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With the additional administration of nelarabine to the Children's Oncology Group’s (COG) augmented Berlin-Frankfurt-Münster (aBFM) regime, first-line treatment in children and adolescents with T-cell Acute Lymphoblastic Leukemia (T-ALL) can achieve unprecedented 4-year survival rates: 90% of patients were still alive 4 years after starting therapy and 84% had not suffered a relapse. This was the result of the four-armed COG-AALL0434 study presented by Kimberly Dunsmore, Virginia Tech Carilion School of Medicine, Roanoke, at the 2018 ASCO Annual Meeting in Chicago on June 2, 2018.
T-ALL and T-cell lymphoma are responsible for 15% of all acute lymphatic leukemias. It is not known whether cytogenetic or other genetic lesions have a prognostic significance. "T-ALL is a disease that requires an intensive and complex therapy regime. About 80% of those affected are still alive 4 years after treatment, but we wanted to do even better," Dunsmore said.
The purine analogue nelarabine is a water-soluble precursor of the deoxyguanosine (dGuo) analogue arabinosylguanine (AraG). In vivo, it is rapidly demethylated by adenosine aminase to AraG and then phosphorylated intracellularly by deoxyguanosine kinase and deoxycytidine kinase. The monophosphate metabolite is then converted into the active 5-triphosphate arabinoside GTP, which accumulates in leukaemic blasts and is preferentially incorporated into the DNA. As a result, DNA synthesis is inhibited and the cell dies. Other mechanisms probably also contribute to the cytotoxic effect of nelarabine. Nelarabine has been approved since 2008 for the treatment of patients with T-ALL and T-cell lymphoma who have not responded to treatment with at least 2 chemotherapy regimens.
The Children's Oncology Group (COG) has now investigated the efficacy and tolerability of an additional dose of nelarabine for COG aBFM in the AALL0434 study. In addition, efficacy and tolerability of high-dose methotrexate with leucovorin should be compared with increasing doses of methotrexate without leucovorin.
The study started in 2007 and included 1,895 patients aged 1 to 30 years with T-ALL (n = 1,545, 94% of study participants) or T-LL (n = 277, 6%) by July 2014. This makes it the largest randomized study ever conducted in these diseases.
All patients received complex induction therapy (COG- augmented Berlin-Frankfurt-Münster chemotherapy - aBFM) with cranial radiation. In addition, they were randomly treated with increasing doses of methotrexate, with high-dose methotrexate, with increasing doses of methotrexate plus nelarabine or with high-dose methotrexate plus nelarabine.
90.2% of patients were still alive after 4 years and 84.1% had no recurrence. Of the T-ALL patients with an increased risk of recurrence, additional administration of nelarabine after 4 years was 88.9% without renewed leukemia, and 83.3% without nelarabine. Nelarabine patients had fewer CNS recurrences. In patients with T-LL, the additional administration of nelarabine had no measurable effect. However, over 85 % still lived without recurrence after 4 years.
In contrast to earlier smaller studies, increasing doses of methotrexate proved favorable compared to high-dose methotrexate treatment (4-year survival 89.8% vs. 78%). Of the T-ALL patients receiving nelarabine and increasing doses of methotrexate, 92.2% were free of leukemia after 4 years.
In many centers, attempts are made to reduce cranial radiation because it can be accompanied by late effects such as cognitive disorders, learning disorders, neuroendocrine changes and secondary malignancies. Therefore, further studies will now investigate the effects of the use of nelarabine in patients who are not exposed to cranial radiation.
Bruce E. Johnson, current ASCO President, Dana Farber Cancer Institute, Boston, pointed out in a press conference that the study had been publicly funded and added: "We now know that we can significantly increase the survival of children and adolescents with rare forms of leukemia and lymphoma without additional serious side effects that can affect the quality of life”.
Dunsmore KP, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. 2018 ASCO Annual Meeting, Chicago, June 1 to 5, 2018, Abstract 10500. http://abstracts.asco.org/214/AbstView_214_218959.html