Bradley Somer, MD
University of Pennsylvania Cancer Center
Last Modified: November 1, 2001
Chronic Myelogenous Leukemia (CML) is a clonal, neoplastic, proliferative disorder of the primitive stem cell. In the early chronic phase, it is typically asymptomatic or presents with abdominal pain and early satiety from splenomegaly and is diagnosed incidentally when patients present with an elevated white blood cell count. Untreated, it typically progresses into blast phase, which is an aggressive acute leukemic phase presenting with fever, pallor, bone tenderness, bleeding, fatigue and/or symptoms and signs of leukostasis.
There are approximately 5000 new cases of CML in the US per year. 95% have the "Philadelphia Chromosome" which involves the balanced translocation between chromosome 9 and 22, t (9; 22)(q34; q11). This results in a gene rearrangement resulting in the bcr-abl fusion genes detected by polymerase chain reaction (PCR). This gene encodes for a 210 kD tyrosine kinase that has increased autophosphorylating activity, which transforms the transfected cells to leukemic cells.
Current therapeutic options for chronic phase CML include hydroxyurea, interferon alpha and allogeneic bone marrow transplant. The first 2 treatment options are used to delay disease progression. Generally, allogeneic BMT is used in an attempt to cure patients who are under 50, without exclusionary medical illness and a good chance for cure. An HLA matched sibling is usually the donor. However, this modality of therapy has a 20-30% chance of treatment related mortality within 6 months and even greater potential morbidity and mortality for matched unrelated donors and with older patients.
In the absence of therapy, CML progresses into "blast crisis" within a median of 4 years. In blast crisis, it is significantly more difficult to treat and certainly to cure. Blasts typically invade organs in the body and patients die from bleeding, infection, or hemorrhage and thrombosis in organs. Initial therapy is to rid the body of the blasts with cytoreductive agents followed by further assessment for other options such as allogeneic BMT. The STI 571 study reported at the 41st American Society of Hematology meeting included patients in this serious phase of the disease. By leveraging the unique molecular aspects of CML, toxicity was minimized.
STI 571 inhibits the signal transduction and transcription activator (STAT) protein known as STAT 5 resulting in reduced levels of BCLXL, an antiapoptotic protein. This results in the induction of apoptosis (programmed cell death). Overall, bcr-abl kinase activity was inhibited. STAT 5 was found to be a major mechanism by which bcr-abl generates an effect.
The results of this early phase study were exciting for numerous reasons. It is an oral preparation and is thus convenient to administer. It has had minimal side effects after increasing through 10 levels of dosing in clinical trials. What is also impressive is the excellent response rate, which appeared to occur in spite of treating those who has failed other therapy and who had advanced disease. As this was a very early clinical trial, can not be used as a standard therapy. However, it is likely that it will become a major part of the treatment of CML. It also remains to be seen how durable the remissions are, whether it can induce a complete remission in subsequent, later phase trials and whether there is synergy with other modalities of treatment. However, this is certainly a great breakthrough, which may have implications throughout a variety of malignancies.
Feb 25, 2011 - The American Society of Clinical Oncology has issued updated guidelines for the use of bone-modifying agents in treating breast cancer patients with bone metastases to include a new drug, denosumab, and provide new advice regarding a potentially serious complication of treatment, osteonecrosis of the jaw; an overview of the guideline update has been published online Feb. 22 in the Journal of Clinical Oncology.