Idelalisib

證據等級: L5

預測適應症: 10 個

Idelalisib: From Chronic Lymphocytic Leukemia/Follicular Lymphoma to Mantle Cell Lymphoma

One-Sentence Summary

Idelalisib is a first-in-class, oral PI3Kδ inhibitor originally developed for relapsed chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and small lymphocytic lymphoma (SLL). The TxGNN model predicts it may also be effective for Mantle Cell Lymphoma (MCL), with 9 clinical trials and 20 publications currently touching on this direction — though the evidence remains early-stage and MCL is not an approved indication for this drug.

Quick Overview

Item	Content
Original Indication	Relapsed CLL, relapsed follicular lymphoma, relapsed small lymphocytic lymphoma (per literature, e.g. PMID 25187123, 25637459)
Predicted New Indication	Mantle Cell Lymphoma (MCL)
TxGNN Prediction Score	99.84%
Evidence Level	L2
Finland Market Status	✗ Not marketed
Number of Authorizations	0
Recommended Decision	Hold (internally staged as "Research Question", decision stage S2)

Why is This Prediction Reasonable?

Formal DrugBank mechanism-of-action data was not retrieved for this candidate (data gap DG002). Based on the literature captured in this evidence pack, idelalisib is described as a first-in-class, orally administered, selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) — an enzyme expressed predominantly in hematopoietic cells that plays a non-redundant role in B-cell receptor (BCR) signaling, a pathway that drives survival, proliferation, and microenvironment retention of malignant B cells.

Idelalisib's original approved population (CLL, FL, SLL) shares this BCR/PI3Kδ dependency with MCL, which is also a B-cell non-Hodgkin lymphoma. This shared pathway is the basis of the TxGNN prediction, and it is reflected in real-world trial design: several early idelalisib studies enrolled MCL patients alongside CLL/FL/iNHL cohorts under a common "B-cell malignancy" umbrella (e.g., NCT01088048, NCT01796470).

However, the mechanistic rationale is only partially borne out clinically. A dedicated Phase 1 study of idelalisib monotherapy in relapsed/refractory MCL (PMID 24615778) and an early cohort report (PMID 24795031) showed some single-agent activity, but subsequent preclinical work (PMID 33850273, PMID 40466505) identified intrinsic resistance of MCL cells to idelalisib, requiring combination strategies (e.g., p300/CBP inhibition, CBX5-mediated ferroptosis induction) to restore sensitivity. As the internal repurposing rationale notes: mechanistically plausible, but single-agent clinical activity is limited and MCL is not a currently approved indication.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01796470	Phase 2	Terminated	66	Entospletinib (GS-9973) + idelalisib in relapsed/refractory hematologic malignancies incl. MCL, CLL, DLBCL, iNHL; direct MCL evaluation but terminated early — Grade A relevance, underpowered
NCT01838434	Phase 1	Completed	106	Idelalisib + lenalidomide in relapsed/refractory MCL; completed combination-therapy exploratory study — Grade B
NCT03151057	Phase 1	Terminated	16	Idelalisib as post-allogeneic HSCT maintenance in B-cell malignancies incl. MCL; terminated, small sample — Grade C
NCT02824159	N/A	Completed	121	Real-life PK/side-effect correlation study of ibrutinib and idelalisib in hematological malignancies incl. MCL
NCT02457598	Phase 1	Terminated	203	Tirabrutinib combined with targeted anti-cancer therapies in B-cell malignancies incl. MCL; terminated
NCT03740529	Phase 1/2	Completed	803	Pirtobrutinib (LOXO-305) in CLL/SLL/NHL populations, including MCL as comparator/reference group
NCT04985214	N/A	Unknown	464	Quality-of-life assessment of oral lymphoma therapies (incl. idelalisib) in patients incl. MCL
NCT01088048	Phase 1	Completed	241	Idelalisib + chemo/immunomodulatory/anti-CD20 agents in relapsed/refractory iNHL, MCL, or CLL
NCT02603445	Phase 1	Completed	20	BCL201 + idelalisib dose-escalation safety study in FL and MCL patients

Literature Evidence

PMID	Year	Type	Journal	Key Findings
24615778	2014	Phase 1 clinical study	Blood	First dedicated Phase 1 study of idelalisib monotherapy in R/R MCL (n=40); defined dosing, evaluated ORR/PFS/DOR
24795031	2014	Cohort	Cancer Discovery	Idelalisib showed single-agent activity in heavily pretreated MCL patients
33850273	2022	Preclinical	Acta Pharmacol Sin	MCL shows intrinsic resistance to idelalisib; p300/CBP inhibitor A-485 restores sensitivity in vitro/in vivo
40466505	2025	Preclinical	Phytomedicine	CBX5 loss drives PI3Kδ-inhibitor resistance in MCL; propolis restores sensitivity via ferroptosis induction
27342398	2017	Preclinical	Clin Cancer Res	Idelalisib inhibits MCL cell growth via disruption of translation-regulatory mechanisms
38815797	2024	Preclinical	Cancer Letters	Idelalisib enhances anti-tumor effect of CDK4/6 inhibitor palbociclib via PLK1 in MCL/DLBCL
24974852	2014	Review	Br J Haematol	Overview of current regimens and novel agents (incl. PI3K inhibitors) for MCL
26360791	2015	Review	Expert Opin Pharmacother	Review of treatment options for MCL, including novel targeted agents
23512567	2013	Review	Curr Treat Options Oncol	Review of current and emerging therapies in MCL
24273091	2013	Review	Am J Hematol	2013 update on MCL diagnosis, risk-stratification, and clinical management

Finland Market Information

Idelalisib is not currently marketed in Finland — 0 authorizations are on file, and the drug's Finnish regulatory status is recorded as "未上市" (not marketed).

Cytotoxicity

Idelalisib is an antineoplastic agent (targeted small-molecule kinase inhibitor used for hematologic malignancies), so this section applies.

Item	Content
Cytotoxicity Classification	Targeted therapy (PI3Kδ inhibitor) — not a conventional cytotoxic chemotherapeutic
Myelosuppression Risk	Formal hematologic toxicity data was not retrieved in this evidence pack (DDI/warnings query returned no results); literature associated with idelalisib in B-cell malignancies notes neutropenia among reported adverse events (PMID 27054023)
Emetogenicity Classification	Not established in the retrieved data; please refer to the package insert
Monitoring Items	CBC with differential (cytopenias), liver function tests (hepatotoxicity), pulmonary symptom monitoring (pneumonitis), GI symptom monitoring (idelalisib-associated colitis/diarrhea, per NCT02928510 and PMID 28775119)
Handling Protection	Yes — as an oral targeted antineoplastic agent, standard cytotoxic/hazardous drug handling precautions should be followed pending confirmation against the local package insert

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: Evidence for idelalisib in MCL is limited to a single dedicated Phase 1 monotherapy study (n=40) and several early-phase or prematurely terminated combination trials (L2 evidence, decision stage S2). Preclinical literature further indicates intrinsic MCL resistance to idelalisib, and MCL is not an approved indication for this drug — mechanistic plausibility exists, but confirmatory efficacy is lacking.

To proceed, the following is needed:

Confirmatory randomized (Phase 2/3) efficacy data specifically in MCL
Resistance-informed combination strategy data (e.g., epigenetic co-inhibition) given reported intrinsic MCL resistance
TFDA/Finland package insert warnings and contraindications (currently a Blocking data gap, DG001) before any S1 safety assessment can proceed
Formal DrugBank-sourced mechanism-of-action documentation (currently a data gap, DG002)
Confirmation of Finland market entry pathway, since the drug is not currently marketed there
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.