Efficacy and safety of nelarabine in patients with relapsed or refractory T-cell acute lymphoblastic leukemia: a systematic review and meta-analysis.

Nelarabine is approved for the treatment of relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) patients who relapse following at least two different chemotherapy regimens. Previous studies have evaluated the efficacy and safety of nelarabine with chemotherapy in the treatment of R/R T-ALL. However, the results are inconsistent. This review aimed to summarize findings on efficacy and safety data in R/R T-ALL patients administered with the drug nelarabine. The present review conducted a comprehensive search of MEDLINE (via PubMed), WHO Clinical Trial Registry, Clinical Trials.gov, and Cochrane Central Register of Controlled Trials until 15 January 2022. Thirteen studies fulfilled the eligibility criteria with a total of 2508 patients. The efficacy of nelarabine was studied in terms of complete remission (CR) and partial remission (PR). Included studies reported overall random-effects pooled prevalence of CR and PR were 37.2 (95% CI: 22.8, 51.5) and 10.2 (95% CI: 4.9, 15.5), respectively. Most common adverse events associated with nelarabine were neutropenia, thrombocytopenia, fatigue, infections, and reversible peripheral neuropathy. Nelarabine is being used as salvage therapy as a bridge to hematopoietic stem cell transplantation and the findings of this meta-analysis indicate that it is an effective and safe treatment to be used in addition to the first-line treatment for R/R T-ALL.

The role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia: literature review and own experience.

AIM: The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. MATERIALS AND METHODS: All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was ad- ministered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. RESULTS: From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. CONCLUSION: The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established dur- ing controlled clinical trials.

Neurotoxic side effects in children with refractory or relapsed T-cell malignancies treated with nelarabine based therapy.

The prognosis in children with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) is poor. Nelarabine (Ara-G) has successfully been used as salvage therapy in these children, but has been associated with significant, even fatal, neurotoxicities. We retrospectively analysed 52 patients with r/r T-ALL/T-LBL aged ≤19 years who were treated with Ara-G alone (n = 25) or in combination with cyclophosphamide and etoposide (n = 27). The majority of patients (45/52) received 1-2 cycles of Ara-G. Seventeen patients (32·7%) had refractory disease, 28 (53·8%) were in first relapse and 7 (13·5%) were in second relapse. A response to Ara-G was achieved in 20 patients and 15 (28·8%) were in remission at last follow-up. Twelve patients (23·1%) had neurotoxic adverse effects (neuro-AE) of any grade, of whom 7 (13·5%) developed neurotoxicity ≥ grade III. The most frequent neuro-AEs were peripheral motor neuropathy (19·2%), peripheral sensory neuropathy (11·5%) and seizures (9·6%). Three patients died of central neuro-AE after 1-2 cycles of combination therapy. Patients with neurotoxicity were significantly older (median 15·17 years) than those without (10·34 years, P = 0·017). No differences were observed between mono- and combination therapy concerning outcome and neuro-AE. The incidence of neuro-AE was not associated with concurrent intrathecal therapy or prior central nervous system irradiation.

Nelarabine in the treatment of pediatric and adult patients with T-cell acute lymphoblastic leukemia and lymphoma.

INTRODUCTION: T-cell acute lymphoblastic leukemia (ALL) and lymphoma (LBL) are aggressive hematologic neoplasms that are treated with combination chemotherapy in the frontline, but have limited options in the relapsed or refractory setting. Based on observations in patients with purine nucleoside phosphorylase (PNP) deficiency, a guanosine nucleoside analogue, arabinosylguanine (ara-G) was developed that provided T-cell specificity. Nelarabine was developed as the water-soluble, clinically useful-prodrug of ara-G and based on its activity was approved for the treatment of relapsed or refractory T-ALL/LBL. Areas covered: In this narrative review, we will summarize the preclinical studies, early dose-finding studies, and efficacy studies that led to approval of nelarabine. The review will succinctly cover response rates and safety signals reported during clinical development. We will also cover more recent work with nelarabine, including combination studies, modified dosing schedules, and frontline treatment approaches. Expert commentary: Based on evidence from the literature review and our own experience with nelarabine, we conclude that it is an effective agent in the treatment of T-cell malignancies. Understanding the factors that modulate the risk of dose-limiting neurotoxicity, how to mitigate this toxicity, and how to safely combine it with other active agents will continue to broaden its use.

A nelarabine-resistant T-lymphoblastic leukemia CCRF-CEM variant cell line is cross-resistant to the purine nucleoside phosphorylase inhibitor forodesine.

BACKGROUND/AIM: Forodesine inhibits purine nucleoside phosphorylase, resulting in an accumulation of intracellular dGTP and consequently cell death. 9-ß-D-Arabinofuranosylguanine (ara-G) is an active compound of nelarabine that is intracellularly phosphorylated to a triphosphate form, which inhibits DNA synthesis. Both agents show cytotoxicity toward T-cell malignancies. In the present study, we investigated the cytotoxicity of forodesine in vitro using ara-G-resistant leukemia cells. MATERIALS AND METHODS: T-Lymphoblastic leukemia cell line CCRF-CEM and ara-G-resistant CEM variant cell line CEM/ara-G that we had previously established were used. RESULTS: A growth-inhibition assay demonstrated that CEM cells were insensitive to single-agent forodesine treatment. The cells were also insensitive to deoxyguanosine at a maximal concentration of 10 µM. CEM/ara-G cells were 80-fold more resistant to ara-G than were CEM cells, and the mode of sensitivity to forodesine and deoxyguanosine was similar to that of CEM cells. In the presence of 10 µM deoxyguanosine, forodesine effectively inhibited the growth of CEM cells but not that of CEM/ara-G cells. Flow cytometric analyses showed that combination of forodesine and deoxyguanosine induced apoptosis of CEM cells but not of CEM/ara-G cells. The addition of ara-G did not augment the cytotoxicity of the forodesine/deoxyguanosine combination towards CEM cells or CEM/ara-G cells. The combination index revealed antagonism between forodesine and ara-G. The intracellular production of ara-G triphosphate was reduced in the presence of forodesine. CONCLUSION: Nelarabine-resistant CEM/ara-G cells are insensitive to forodesine.

Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia.

Nelarabine is the prodrug of 9-beta-arabinofuranosylguanine (ara-G) and is therapeutically classified as a purine nucleoside analog. Nelarabine is converted to ara-G by adenosine deaminase and transported into cells by a nucleoside transporter. Ara-G is subsequently phosphorylated to ara-G triphosphate (ara-GTP), thereby initiating the therapeutic effect by inhibiting DNA synthesis. Nelarabine has been extensively studied in regards to its pharmacokinetics, and the data have demonstrated that ara-GTP preferentially accumulates in malignant T-cells. Clinical responses to nelarabine have been demonstrated in various T-cell malignancies and appear to correlate with a relatively high intracellular concentration of ara-GTP compared to nonresponders. Therefore, this unique drug feature of nelarabine accounts for clinical utilization in treating adult and pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Neuropathy is the most predominant adverse effect associated with nelarabine and the incidence correlates with the dose administered. Myelosuppression has been observed, with thrombocytopenia and neutropenia as the most common hematologic complications. This article reviews the pharmacology, mechanism of action, and pharmacokinetic properties of nelarabine, as well as nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies. The toxicity profile, dosage, and administration, and areas of ongoing and future research, are also presented.