Background - Chronic Myelogenous Leukemia (CML)

 

More than twenty two thousand people live with chronic myelogenous leukemia in the United States, with more than five thousand people expected to be diagnosed this year. The majority of patients with this disease are diagnosed in what is called the chronic phase. The standard treatment for this phase of the disease is therapy with a medication called imatinib. Chronic Myelogenous Leukemia (CML) is a malignant myeloproliferative neoplasm that is associated with the Philadelphia chromosome, in which translocation of chromosomes 9 and 22 [t(9;22)] generates the BCR-ABL oncogene. This abnormal oncogene gives rise to the BCR-ABL fusion protein, whose deregulated tyrosine kinase activity is central in the pathogenesis of CML.


The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, nilotinib and bosutinib target BCR-ABL and can induce complete hematological and cytogenetic responses (CCR) and reduce the levels of BCR-ABL transcripts in vaste majority of patients with CML. This treatment can diminish the amount of disease to very low levels that only very sensitive and specialized techniques can measure; it does not, however, provide a cure. The CML stem cells (LSCs) are resistant to TKIs and continuous treatment is necessary. The prolonged exposure to TKIs leads to several issues: side effects, which may lead to discontinuation of therapy or non-compliance of patients with CML. In addition CML LSCs are known to give rise to resistant clones. So even patients with excellent responses (cytogenetic or molecular response) experience relapses. These relapses occur from a rare population of quiescent LSCs . We and others hypothesize that targeting of LSCs is essential for curative therapy of CML.
Emerging Leukemic Stem Cell Specific Therapy

Dr. Shaoguang Li and colleagues at University of Massachusetts have published a unique discovery that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) is a critical regulator for LSCs in BCR-ABL–induced CML (Chen Y et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). In the absence of Alox5, BCR-ABL failed to induce CML in preclinical studies. While deficiency in Alox5 had no effect on normal hematopoiesis, impairment of the LSCs function through differentiation and cell division of CML LSCs was observed. This defect led to a depletion of LSCs and a failure of CML development. Treatment with a 5-LO inhibitor also impaired the function of LSCs and their prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells, and its inhibition can completely inhibit the function of these stem cells.


These findings provide an exciting opportunity to develop the first anti-cancer stem cell therapy for treating CML. We have initiated our first study to evaluate the safety of the standard anti-cancer drug imatinib combined with a the new experimental drug.


The "Usual" Design of an Oncology Trial

Many promising therapies in oncology do not end up bringing the results that everyone hoped for. Every new drug has to prove itself in phase I studies (safety/toxicity and finding the appropriate dose; maximal tolerated dose- MTD), followed by phase II studies (activity, responses, survival) and phase III studies (comparison with the best standard therapy; usually multicenter).
Any new drug that is capable of killing cancer in a pre-clinical model may have side effects on humans, and thus phase I trials usually enroll patients that have failed previous lines of therapies. Because the toxicities are unknown, patients are enrolled in study groups who receive different doses of a drug (starting from sub-therapeutic level and going higher). Cohorts of patients are enrolled gradually and may need to be expanded if toxicities occur.

Our CML study.

Our study (Phase I Study to Evaluate the Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in Patients With Chronic Myelogenous Leukemia) uses a drug with a known toxicity profile. We do not intend to modify the standard treatment of CML (tyrosine kinase inhibitor, TKI) that patients are on unless we have to. We plan to enroll patients who are currently on imatinib (and we are considering other TKIs in the near future) as a standard therapy and who are doing well. We hope that this approach will help us cleanly distinguish the side effects coming from the new drug versus the disease or TKI itself. Patients with a high leukemia burden may have side effects, which will be difficult to distinguish from disease activity or TKI side effects. These patients may be able to participate in our subsequent studies.


Enrolled patients are observed closely for side effects, while at the same time standard evaluations of the disease are performed. We are also planning to perform different assays to evaluate the residual LSCs (these are research only as there is no standard). Using this approach we will be able to establish an appropriate dose of the new combination and also in some patients (with detectable disease) its effectiveness.


Our ultimate goal is to move smoothly to other phases of clinical studies when we know the effects and side effects of this novel therapy, so that these could be offered to more patients on a large scale basis.

Other sites with information related to our projects can be found here.

Investigators

Cerny

Jan Cerny, MD, PhD
Assistant Professor Hematology/Oncology @JanCernyMDPhD

Li S

Shaoguang Li, MD PhD
Associate Professor Hematology/Oncology

Rosmarin

Alan Rosmarin, MD
Professor of Medicine Division Chief, Hematology/Oncology