Belinostat: Uses, Dosage, Side Effects and Interactions

Belinostat is a novel anticancer drug that has attracted attention for its unique mechanism and its applications in treating challenging cancers. As a histone deacetylase inhibitor (HDACi), it acts by influencing gene expression and cellular behavior, offering hope especially for patients with difficult-to-treat lymphomas and solid tumors. This article delves into the clinical uses, dosing strategies, side effects, and key drug interactions for belinostat, synthesizing the latest evidence to support patients and healthcare professionals in making informed decisions.

Uses of Belinostat

Belinostat has emerged as an important therapy for several rare and aggressive cancers, particularly where other treatments have failed. Its ability to target the epigenetic machinery of cancer cells opens doors to new ways of controlling tumor growth.

Indication	Patient Group	Efficacy/Response	Source(s)
Peripheral T-cell Lymphoma (PTCL)	Relapsed/Refractory patients	25.8% Overall Response Rate (ORR); Includes 10.8% Complete Response	1, 4, 5
Cutaneous T-cell Lymphoma (CTCL)	Relapsed/Refractory patients	14% ORR	5
Thymic Epithelial Tumors (TET)	Advanced, pretreated patients	8% Partial Response in Thymoma; Disease stabilization observed	10, 11
Hepatocellular Carcinoma (HCC)	Unresectable, advanced	2.4% Partial Response; 45.2% Stable Disease	7
Prostate Cancer (preclinical)	Cell lines/animal models	Inhibition of tumor growth, metastasis	2
Other Solid Tumors (investigational)	Various advanced cancers	Stable disease in some patients	6, 8, 9

Table 1: Key Clinical Uses and Evidence for Belinostat

Approved Uses

Belinostat is FDA-approved for treating relapsed or refractory peripheral T-cell lymphoma (PTCL), a rare and aggressive non-Hodgkin lymphoma. This approval is rooted in data showing a 25.8% overall response rate—including complete and partial responses—in heavily pretreated patients. The responses were often durable, and some patients went on to successful stem cell transplantation after belinostat therapy 1, 4, 5.

Investigational and Off-Label Uses

• Cutaneous T-cell Lymphoma (CTCL): Belinostat has shown activity, with a 14% response rate in relapsed/refractory cases, though not formally approved for this indication 5.
• Thymic Epithelial Tumors (TET): Clinical trials in patients with advanced thymoma and thymic carcinoma have demonstrated modest activity, including disease stabilization and occasional responses, especially in thymoma 10, 11.
• Hepatocellular Carcinoma (HCC): Although not leading to high response rates, belinostat provided disease control and was well-tolerated in patients with unresectable HCC 7.
• Solid Tumors and Mesothelioma: Trials in various advanced cancers and mesothelioma have shown limited efficacy as monotherapy, with stable disease in some patients 6, 8, 9.

Preclinical and Combination Therapy

Belinostat is being explored in combination with checkpoint inhibitors for hepatocellular carcinoma and with chemotherapy in solid tumors, showing potential to enhance effectiveness—especially by modulating the immune response and augmenting the activity of cytotoxic drugs 3, 9, 10.

Dosage of Belinostat

Belinostat's dosing strategies are designed to maximize efficacy while maintaining safety. The most common route is intravenous, with regimens tailored according to the type of cancer and combination with other therapies.

Regimen	Details	Patient Context	Source(s)
Standard Monotherapy	1,000 mg/m² IV over 30 min days 1–5 every 21 days	PTCL, CTCL, Thymic Tumors	1, 4, 5, 11
Combination Therapy	1,000 mg/m² IV with chemotherapy (e.g., PAC)	Thymic tumors, solid tumors	9, 10
Dose Escalation	Up to 1,400 mg/m² (MTD not reached in HCC)	HCC, solid tumors (phase I/II)	6, 7
Preclinical Schedules	600–1,200 mg/m² IV, varying cycles	Advanced/refractory solid tumors	2, 6

Table 2: Dosing Strategies and Clinical Context for Belinostat

Standard Dosing in Lymphoma

• PTCL and CTCL: The recommended dose is 1,000 mg/m² administered intravenously over 30 minutes once daily on days 1 through 5 of a 21-day cycle. This regimen was used in pivotal trials and forms the basis for FDA approval 1, 4, 5.
• Dosing continues until disease progression or unacceptable toxicity, with dose modifications for adverse effects as needed.

