Dan Douer, MD
The treatment landscape for acute lymphoblastic leukemia (ALL) is changing, pointing to promising new approaches clinicians can use in practice. These include deploying pediatric regimens in the adult setting, recognizing genetic alterations beyond the Philadelphia chromosome that can be manipulated with targeted agents in “Philadelphia-like” disease, and modifying autologous T-cells with new treatment modalities.
This is all good news for patients, said Dan Douer, MD, in reviewing some of the latest ALL research at the 19th Annual Congress on Hematologic Malignancies. Douer, an attending physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center, cautioned that while “best clinical practice is changing, what we think today also may change,” in a setting where the response rate is low in patients who relapse, and where there is still no standard classification of risk.
Some of the more provocative questions surrounding ALL treatment, he said, include whether it makes sense to shift standard of care at an age around puberty to 21 years, which he deemed “an administrative decision,” not grounded in the latest research.
Another question involves the use of heavily myelosuppressive, “AML-like” drugs. He argued that myelosuppression is a side effect and not a goal in ALL, noting that research has demonstrated no added benefit for anthracycline intensification and that non-myelosuppressive drugs, including steroids and vincristine, elicit a high response rate in adults with ALL.
Douer also explored the question of why asparaginase is underused in adult patients, a decision he attributed to the belief that it is more toxic in adults than in children where research has demonstrated increasing duration of asparaginase improves overall outcomes. “My concern is that this fear, this reluctance, has not gone away.”Pediatric Protocols in Adults
Douer noted that adult ALL patients have a higher range of biologically unfavorable disease, presenting a particular challenge for clinicians. He reviewed studies conducted over the last several years utilizing “pediatric-inspired” regimens in adults, including early results from the US Intergroup Trial C10403 (CALGB 10403) which were presented at the 2014 ASH Annual Meeting in December.1
This trial involved 296 newly diagnosed adolescent and young adult (AYA) patients (median age = 24 years, range 17-39), the majority (76%) of whom had B-precursor ALL. The study built on research from the successful Children's Oncology Group (COG) Study AALL0232.2
For the AYA study reported at ASH, the experimental regimen was identical to the standard arm (Capizzi escalating methotrexate plus PEG asparaginase) used in the COG 0232 study.
When this intensive pediatric regimen was used in the AYA group, 2-year overall survival (OS) was 78%, and event-free survival was 66%. Toxicities in the AYA cohort were similar to those experienced by pediatric patients receiving the regimen in the COG 0232 study, including ALT elevation in approximately 50% of patients in both in the AYA and pediatric populations and hyperbilirubinemia (~25%).
Douer and colleagues adapted the COG 0232 regimen to reduce toxicities in a study involving 51 patients (median age = 32 years, range 18-57) who received six doses of intravenous pegaspargase at 2000 IU/m2 per dose.3
The approach involved longer intervals between doses, more rational synchronization with other chemotherapy drugs to prevent overlapping toxicities, and administration with steroids to reduce hypersensitivity. Complete remission was achieved in 96% of patients, and notably, said Douer, most patients entered complete remission after one cycle of therapy.
Investigators reported 7-year disease-free and OS rates of 58% and 51%, respectively. Douer added that for standard-risk patients, OS was 74% and for high-risk patients, 40%.
The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia (31%) and transaminitis (63%), and these occasionally resulted in treatment delays.
“What’s really emerging now are the liver toxicities,” said Douer, prompting many physicians to discontinue use of the drug. He stressed that these toxicities occur mostly after the first dose and may last as long as 1 month, but, “if you continue giving the drug, the toxicity doesn’t necessarily recur after subsequent doses.”