^
    22d
    Precision Medicine in Non-Hodgkin Lymphoma: Advances in BTK Inhibition, CD30-Directed Antibody-Drug Conjugates, and HDAC-Mediated Epigenetic Therapy with Pirtobrutinib, Brentuximab Vedotin, and Belinostat. (PubMed, J Clin Med)
    Cumulatively, these therapies illustrate both the progress and the ongoing challenges of biomarker-driven treatment in NHL, including resistance mechanisms, toxicity management, optimal therapeutic sequencing, and variability in evidence maturity across targeted strategies. While pirtobrutinib and brentuximab vedotin are supported by increasingly robust clinical evidence in selected lymphoma subtypes, the role of belinostat remains constrained by modest response rates and limited randomized data, underscoring the continued need for biomarker refinement and more precisely individualized therapeutic approaches in NHL precision medicine.
    Review • Journal
    |
    TNFRSF8 (TNF Receptor Superfamily Member 8)
    |
    TNFRSF8 expression
    |
    Adcetris (brentuximab vedotin) • Jaypirca (pirtobrutinib) • Beleodaq (belinostat)
    23d
    A Study of Pirtobrutinib in Participants With Immune Thrombocytopenia (clinicaltrials.gov)
    P1/2, N=68, Recruiting, Eli Lilly and Company | Trial completion date: Feb 2027 --> May 2029 | Trial primary completion date: Dec 2026 --> May 2028
    Trial completion date • Trial primary completion date
    |
    Jaypirca (pirtobrutinib)
    1m
    Adding Pirtobrutinib to the Usual Treatment for People With Newly Diagnosed Richter Transformation, The PIRAMID Trial (clinicaltrials.gov)
    P3, N=102, Not yet recruiting, SWOG Cancer Research Network | Initiation date: May 2026 --> Aug 2026
    Trial initiation date
    |
    doxorubicin hydrochloride • cyclophosphamide • vincristine • Jaypirca (pirtobrutinib) • Truxima (rituximab-abbs) • Rituxan Hycela (rituximab/hyaluronidase) • Mabtas (rituximab biosimilar)
    1m
    BRUIN-CLL-314: A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (clinicaltrials.gov)
    P3, N=737, Recruiting, Loxo Oncology, Inc. | Trial primary completion date: Jun 2025 --> Oct 2027
    Trial primary completion date
    |
    Imbruvica (ibrutinib) • Jaypirca (pirtobrutinib)
    1m
    Pirtobrutinib Maintenance After CAR-T Therapy in Relapsed or Refractory B-Cell Lymphoma (clinicaltrials.gov)
    P2, N=20, Not yet recruiting, Sun Yat-sen University
    New P2 trial
    |
    Jaypirca (pirtobrutinib)
    2ms
    PRIME-PCNSL: A Multicenter, Prospective Clinical Trial With a Concurrent Control Evaluating Methotrexate Combined With Rituximab,Sintilimab and Pirtobrutinib vs. Investigator-Selected Standard of Care in Treatment-Naive PCNSL (clinicaltrials.gov)
    P2, N=77, Recruiting, Tongji Hospital | N=110 --> 77
    Enrollment change
    |
    Rituxan (rituximab) • Tyvyt (sintilimab) • temozolomide • cytarabine • Jaypirca (pirtobrutinib)
    2ms
    Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia (clinicaltrials.gov)
    P2, N=46, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting
    Enrollment closed • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
    |
    Venclexta (venetoclax) • Jaypirca (pirtobrutinib)
    2ms
    Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations. (PubMed, Blood Cancer J)
    Covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib are effective but alterations in the kinase domain at C481 or BTK gatekeeper residue T474 mutations result in development of resistance...We evaluated the efficacy of a new ncBTKi, docirbrutinib (AS-1763), against 14 BTK mutants, including C481S, T474x, and L528x, as well as gatekeeper and kinase domain double mutants, using biochemical assays, cell-line models, and primary CLL lymphocytes. Docirbrutinib potently inhibited BTK autophosphorylation and mutant BTK-driven cell proliferation, with greater effects than ibrutinib and pirtobrutinib against certain mutants. In treatment-naïve and relapsed/refractory CLL samples, docirbrutinib disrupted B-cell receptor signaling and sensitized cells to apoptosis induced by venetoclax and AZD5991. In a dose-escalation trial (NCT05602363), docirbrutinib decreased CCL3/CCL4 biomarkers and inhibited the B-cell receptor pathway signaling in longitudinal samples from patients with relapsed/refractory CLL. These findings establish docirbrutinib as a pan-mutant ncBTKi with potential to improve outcomes for CLL patients, including those with disease resistant to cBTKi and other ncBTKi.
    Preclinical • Journal
    |
    CCL3 (C-C Motif Chemokine Ligand 3)
    |
    BTK C481S
    |
    Venclexta (venetoclax) • Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib) • AZD5991 • docirbrutinib (AS-1763)
    3ms
    ROCKET-CLL Global Phase 3 Study: Rocbrutinib vs Pirtobrutinib in cBTKi-Pretreated R/R CLL/SLL (clinicaltrials.gov)
    P3, N=306, Recruiting, Newave Pharmaceutical Inc | Not yet recruiting --> Recruiting
    Enrollment open
    |
    TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2)
    |
    TP53 mutation
    |
    Jaypirca (pirtobrutinib) • rocbrutinib (LP-168)
    3ms
    Mosunetuzumab in Combination With Pirtobrutinib in Patients With Relapsed or Refractory Waldenstrom Macroglobulinemia (MPOWER) (clinicaltrials.gov)
    P2, N=25, Not yet recruiting, University of Utah
    New P2 trial
    |
    Jaypirca (pirtobrutinib) • Lunsumio (mosunetuzumab-axgb)
    3ms
    Dissecting Pirtobrutinib Resistance in Mantle Cell Lymphoma Through Single-Cell Multi-Omics. (PubMed, Am J Hematol)
    A stem-like malignant B cell population enriched in resistant samples exhibited features of metabolic reprogramming and epithelial-mesenchymal transition. Together, our findings highlight heterogeneous, multi-layered mechanisms of PBN resistance and suggest chromatin regulators as potential therapeutic targets to overcome PBN resistance in MCL.
    Journal
    |
    RAD21 (RAD21 Cohesin Complex Component)
    |
    Jaypirca (pirtobrutinib)
    3ms
    A Study of Pirtobrutinib (LY3527727) in Participants With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (clinicaltrials.gov)
    P4, N=150, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting
    Enrollment open
    |
    Zydelig (idelalisib) • Jaypirca (pirtobrutinib)