First-Line Nelarabine Prolongs T-Cell ALL Remission

CHICAGO -- Adding nelarabine (Arranon) to chemotherapy improved 4-year disease-free survival (DFS) in patients with newly diagnosed T-cell acute lymphoblastic leukemia (ALL), a randomized trial found.

Across two chemotherapy regimens, the 4-year DFS rate was 88.9% among 323 patients with intermediate- or high-risk T-cell ALL who were also treated with nelarabine compared with 83.3% in 336 patients who received chemotherapy alone (P=0.0332), reported Kimberly Dunsmore, MD, of the Virginia Tech Carilion School of Medicine in Roanoke, and colleagues.

"Nelarabine improved the outcomes for T-cell leukemia patients," said Dunsmore, during a news briefing ahead of the American Society of Clinical Oncology (ASCO) meeting to be held here in June, highlighting that overall the study demonstrated "the best reported survival for patients with T-cell leukemia."

Among all 1,545 randomized T-cell ALL patients included in the study, the rates of DFS and overall survival at 4 years were 84.1% and 90.2%, respectively. And those patients who also received nelarabine had both better survival and fewer central nervous system (CNS) relapses, Dunsmore noted.

From 2007 to 2014, the Children's Oncology Group (COG) AALL0434 trial enrolled 1,895 patients (ages 1-30) with T-cell ALL or T-cell lymphoblastic lymphoma -- the largest clinical trial ever conducted for children and young adults with T-cell malignancy. ALL patients made up the vast majority (94%).

In addition to the COG augmented Berlin-Frankfurt-Münster regimen, patients were randomized in a 2 × 2 design, to either of two methotrexate dosing regimens:

• Escalating doses of methotrexate (CMTX) with or without six courses of nelarabine (5-day courses at 650 mg/m²/day)
• High-dose methotrexate (HDMTX) with or without six courses of nelarabine

Patients with T-cell ALL also received either prophylactic or therapeutic cranial irradiation. The next step will be to test nelarabine in protocols without cranial irradiation to decrease long-term neurologic side effects, said Dunsmore. "We think it may be possible since nelarabine offered fewer CNS relapses."

In commenting on the study, ASCO President Bruce E. Johnson, MD, commended the researchers for effectively accruing patients with a rare disease to such a study.

"Before they embarked on this, about only 80% of the patients were surviving up until 4 to 5 years, and this improved it by about 10%," he said. "Nelarabine, the drug that was employed here, had been approved for relapsed or recurrent disease and in this particular setting moving it upfront, closer to the initial treatment, improved the outcomes for those patients. "

Among the 361 T-cell ALL patients treated with HDMTX, those randomized to nelarabine saw a significant improvement in 4-year DFS (86.2% versus 78.0%, P=0.024). Among the 298 T-cell ALL patients treated with CMTX, the 4-year DFS was 91% with nelarabine versus 89.8% without, though this did not reach statistical significance (P=0.3825).

This 4-year DFS advantage with nelarabine, however, was not seen among the 118 patients with T-cell lymphoblastic lymphoma (85% with versus 89% without, P=0.2788).

These updated results confirm earlier data showing an improved benefit of CMTX over HDMTX.

In a group of 43 T-cell ALL patients who had failed induction therapy and were non-randomly assigned to HDMTX plus nelarabine, the rate of DFS at 4 years was 54.8% (8.9%). "This is important because it's more than double the past survival rates," said Dunsmore.

No significant differences were seen between patients treated with or without nelarabine in terms of neurotoxicity or overall toxicity. The rate of grade 3/4 peripheral neurotoxicity (including motor or sensory neuropathy) was 8%, with no arm going above 9%.

Nelarabine, an injectable purine nucleoside antimetabolite, was first granted accelerated approval in 2005 for the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma who had failed at least two previous chemotherapy regimens. The approval was based on complete response data, and doubts about the drug's efficacy had been raised while awaiting confirmatory trials such as AALL0434.