Adding nelarabine to a standard chemotherapy regimen improved disease-free survival (DFS) in children and young adults with T-cell acute lymphocytic leukemia (TALL), compared with the chemotherapy regimen alone, according to results from the Children’s Oncology Group (COG) AALL0434 trial. With a four-year overall survival (OS) rate of 90 percent in the nelarabine-treated group, “survival [for this patient population] is better than it has ever been,” lead author Kimberly P. Dunsmore, MD, told ASH Clinical News.
Dr. Dunsmore, professor at Virginia Tech Carilion School of Medicine, presented the results from COGAALL0434 at the 2018 ASCO Annual Meeting. “[This] is the largest trial ever conducted for newly diagnosed T-ALL and T-cell lymphocytic lymphoma (T-LLy), showed outstanding overall outcomes, and [nelarabine] should become a new standard of care for [T-ALL],” she added.
The randomized, phase III trial enrolled 1,545 children and young adults (age range = 1-30 years) with newly diagnosed T-ALL between January 2007 and July 2014. The protocol was later amended to include patients with T-LLy (6%; n=277), though the trial was underpowered to detect a survival benefit with nelarabine in this patient population.
The trial was designed to answer two questions, Dr. Dunsmore explained: “Would nelarabine added into a backbone of chemotherapy be effective and safe in patients with T-cell leukemia? And, second, what is the best way to give methotrexate – high-dose or escalating-dose?”
All participants were treated with a standard four-drug induction regimen (the Berlin-Frankfurt-Munster [BFM] regimen, comprising: prednisone, vincristine, pegaspargase, daunorubicin, intrathecal cytarabine, and intrathecal methotrexate). Then, during consolidation, patients with intermediate- and high-risk disease (68.2% and 19.1%, respectively) received an augmented BFM chemotherapy regimen with or without nelarabine 650 mg/m2 daily in six 5-day courses (n=323 with; n=336 without).
During maintenance, patients were randomized to receive either high-dose methotrexate (four doses at 5 g/m2 without asparaginase) or escalating-dose methotrexate (100-300 mg/m2 with two doses of asparaginase). Patients with intermediate- and high-risk T-ALL also received prophylactic or therapeutic cranial irradiation at 1,200 cGy or 1,800 cGy for central nervous system (CNS) disease stage 3, respectively.
Subjects with low-risk T-cell disease were ineligible to receive nelarabine and were only randomized between the methotrexate arms; these patients did not receive cranial irradiation, the investigators noted. Also, 3.4 percent of patients were not randomized to methotrexate or nelarabine based on induction failure.
After four years of follow-up, the DFS and OS rates among T-ALL patients were:
- DFS: 84.1%
- OS: 90.2%
Treatment with nelarabine improved DFS: 88 percent versus 83 percent (p=0.045).
The authors also reported no significant differences between rates of four-year DFS in the participants receiving escalating-dose, regardless of nelarabine exposure:
- escalating-dose methotrexate with nelarabine (n=147): 91%
- escalating-dose methotrexate without nelarabine (n=151): 89% (p=0.28)
However, in those randomized to high-dose methotrexate, nelarabine was associated with a significantly higher four-year DFS rate:
- high-dose methotrexate with nelarabine (n=176): 87%
- high-dose methotrexate without nelarabine (n=185): 78% (p=0.011)
Combining nelarabine with BFM chemotherapy was not associated with additional toxicity: In the nelarabine-treated group, 50 patients experienced a disease relapse, secondary myeloid neoplasm, or death, compared with 57 patients in the non–nelarabine-treated group. “Nelarabine is known to have some serious neurotoxic effects, but we found that incidences of neurotoxicity were similar across all four treatment arms,” Dr. Dunsmore reported, adding that nelarabine was associated with fewer CNS relapses (n=1 and n=14, respectively).
Incidence of grade 3/4 peripheral neuropathy also were similar (6% and 9%, respectively).
Dr. Dunsmore noted that the trial was limited by the small number of patients with T-LLy and added that future trials will have to determine whether nelarabine will have a survival advantage in a protocol without cranial irradiation.
The corresponding authors report financial relationships with Novartis, which provided support for the study, along with the Cancer Therapy Evaluation Program of the National Cancer Institute/National Institutes of Health, GlaxoSmithKline, Novartis, and St. Baldrick’s Foundation.
Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. Abstract #10500. Presented at the 2018 ASCO Annual Meeting, June 2, 2018; Chicago, IL.