Pediatric treatment regimens for adults with acute lymphoblastic leukemia (ALL) continue to be explored as therapeutic approaches that may lead to better overall survival. Age coupled with the presence of cytogenetic abnormalities are key determinants when making treatment decisions for patients with ALL as stated by Daniel J. DeAngelo, MD, at the National Comprehensive Cancer Network® (NCCN®) 6th Annual Congress: Hematologic Malignancies™.
FORT WASHINGTON, PA — Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children; however with improvements in treatments, approximately 80 percent of young patients can be cured from the disease. There has been increasing interest in extending pediatric regimens to adult populations, but challenges remain noted Daniel J. DeAngelo, MD, of Dana-Farber Cancer Institute and an expert panel member of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for ALL. The impact of age in the selection of treatment for ALL was the center of a presentation given by Dr. DeAngelo at the recent NCCN 6th Annual Congress: Hematologic Malignancies™.
"Considerable disparity exists between adults and children with ALL including the presence of and prognostic indications associated with cytogenetic abnormalities," said Dr. DeAngelo.
A key discriminating cytogenetic abnormality is the Philadelphia chromosome. Philadelphia-positive (Ph+) is rare in children, very common in adults, and associated with poor prognosis; the incidence of Ph+ ALL increases with age, and is therefore most commonly seen in older adult patients.
Treatment for ALL is often dependent on a patient's Philadelphia chromosome status as well as their age. For example, Dr. DeAngelo discussed research showing that imatinib (Gleevec®, Novartis Oncology) with a hematopoietic stem cell transplant (SCT) improved outcomes in younger adults with Ph+ ALL.
"Cytogenetic abnormalities such as the Philadelphia chromosome confer important prognostic information and can help to identify high-risk and low-risk patients at the time of diagnosis as well as guide treatment decisions," said Dr. DeAngelo.
Commonly used regimens for adults with ALL stem from a series of clinical trials conducted by The Cancer and Leukemia Group B (CALGB), including the CALGB 8811 (Larson) regimen that used a five-drug regimen for induction therapy. Six sequential CALGB studies were conducted from 1988 through 2007 that included similar dose-intensive treatment regimens. Hyper-CVAD is a second chemotherapy regimen often used in adults with ALL based upon results from trials showing improvement in complete remission and overall survival.
Consistent with previous studies, results from both series of trials (CALGB regimens or Hyper-CVAD) indicated that younger patients treated with any of the regimens had a markedly improved outcome compared to their older counterparts.
Identifying certain biologic factors associated with poor outcomes, namely complex cytogenetics, has also allowed researchers to modify and improve upon existing chemotherapy regimens.
"Studies have shown that the incorporation of rituximab (Rituxan®, Genentech BioOncology and Biogen Idec) into the Hyper-CVAD regimen appears to improve outcome for younger patients with CD20-positive, Ph-negative, precursor B-lineage ALL," said Dr. DeAngelo.
Specific immunophenotypes have also been used to identify adults as standard- or high-risk patients with ALL. Studies continue to support allogeneic SCT as a recommended treatment option for the high-risk population.
"Research needs to continue to focus on risk-adapted therapies in adults with ALL," said Dr. DeAngelo.
Various clinical trials have indicated that a pediatric treatment regimen is more effective than an adult treatment regimen used in young adults of the same age, but deciphering at what age older adolescents/young adults should be considered adults continues to be a challenge.
"The adolescent and young adult definition is a relatively loose term with some groups including the age range of 15-60 in this population," said Dr. DeAngelo.
He noted a study that evaluated ten-year consecutive trials of young adults (ages 16-21 years) who were participating in either Children's Cancer Group (CCG) or adult CALGB trials. The report showed that although complete remission rates between patients entered into either CCG or CALGB studies were identical, the event-free survival was dramatically different.
"Event-free survival of patients in CCG trials was 64 percent compared to only 36 percent event-free survival of patients in CALGB studies," said Dr. DeAngelo.
Based on these data, researchers are extending the evaluation of pediatric-like regimens on adults older than 21 to determine if similar outcomes can be achieved.
"Future research needs to continue to target more specific age ranges in this often broad categorization of adolescent and young adults," noted Dr. DeAngelo.
Dr. DeAngelo reiterated that although there has been some improvement in the treatment of adult ALL, there is still a lack of understanding of the biology of the disease in older populations. He noted the importance of increasing participation of adults in clinical trials as well as researching further potential prognostic indicators including molecular markers such as the IKZF1, JAK, and CRLF2 gene mutation as a marker for high-risk disease.
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