Comparison of First-Line Chemotherapy for Adults with Acute Lymphoblastic Leukemia

Survival of adult patients with acute lymphoblastic leukemia (ALL) remains low and there has been sparse data to compare first-line therapies, specifically in younger adults. To address this knowledge gap, researchers conducted a retrospective analysis of intensive chemotherapy regimens administered to adult patients with ALL at Cleveland Clinic.

The study found the overall survival of adults receiving hyper-CVAD was 71% compared to 49% of those receiving CALB-19802. Hyper-CVAD was also associated with higher FC-MRD negative response.

Background

The management of ALL varies by age, with much debate remaining, particularly in how to treat young adults. A pediatric-inspired regimen called CALGB 10403 is commonly used in the northeast U.S. and Europe, consisting of a backbone of chemotherapy in combination with asparaginase. In the southern U.S. and other places, hyper-CVAD is often prescribed.

There has never been a head-to-head comparison of the two treatments in a randomized trial. “This raises the question about the utility of asparaginase,” says Moaath Mustafa Ali, MD, a hematologist/oncologist with Cleveland Clinic Cancer Institute and senior author of the study. “The problem with asparaginase is that it causes a lot of toxicity, including hypersensitivity reaction, pancreatitis, liver issues, as well as the risk of thrombosis and concurrent bleeding. It has a unique side effect profile, and is not an easy medication to tolerate. It's a medication that frequently gets stopped due to complications. Hence, it's important to know what the utility of this drug is.”

Study details

One hundred and sixty-one adult patients with ALL were seen at Cleveland Clinic between January 2017 and August 2023, 100 of whom received an intensive regimen. Thirty-three patients received a pediatric-inspired regimen (mostly CALGB 10403), 32 patients received another asparaginase-containing regimen called CALGB 19802 and another 28 patients received hyper-CVAD. The median age was 27 for the pediatric-inspired regimen group, 59 for the CALGB group and 57 for the hyper-CVAD group.

In the retrospective analysis, the researchers studied outcomes, including composite complete response (CCR), flow cytometry measurable residual disease (MRD) response, overall survival and event-free survival.

Study outcomes

Hyper-CVAD was associated with higher odds of FC-MRD negative response when compared to CALGB-19802. The overall survival of the hyper-CVAD group was also higher than the CALGB-19802 group. The long-term survival outcomes for young patients receiving pediatric-inspired regimens were comparable to those in the hyper-CVAD group.

Although the study included a relatively small sample size, the data findings were eye opening. “We found that hyper-CVAD was superior to CALGB 19802 in terms of achieving higher MRD negative responses as well as a trend to improvement in overall survival and event-free survival,” says Dr. Mustafa Ali.

“That was a somewhat unexpected outcome,” Dr. Mustafa Ali continued. “There’s a perception that adding asparaginase to chemotherapy makes a really big difference. We found that wasn’t the case. Hyper-CVAD performed better in achieving deeper responses than CALGB 19802, the latter of which contained asparaginase.”

Another notable finding was that hyper-CVAD was not inferior to the pediatric-inspired regimen CALGB 10403, which contraindicates common beliefs in the field. Hyper-CVAD had a similar overall survival and event-free-survival to CALB 10403.

What's next

As bispecific T-cell engagers like blinatumomab have been introduced, there has been less focus on comparing hyper-CVAD to CALGB 10403. “The challenge is that there already are fixed regimens that have asparaginase integrated into them, yet the benefit of asparaginase remains unclear in the frontline setting,” says Dr. Mustafa Ali.