A 58-year-old man with newly diagnosed acute myeloid leukemia (AML) is started on high-dose cytarabine (ara-C) as part of induction chemotherapy. Regarding the pharmacology and clinical use of antimetabolites in hematologic malignancies, all of the following are true EXCEPT:

Explanation

## Antimetabolites in Hematologic Malignancies **Key Point:** Different antimetabolites have distinct mechanisms of activation, metabolism, and clinical indications. Understanding these differences is critical for appropriate drug selection and toxicity management. ### Mechanism of Action and Metabolism | Agent | Class | Activation | Mechanism | Metabolism | |-------|-------|-----------|-----------|------------| | Cytarabine (ara-C) | Pyrimidine | Deoxycytidine kinase → ara-CTP | Inhibits DNA polymerase, chain termination | Deamination by cytidine deaminase | | 6-Mercaptopurine (6-MP) | Purine | HGPRT → 6-MP ribonucleotide | Inhibits PRPP amidotransferase | **Xanthine oxidase** (↓ with allopurinol) | | Fludarabine | Purine | Deoxycytidine kinase → fludarabine-TP | Resistant to adenosine deaminase | Renal excretion | | Methotrexate | Folate antagonist | Direct inhibitor | Inhibits DHFR → ↓ reduced folates | Renal excretion (high-dose) | ### Clinical Indications for Specific Agents **High-Yield:** Fludarabine is the preferred agent for **chronic lymphocytic leukemia (CLL)**, NOT cytarabine. Cytarabine is the standard for **acute myeloid leukemia (AML)** and acute lymphoblastic leukemia (ALL). Fludarabine's resistance to adenosine deaminase makes it more effective in lymphoid malignancies. ```mermaid flowchart TD A[Acute Leukemia]:::outcome --> B{Myeloid or Lymphoid?}:::decision B -->|Myeloid AML| C[Cytarabine + Anthracycline]:::action B -->|Lymphoid ALL| D[Cytarabine ± Other agents]:::action E[Chronic Lymphocytic Leukemia]:::outcome --> F[Fludarabine preferred]:::action G[Chronic Myeloid Leukemia]:::outcome --> H[Tyrosine kinase inhibitors]:::action ``` ### Toxicity and Drug Interactions **Clinical Pearl:** 6-Mercaptopurine is metabolized by xanthine oxidase; concurrent allopurinol (which inhibits xanthine oxidase) increases 6-MP levels and requires dose reduction by 65–75%. **Warning:** Methotrexate toxicity can be mitigated by folinic acid (leucovorin) rescue in high-dose regimens. Leucovorin bypasses the DHFR block and replenishes reduced folate pools. **Mnemonic:** **DAMP** = Deaminase-resistant Antimetabolite Makes Purines (fludarabine is resistant to adenosine deaminase, making it ideal for lymphoid malignancies).