New evidence suggests that using advanced genetics technologies to monitor for remaining cancer cells after treatment may soon become an effective tool to inform treatment decisions and ultimately predict patient outcomes for patients with a particularly aggressive form of acute lymphocytic leukemia (ALL). Study results were published online today in Blood, the Journal of the American Society of Hematology (ASH).
Approximately 25 to 30 percent of all adults with ALL, the second most common type of acute leukemia, have what is known as Philadelphia chromosome-positive (Ph+) ALL, a rapidly progressing form of the disease caused by a genetic abnormality that is associated with a poor prognosis. Following their first complete remission, one of the most common preventive treatments Ph+ ALL patients undergo is an allogeneic stem cell transplant, in which a patient receives stem cells from a sibling or unrelated matched donor; however, this procedure can be associated with harsh side effects and may not be universally available. Some research conducted since the introduction and subsequent success of a new class of cancer drugs called tyrosine kinase inhibitors (TKIs), which target the abnormal, leukemia-causing protein BCR-ABL and have greatly improved survival rates, suggests that stem cell transplantation may not be necessary for some Ph+ ALL patients. However, clinicians lack a reliable method for predicting disease progression and determining whether a patient's disease is aggressive enough to warrant a stem cell transplant or if TKI therapy plus chemotherapy will likely eradicate the disease.
Despite the advent of these powerful, targeted cancer therapies, some cancer cells may linger in a patient's body following the primary course of treatment. However, data from several recent studies have suggested that monitoring the amount of this remaining cancer cell population, known as minimal residual disease (MRD), may be an effective indicator of a patient's risk of relapse. Consequently, clinicians have increasingly employed several highly sensitive monitoring tools to detect MRD, such as multi-parameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RQ-PCR), that search for genetic aberrations in a patient's blood and bone marrow that indicate the presence of cancerous cells. Although this method has proved effective for several other types of leukemia, the reliability of these tools specific to Ph+ ALL is not yet fully understood.
"The arrival of tyrosine kinase inhibitors has marked the beginning of an exciting era in which we can begin considering alternative preventive cancer treatments and look to spare patients from the risk of toxicities that often accompany stem cell transplants," said lead study author Farhad Ravandi, MD, of The University of Texas MD Anderson Cancer Center in Houston. "Now that we know that these drugs are effective, we can take the next step and focus on studying lingering disease in Ph+ ALL patients to guide more effective treatments and ultimately predict and manage possible relapse."
To better understand how technology that tracks indicators of MRD could potentially predict Ph+ ALL patients' survival and inform treatment decisions, Dr. Ravandi and a team of MD Anderson researchers conducted a decade-long study to monitor whether a negative MRD reading was associated with prolonged survival. Between 2001 and 2011, Dr. Ravandi's team monitored 76 adult patients (average of 54 years old) with Ph+ ALL who had achieved complete remission after a treatment regimen including at least one course of induction chemotherapy plus a TKI followed by treatment with a TKI (either dasatinib or imatinib) and chemotherapy, and two years of TKI maintence therapy. All study participants began with fewer than 5 percent cancer cells in their body and none had undergone stem cell transplant, nor were they at an otherwise hightened risk of relapse. Utilizing MFC and RQ-PCR technologies, investigators monitored patients for MRD after first remission and every three months thereafter.
Results from the investigation suggested that when used together, MFC and RQ-PCR monitoring technologies were effective in predicting the majority of disease progression and patient outcomes in this population. Among 44 patients who showed evidence of MRD in the first year of follow-up (either by MFC or RQ-PCR results), 13 relapsed, including 9 of 22 of the highest risk patients who showed positive MFC at three months and beyond. Thirteen of 54 patients who maintained negative MRD from three months and beyond had relapsed.
While the MRD readings observed by Dr. Ravandi and his team did not accurately predict all patient outcomes in the study population, researchers note that these results indicate that the combination of MFC and RQ-PCR technologies represents a valuable prognostic tool to measure the likelihood of a patient relapse. However, researchers caution that it is too early to integrate the use of these technologies into treatment guidelines regarding the neccessity of stem cell transplant for Ph+ ALL patients.
"While our results aligned with our observed outcome in this study and the MFC and RQ-PCR technologies are very sensitive, these tools do not yet provide absolute results. We advise that each treatment decision be made on a patient-to-patient basis to take into account each patient's different genetics," said Dr. Ravandi. "The next step is to refine and standardize our approach to better define which patients are truly disease-free and who should be recommended for more aggressive treatment."
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