Molecular and Pharmacologic Monitoring in Patients with Chronic Myeloid Leukemia

By Christin Melton
Published: Friday, May 21, 2010
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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.

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