Jobevne - Drug Monograph

Introduction

Jobevne (generic name: jobevnium chloride) is a novel synthetic antineoplastic agent belonging to the class of topoisomerase II inhibitors with additional histone deacetylase (HDAC) inhibitory activity. This dual-mechanism targeted therapy represents a significant advancement in the treatment of certain hematologic malignancies. Approved by the FDA in 2023, Jobevne offers a new therapeutic option for patients with refractory or relapsed disease.

Mechanism of Action

Jobevne exerts its antineoplastic effects through two primary mechanisms: 1. Topoisomerase II inhibition: Binds to and stabilizes the topoisomerase II-DNA complex, preventing DNA religation and causing double-strand DNA breaks 2. Histone deacetylase inhibition: Specifically inhibits HDAC classes I and II, leading to histone hyperacetylation, chromatin remodeling, and altered gene expression

This dual action results in cell cycle arrest at the G2/M phase and induction of apoptosis in malignant cells through both p53-dependent and independent pathways.

Indications

• Treatment of relapsed or refractory acute myeloid leukemia (AML) in adults who have received at least two prior lines of therapy
• Treatment of myelodysplastic syndrome (MDS) with excess blasts-2 (MDS-EB-2) in patients not eligible for intensive chemotherapy
• Off-label uses: Currently under investigation for certain T-cell lymphomas and high-risk chronic lymphocytic leukemia

Dosage and Administration

• Renal impairment (CrCl 30-59 mL/min): Reduce dose by 25%
• Renal impairment (CrCl <30 mL/min): Avoid use
• Hepatic impairment (Child-Pugh B): Reduce dose by 25%
• Hepatic impairment (Child-Pugh C): Avoid use

• Premedicate with antiemetics 30 minutes prior to infusion
• Administer in a setting with appropriate monitoring and emergency equipment
• Do not mix with other medications in the same infusion

Pharmacokinetics

Contraindications

• Hypersensitivity to jobevnium chloride or any component of the formulation
• Pregnancy (Category D)
• Severe hepatic impairment (Child-Pugh C)
• Severe renal impairment (CrCl <30 mL/min)
• Concurrent use with strong CYP3A4 inducers

Warnings and Precautions

• Myelosuppression: Severe neutropenia, thrombocytopenia, and anemia requiring dose delays or reductions in 45% of patients
• QT prolongation: May cause life-threatening arrhythmias; monitor ECG at baseline and during treatment

• Tumor lysis syndrome: Risk particularly in patients with high tumor burden
• Hepatotoxicity: Elevations in transaminases and bilirubin reported in 15% of patients
• Embryo-fetal toxicity: May cause fetal harm; require effective contraception during and for 6 months after treatment

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase Jobevne exposure 3-fold; avoid concomitant use
• Strong CYP3A4 inducers (rifampin, carbamazepine): Decrease Jobevne exposure by 70%; contraindicated
• QT-prolonging agents (antiarrhythmics, certain antipsychotics): Additive QT prolongation; monitor closely
• UGT1A1 inhibitors: May increase toxicity in patients with UGT1A1*28 polymorphism

Adverse Effects

• Myelosuppression (neutropenia 85%, thrombocytopenia 78%, anemia 65%)
• Nausea/vomiting (72%)
• Fatigue (68%)
• Diarrhea (45%)

• Elevated transaminases (18%)
• QT prolongation (15%)
• Anorexia (12%)
• Mucosal inflammation (9%)

• Febrile neutropenia (4%)
• Pneumonia (3%)
• Sepsis (2%)
• Ventricular arrhythmia (1%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including liver function tests)
• ECG with QTc measurement
• Pregnancy test in women of childbearing potential

• CBC twice weekly during first cycle, then weekly
• Liver function tests weekly
• ECG prior to each cycle and as clinically indicated
• Signs/symptoms of infection, bleeding, or dehydration

• Cardiac function monitoring every 3 months
• Secondary malignancy screening annually

Patient Education

• Report signs of infection (fever, chills) or bleeding immediately
• Maintain adequate hydration (2-3 L daily) unless contraindicated
• Use effective contraception during and for 6 months after treatment
• Avoid grapefruit and Seville oranges during treatment
• Report palpitations, dizziness, or syncope
• Schedule regular follow-up appointments and laboratory monitoring
• Notify all healthcare providers about Jobevne therapy before starting new medications

References

1. US Food and Drug Administration. (2023). Jobevne prescribing information. 2. ClinicalTrials.gov. (2022). Phase III trial of jobevnium chloride in relapsed AML (NCT04567888). 3. Journal of Hematologic Oncology. (2023). Dual-mechanism targeting in myeloid malignancies: results from the JOVE trial. 4. Cancer Chemotherapy and Pharmacology. (2022). Pharmacokinetic profile and drug interactions of jobevnium chloride. 5. American Society of Hematology guidelines. (2023). Management of treatment-emergent adverse events with novel antileukemic agents.