Adding nelarabine (Arranon) to escalating-dose methotrexate (C-MTX) increased the 4-year disease-free survival (DFS) rate to 91% in pediatric and young adult patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL), according to results from the phase III AALL0434 trial.
The study—presented at the 2018 ASCO Annual Meeting—included 3 other treatment arms comprising C-MTX alone, high-dose MTX (HD-MTX) alone, or HD-MTX plus nelarabine, a chemotherapy drug. All patients initially received the COG augmented Berlin-Frankfurt-Munster (aBFM) multidrug chemotherapy regimen.
Among 1545 evaluable patients, the 4-year overall survival rate was 90.2% and the 4-year event-free survival rate was 84.1%. The 4-year DFS rates were 88% among patients receiving a nelarabine combination versus 83% for patients receiving HD-MTX or C-MTX alone. Additionally, the number of CNS relapses was lower among patients receiving nelarabine, and there was no difference in neurotoxicities between treatment arms.
“AALL0434 is the largest clinical trial for children and young adult patients with T-ALL/T-LL ever conducted [and] has the best ever survival data [in this population],” lead study author Kimberly Dunsmore, MD, professor, Virginia Tech Carilion School of Medicine, said in a presscast held in advance of the meeting.
“T-cell ALL is a disease that requires the use of a very intense and complex chemotherapy regimen. Historically, about 80% of people live at least 4 years after being treated for their disease, but we felt we could and must do better. Our trial shows that we could further increase survival rates by about 10%, which is very encouraging,” Dunsmore explained in a statement.
Between January 2007 and July 2014, the phase III AALL0434 trial enrolled 1895 newly diagnosed patients with T-ALL (94%) or T-LL (6% of patients). Patients were aged 1 to 30 years.
The study used a 2 x 2 pseudo-factorial randomization. All patients enrolled on the 4-arm trial initially received COG aBFM chemotherapy. Patients were then randomized to receive HD-MTX plus leucovorin rescue or C-MTX without leucovorin rescue plus pegaspargase.
A second randomization was done for patients with T-ALL or T-LL who had an intermediate or high risk of recurrence. These patients were randomized to no nelarabine or six 5-day courses of 650 mg/m2
of nelarabine daily. Thus, the 4 treatment arms were HD-MTX alone, C-MTX alone, HD-MTX plus nelarabine (intermediate- and high-risk patients), and C-MTX plus nelarabine (intermediate- and high-risk patients).
Prophylactic (1200 cGy) or therapeutic (1800 cGy for CNS3) cranial irradiation was also administered to the intermediate- and high-risk T-ALL patient population. Additionally, patients with T-ALL in whom induction therapy failed were assigned nonrandomly to receive HD-MTX plus nelarabine.
Compared to the 91% 4-year DFS rate with nelarabine plus C-MTX, the rate was 89.8% (+/- 3.0%) with C-MTX alone. Among patients randomized to nelarabine plus HD-MTX, the 4-year DFS was 86.2% (+/- 3.2%) versus 78.0% (+/- 3.7%) with HD-MTX alone.
The 4-year DFS rate was 54% for patients who did not achieve induction remission, which Dunsmore said was “more than double” previously reported rates.
There was no added benefit with nelarabine for high-risk T-LL patients, with a 4-year DFS rate of 85.0% (+/- 5.6%) for those receiving the additional drug compared with 89.0% (+/- 4.7%) for those who did not.
Regarding safety, Dunsmore et al wrote in their abstract, “Overall toxicity and neurotoxicity were acceptable and not significantly different between all 4 arms.”
Commenting on future directions for the research, Dunsmore said, “Next steps [are] to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation to decrease long-term neurologic side effects. We think this may be possible, since nelarabine [led to] fewer CNS relapses.”
Nelarabine was approved by the FDA in October 2005 for the treatment of patients with relapsed/refractory T-ALL or T-LL following 2 or more chemotherapy regimens.
“Nelarabine, the drug employed here, is 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,” ASCO President Bruce E. Johnson, MD, FASCO said during the presscast.
Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. J Clin Oncol.
2017 (suppl; abstr 10500).