Upfront Use of Nelarabine Plus Chemotherapy Improves Disease-Free Survival in T-Cell Malignancies

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Upfront use of nelarabine plus standard Children’s Oncology Group–augmented Berlin-Frankfurt-Münster (aBFM) chemotherapy boosted survival rates in children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic leukemia (T-LL), according to the results of a large phase III federally funded trial to be presented at the 2018 ASCO Annual Meeting.1

Overall survival for all patients entered into the trial was 90.2% at 4 years, and event-free survival was 84.1% at 4 years. In patients who were at moderate or high risk of T-ALL recurrence, the addition of nelarabine to aBFM chemotherapy achieved 4-year disease-free survival in 88% compared with 83% for patients not randomized to receive nelarabine.

These are the highest survival rates for these T-cell malignancies reported to date, and this is the largest randomized clinical trial to be performed in these relatively uncommon diseases.

These are outstanding overall outcomes. Nelarabine improves disease-free survival for children and young adults with T-ALL and should become a new standard of care for this population.
— Kimberly Dunsmore, MD

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“T-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,” said lead study author Kimberly Dunsmore, MD, Professor at Virginia Tech Carilion School of Medicine, Roanoke. “Our trial shows we could further increase survival rates by about 10%, which is very encouraging.”

“These are outstanding overall outcomes. Nelarabine improves disease-free survival for children and young adults with T-ALL and should become a new standard of care for this population,” she said.

Nelarabine was approved in 2005 by the U.S. Food and Drug Administration for the treatment of T-ALL and T-LL that progressed on at least two previous chemotherapy regimens. This study evaluated nelarabine upfront in newly diagnosed patients.

Study Details

The randomized, phase III clinical trial was initiated in 2007 and enrolled 1,545 participants (aged 1 to 30 years old) with either T-ALL (94%) or T-LL (6%). The trial had a complex 2 x 2 factorial design. All patients received aBFM. Patients were randomly assigned to receive aBFM, high-dose methotrexate, plus leucovorin rescue as inpatients or aBFM and an escalating dose of methotrexate with or without leucovorin rescue plus pegaspargase (Oncaspar) as outpatients. Patients with intermediate- and high-risk T-ALL and T-LL were randomized to receive six 5-day courses of nelarabine or no nelarabine; intermediate- and high-risk T-ALL patients also received prophylactic or therapeutic cranial irradiation. All patients with T-ALL who failed to respond to induction therapy received high-dose methotrexate plus nelarabine.

Key Results

In the entire study, the 4-year rate of overall survival was 90.2%, and the 4-year event-free survival rate was 84.1%. In T-ALL patients at moderate to high risk of recurrence, the 4-year overall survival rate was 88% in those treated with nelarabine in addition to standard chemotherapy versus 83% in those who did not receive nelarabine. Patients with T-LL (comprising 6% of study participants) did not benefit from the addition of nelarabine, but 4-year disease-free survival was more than 85% for this group of patients.


  • In the largest randomized clinical trial to date in T-ALL and T-LL, the upfront use of nelarabine plus standard chemotherapy achieved the best survival rates ever reported in patients with these hematologic malignancies.
  • In the present study, overall the rate of peripheral neurotoxicity was 8%—lower than that reported in previous phase I and II studies of nelarabine alone or combined with other agents that increase neurotoxicity.
  • The investigators concluded that nelarabine should be a new standard of care when combined with aBFM chemotherapy, although these results should not be extrapolated to other regimens.

In contrast to other smaller trials in T-ALL, patients treated with escalating doses of methotrexate did better in this trial than did those treated with high-dose methotrexate: 4-year disease-free survival was 89.8% vs 78%, respectively. The arm with the best outcome was nelarabine plus escalating doses of methotrexate, with a 4-year disease-free survival rate of 91%.

“We have previously shown that escalated-dose methotrexate was more effective than high-dose methotrexate. Adding nelarabine further improves survival,” stated Dr. Dunsmore.

Patients who failed to achieve remission after induction chemotherapy (n = 43) were nonrandomly assigned to receive high-dose methotrexate plus nelarabine. Of them, 54.8% achieved disease-free survival at 4 years, more than double historical rates, Dr. Dunsmore commented. Historically, about 20% of those with T-ALL who failed to achieve remission on induction chemotherapy survived for an additional 3 years.


Fewer patients had central nervous system relapses with nelarabine than without it. Toxicity and neurotoxicity were not significantly different among the four arms of the trial. Dr. -Dunsmore noted that previous phase I and II studies of nelarabine alone or combined with other agents that increase neurotoxicity showed peripheral neurotoxicity rates of between 9% and 15%. In the present study, overall the rate of peripheral neurotoxicity was 8%. “In no arm of the trial did the rate of peripheral neurotoxicity exceed 9%,” she stated.

The next step is to try to reduce side effects from cranial irradiation by evaluating the omission of cranial radiation with these chemotherapy protocols. Late effects of cranial radiation include cognitive changes, learning disabilities, neuroendocrine changes, and development of secondary malignancy.

Additional Commentary

ASCO President Bruce E. Johnson, MD, FASCO, who moderated the premeeting press briefing where this abstract was discussed, commented: “As oncologists, we are constantly striving for better care and outcomes for our patients, even in cancers where survival rates are relatively high compared with others. We now know it is possible to significantly boost survival in children and young adults with rare forms of leukemia and lymphoma, without introducing additional harsh side effects that can impair their quality of life.”

“Previously, only 80% of patients with these T-cell malignancies survived for 4 or 5 years. Nelarabine plus standard chemotherapy did not increase side effects. Nelarabine is approved for relapse, and this study shows upfront use of nelarabine improves survival,” Dr. Johnson said. ■

DISCLOSURE: Dr. Dunsmore reported an immediate family member is employed by TypeZero Technologies. She also has received travel expenses from Novo Nordisk, and a member of her family has received travel expenses from Tandem Diabetes Care. For Dr. Johnson’s disclosure, see page 5.


1. Dunsmore KP, Winter S, Devidas M, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. 2018 ASCO Annual Meeting. Abstract 10500. To be presented June 2, 2018.

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