Chronic Myelogenous Leukemia [CML] is a common type of leukemia, in which certain types of white blood cells multiply in an uncontrolled manner in the bone marrow. Currently, there are approximately 30,000 people living with CML in the US, with more than 4500 cases diagnosed per year. Mortality rate is relatively low, with a five-year survival rate among leukemia patients recently reported to be 89%. The low mortality rate is achieved thanks to continuous treatment with Novartis’ Glivec, a potent inhibitor of the protein BCR-ABL, which was approved in 2001. BCR-ABL has been proven to be essential for the development of the disease, making it a desirable target for inhibition. It is also considered to be an accurate genetic marker for assessing disease stages and progression.
CML has three phases: chronic-phase, accelerated-phase and blast-crisis CML. Without any intervention, patients gradually progress to the accelerated phase, and finally to myeloid blast crisis, which eventually leads to death. Fortunately, the majority of patients are diagnosed in the chronic phase and maintained in that condition for many years thanks to Glivec therapy.
Glivec is extremely effective among the vast majority of patients, however, it rarely cures the disease. Only 10%-20% of CML patients achieve complete remission of the disease with Glivec, with the rest maintaining detectable disease despite taking Glivec on a regular basis. In addition, a 4% per year incidence of Glivec resistance has been documented among Glivec recipients. In this case, Glivec is no longer effective and other strategies are sought after. The only viable alternative curative therapy for CML is stem-cell transplantation. Unfortunately, this kind of treatment is impractical in the majority of cases because of elderly patients’ inability to tolerate the severe side effects and lack of a suitable stem-cell donor. Thus there is room in the CML market for treatments which can be used either as a second-line therapy in cases where Glivec fails, or to augment Glivec’s therapeutic activity.
Cell Genesys published results from a rather small phase II clinical trial at the annual meeting of the American Society of Clinical Oncology [ASCO] in June 2006. Nineteen CML patients with molecular evidence of persistent leukemia, despite taking Glivec for more than one year, were treated with GVAX for leukemia in combination with Glivec. The addition of GVAX demonstrated impressive results, with five patients achieving complete disappearance of BCR-ABL and additional five achieving a greater than 90% reduction in the levels of this important marker. As previously mentioned, lower levels of BCR-ABL have been proven to be strongly correlated with overall and progression –free survival. Encouragingly, responses were ongoing in 9 out of the 10 responders, when examined 14 months post treatment. Although the size of the trial makes it very hard to project the real effect of the drug, the fact GVAX was proven highly effective in over 50% of patients is very encouraging.
At the moment, there are three ongoing trials assessing GVAX for treatment of CML. Most of the expenses related to these trials are financed by The Johns Hopkins Kimmel Cancer Center.
The first trial is an extension study of the initial Phase 2 trial involving 11 patients who had a decrease in their BCR-ABL levels, but could not reach a sustained complete response. This trial examines continuous GVAX administration over a longer period of time, similar to the trials in pancreatic cancer.
A second trial currently being conducted is a phase II randomized trial in 56 patients with CML who have persistent molecular evidence of disease following Glivec therapy. Patients were divided into two cohorts, one receiving GVAX + Glivec and the other receiving interferon-alpha + GM-CSF + Glivec. Interferon-alpha is another naturally occurring stimulator of the immune system. The comparison between GM-CSF secreting cells [GVAX] and free interferon-alpha + GM-CSF is very interesting because it can demonstrate the advantages of a specific, directed stimulation of the immune response, versus a general, untargeted stimulation. In other words, the fact that GM-CSF is secreted in a specific context (by the GVAX cells) as oppose to evenly distributed through the body, will hopefully lead to a more focused response against leukemia cells.
The third trial is a Phase I trial in 18 patients with poor risk myelodysplastic syndrome, an earlier stage of leukemia, which might transform in time into Leukemia.