Panobinostat - the HDAC inhibitor this graph has reasoned about for cycles without having an entry for, with strong KMT2A-rearranged xenograft activity and a terminated adult trial
also called LBH589 · Farydak · panobinostat lactate
Panobinostat is an approved drug that blocks histone-deacetylase enzymes very broadly. In mice carrying human MLL-rearranged leukaemia it works well on its own, and it reaches a chemical pathway no other clinical drug touches - but the one trial that asked whether it works in adults with relapsed acute leukaemia was stopped early because it did not.
The same thing, for a scientist
Panobinostat is a hydroxamic-acid **pan-HDAC inhibitor** approved for multiple myeloma. This graph already carries `mechanism-panobinostat-depletes-h2bub-mll-r-all` and `ana-unstated-system-panobinostat-h2bub-resolved`, and has reasoned about the agent across several cycles **with no drug entry to hang those mechanisms on**; this entry closes that gap rather than re-deriving them. The preclinical case is real: panobinostat monotherapy has strong in vivo anti-leukaemic effects in xenograft models of MLL-rearranged ALL, extending survival and reducing disease burden, and the activity involves **depletion of H2B ubiquitination via suppression of the RNF20/RNF40/WAC E3 ligase complex** [E1]. It is also active in combination - the curaxin CBL0137 plus panobinostat delays KMT2A-rearranged leukaemia progression [E4]. The clinical counterweight is the entry's most important content: **NCT00723203**, the only efficacy-endpoint trial of panobinostat in acute leukaemia in this graph, enrolled 16 adults with relapsed or refractory ALL or AML and was **TERMINATED**, the registry's `whyStopped` field reading *'Terminated early due to a lack of efficacy'* [E2]. A separate paediatric phase 1, **NCT01321346**, enrolled 30 children aged 8-21 with refractory haematological malignancies and completed [E3]. **Neither trial selected for KMT2A rearrangement and neither measured H2B ubiquitination**, so the mechanism that makes panobinostat interesting here has never been tested in a patient. Like every agent in this beat it is multi-isoform, so no result attributes to an HDAC enzyme.
The one axis panobinostat reaches that nothing else does
The reason this compound earns an entry rather than a footnote is the H2B-ubiquitination route already recorded in mechanism-panobinostat-depletes-h2bub-mll-r-all. Garrido Castro et al. showed the anti-leukaemic activity involves suppression of the RNF20/RNF40/WAC E3 ligase complex, which they describe as a pivotal pathway for MLL-rearranged leukaemic maintenance, with WAC knockdown phenocopying H2Bub loss and inducing cell death 1.
Two things about that are worth restating precisely:
- The route is indirect. Panobinostat does not inhibit the ligase; the ligase complex is transcriptionally suppressed downstream of HDAC inhibition 1. An agent's reaching an axis by transcriptional consequence is weaker than reaching it by binding, because everything about the effect depends on dose, schedule and cell state.
- The authors themselves state panobinostat cross-inhibits multiple epigenetic pathways 1. So H2Bub depletion is an explanation, demonstrated, but not established as the explanation.
And it has never been measured in a human. Neither registered trial read out H2B ubiquitination 23. So this graph holds a well-supported preclinical mechanism, a failed clinical trial, and no bridge between them - which is a specific, fixable gap rather than a vague one. See exp-catalytic-dead-versus-degrader-test-of-class-iia-hdac-function-in-kmt2a-r-all.
The terminated trial, and how much it is allowed to conclude
NCT00723203 is the single strongest negative in this beat and it must be weighted correctly, in both directions.
What it establishes: panobinostat monotherapy in relapsed or refractory acute leukaemia, in adults, unselected for genotype, was stopped early for lack of efficacy after 16 patients, by the sponsor's own statement 2. That is the registry's plain language and not an inference.
What it does not establish:
- Nothing about KMT2A-rearranged disease specifically. The trial did not select for it, and 16 patients cannot support a subgroup claim even if they had been genotyped.
- Nothing about infants, whose disease biology, marrow reserve and drug handling all differ.
- Nothing about combination use. The preclinical work that motivates interest here is monotherapy in xenografts 1 and combination with CBL0137 4; a monotherapy failure in heavily pretreated adults does not test a combination in newly diagnosed infants.
- Nothing about target engagement. With no pharmacodynamic readout, a null is consistent with an ineffective mechanism and equally consistent with never reaching the target.
