Efficacy and Safety of Nelarabine in Different Age Groups with T-Cell Hematological Malignancies: A Systematic Review of Clinical Trials

Background:

The survival rates of patients with T-cell malignancies especially acute lymphoblastic leukemia (ALL) have significantly improved in the last decade. The survival rates of T- cell lineage ALL are relatively inferior to survival rates of B-cell lineage ALL. Nelarabine is a prodrug for araguanosine that metabolizes into arabinosylguanine nucleotide triphosphate and acts as a DNA terminating nucleoside. In this review, we assessed the efficacy and safety of nelarabine in T-cell hematological malignancies in different age groups of patients.

Methods:

A literature search was performed on PubMed, Web of Science, Embase (OVID), and clinicaltrials.gov with Mesh terms for, "Nelarabine" AND "Leukemia OR Lymphoma" from the inception of data till June 10, 2022. Out of 1,051 articles, we included 4 randomized clinical trials (RCTs, N=980) and 2 non-randomized clinical trials (nRCTs, N=246) based on the inclusion criteria. We excluded all case reports, review articles, retrospective studies, pre-clinical studies, and meta-analyses. PRISMA guidelines were followed in this systematic review.

Results:

2 clinical trials (N=812) included children and young adult patients, 3 clinical studies (N=321) included adult patients and 1 clinical study (N=93) included both children and adults. 1,102 patients had T-cell ALL, 35 had T-cell non-Hodgkin lymphoma, 11 had T-cell pleomorphic lymphoma, and 56 had other hematological malignancies. 945 patients had a newly diagnosed (ND) malignancy while 281 had relapsed/refractory (RR) malignancy. Nelarabine was given to 740 patients while 486 were treated with standard therapy.

In an RCT on pediatric patients with ND T-cell ALL (N=659), 5-year disease-free survival (DFS), overall survival (OS), and relapse rate (RR) were 88.2%, 90.3%, and 1.3%, respectively, in patients treated with nelarabine + standard therapy, vs. 82.1%, 87.9%, and 6.9%, respectively, in patients treated with standard therapy. In a trial on RR T-cell ALL/non-Hodgkin (NH) pediatric patients (N=153), the overall response rate (ORR) was 25.7% and complete response (CR) was 29%.

In two RCTs (N=286) on adult patients with ND T-cell ALL, 3-year OS and CR were 65% and 87-93%, respectively, in patients treated with nelarabine + standard therapy vs. 3-year OS and CR of 61.7-64% and 88-90.7%, respectively in patients treated standard therapy only. In phase I clinical trial (N=35) on adult patients with RR indolent leukemias, CR and ORR were 4% and 15%, respectively in patients treated with nelarabine and CR and ORR were 11% and 66% in patients treated with nelarabine + fludarabine.

In an RCT by Kurtzberg et al. (N=93) on pediatric and adult patients with RR malignancies, CR was 11% and ORR was 31%.

Neurotoxicity, infection, hypokalemia, ALT/AST elevation, malaise, and confusion were the common ≥ Grade 3 adverse events reported in patients with T-cell malignancies treated with nelarabine. Table 1, 2.

Conclusion:

Nelarabine was well tolerated by most of the patients with T-cell malignancies. Nelarabine addition to standard therapy was significantly more effective than placebo in ND T-ALL pediatric patients. However, the addition of nelarabine to standard therapy in adult patients with ND T-ALL did not improve survival or response rates. Nelarabine was also effective in pediatric and adult patients with RR T-ALL, T-NHL, and T-cell indolent leukemias in early phase clinical trials. More randomized double-blind multicenter clinical trials are needed to confirm these results.

No relevant conflicts of interest to declare.