Clinical Trials

Current goals of CML research are to

• Develop truly curative therapies
• Develop therapies that can work when others have failed
• Decrease the side effects of treatment

The following approaches are under study in clinical trials for the treatment of patients with CML.

Improving Current Treatments. Despite the great results of TKI therapy in chronic phase CML, many trials are looking at further optimization. Research includes

• Determining which chronic-phase patients should receive which TKI as initial therapy
• Establishing the best time to switch patients to second-line therapy
• Finding out whether deeper responses are achieved when other agents are added to TKIs
• Preventing and/or predicting long-term side effects of TKIs
• Determining which patients can successfully discontinue TKI therapy

 
New Drug Therapies. TKIs treat CML by targeting the BCR-ABL protein that directs the growth of the leukemia cells. It is not uncommon, however, for CML not to respond, to respond partially, or to become resistant to these drugs. ABL001 is an investigational drug designed to deactivate the BCR-ABL protein. Currently, TKI treatments target the BCR-ABL protein, but ABL001 targets a different location on the protein. Researchers are also studying the drug rebastinib. Rebastinib is a new TKI that is also designed to overcome imatinib resistance by binding to a different location on the BCR-ABL protein. Rebastinib may work against resistant mutations including the T315I mutation.

Disease Eradication Strategies. Even after it seems as though CML has been successfully treated, a very small number of leukemia stem cells may remain in the patient’s blood and marrow. This condition is referred to as “minimal residual disease” (MRD). These stem cells appear to be resistant to TKI therapy. This has led to strategies aimed at targeting the stem cell signaling pathways that are involved in the cells’ survival. Researchers are trying to obtain a better understanding of the mechanisms leading to CML leukemic stem cell survival. One area of research involves inhibitors of a protein called “smoothened” (SMO). The inhibitors are expected to target the SMO protein found on CML stem cells while sparing normal blood stem cells. A number of additional pathways are being studied, and there are ongoing efforts to assess their importance in CML patients.
 
TKI Discontinuation Studies. Treatment of CML with TKIs has advanced to a point where many patients achieve either very low or undetectable levels of the BCR-ABL gene in their blood. Researchers are studying whether some patients with deep and sustained molecular responses can safely discontinue TKI treatment and experience a treatment-free remission. 

In one clinical trial, approximately 40 percent of CML patients who had achieved a complete molecular remission for at least 2 years were able to stop their TKI therapy without relapsing. Further, those who did relapse were able to restore remissions by resuming their TKI therapy. Additional research is still needed to establish criteria for safely ending TKI therapy. At this time, discontinuing TKI therapy should only be done within the confines of a clinical trial.
 
Vaccine Therapy. Various forms of vaccine therapy are being studied to see whether they can reduce or eliminate residual leukemia cells in CML patients. TKIs destroy most leukemic cells in the body, but in most patients, some of the cancerous cells remain. These remaining cells can cause a relapse, especially if the TKI therapy is stopped. Researchers are trying to find ways to help the immune system recognize the difference between normal cells and CML cells so the immune system can attack the cancer cells remaining after TKI therapy. See the free LLS booklet, Immunotherapy Facts for information about the development of blood cancer vaccines.
                                           
Reduced-intensity Stem Cell Transplantation. A modified form of allogeneic transplantation known as “reduced-intensity” or “nonmyeloablative” allogeneic stem cell transplantation may be an option for CML patients who do not respond to other treatments. Patients being prepared for a reduced-intensity transplant receive lower doses of chemotherapy drugs and/or radiation in preparation for the transplant, compared to the doses given to patients receiving an allogeneic transplant. Immunosuppressive drugs are used to prevent rejection of the donor stem cells. The engraftment of donor immune cells may allow these cells to attack the patient’s CML cells (a result called “graft-versus-tumor effect”). The theory being tested with a reduced-intensity transplant is that by undergoing less toxic procedures prior to the transplant, the body is better able to withstand the transplant. However, full donor engraftment would still take place, and the desired graft-versus-leukemia effect would still occur.
 
Other drugs are being tested in clinical trials to enhance the graft-versus-leukemia effect of stem cell transplantation and to reduce the risks of graft-versus-host disease.
 
In addition, research is underway evaluating the use of umbilical cord blood as a source of stem cells for transplantation in children and adults. Cord blood provides another potential source of matched, unrelated stem cells for patients who do not have a matched, related stem cell donor. Results from cord-blood stem cell transplants have been promising, and there appears to be a reduced risk of acute graft-versus-host disease in younger cord-blood transplant patients. For more information about all types of stem cell transplantation, see the free LLS booklet, Blood and Marrow Stem Cell Transplantation.

Related Links

• Clinical  Trials
• Download or order The Leukemia & Lymphoma Society's free booklet, Chronic Myeloid Leukemia