Pediatric regimens may provide insight into treatment of adult ALL

Treatment for acute lymphoblastic lymphoma in adults is not standardized and has been linked to lower success rates than have been observed in children and adolescents.

Clinicians and researchers such as Dan Douer, MD, leader of the Acute Lymphoblastic Leukemia Program at Memorial Sloan-Kettering Cancer Center, have started to scrutinize the disease with the hope of improving outcomes in adult patients.

“In adult ALL, clinicians choose their favorite regimen, or the regimen they were trained on,” Douer, who presented findings on the topic at the Acute Leukemia Forum in San Francisco earlier this year, told HemOnc Today. “They choose from ones that have been published and follow the literature for front-line therapy. We need to look at this disease more closely.”

Douer’s presentation focused on the use of pediatric-inspired regimens. He also covered prognosis based on minimal residual disease testing, gene profiling and expression in adult ALL, and he emphasized the need for identifying novel target therapy.

“We can cure about 80% of all pediatric ALL patients, but we are not able to do this in adults,” Douer said. “The cure rate may be about 40% in adults. My question is why?”

Success in children

ALL acquired by children is more sensitive to chemotherapy, and protocols for pediatric chemotherapy are more aggressive.

In a study published in the Journal of Clinical Oncology, Boissel and colleagues retrospectively evaluated the outcomes of young adults treated on pediatric (FRALLE) and adult (LALA) therapeutic regimens, and they discovered several differences.

“The pediatric regimens included more vincristine, steroids and asparaginase,” Anjali Advani, MD, staff physician in hematologic oncology and blood disorders at Taussig Cancer Institute at Cleveland Clinic, told HemOnc Today. “Most pediatric regimens also include prolonged maintenance and more intensive central nervous system treatment.”

Compliance also may be a factor, Douer said. Parents are likely to take their children for treatment, whereas adults are more likely to delay treatment.

“Adults have to work. There are life factors involved,” Douer said. “Treatments require a lot of commitment and time, which many adults don’t have. This could be contributing to higher success rates in children and lower success rates in adults.”

No standard approach

There is no state-of-the-art treatment for ALL in adults, and there is no standard approach for treating the disease, Douer said. The success rate in treating children has been largely due to successive trials that built on one another.

“Forty years ago, the success rate for treating children was about 20%,” he said. “Now it is between 80% and 90%. Without any new drugs, the pediatricians have just gotten better at manipulating the drugs we have. We are not seeing this kind of rigor in adult patients, and the lack of standards reflects that.”

Advani serves as the SWOG principal investigator for a national intergroup trial being led by CALGB, in which researchers hope to answer some of the lingering questions. The researchers have collaborated with pediatricians to enroll approximately 300 patients aged up to 40 years. Their goal is to evaluate outcomes — including complete response rate, event-free survival, DFS and OS — and determine whether it may be feasible to extend the pediatric approach to patients aged up to 40 years.

One challenge is the lack of a clear definition for what constitutes the adult patient population. The NCI suggests patients aged 16 to 39 years may be able to tolerate pediatric protocols, but they also have grouped adults into age ranges of 40 to 60 years, and then aged at least 60 years, Douer said.

“This wide range of ages makes it very difficult to use the same treatments for everybody,” he said.

There also is uncertainty about bone marrow transplantation.

“Some say it is better in patients with a high risk for relapse, and some say better in low-risk patients,” he said. “Risk is mostly determined by chromosomal abnormalities patients have.”

Douer said there are complications with classifying patients based on minimal residual disease status.

“One problem is that we do not know the threshold for the number of cells in adults,” he said. “Another problem is that there are regulatory issues related to it.”

Douer said gene profiling likely will have prognostic significance and could lead to more targeted therapies. Rituximab (Rituxan, Genentech/Idec) may improve outcomes in ALL, he added. Other investigational targeted therapies include alemtuzumab, blinatumomab, enzyme therapy, imatinib (Gleevec, Novartis) and other tyrosine kinase inhibitors.

“Some of these treatments may change practice, but we are still investigating them,” Douer said. “Another option is nilotinib (Tasigna, Novartis), which has been linked to an extremely high rate of efficacy as single agent. The problem is that the effect does not sustain.”

Despite these ongoing challenges, Advani and Douer expressed hope for the future.

“After many years of seeing this disease be neglected in adults and reluctance to the use of asparaginase, maybe with some combination of these new drugs, pediatric protocols, and minimal residual disease in defining who is eligible for treatment, we will see better results,” Douer said. “If we continue to refer patients to centers that are employing these strategies, the results will come that much faster.”         

References:
  • Boissel N. J Clin Oncol. 2003;21:774-780.
  • Stock W. Blood. 2008;112:1646-1654.