The honest summary is that the mechanism and the clinical test have never met. This graph's standing rule that an absence of testing is not a negative result applies to the KMT2A subgroup here; the overall futility finding, however, is a real negative and this entry does not soften it.
| target | gene-hdac3 |
|---|---|
| target note | Pan-HDAC, class I and II. gene-hdac3 is named in the schema-required target field only because it is the best genetically attributed HDAC in this disease. Panobinostat is NOT HDAC3-selective and no panobinostat result in this graph attributes to any single enzyme. |
| modality | small molecule, hydroxamic acid, oral pan-HDAC inhibitor |
| status | FDA approved for multiple myeloma (in combination with bortezomib and dexamethasone); investigational and not in active development for KMT2A-rearranged leukaemia |
| preclinical result | monotherapy in vivo efficacy in MLL-rearranged ALL xenografts; WAC knockdown phenocopies H2Bub loss and kills; combination with CBL0137 delays KMT2A-rearranged leukaemia progression |
| distinctive mechanism | transcriptional suppression of the RNF20/RNF40/WAC E3 ligase complex, depleting H2B ubiquitination - the only route by which a clinical-stage molecule reaches this axis |
| mechanism is indirect | true |
| pharmacodynamic marker measured in any trial | false |
| kmt2a selection in any trial | false |
| attribution to an hdac enzyme | false |
| closes gap | mechanism-panobinostat-depletes-h2bub-mll-r-all and ana-unstated-system-panobinostat-h2bub-resolved both existed with no drug entry to attach to |
trials
[ "NCT00723203", "NCT01321346" ]
clinical record
[
{
"nct": "NCT00723203",
"phase": "2",
"status": "TERMINATED",
"why_stopped": "Terminated early due to a lack of efficacy",
"n": 16,
"ages": "18+",
"population": "relapsed/refractory ALL or AML, unselected for KMT2A"
},
{
"nct": "NCT01321346",
"phase": "1",
"status": "COMPLETED",
"n": 30,
"ages": "8-21",
"population": "children with refractory haematologic malignancies; infants excluded by age criteria"
}
]key ae
[ "not enumerated in this entry; panobinostat's label carries boxed warnings for severe diarrhoea and for cardiac toxicity including severe arrhythmias and ECG changes, which this entry records as a pointer and did not verify against the label in this beat" ]
resistance
[ "not characterised in KMT2A-rearranged leukaemia", "the H2Bub route is transcriptional and indirect, so any adaptation that restores RNF20/RNF40/WAC expression would defeat it without altering the drug's target" ]
- The clinical record on this agent in acute leukaemia is a termination for lack of efficacy. Any proposal to bring it back needs to say what is different, and 'we will select for KMT2A' is a hypothesis rather than a difference until it is tested.
- Panobinostat carries boxed warnings for severe diarrhoea and for cardiac arrhythmia. In infants, whose fluid balance has no reserve and in whom an arrhythmia is harder to detect early, those are not ordinary label warnings.
- The H2Bub mechanism is indirect and transcriptional, which means the cell can restore the ligase complex without any change to the drug's actual target. That is a resistance route invisible to every assay that looks for target-site mutation.
- Because no trial measured a pharmacodynamic marker, a future negative trial would be uninterpretable in exactly the same way as the last one. Fixing that costs one assay and would convert any result, positive or negative, into information.
- Pan-HDAC inhibition in an infant acts on every tissue. The preclinical rationale here is a specific chromatin axis; the drug delivering it is not specific at all, and the toxicity is set by the drug, not by the rationale.
- Has panobinostat ever been given to a KMT2A-rearranged patient with H2B ubiquitination measured before and after? The mechanism and the clinical test have never met.
- Would the futility result have differed in a genotype-selected population? Sixteen unselected adults cannot answer this, and no one has run the selected trial.
- Is the H2Bub depletion route shared by other pan-HDAC inhibitors - vorinostat, romidepsin, chidamide - or is it specific to panobinostat? If it is shared, it becomes a class mechanism; if not, panobinostat is not interchangeable with the agents actually being trialled in infants.
- Panobinostat's paediatric trial excluded children under 8. What is the lowest age at which this agent has any pharmacokinetic data, and is that gap the reason vorinostat rather than panobinostat reached the infant trial?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Panobinostat (LBH589) monotherapy exerts strong in vivo anti-leukaemic effects in xenograft mouse models of MLL-rearranged acute lymphoblastic leukaemia, extending survival and reducing overall disease burden, and molecular analyses show the activity involves depletion of H2B ubiquitination via suppression of the RNF20/RNF40/WAC E3 ligase complex, with WAC knockdown phenocopying H2Bub loss and inducing cell death.
The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. · Garrido Castro P, van Roon EHJ, Pinhancos SS, Trentin L, Schneider P, Kerstjens M, et al. · Leukemia 32(2):323-331 2018What this evidence cannot show
Xenograft models, not patients. The mechanism is indirect - the ligase complex is transcriptionally suppressed downstream of HDAC inhibition rather than inhibited directly - and the authors state panobinostat cross-inhibits multiple epigenetic pathways, so H2Bub depletion is demonstrated as a contributing route and not established as the sole route. Panobinostat is pan-HDAC, so nothing here attributes to an HDAC enzyme. The PMID, title, journal and DOI were fetched from PubMed in this session rather than copied from the sibling entry mechanism-panobinostat-depletes-h2bub-mll-r-all, per this project's citation rule.
