Acalabrutinib
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
- Acalabrutinib
- Acalabrutinib: From Mantle Cell Lymphoma to Non-Hodgkin Lymphoma (Familial, Generic Node)
Acalabrutinib: From Mantle Cell Lymphoma to Non-Hodgkin Lymphoma (Familial, Generic Node)
One-Sentence Summary
Acalabrutinib is a covalent BTK inhibitor, originally used for mantle cell lymphoma and other B-cell neoplasms. The TxGNN model predicts it may be effective for lymphoma, non-Hodgkin, familial, a generic model node. The supporting evidence actually concerns sporadic B-cell NHL subtypes (DLBCL, indolent NHL, Richter's syndrome), with 14 clinical trials and 20 publications currently linked to this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Mantle cell lymphoma, B-cell neoplasm, lymphosarcoma (the Singapore licence records contain no approved indication text) |
| Predicted New Indication | Lymphoma, non-Hodgkin, familial |
| TxGNN Prediction Score | 97.64% |
| Evidence Level | L2 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Based on known information, acalabrutinib is a covalent Bruton tyrosine kinase (BTK) inhibitor. BTK blocks B-cell receptor signalling, which drives survival and proliferation in many B-cell non-Hodgkin lymphomas.
Its efficacy in mantle cell lymphoma is established, and it is mechanistically applicable to other B-cell NHL subtypes that depend on the same pathway.
One caveat: "familial NHL" is a generic node in the TxGNN knowledge graph. The trials and publications found concern sporadic B-cell NHL (MCL, DLBCL, indolent NHL), not a familial form specifically. The repurposing value therefore lies mainly in other NHL subtypes and in combinations (R-CHOP, CAR-T, venetoclax, obinutuzumab).
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03899337 | Phase 2 | Active, not recruiting | 72 | Randomised: CHOP-R + acalabrutinib vs CHOP-R in newly diagnosed Richter's syndrome |
| NCT03571308 | Phase 1b/2 | Completed | 39 | Acalabrutinib + R-CHOP in untreated DLBCL; safety and preliminary efficacy |
| NCT04546620 | Phase 2 | Active, not recruiting | 453 | Randomised molecular-guided study adding acalabrutinib to R-CHOP in untreated DLBCL |
| NCT04094142 | Phase 2 | Completed | 66 | Acalabrutinib + rituximab + lenalidomide in relapsed/refractory B-cell NHL |
| NCT02180711 | Phase 1b/2 | Active, not recruiting | 113 | Acalabrutinib alone or combined in B-cell NHL (follicular and marginal zone lymphoma) |
| NCT05583149 | Phase 2 | Active, not recruiting | 28 | Acalabrutinib + liso-cel (CAR-T) in relapsed/refractory aggressive B-cell lymphoma |
| NCT04257578 | Phase 1/2 | Active, not recruiting | 23 | Acalabrutinib + anti-CD19 CAR-T (axicabtagene ciloleucel) in B-cell lymphoma |
| NCT04883437 | Phase 2 | Recruiting | 49 | Acalabrutinib + obinutuzumab in untreated low-tumour-burden follicular lymphoma |
| NCT02362035 | Phase 1b/2 | Completed | 161 | Acalabrutinib + pembrolizumab in haematologic malignancies |
| NCT04502394 | Phase 1b/2 | Recruiting | 84 | KRT-232 + acalabrutinib in relapsed/refractory DLBCL or CLL (indirect evidence) |
Several other registered trials are of limited value: NCT04836832 was withdrawn (0 participants), NCT04419389 was terminated after 1 participant, and NCT06564038 and NCT03571568 are early-phase studies where acalabrutinib is a combination partner.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 40311141 | 2025 | RCT | J Clin Oncol | Acalabrutinib + bendamustine-rituximab in untreated MCL, with the rationale of better tolerability than ibrutinib |
| 29241979 | 2018 | Single-arm Phase 2 | Lancet | ACE-LY-004: acalabrutinib in relapsed/refractory MCL |
| 37470152 | 2024 | Phase 2 (final results) | Haematologica | Final and overall survival data for acalabrutinib monotherapy in relapsed/refractory MCL |
| 38781315 | 2024 | Phase 1b/2 | Blood Adv | Acalabrutinib + venetoclax + rituximab in untreated MCL, 2-year safety and efficacy (21 patients) |
| 30967367 | 2019 | Review | Blood | Acalabrutinib approved for relapsed MCL based on an 81% overall response rate |
| 35266562 | 2022 | Review | Am J Hematol | Comprehensive update on MCL pathogenesis and treatments |
| 32715803 | 2020 | Review | Expert Opin Drug Saf | Safety considerations for targeted therapies in B-cell NHL |
| 29781323 | 2018 | Review | Expert Opin Emerg Drugs | Review of BCR-pathway inhibitors (SYK, BTK, PI3K) in NHL |
| 40889741 | 2025 | Indirect comparison | Leuk Lymphoma | Zanubrutinib vs acalabrutinib in relapsed/refractory MCL (unanchored comparison) |
| 28439883 | 2017 | Review | Br J Haematol | Update on Richter syndrome, a chemotherapy-resistant aggressive lymphoma |
Most of the literature concerns MCL, which is already an approved use, rather than the predicted familial NHL node.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15753P | CALQUENCE HARD CAPSULES 100MG | Capsule | Not recorded |
| SIN16875P | CALQUENCE FILM-COATED TABLET 100MG | Film-coated tablet | Not recorded |
Both are valid single-ingredient licences held by AstraZeneca AB, for oral use.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (covalent BTK inhibitor) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count, and liver and renal function (general oncology practice; confirm against the package insert) |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
- Drug Interactions: The interaction screen returned 100 interacting drugs in total; the list available here covers 20. Major-level interactions include:
- Aprepitant
- Acetylsalicylic acid
- Clarithromycin
- Dexlansoprazole
- Esomeprazole
- Lansoprazole
Moderate-level interactions include antacids (aluminium hydroxide, calcium carbonate, magnesium salts), H2 blockers (cimetidine, famotidine), clotrimazole, dexamethasone, fenfluramine and dexfenfluramine, glycerol phenylbutyrate, and metreleptin.
For warnings and contraindications, please refer to the package insert.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Several Phase 2 studies, including randomised and completed ones, support acalabrutinib in B-cell NHL subtypes (DLBCL, indolent NHL, Richter's syndrome), and the drug is already marketed in Singapore. However, the predicted node is a generic "familial NHL" label with no direct evidence, and most results are still pending or come from combination regimens. Other predictions on the list (colon adenocarcinoma, Burkitt lymphoma, site-specific MALT lymphomas, polyclonal hypergammaglobulinemia) have no supporting trials and should remain on Hold. The "neoplasm of mature B-cells" prediction largely overlaps with existing approved uses and is not a novel signal.
To proceed, the following is needed:
- Package insert warnings and contraindications from HSA (currently a blocking gap for safety screening)
- Mechanism of action data from DrugBank
- Approved indication text for the two Singapore licences
- Results from the randomised Phase 2 DLBCL and Richter's syndrome trials (NCT04546620, NCT03899337)
- Subtype-specific definition of the target population, since "familial NHL" is not a clinically actionable category
- A management plan for the major interactions (acid-reducing agents, CYP3A inhibitors such as clarithromycin, and antiplatelet agents)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.