Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Purine Analogues:

    • Nelarabine (Arranon)

      • Overivew:

        • Nelarabine is a relatively recently FDA approved purine analog (2005).^1,8 

          • Its clinical indication is for treatment of T-cell acute leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) not responding (or relapsed) after a minimum of two previous chemotherapy protocols.

            • Nelarabine (Arranon) in Newly Diagnosed T-Cell Malignancies⁹  

              Attribution: Link M Nelarabine in Newly Diagnosed T-Cell Malignancie shttps://www.youtube.com/watch?v=Xzy_C6-QVsQ 7.2018 OncLiveTV Youtube Channel:  https://www.youtube.com/channel/UC3aRpa3CR_w4JrxYv_r_pDg

            •  

              "Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma"*¹⁰

              Attribution:   Dunsmore K Results of the COG AALL0434 trial (NCT00408005) for T-cell Malignancies https://www.youtube.com/watch?v=PvndODLfCZk (8/2018) VJHemonc-Video Journal of Hematological Oncology Youtube Channel: https://www.youtube.com/channel/UCsQXL4_zTA-FoG9RA1tEGiw *COG AALL0434 trial: Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma11

            • Nelarabine (6-methoxy-arabinosyl-guanine) has the distinction of being the singular guanine nucleotide use clinically.¹ 

          • When used in the treatment of acute T-cell leukemia about 1/5 (20%) of patients exhibits complete responses.⁸ 

          • The underlying mechanism of action is similar to previous purine analogs that require activation by sequential phosphorylation steps.

            • Ultimately, ara-G upon phosphorylation to ara-GTP is incorporated into DNA, thereby terminating DNA elongation resulting in DNA synthesis inhibition and cell death.⁸

      • Mechanism of Action:

        • DNA synthesis is inhibited with increasing concentrations of intracellular deoxyguanosine.

          • Ara-Gt exhibits limited solubility.

          • Nelarabine is related to ara-G given that it is a soluble prodrug.

            • Therefore, nelarabine is a prodrug of ara-G and is converted to ara-G by the action of the enzyme adenosine deaminase (ADA).

              • Ara-G is phosphorylated to ara-GTP using to enzymes, deoxycytidine kinase and deoxyguanosine kinase.

              • Ara-GTP upon incorporation into DNA results in termination of DNA elongation and subsequently to DNA synthesis inhibition and cell death.

                • The likelihood of a clinical response to nelarabine treatment is significantly dependent on adequate nelarabine uptake and significant accumulation of ara-GTP by the target leukemic cells.

        • Absorption, Distribution, Biotransformation, Excretion:¹

          • Nelarabine is administered by the intravenous route of administration.¹ 

            • Nelarabine, a prodrug, must be activated for realization of his neoplastic activity.

              • The initial step in activation is an enzyme catalyzed removal of a methyl group resulting in ara-G which is phosphorylase resistant.

            • The half-life (plasma t_1/2) of ara-G is about 3 hours.

              • Ara-G is transported into tumor cells and then activated by deoxycytidine kinase and deoxyguanosine kinase to a triphosphate form, ara-GTP.

                • This metabolite is incorporated into DNA, terminating its synthesis.

            • Nelarabine as well as ara-G are mainly eliminated by metabolism to guanine.

            • Renal excretion is responsible for a small elimination fraction; however, in cases of significant renal dysfunction, nelarabine administration should be accompanied by careful clinical assessments.¹

        • Toxicity:⁸

          • The major nelarabine toxicities are associated with central nervous system (CNS) effects.

            • These effects include:

              • Seizures

              • Encepalopathy

              • Obtundation (reduced alertness) and

              • Peripheral neurotoxicity.

            • Uncommonly, ascending myelopathy may occur exhibiting sensory and motor loss along with posterior column changes noted on MRI imaging.

            • With respect to most common adverse effects, malaise, headache, somnolence, nausea, fever, peripheralneuropathy and myelosuppression have been reported.

            • Notable neurologic events (grade 3 or 4) appear to occur with a frequency of about 10% to 15%.⁸

        • Clinical Uses:⁸

          • The primary clinical use for nelarabine is in the treatment of individuals with acute lymphoblastic leukemia and lymphoblastic lymphoma (LBL).

            • In the case of patients exhibiting relapsed or refractory T-cell malignant disease, response rates are relatively low, ranging from about 20% in pediatric patients to about 30% in adults.

              • Some patients may be candidates for stem cell transplantation treatment.⁸