Idelalisib
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Idelalisib: From B-Cell Lymphoid Malignancies (CLL/FL/SLL) to Mantle Cell Lymphoma
One-Sentence Summary
Idelalisib is an oral, selective PI3Kδ (phosphatidylinositol 3-kinase delta) inhibitor with an established evidence base in B-cell lymphoid malignancies such as chronic lymphocytic leukaemia (CLL), follicular lymphoma (FL) and small lymphocytic lymphoma (SLL), as reflected throughout the published literature in this evidence pack. The TxGNN model’s top-ranked candidate indication is Mantle Cell Lymphoma (MCL), a related B-cell malignancy in which idelalisib has been studied but is not an approved indication. This direction is currently supported by 9 clinical trials and 20 publications, though several trials were terminated early and intrinsic drug resistance has been reported, indicating meaningful but incomplete evidence.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic Lymphocytic Leukemia (CLL), Follicular Lymphoma (FL), Small Lymphocytic Lymphoma (SLL) — established per the literature evidence in this pack; formal product/registration data for the original indication is not yet available (see Data Gaps below) |
| Predicted New Indication | Mantle Cell Lymphoma |
| TxGNN Prediction Score | 99.84% |
| Evidence Level | L2 |
| Denmark Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed, structured mechanism-of-action data was not available from the drug record used to build this evidence pack. However, based on the published literature cited within this pack, idelalisib is consistently described as a first-in-class, orally administered, selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ), a lipid kinase expressed predominantly in hematopoietic cells. PI3Kδ sits downstream of the B-cell receptor (BCR) and is essential for the survival, proliferation, and microenvironment interaction of malignant B cells.
MCL and idelalisib’s better-characterised indications (CLL, FL, SLL) are all B-cell-derived lymphoproliferative disorders that share BCR-pathway dependence, which provides a coherent mechanistic rationale for testing idelalisib in MCL. This is corroborated by direct clinical evidence: a Phase 1 study (PMID 24615778, Kahl et al., Blood 2014) and a related Phase 2 single-arm report (PMID 24795031, Cancer Discovery 2014) both describe measurable anti-tumour activity of idelalisib in relapsed/refractory MCL.
At the same time, the mechanistic link is not as strong as in CLL/FL/SLL. MCL frequently harbours additional oncogenic drivers — SOX11 overexpression, CCND1/cyclin D1 dysregulation via t(11;14) — that operate largely independent of BCR/PI3Kδ signalling. Preclinical work in this pack (PMID 33850273, PMID 40466505) reports intrinsic resistance to idelalisib in MCL cell models, and several combination trials in MCL/B-cell malignancies were terminated early (e.g., NCT01796470, NCT02457598), which is consistent with a real but incomplete and resistance-prone signal rather than a robust monotherapy effect.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01088048 | Phase 1 | Completed | 241 | Idelalisib + chemotherapy/immunomodulatory agent/anti-CD20 mAb in relapsed/refractory iNHL, MCL, or CLL; safety-focused, directly evaluates idelalisib |
| NCT01838434 | Phase 1 / Randomized Phase 2 | Completed | 106 | Idelalisib + lenalidomide vs. lenalidomide alone in relapsed/refractory MCL; direct efficacy/safety evaluation of idelalisib combination |
| NCT01796470 | Phase 2 | Terminated | 66 | Entospletinib + idelalisib in relapsed/refractory hematologic malignancies incl. MCL; terminated, reflecting a toxicity signal |
| NCT02603445 | Phase 1 (1b) | Completed | 20 | BCL201 + idelalisib dose-escalation study in follicular lymphoma and MCL; safety/tolerability endpoint |
| NCT02824159 | N/A | Completed | 121 | Real-world assessment of adverse effects vs. plasma concentrations of ibrutinib and idelalisib (includes MCL patients) |
| NCT02457598 | Phase 1b | Terminated | 203 | Tirabrutinib ± other targeted agents (including idelalisib combinations) in relapsed/refractory B-cell malignancies |
| NCT03151057 | Phase 1 | Terminated | 16 | Idelalisib as post-allogeneic HSCT maintenance in B-cell malignancies; safety focus (cytopenias, GVHD, GI tolerance) |
| NCT04985214 | N/A | Unknown | 464 | Quality-of-life assessment of lymphoma patients (incl. MCL) on oral therapies such as idelalisib |