Evidence that argues against this (1)
- The only efficacy-endpoint trial of panobinostat in acute leukaemia was terminated early for lack of efficacy after 16 patients. Preclinical xenograft activity and clinical futility are both real, and the gap between them is the central fact about this agent in this disease. City of Hope Medical Center; National Cancer Institute 2010
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
NCT00723203, a phase 2 study of panobinostat in relapsed or refractory acute lymphoblastic leukaemia or acute myeloid leukaemia sponsored by City of Hope Medical Center with the National Cancer Institute, enrolled an actual 16 participants aged 18 and over between April 2008 and September 2010 and has overall status TERMINATED, with the registry's whyStopped field reading 'Terminated early due to a lack of efficacy'.
Panobinostat in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia · City of Hope Medical Center; National Cancer Institute · ClinicalTrials.gov 2010What this evidence cannot show
This registry fact is carried forward from mechanism-panobinostat-depletes-h2bub-mll-r-all, which resolved it against the raw ClinicalTrials.gov API per this project's whyStopped rule; it was not independently re-fetched in this beat, and a reader who needs it to be load-bearing should re-run the raw API call. n = 16 adults, unselected for KMT2A rearrangement, heavily pretreated, monotherapy. A futility termination at this size cannot exclude activity in a genotype-selected or combination setting, and says nothing about infants.
Evidence that argues against this (1)
- An absence of testing is not a negative result. The trial did not select for KMT2A rearrangement and did not measure any pharmacodynamic marker, so a null is equally consistent with an ineffective mechanism and with the target never having been engaged. Garrido Castro P et al. 2018
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
NCT01321346, a phase 1 study of panobinostat in children with refractory haematological malignancies including childhood acute lymphoblastic and myelogenous leukaemia, Hodgkin's disease and non-Hodgkin lymphoma, run by the Therapeutic Advances in Childhood Leukemia Consortium with Novartis, enrolled an actual 30 participants aged 8 to 21 years from March 2011 and has overall status COMPLETED.
A Study Of Panobinostat In Children With Refractory Hematologic Malignancies · Therapeutic Advances in Childhood Leukemia Consortium; Novartis · ClinicalTrials.gov 2011What this evidence cannot show
Carried forward from mechanism-panobinostat-depletes-h2bub-mll-r-all rather than independently re-fetched in this beat. The eligible age range is 8 to 21 years, so this trial says nothing about infants - the population this graph exists to serve is excluded by the protocol. Phase 1, refractory, mixed diagnoses, no KMT2A selection and no H2Bub readout.
Evidence that argues against this (1)
- A registry record is a PLAN, not a result. Registration states what a sponsor intended to do; it does not establish that the trial completed, that it enrolled the KMT2A-rearranged subgroup in usable numbers, or that any effect was seen - and this beat's clearest cautionary case is an HDAC-directed agent that eradicated KMT2A-rearranged ALL in vitro and then failed in vivo at the maximum achievable dose. A registry entry cited as evidence of activity is citing the hypothesis, not the test. Verbeek TCAI et al. 2024
- E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The combination of the curaxin CBL0137 and the histone deacetylase inhibitor panobinostat delays KMT2A-rearranged leukaemia progression.
The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression. · Xiao L, Karsa M, Ronca E, Bongers A, Kosciolek A, El-Ayoubi A, et al. · Frontiers in Oncology 12:863329 2022What this evidence cannot show
Only the title and journal were read for this entry; the abstract was retrieved but the full text was not. Title, authors, journal, article number and DOI were all copied from a single fetched PubMed record on 2026-09-20 after an initial draft of this entry carried a wrong first author and a wrong DOI written from recall - the exact failure mode this project's citation rule exists to prevent. 'Delays progression' is the claim in the title and is weaker than a survival or cure endpoint. Preclinical. CBL0137 is itself an investigational agent with no approval, so this is a combination of two non-standard agents. Confidence is 'moderate' because this entry rests on the title-level claim rather than on a read of the experiments.
Evidence that argues against this (1)
- A delay in progression in a combination arm does not establish that the HDAC inhibitor is the active partner: CBL0137 is a curaxin with its own chromatin activity, and the design reported here cannot separate the contributions. Panobinostat is also pan-HDAC, so even a clean single-agent effect would not identify an enzyme. Matthews GM et al. 2015
pan-HDAC, class I and II
- treated by →KMT2A-rearranged acute lymphoblastic leukaemia
monotherapy in vivo efficacy in MLL-rearranged ALL xenografts; the one efficacy-endpoint trial in acute leukaemia was terminated for futility
this entry supplies the drug node the existing mechanism entry had no target for
pan-HDAC coverage means no panobinostat result can attribute to an enzyme