Molecular and Pharmacologic Monitoring in Patients with Chronic Myeloid Leukemia

OBTNNovember 2008
Volume 2
Issue 10

Blood testing plays a critical role in diagnosis and treatment of chronic myeloid leukemia (CML).

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Blood testing plays a critical role in diagnosis and treatment of chronic myeloid leukemia (CML). This cancer accounts for 20% of leukemia diagnoses in adults, and SEER estimates that in 2008, ~4830 men and women will receive a diagnosis of CML. The condition is often discovered incidentally, when a complete blood count (CBC) indicates an elevated level of white blood cells (WBCs) in conjunction with immature WBCs.

Diagnosing CML.

CML progresses through 3 phases of disease: chronic, accelerated, and blast. Patients with first-phase, or chronic, CML may complain of nonspecific symptoms, such as episodes of fatigue and shortness of breath, loss of appetite, weight loss, localized abdominal discomfort, and night sweats. A physical examination may reveal indications of easy bruising, an enlarged spleen, and abdominal tenderness.

When CML is suspected, a bone marrow biopsy is obtained and blood and bone marrow samples undergo cytogenetic analysis for the Philadelphia (Ph) chromosomal abnormality. Between 90% and 95% of patients with CML have the Ph chromosome, which results from gene translocation between chromosomes 9 and 22. Part of the ABL (Abelson) gene from chromosome 9 fuses with the BCR (breakpoint cluster region) gene from chromosome 22, creating the BRC-ABL gene [t(9;22)(q34;q11)] on a shortened chromosome 22 (the Ph chromosome). BRC-ABL signals the abnormal blood cells to produce excessive amounts of tyrosine kinase and is strongly implicated in CML.

Because a small percentage of patients with other types of leukemia test positive for the Ph abnormality, it is not definitive for CML. Additionally, 5% to 10% of patients with CML are Ph-. Further analysis using methods such as fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or reverse-transcriptase (RT)-PCR is required to identify the chimeric BRC-ABL gene. The presence of the Ph abnormality, the BRC-ABL gene, and signs and symptoms of CML all factor into making a conclusive diagnosis.

Treatment. The goal of treatment for patients with CML is to induce long-term remission. The most common and effective treatment is imatinib mesylate (Gleevec), a tyrosine kinase inhibitor approved by the FDA in 2001 as a firstline treatment for advanced CML (indications for imatinib were later expanded to include all 3 phases of CML). Imatinib targets the BRCABL protein while sparing noncancerous cells. Recently approved second-line treatments for patients unresponsive or resistant to imatinib include dasatinib (Sprycel) and nilotinib (Tasigna), which also work by blocking tyrosine kinase.

Immunotherapy with interferon alpha is an option for some patients with chronic CML, and it can produce a period of remission lasting as long as 10 years. Immunotherapy is associated with high levels of toxicity and adverse effects, however, and fewer than 50% of patients are able to complete the therapy regimen.

Bone marrow (stem cell) transplantation is the only treatment that has the potential to cure CML, but it is a risky procedure and requires finding a matching (or nearly matched) donor. Additionally, the majority of patients with CML who undergo autologous or allo- geneic bone marrow transplantation will relapse. Several studies are currently looking for ways to improve rates of disease-free survival after transplantation.

Molecular monitoring of imatinib mesylate response. For most patients with CML, imatinib remains the gold standard for treatment. It does not cure CML, so patients must continue to take the oral medication indefinitely to trigger and sustain remission. Patients treated with imatinib undergo frequent hematologic testing to assess the rate at which their levels of WBCs, red blood cells (RBCs), and platelets return to normal, known as a “complete hematologic response.” On average, 90% of patients experience a complete hematologic response 3 months after initiation of treatment; 50% eventually go into cytogenetic remission (when the Philadelphia chromosome is undetectable using cytogenetic analysis). Less than 10% of patients develop molecular remission (when PCR does not detect any Ph chromosomes).

Over time, 4% to 5% of initially responsive patients develop resistance to imatinib therapy, which is why regular molecular monitoring is imperative. Typically, blood samples are analyzed using a FISH assay, which can detect the presence of Ph chromosomes.

