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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Also developed in the 1990s, Nelarabine (AtrianceTM) is the latest purine antimetabolite to be approved (i.e., Accelerated Approval by the FDA in 2005) (Figure 3.10). The β-D-arabinofuranosyl sugar moiety attached to the 9-position of the purine ring is identical to that in fludarabine, but the 2-fluoro and 6-amino substituents of the purine nucleus have been replaced with amino and methoxy substituents, respectively. Nelarabine is a prodrug of 6-methylguanine arabinoside and is metabolized by adenosine deaminase to the deoxyguanosine analogue ARA-G, which then enters cells through a nucleoside transporter. Once within a cell, the ARA-G is phosphorylated to ARA-GTP by cellular kinases and then incorporated into DNA, where it acts as a false substrate, leading to a cytotoxic effect. Given by intravenous infusion, nelarabine is approved for use in acute lymphoblastic T-cell leukemia and T-cell lymphoblastic lymphoma in patients who have relapsed or are refractory after receiving at least two previous regimens.
Specific Therapy for Leukemias
Published in Tariq I Mughal, John M Goldman, Sabena T Mughal, Understanding Leukemias, Lymphomas, and Myelomas, 2017
Tariq I Mughal, John M Goldman, Sabena T Mughal
In the rare subtype, T-cell CLL, which represents less than 3% of all European and US patients with CLL, but is the dominant form of CLL in Asia, patients often present with low blood counts (pancytopenia) and prominent splenomegaly; the lack of lymphadenopathy is noteworthy. The general prognosis is similar to poor-risk CLL and most patients tend to be refractory to chlorambucil and fludarabine treatment. Studies using the drug nelarabine (Arranon) are in progress.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
Phase 2 studies were conducted to demonstrate the efficacy of nelarabine in patients with R/R T-ALL and T-lymphoblastic lymphoma. In one study of 106 evaluable patients refining the treatment dose to 650 mg/m2/d for 5 days in children, the overall response rate (ORR) was 33% [12]. Overall 18% of the patients developed a severe neurotoxicity, which was dose-dependent. Another study confirmed the efficacy of nelarabine in a series of 39 R/R adult patients with T-cell malignancies [26]. The dosing regimen was 1500 mg/m2/d on days 1, 3, and 5 every 3 to 4 weeks. The ORR was 41%, including 31% of complete response (CR) plus complete response with incomplete peripheral cell recovery (CRi). The median DFS was 20 weeks, and the median OS was also 20 weeks with a one-year OS of 28%. A large phase 2 study of 126 patients from the German Multicenter Study Group for Adult ALL (GMALL) confirmed the efficacy of single-agent nelarabine given at a dose of 1500 mg/m2 on days 1, 3, and 5 every 3 weeks [27]. The ORR was 46%, with 36% of CR. Severe neurotoxicity was only 7%. The median OS was 6 months, with a one-year OS of 25%. Eighty percent of the remitters went on allogeneic HSCT with a 3-year OS of 31%. Overall, phase 2 studies showed a positive impact of nelarabine on survival in T-ALL and a decreased risk of CNS relapse. Based on these studies in a context of critical unmet need, nelarabine was approved by the US Food and Drug Administration (FDA) for the treatment of patients with R/R T-ALL or T-lymphoblastic lymphoma [28], and subsequently tested in combination with other anti-leukemia drugs with non-overlapping toxicities.
Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens, and clinical considerations
Published in Expert Review of Clinical Pharmacology, 2021
Maria Siddiqui, Marina Konopleva
The prognosis of RR T-cell ALL is dismal with extremely limited salvage options [88]. Nelarabine is the only drug that has been approved by the Food and Drug Administration [89]. Preclinical studies have identified sensitivity of ETP-ALL cells to venetoclax [90]. In a retrospective review conducted by Richard-Carpentier et al., the outcomes of venetoclax in combination with different chemotherapy agents were reported. The study included 13 patients (ETP-ALL n = 5), with a median of 2 previous treatment lines, with 4 patients having undergone prior HSCT. Common backbones used with venetoclax were hyper-CVAD in 38% patients, asparaginase and vincristine in 23% patients, and decitabine in 23% of patients. Bone marrow responses were evaluable in 10 patients and showed an ORR of 60% with a CR/CRi rate of 40%. In the remaining 3 patients, one died, one with ETP ALL who was in CR but MRD+ve achieved MRD-ve response and the third with T cell lymphoblastic lymphoma with a mediastinal mass of 14.6 cm and MRD+ve bone marrow achieved a partial response [91]. At a median follow-up of 10.4 months, the median OS was 7.7 months. The responses, albeit short-lasting [relapse-free survival (RFS) 4 months], were higher than with nelarabine monotherapy (ORR 46%, CR 36%) [92] or with intensive chemotherapy (CR rate 34%) [84]. 2 patients were alive at the time of report and both had ETP-ALL with one undergoing HSCT. Despite retrospective nature of this analysis and a small sample size, this study signifies a potential role of venetoclax in combination with chemotherapy with RR T cell ALL, particularly ETP-ALL offering a potential route to cure upon bridging to HSCT [91].
Safety of nelarabine in adults with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma
Published in Expert Opinion on Drug Safety, 2021
Anna Candoni, Davide Lazzarotto, Giuseppe Petruzzellis
Neurological and hematological toxicities are the most frequent adverse events of Nelarabine, and neurotoxicity is the dose-limiting toxicity of this drug. As reported in Table 2, at the recommended and approved adult dose of 1.500 mg/m2 for 3 days, the most common toxicity is motor and/or sensitive peripheral neuropathy with an incidence of 30%, usually reversible. Common signs and symptoms include paresthesia, hypoesthesia, ataxia, tremor, numbness, hyporeflexia, neuropathic pain, peroneal nerve palsy [6,7,11].