| NCT03740529 | Phase 1/2 | Completed | 803 | Pirtobrutinib study in CLL/SLL/NHL; idelalisib appears only as a comparator/prior-therapy context, not the primary study drug |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24795031 | 2014 | Phase 2 single-arm trial | Cancer Discovery | Idelalisib showed measurable activity in heavily pretreated relapsed/refractory MCL patients |
| 24615778 | 2014 | Phase 1 clinical trial | Blood | 48-week Phase 1 study (n=40) of idelalisib in R/R MCL; primary endpoint safety/DLT, secondary ORR/PFS/DOR |
| 24974852 | 2014 | Review | British Journal of Haematology | Overview of current and novel MCL regimens, including PI3K-pathway-targeted agents |
| 28775119 | 2017 | Review | Haematologica | Practical guidance on incidence and management of toxicity associated with ibrutinib and idelalisib |
| 26841011 | 2016 | Review | Cancer Journal | Overview of idelalisib targeting the PI3K pathway in non-Hodgkin lymphoma, including MCL context |
| 23512567 | 2013 | Review | Current Treatment Options in Oncology | Review of current and emerging therapies in mantle cell lymphoma |
| 33850273 | 2022 | Preclinical | Acta Pharmacologica Sinica | p300/CBP inhibitor A-485 overcomes intrinsic idelalisib resistance in MCL cells in vitro/in vivo |
| 40466505 | 2025 | Preclinical | Phytomedicine | CBX5 loss drives PI3Kδ-inhibitor resistance in MCL; propolis restores sensitivity via ferroptosis |
| 27342398 | 2017 | Preclinical | Clinical Cancer Research | Idelalisib inhibits translation-regulatory mechanisms controlling MCL cell growth |
| 38815797 | 2024 | Preclinical | Cancer Letters | Idelalisib + palbociclib (CDK4/6 inhibitor) combination enhances anti-tumour effect via PLK1 in B-cell lymphoma including MCL |
Denmark Market Information
Idelalisib currently holds no marketing authorisation in Denmark (market status: Not marketed; 0 authorisations on file). No Laegemiddelstyrelsen (national) or EMA centralised authorisation records were available in this evidence pack to populate a licence table.
Cytotoxicity
Idelalisib is an antineoplastic agent (small-molecule, targeted kinase inhibitor used in B-cell lymphoid malignancies), so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (selective PI3Kδ inhibitor; not a conventional cytotoxic chemotherapeutic) |
| Myelosuppression Risk | Please refer to the Summary of Product Characteristics (SmPC) warnings and precautions. Published trial data note cytopenias monitored in the post-transplant maintenance setting (NCT03151057) |
| Emetogenicity Classification | Please refer to the Summary of Product Characteristics (SmPC) warnings and precautions |
| Monitoring Items | CBC with differential, liver function tests, and pulmonary status — reflecting class-associated toxicities (hepatotoxicity, pneumonitis, colitis/diarrhoea) reported in the review literature (e.g., PMID 28775119) |
| Handling Protection | Oral small-molecule targeted agent; confirm handling requirements against the local (Danish) hazardous/oral-oncolytic drug handling protocol, as formal product handling guidance was not available in this evidence pack |
Safety Considerations
Please refer to the approved Summary of Product Characteristics (SmPC) for safety information. No structured warnings, contraindications, or drug–drug interaction data were available in this evidence pack.
Conclusion and Next Steps
Decision: Hold
Rationale:
- Evidence for the mantle cell lymphoma indication is real but incomplete (L2): supportive Phase 1/Phase 2 data exist, but several combination trials were terminated early and preclinical literature documents intrinsic PI3Kδ-inhibitor resistance in MCL.
- Idelalisib is not currently marketed in Denmark (0 authorisations), and — critically — a Blocking data gap (TFDA/product label warnings and contraindications, DG001) prevents this candidate from even entering the initial safety screening stage (S1). No repurposing recommendation can be finalised until this is resolved.
To proceed, the following is needed:
- Official product label (SmPC) warnings, contraindications, and interaction data to resolve the Blocking data gap (DG001)
- Formal mechanism-of-action documentation from DrugBank or the regulatory dossier to resolve the High-severity MOA gap (DG002)
- Confirmation of idelalisib’s currently approved indications and regulatory status relevant to Denmark (including any EMA restrictions applied after post-marketing safety signals)
- An updated efficacy/safety synthesis specific to MCL, accounting for the intrinsic resistance mechanisms and early trial terminations identified in the literature
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.