FISH testing is not as sensitive as PCR testing, however, and the NCCN guidelines recommend that patients receive PCR testing every 3 months to assess their BCR-ABL levels. Declining effectiveness of ther therapy corresponds to an increase in the level of BCR-ABL. In patients who show signs of relapse, NCCN guidelines suggest monthly PCR testing that includes screening for new ABL mutations, which researchers believe are indicative of emerging resistance to imatinib mesylate.

In 2007, Genzyme Genetics agreed to offer its proprietary real-time quantitative (RQ)-PCR assay for CML patients through CML Alliance (, a support program developed by Novartis for patients with CML and their physicians. MolecularMD also offers PCR testing through CML Alliance. Keeping up-to-date on patients’ molecular response to therapy allows physicians to respond timely to regression and modify treatment appropriately. To accurately assess progress toward major molecular response, it is helpful to obtain baseline measures by conducting RQ-PCR testing prior to initiating therapy. Less than 10% of patients treated with imatinib experience molecular remission— elimination of the Ph chromosome.

Monitoring imatinib mesylate blood plasma levels. A phase II study presented in January at the 2008 ASCO GI Cancers Symposium reported that patients with nonresectable/metastatic gastrointestinal stromal tumors (GIST) processed oral imatinib at different rates. George Demetri, associate professor of medicine, Harvard Medical School, and director of the Center for Sarcoma and Bone Oncology, Department of Medical Oncology, at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, Massachusetts, noted that, as a result, minimum blood plasma concentration (“trough” levels) varied significantly between patients receiving the same treatment regimen. The variation in trough levels was independent of age, gender, or body weight. Findings suggest that the imatinib dosage does not predicate a patient’s level of imatinib exposure.

Patients with GIST whose blood levels contained the lowest level of imatinib had poorer outcomes than those with the highest imatinib blood plasma levels, including a lower rate of objective response and shorter time to progression. “The quartile that had the lowest drug exposure progressed significantly faster than the other quartiles put together,” said Dr. Demetri.

Although the study by Demetri et al included only patients with GIST, it seems likely that similar results would be seen in patients with CML who were being treated with imatinib. Researchers in the European Union collaborated with Novartis’ CML Alliance to create a registry of CML patients that could be used to assess worldwide management of the disease. For 1 year, EUTOS (European Treatment and Outcome Study) collected data on 2500 patients with CML from more than 20 countries.

Results were presented in October at a meeting of the European LeukemiaNet in France. Francois Guilhot, MD, head of Oncology, Hematology, and Cell Therapy, University Hospital Center, Poitiers, France, reported that at 1 year, 1100 patients were not responding to imatinib therapy as expected. Hematologic analysis found that ~60% of patients had imatinib blood plasma levels considered less than optimal for maximum efficacy. Dr. Guilhot noted that “pharmacological testing is not widely used in clinical practice,” and said it is a “simple and effective way to help ensure patients benefit from their treatment and that treatment is used cost-effectively.”

The EUTOS researchers recommend that guidelines for standardized molecular and pharmacological monitoring be developed and implemented, which they believe would “allow patients to achieve improved response to treatment, and have a better chance of survival.” The investigators plan to recruit an additional 1700 patients with CML for a prospective study on the impact of implementing their proposals for blood level monitoring.

CML Alliance encourages regular pharmacological blood level testing to ensure that patients are taking their medications appropriately. The Website notes that after 4 months of oral treatment, cancer patients’ adherence to therapy steadily declines and they are not always up front about missing doses with their physicians. One study of patients with cancer on oral medication (N = 4043) found that in a 14-month period, patients were only 75% in compliance with their prescribed therapy regimen.

Blood level testing for patients with CML is useful in other circumstances, as well, such as investigating possible drug interactions, poor therapeutic response, or unexpectedly severe adverse effects. Any of these problems might arise if a patient is not metabolizing imatinib as anticipated. CML Alliance offers pharmacological blood level testing for patients with CML at no cost through its Website. Novartis notes that testing “will be performed by a CLIA-certified clinical laboratory with significant expertise in blood level testing.”

CML Alliance, in conjunction with EU researchers, continues to study this issue, working to standardize guidelines for blood level and molecular monitoring. Demetri and associates are weighing whether to mount a larger trial in an effort to determine why patients taking imatinib metabolize the drug at different rates, its effect on outcomes, and how to address the problem.

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