Palbociclib
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Palbociclib: From Hormone Receptor-Positive Breast Cancer to Myeloid Leukemia
Note on prediction selection: This Evidence Pack contains 10 TxGNN-predicted indications for Palbociclib. The top-ranked prediction by TxGNN score alone (hyperthyroidism, 99.44%) has zero supporting clinical trials or literature, and the model’s own rationale explicitly states there is no known mechanistic link. Of all 10 candidates, only myeloid leukemia (rank 6) is backed by actual clinical trial and literature evidence (L2, 5 trials, 20 publications). This report therefore evaluates that candidate rather than the highest raw-score, evidence-free prediction.
One-Sentence Summary
Palbociclib is a CDK4/6 inhibitor whose clinical use — as reflected throughout the trial evidence in this pack — centers on hormone receptor-positive (HR+), HER2-negative advanced/metastatic breast cancer, typically combined with endocrine therapy (fulvestrant, letrozole, aromatase inhibitors). The TxGNN model predicts potential efficacy in Myeloid Leukemia, particularly CDK4/6-dependent subtypes such as MLL-rearranged, t(8;21), and NUP98-translocated acute myeloid leukemia (AML), with 5 clinical trials and 20 publications currently supporting this direction — though evidence remains early-phase and preclinical/Phase 1-2 in nature.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not marketed in India; based on trial evidence in this pack, Palbociclib is historically used for HR+/HER2-negative advanced/metastatic breast cancer in combination with endocrine therapy |
| Predicted New Indication | Myeloid Leukemia (notably MLL-rearranged, t(8;21), and NUP98-translocated AML subtypes) |
| TxGNN Prediction Score | 98.94% |
| Evidence Level | L2 |
| India Market Status | Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Hold (flagged internally as “Research Question”) |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data for Palbociclib is not available in this Evidence Pack (marked as a High-severity data gap, DG002). Based on known information embedded in the trial evidence itself, Palbociclib is a CDK4/6 inhibitor whose efficacy in HR+/HER2-negative breast cancer is well established across numerous Phase 1–4 trials (e.g., NCT01942135, NCT03355157), and mechanistically its cell-cycle arrest activity may extend to hematologic malignancies driven by dysregulated CDK4/6 signaling.
CDK4/CDK6–RB pathway activity is known to be elevated in AML, and several leukemia subtypes appear selectively dependent on this pathway: t(8;21) AML shows CCND2 deregulation and increased sensitivity to CDK4/6 inhibition; FLT3-ITD-mutated AML depends on CDK6 for proliferation; and NUP98-rearranged leukemias rely on CDK6/FLT3 co-signaling. Preclinical work further shows Palbociclib synergizes with venetoclax and azacitidine by enhancing BCL-2-pathway-mediated apoptosis, which is directly relevant to overcoming venetoclax resistance — a major unmet need in AML treatment.
This mechanistic rationale is supported by an active clinical program: multiple Phase 1/1b/2 trials combine Palbociclib with CPX-351, venetoclax, or azacitidine in relapsed/refractory AML. However, the evidence base is still early — no completed Phase 3 trials exist, one trial (NCT02310243) has UNKNOWN status, and another (NCT03878524) was terminated after enrolling only 2 patients.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03844997 | Phase 1/2 | Completed | 35 | CPX-351 + Palbociclib in AML; evaluated safety, tolerability, and overall response rate (CR/CRi) — the strongest completed evidence source for this indication |
| NCT03132454 | Phase 1 | Active, not recruiting | 32 | Palbociclib alone or combined with sorafenib, decitabine, or dexamethasone in relapsed/refractory leukemia |
| NCT05627232 | Phase 1 | Recruiting | 24 | Palbociclib pre-treatment followed by CPX-351 in relapsed/refractory AML (Part 2 of a two-part study) |
| NCT02310243 | Phase 1b/2a | Unknown | 50 | Palbociclib in MLL-rearranged acute leukemias (AML/ALL); dosing based on prior solid-tumor experience; status needs follow-up |
| NCT03878524 | Phase 1 | Terminated | 2 | SMART PRIME trial testing multiomic-guided drug combinations; terminated with minimal enrollment, limited informational value |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36400926 | 2023 | Review | Leukemia | Reviews targeting cell cycle and apoptosis pathways (including CDK4/6) to overcome chemotherapy resistance in AML |
| 38430306 | 2024 | Case Report | Cancer Chemother Pharmacol | Successful use of Palbociclib + Venetoclax + Azacitidine in an adult with refractory/relapsed therapy-related AML |
| 40330925 | 2025 | Case Report | AME Case Reports | Chronic myeloid leukemia arising in a breast cancer patient treated with Palbociclib + exemestane |
| 36076608 | 2022 | Preclinical | Biomed Pharmacother | Palbociclib promotes the antitumor activity of Venetoclax + Azacitidine against AML |
| 40482924 | 2025 | Preclinical | J Control Release | Antibody-mediated dual delivery of FLT3 (gilteritinib) and CDK4/6 (palbociclib) inhibitors for targeted AML treatment |
| 33068248 | 2021 | Preclinical | Int J Hematol | CDK4/6 + autophagy co-inhibition synergistically induces apoptosis in t(8;21) AML cells |
| 41468895 | 2026 | Preclinical | Cell Reports Medicine | CDK4/6 inhibition (with Palbociclib) overcomes venetoclax resistance mechanisms in 302 AML patient samples and PDX models |
| 30381403 | 2018 | Preclinical | Blood Advances | Recurrent CCND3 mutations identified in MLL-rearranged AML, supporting a CDK-pathway dependency rationale |
| 29291023 | 2017 | Preclinical | Oncotarget | Combined venetoclax and the CDK inhibitor alvocidib in AML, supporting the broader CDK-inhibitor + BCL-2-inhibitor combination rationale |
| 27323399 | 2016 | Preclinical | Oncotarget | Identifies an essential FLT3-ITD–HCK–CDK6 signaling pathway in AML, providing mechanistic basis for CDK6-directed therapy |
India Market Information
Palbociclib currently has no registrations in India (market status: Not Marketed; 0 total licenses on file). No authorization, product, or approved-indication data is available in this Evidence Pack.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (CDK4/6 inhibitor) — not conventional cytotoxic chemotherapy |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Please refer to the package insert for safety information. (Key warnings, contraindications, and DDI data are marked as unresolved data gaps in this pack — notably DG001, a Blocking-severity gap for TFDA/India label warnings and contraindications, which must be resolved before any S1 safety assessment.)
Conclusion and Next Steps
Decision: Hold
Rationale: CDK4/6 inhibition has a biologically plausible and increasingly literature-supported role in specific AML subtypes (MLL-rearranged, t(8;21), NUP98-translocated, and venetoclax-resistant disease), backed by one completed and several active/recruiting Phase 1–2 combination trials. However, evidence is confined to L2 (early-phase/preclinical), no Phase 3 data exists, one key trial is of unknown status and another was terminated early, and this candidate lacks all Taiwan/India regulatory, safety, and MOA documentation — insufficient to proceed beyond a research hypothesis at this time.
To proceed, the following is needed:
- Resolve DG001 (Blocking): TFDA/India label warnings and contraindications
- Resolve DG002 (High): detailed mechanism of action documentation
- Fix the DDI data source error (missing
ddinter_code_A.csv) and rerun the interaction query - Follow-up on NCT02310243 (UNKNOWN status) and mature results from NCT05627232 and NCT03132454
- Phase 2/3 controlled trial data specifically in AML before any Go/Proceed-with-Guardrails consideration
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.