Palbociclib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Palbociclib
- Palbociclib: From Its Licensed Use to Hyperthyroidism (Top TxGNN Prediction), with Myeloid Leukemia as the Best-Supported Candidate
Palbociclib: From Its Licensed Use to Hyperthyroidism (Top TxGNN Prediction), with Myeloid Leukemia as the Best-Supported Candidate
One-Sentence Summary
Palbociclib is a CDK4/6 inhibitor (Ibrance) that is marketed in Singapore as an oral film-coated tablet. The TxGNN model's top-ranked prediction is hyperthyroidism, but this is a graph-based prediction only, with 0 clinical trials and 0 publications. Among the ten predictions, myeloid leukemia has the most support (4 clinical trials, early-phase, and 20 publications, mostly preclinical), followed by rheumatoid arthritis (preclinical data and one case report).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available in the data compiled for this report (the Singapore licence records contain no indication text) |
| Predicted New Indication | Hyperthyroidism (rank 1); the best-supported alternative is myeloid leukemia (rank 6) |
| TxGNN Prediction Score | 99.44% (hyperthyroidism); 98.94% (myeloid leukemia) |
| Evidence Level | L5 for hyperthyroidism (model prediction only); L3 for myeloid leukemia |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 3 |
| Recommended Decision | Hold (hyperthyroidism); myeloid leukemia and rheumatoid arthritis are best treated as research questions |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Palbociclib is known as a CDK4/6 inhibitor used in hormone receptor-positive, HER2-negative breast cancer. It blocks cell-cycle progression by inhibiting CDK4/6.
Hyperthyroidism (rank 1): There is no clear mechanistic link. CDK4/6 inhibition has no established role in thyroid hormone excess. The high score is a graph-based artifact, and the other thyroid-related predictions (thyroid hormone resistance, hyperthyroxinemia) appear to cluster for the same reason. The same applies to the congenital syndromes and Prinzmetal angina in the list.
Myeloid leukemia (rank 6): This is the most biologically plausible oncology extension. Leukemic cells, particularly MLL-rearranged, NUP98-rearranged and FLT3-driven subtypes, depend on CDK6. Preclinical studies show palbociclib enhances venetoclax plus azacitidine and helps overcome venetoclax resistance. Co-targeting CDK6 with LSD1 or menin inhibitors is synergistic. A 2026 review-style abstract notes that CDK4/6 inhibitor monotherapy was disappointing in clinical trials, so combinations are the likely route.
Rheumatoid arthritis (rank 2): CDK6 drives synovial fibroblast proliferation. Mouse models show CDK6-dependent synovial hyperplasia, and cell-cycle inhibition combined with cytokine blockade improved arthritis. One case report describes RA improvement in a breast cancer patient on palbociclib. There are no clinical trials.
Thrombotic disease (rank 3): The literature points the opposite way. Pharmacovigilance studies report thromboembolism as an adverse event of CDK4/6 inhibitors. This is a safety concern, not therapeutic support.
Multiple endocrine neoplasia (rank 7): Cell-cycle dysregulation in MEN1 and MEN4 makes CDK4/6 inhibition plausible in principle, but the linked trials are in breast cancer or tumor-agnostic platforms. There is no MEN-specific evidence.
Clinical Trial Evidence
Trials linked to myeloid leukemia (the best-supported prediction):
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02310243 | Phase 1/2 | Unknown | 50 | Palbociclib in MLL-rearranged acute leukemias; no results provided |
| NCT03132454 | Phase 1 | Active, not recruiting | 32 | Palbociclib alone and with sorafenib, decitabine or dexamethasone in relapsed/refractory leukemia; safety and dose focus |
| NCT05627232 | Phase 1 | Recruiting | 24 | Palbociclib pre-treatment followed by CPX-351 (and a tazemetostat arm) in relapsed/refractory AML |
| NCT03878524 | Phase 1 | Terminated | 2 | Precision-oncology platform trial; negligible evidence |
Trials linked to multiple endocrine neoplasia have low relevance. NCT03355157 (Phase 4) and NCT02894398 (Phase 2) are breast cancer studies, and NCT02465060 (NCI-MATCH, Phase 2, 6,452 patients) is a tumor-agnostic basket trial. None enrolled MEN patients specifically as far as the data show.
No clinical trials are registered for hyperthyroidism, rheumatoid arthritis or thrombotic disease.
