Panobinostat
| Evidence Level: L2 | Predicted Indications: 1 |
Table of Contents
Panobinostat: From Multiple Myeloma to Myeloid Leukemia
One-Sentence Summary
Panobinostat is an oral histone deacetylase (HDAC) inhibitor, originally authorised in the EU for relapsed and/or refractory multiple myeloma in combination with bortezomib and dexamethasone. The TxGNN model predicts it may be effective for myeloid leukemia, with 17 clinical trials and 20 publications compiled for this direction. Most trials are early-phase, and the only Phase 3 trial was terminated early.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Relapsed and/or refractory multiple myeloma (with bortezomib and dexamethasone) after at least two prior regimens including bortezomib and an immunomodulatory agent |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 99.70% |
| Evidence Level | L2 |
| EU Market Status | ✗ Cancelled only (no currently valid authorisation) |
| Number of Authorizations | 1 (cancelled) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. Panobinostat is, however, a well-known pan-HDAC inhibitor. In myeloid leukemia, especially acute myeloid leukemia (AML), abnormal epigenetic silencing blocks cell differentiation. Oncogenic fusion proteins such as AML1-ETO and PML-RARA recruit HDACs to do this. Inhibiting HDACs can restore histone acetylation, reactivate tumour-suppressor genes, and induce differentiation and cell death.
Multiple myeloma and myeloid leukemia are both haematological malignancies in which epigenetic dysregulation plays a role. Preclinical work supports this link:
- Panobinostat drives plasmacytoid dendritic cell activation and IFNAR-dependent differentiation in AML models.
- It is active in bortezomib-resistant AML models.
- It shows synergy with hypomethylating agents (azacitidine), cytotoxic chemotherapy, and other targeted agents.
The TxGNN score is a computational prediction only and was not treated as clinical evidence.
Clinical Trial Evidence
The table lists the 10 most relevant of the 17 trials compiled.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04326764 | Phase 3 | Terminated | 52 | Panobinostat maintenance plus donor lymphocyte infusion vs DLI alone after allogeneic transplant in high-risk AML/MDS; underpowered after early termination |
| NCT00946647 | Phase 1/2 | Completed | 113 | Panobinostat plus azacitidine vs azacitidine alone in MDS, CMML, or AML |
| NCT01242774 | Phase 1 | Completed | 46 | Dose-finding with idarubicin and cytarabine induction in adults ≤65 with AML |
| NCT00880269 | Phase 2 | Completed | 59 | Single-agent oral panobinostat in refractory de novo or secondary AML |
| NCT01055483 | Phase 1 | Completed | 59 | Dose-finding with Ara-C and mitoxantrone as salvage therapy in relapsed/refractory AML |
| NCT00691938 | Phase 1/2 | Completed | 52 | Panobinostat plus decitabine in patients ≥60 with high-risk MDS or AML |
| NCT00840346 | Phase 1/2 | Completed | 46 | Single-arm study with idarubicin and cytarabine in AML patients aged 65 or older |
| NCT01451268 | Phase 1/2 | Unknown | 62 | Maintenance after allogeneic transplant in high-risk MDS/AML (PANOBEST) |
| NCT01463046 | Phase 1 | Completed | 29 | Dose-finding with cytarabine and daunorubicin in older patients with untreated AML or advanced MDS |
| NCT02676323 | Phase 1 | Terminated | 19 | Panobinostat with fludarabine and cytarabine in paediatric relapsed/refractory AML or MDS; limited by early termination |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24413064 | 2014 | Phase Ib/II study | Blood Cancer J | Panobinostat plus azacitidine in 39 patients (29 AML, 10 high-risk MDS) naïve to intensive chemotherapy; assessed maximum tolerated dose and preliminary efficacy |
| 32809242 | 2020 | Clinical study | Cancer | Safety, pharmacokinetics and pharmacodynamics of panobinostat in children, adolescents and young adults with relapsed AML |
| 27485472 | 2016 | Review | Expert Opin Investig Drugs | Overview of panobinostat in AML, especially for older and unfit patients |
| 31739588 | 2019 | Review | Cancers | Rationale for HDAC inhibitors in AML |
| 23826641 | 2013 | Review | Expert Opin Investig Drugs | Panobinostat in lymphoid and myeloid malignancies |
| 38965693 | 2024 | Guideline | Pediatr Blood Cancer | Lists azacitidine ± panobinostat as an option for relapsed/refractory myeloid leukemia in Down syndrome |
| 35311997 | 2022 | Preclinical | Cancer Discov | Panobinostat-mediated AML differentiation required plasmacytoid DC activation and IFNAR signalling |
| 25612941 | 2015 | Preclinical | Leuk Res | Panobinostat plus marizomib was active in AML and bortezomib-resistant models |
| 27725868 | 2016 | Preclinical | Am J Transl Res | Synergy between ABT-199 (venetoclax) and panobinostat in AML ex vivo |
| 26529495 | 2015 | Preclinical | Cancer Biol Ther | Synergy between panobinostat and the Wee1 inhibitor MK-1775 in AML cell lines and patient samples |
EU Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| EMEA/H/C/003725 (cancelled) | Farydak | Not specified | In combination with bortezomib and dexamethasone for adults with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomi… |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted epigenetic therapy (HDAC inhibitor) used as an antineoplastic |
| Myelosuppression Risk | Please refer to the SmPC warnings and precautions |
| Emetogenicity Classification | Please refer to the SmPC warnings and precautions |
| Monitoring Items | Please refer to the SmPC warnings and precautions; at minimum CBC with differential and liver and renal function |
| Handling Protection | Follow local cytotoxic/antineoplastic drug handling regulations |
Safety Considerations
- Drug Interactions: 527 interactions were identified in the data compiled for this report. Selected examples:
- Major: acetylsalicylic acid, clarithromycin, levofloxacin, dolasetron, palonosetron, eliglustat, picosulfuric acid, sodium sulfate, polyethylene glycol (3350 with electrolytes)
- Moderate: dexamethasone, aprepitant, famotidine, cimetidine, loperamide, metoclopramide, bisacodyl, naltrexone, metreleptin, miconazole
- Minor: metronidazole
Several of the major interactions involve QT-prolonging drugs (e.g. dolasetron, palonosetron, levofloxacin, clarithromycin). A formal review of these is needed before any clinical use.
For warnings and contraindications, please refer to the SmPC.
Conclusion and Next Steps
Decision: Hold
Rationale: The evidence is L2: several completed Phase 1/2 trials of panobinostat in AML/MDS, but no completed randomised Phase 3 evidence. The only Phase 3 trial (NCT04326764) was terminated after 52 patients. The EU authorisation has been cancelled, so no marketed product is currently available. The label safety data (warnings and contraindications) could not be retrieved, so safety screening cannot proceed. The high TxGNN score (99.70%) is a prediction only and does not change this assessment.
To proceed, the following is needed:
- Retrieve and parse the SmPC (warnings and contraindications) to complete safety screening
- Obtain mechanism-of-action data from DrugBank
- Check why NCT04326764 was terminated and whether any results were reported for it and the completed Phase 2 trials (e.g. NCT00946647, NCT00880269)
- Confirm the regulatory pathway and product availability, given the cancelled EU authorisation
- Assess the QT and drug-interaction risks of combination regimens with standard AML chemotherapy and supportive care
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.