Combination Regimens

• With Chemotherapy: In thymic epithelial tumors, belinostat (1,000 mg/m²) was combined with cisplatin, doxorubicin, and cyclophosphamide, delivered as a continuous 48-hour infusion or 30-minute bolus administrations, depending on study design 9, 10.
• With Other Agents: Preclinical and early clinical studies are exploring combinations with immune checkpoint inhibitors and proteasome inhibitors, with doses often similar to single-agent schedules 3, 12, 13.

Dose Escalation and Special Populations

• Solid Tumors and HCC: Phase I studies escalated doses up to 1,400 mg/m² IV, with the maximum tolerated dose not reached in some settings 6, 7. However, most subsequent studies use 1,000 mg/m² as the recommended dose.
• Renal or Hepatic Impairment: There are no robust data for severe impairment—caution and dose adjustment may be required.

Administration and Monitoring

• Administration: Belinostat is given intravenously, typically in a hospital or infusion center.
• Monitoring: Frequent blood counts and clinical evaluation are essential to detect myelosuppression and other toxicities early.

Side Effects of Belinostat

As with most cancer treatments, belinostat can cause side effects. The frequency and severity can vary depending on the individual, tumor type, and whether it is used alone or in combination with other therapies.

Adverse Event	Frequency/Severity	Notes/Outcomes	Source(s)
Nausea/Vomiting	Common (>25%)	Usually mild/moderate, manageable	4, 5, 6, 8, 11
Fatigue	Common (>25%)	Occasionally severe (Grade 3/4)	4, 5, 6, 8
Anemia	10–11% (Grade 3/4)	May require transfusion	1, 4, 5, 9
Thrombocytopenia	7–13% (Grade 3/4)	Bleeding risk	1, 4, 5, 9, 10
Neutropenia	6–30% (Grade 3/4)	Infection risk	1, 4, 9, 10
Dyspnea	6% (Grade 3/4)	Shortness of breath	1, 4
Infusion Site Pain	~13%	Localized, resolves after infusion	5
Serious Events	Rare (e.g., arrhythmia, pneumonia, DVT)	Occasional fatal toxicity	5, 6, 8

Table 3: Common and Serious Side Effects of Belinostat

Common Adverse Effects

• Gastrointestinal Symptoms: Nausea, vomiting, and constipation are frequently reported. These are generally manageable with supportive care 4, 5, 6, 8.
• Fatigue: Fatigue is common and can limit daily activities; occasionally, it can be severe enough to warrant dose reduction or discontinuation 4, 6, 8.
• Anemia and Cytopenias: Myelosuppression—including anemia, neutropenia, and thrombocytopenia—occurs in a significant minority of patients, necessitating monitoring and sometimes supportive interventions like transfusions or growth factors 1, 4, 5, 9.

Serious and Less Common Adverse Effects

• Cardiac Toxicity: Rare cases of arrhythmia, including ventricular fibrillation, have been reported. Caution is advised in patients with pre-existing cardiac conditions, and monitoring is recommended 5, 6, 8.
• Lung and Infection Risks: Dyspnea and pneumonia (sometimes severe) have occurred, especially in patients with underlying lung disease or prolonged neutropenia 1, 4.
• Infusion Reactions: Mild infusion site pain or localized reactions are possible but typically resolve 5.