Literature Evidence
Myeloid leukemia (selected; mostly preclinical):
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 41468895 | 2026 | Preclinical | Cell Reports Medicine | Venetoclax plus palbociclib is synergistic in AML cell lines and xenografts, overcoming venetoclax resistance |
| 36076608 | 2022 | Preclinical | Biomed Pharmacother | Palbociclib boosts venetoclax plus azacitidine activity against AML |
| 42312423 | 2026 | Preclinical | Haematologica | Dual CDK2 and CDK4/6 inhibition enhances anti-leukemic activity; CDK4/6 monotherapy trials were disappointing |
| 40883610 | 2025 | Preclinical | EMBO Mol Med | Dual CDK6 and LSD1 targeting is synergistic in AML |
| 38890447 | 2024 | Preclinical | Leukemia | Menin plus kinase inhibitors (including CDK6) in NUP98-rearranged leukemia |
| 38430306 | 2024 | Case report | Cancer Chemother Pharmacol | Palbociclib with venetoclax and azacitidine used successfully in refractory therapy-related AML |
Rheumatoid arthritis:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 40504547 | 2025 | Cohort | The Oncologist | Pre-existing and emerging immune-mediated diseases in breast cancer patients on CDK4/6 inhibitors; indirect context |
| 33587021 | 2021 | Case report | Mod Rheumatol Case Rep | RA improved in a breast cancer patient treated with palbociclib |
| 25165034 | 2016 | Preclinical (animal) | Ann Rheum Dis | Cell-cycle inhibition plus cytokine blockade enhanced antiarthritic effect without added immune suppression |
| 39940918 | 2025 | Preclinical | Int J Mol Sci | CDK6-dependent, CDK4-independent synovial hyperplasia in arthritic mice |
Thrombotic disease (safety signal, not efficacy):
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36794339 | 2023 | Pharmacovigilance and systematic review | Expert Opin Drug Saf | Thromboembolism associated with CDK4/6 inhibitors in real-world data |
| 39123221 | 2024 | Pharmacovigilance (FAERS) | BMC Pharmacol Toxicol | Comparative adverse event profiles of the three CDK4/6 inhibitors |
No literature was found for hyperthyroidism, thyroid hormone resistance, hyperthyroxinemia, Prinzmetal angina, or the two congenital syndromes.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16322P | IBRANCE Film Coated Tablet 75 mg | Tablet, film coated | Not stated in the licence record |
| SIN16323P | IBRANCE Film Coated Tablet 100 mg | Tablet, film coated | Not stated in the licence record |
| SIN16324P | IBRANCE Film Coated Tablet 125 mg | Tablet, film coated | Not stated in the licence record |
All three licences are valid single-ingredient products from Pfizer Manufacturing Deutschland GmbH, and the only route is oral.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (CDK4/6 inhibitor), not a conventional cytotoxic |
| Myelosuppression Risk | High. Pharmacovigilance literature and preclinical work describe palbociclib-associated myelosuppression |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count with differential; liver and renal function |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
- Drug Interactions: The interaction screen returned 100 interacting drugs; the 20 reviewed include these main ones:
- Major: clarithromycin, cobicistat, deferiprone, samarium (153Sm) lexidronam.
- Moderate: aprepitant, dexamethasone, cimetidine, saxagliptin, eliglustat, metreleptin, miconazole, nitisinone, cisapride, clotrimazole, simvastatin, troglitazone, deferasirox, strontium chloride Sr-89, cilostazol.
- Minor: prucalopride.
- Literature-based signals: Venous thromboembolism and interstitial lung disease/pulmonary toxicity are reported for CDK4/6 inhibitors in pharmacovigilance studies. Myelosuppression is also described.
Please refer to the package insert for warnings and contraindications, as label-based data was not available.
Conclusion and Next Steps
Decision: Hold for the top-ranked prediction (hyperthyroidism). Myeloid leukemia and rheumatoid arthritis are best classed as research questions.
Rationale:
- Hyperthyroidism has no mechanistic link and no trials or literature, so the 99.44% score reflects graph structure only. Thrombotic disease carries a safety signal that argues against repurposing.
- Myeloid leukemia has plausible biology and four early-phase trials, but no efficacy results, and CDK4/6 monotherapy has been disappointing. Any benefit appears to lie in combinations such as venetoclax plus azacitidine.
- Rheumatoid arthritis rests on preclinical data and one case report.
To proceed, the following is needed:
- The Singapore package insert (warnings, contraindications and approved indications), as the licence records contain no indication text
- Mechanism of action data from DrugBank
- Results from the Phase 1/2 leukemia trials (NCT02310243, NCT03132454, NCT05627232)
- A prospective clinical study for rheumatoid arthritis, with a myelosuppression and thromboembolism risk assessment
- Review of the major interacting drugs (for example clarithromycin and cobicistat) before any combination use
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.