Management and Monitoring

• Prevention: Prophylactic antiemetics may be used for nausea.
• Monitoring: Routine blood counts and clinical assessment for early detection of cytopenias or organ toxicity.
• Dose Adjustments: Dose reductions, delays, or discontinuation may be necessary for significant side effects.

Interactions of Belinostat

Drug interactions play a crucial role in the safety and effectiveness of belinostat, especially as it is often used in combination regimens in oncology.

Interaction Partner	Effect/Impact	Clinical Relevance	Source(s)
Proteasome Inhibitors (e.g., Bortezomib)	Synergistic cell death, enhanced efficacy	Promising in CLL, AML, ALL; minimal added toxicity to normal cells	12, 13
Chemotherapy Agents (e.g., Carboplatin, Paclitaxel, PAC regimen)	No significant pharmacokinetic interaction; increased myelosuppression	Used in advanced solid tumors, thymic tumors	9, 10
Immune Checkpoint Inhibitors	Enhanced immunomodulation and antitumor effect	Investigational; promising in HCC	3
Other Drugs (General)	No major CYP-mediated interactions reported	Monitor for additive toxicity	6, 9

Table 4: Key Drug Interactions Involving Belinostat

Synergistic Interactions

• With Proteasome Inhibitors: Co-administration of belinostat and bortezomib leads to synergistic cancer cell death in leukemia and lymphoma cell models. This effect is due to combined disruption of NF-κB signaling and upregulation of pro-apoptotic proteins, with little additional toxicity to normal cells 12, 13.
• With Chemotherapy: Belinostat has been safely combined with carboplatin, paclitaxel, and PAC (cisplatin, doxorubicin, cyclophosphamide) regimens. These combinations did not result in significant drug-drug pharmacokinetic interactions, though cumulative myelosuppression (e.g. neutropenia, thrombocytopenia) can occur 9, 10.

Immunotherapy Combinations

• Checkpoint Inhibitors: Preclinical studies suggest belinostat can enhance the effect of immune checkpoint inhibitors (like anti-CTLA-4, anti-PD-1) by modulating T-cell function. This combination is under investigation for advanced cancers, including hepatocellular carcinoma 3.

Pharmacokinetics and Metabolism

• Drug Metabolism: Belinostat is primarily metabolized by liver enzymes (glucuronidation via UGT1A1), with minimal involvement of cytochrome P450 (CYP) pathways. Thus, classic CYP-mediated drug interactions are not expected to be significant, but caution is advised when combining with drugs that may affect liver function 6, 9.
• No Major Accumulation: Studies show linear pharmacokinetics with no evidence of drug accumulation over repeated cycles 6, 7.

Clinical Considerations

• Monitor for Additive Toxicity: When used with other myelosuppressive agents, monitor closely for enhanced bone marrow suppression.
• No Known Food Interactions: As belinostat is administered intravenously, food interactions are not a concern.

Conclusion

Belinostat represents a significant step forward in the treatment of select hematologic and solid cancers, particularly for patients with limited options. Its epigenetic mechanism offers unique potential both as monotherapy and in combination with other agents.

Key Takeaways:

• Approved for Relapsed/Refractory PTCL: Offers durable responses for a challenging lymphoma subtype 1, 4, 5.
• Dosing: Standard regimen is 1,000 mg/m² IV daily for five days every three weeks, with flexibility for combination approaches 1, 4, 5, 9, 10.
• Side Effects: Generally manageable, with the most common being nausea, fatigue, and cytopenias; rare but serious risks include arrhythmia and infection 4, 5, 6, 8, 9, 10.
• Interactions: Synergizes with proteasome inhibitors and checkpoint inhibitors; safe to combine with standard chemotherapies, with careful monitoring for additive toxicity 3, 9, 10, 12, 13.
• Ongoing Research: Continues to expand its role, especially in combination regimens and new cancer types 2, 3, 7, 8, 11.

Patients and providers should engage in shared decision-making, considering both the benefits and potential risks of belinostat to optimize cancer care.