Zydelig (idelalisib) / Gilead - LARVOL DELTA

Large-scale drug screening identifies clinically actionable combinations to overcome BTK/PI3K inhibitor resistance in marginal zone lymphoma (AACR 2026) - "Here, we present data from a large pharmacological screen involving over 3,500 compounds in 2 MZL models with secondary resistance to BTK/PI3Ki, developed through prolonged exposure to idelalisib (Arribas 2022) or ibrutinib (Arribas 2025).Methods...Adding the alisertib (AURKAi), rigosertib (PLKi), fimepinostat (PI3K/HDACi), lanatoside-C (Na+K+ATPase), astragalin (apoptosis), astragaloside-I (WNT) and oridonin (AKT) was of benefit (additivity or synergism) in both parental and resistant cells.Conclusions...Several clinically advanced agents—particularly PAK4/NAMPT, AURKA, WNT, and Na⁺/K⁺-ATPase inhibitors—enhanced or restored the activity of BTKi/PI3Ki. These findings highlight new therapeutic strategies for relapsed/refractory MZL and support clinical evaluation of targeted combinations to overcome acquired resistance."

Clinical • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • AURKA • NAMPT

A comprehensive analysis of pirtobrutinib in Chinese patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL): Results from the phase 3 study BRUIN CLL-321. (PubMed, Br J Haematol) - "In this heavily pretreated population, pirtobrutinib significantly improved progression-free survival (PFS) compared to investigator's choice (IC) of idelalisib/rituximab (IdelaR) or bendamustine/rituximab (BendaR). Pirtobrutinib showed a favourable safety profile, with fewer grade ≥3 treatment-emergent adverse events (36.8% vs. 93.3%) and serious adverse events (15.8% vs. 46.7%). These findings support pirtobrutinib as a clinically active and tolerable option for cBTKi-pretreated Chinese CLL/SLL population."

Journal • P3 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

AURORA: A Phase 2 Study of CAL101 in Patients With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: Calluna Pharma AS | Recruiting ➔ Active, not recruiting

Enrollment closed • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Roginolisib stabilizes inactive PI3Kdelta to deliver specific target blockade with reduced immune toxicity (AACR 2026) - "Structural and biophysical analyses—including X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry—demonstrate that roginolisib, unlike the first-generation inhibitor idelalisib, stabilizes the catalytic C-terminal helix (k-alpha12) of PI3Kdelta. This mechanism of inhibition, likely based on conformational stabilization of the inactive kinase, is novel for PI3K small-molecule inhibitors. Hence, our findings may enable the development of more effective and better-tolerated PI3K inhibitors."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD4 • CD8 • PIK3CD

Antiproliferative screening in B cell lymphoma: Ghanaian medicinal plants and their phytochemical correlates (AACR 2026) - "We screened 48 samples (single species, mixtures, purified compounds, fractions, extracts) in VL51, SSK41, Karpas1718parental and their resistant derivatives (VL51 ibrutinib resistant, SSK41 venetoclax resistant, and Karpas1718 idelalisib resistant) at 10 and 1 µg/mL for 72 h (MTT). We observed a strong chemotype-activity pattern: stilbenoids and ent-kaurane diterpenoids were the most potent profiles, while alkaloids exhibited narrower, context-specific effects; fatty ester-rich samples were mostly inactive. The sharp dose dependence of Dichapetalum and Xylopia fractions with activity in resistant and TP53-defective models suggests that they are priority leads for mechanism-of-action studies and optimization against drug-resistant B-cell lymphomas."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • TP53

BUDGET IMPACT OF INTRODUCING PIRTOBRUTINIB AFTER COVALENT BRUTON TYROSINE KINASE INHIBITOR THERAPY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA IN THE US (ISPOR 2026) - P3 | "OBJECTIVES: Pirtobrutinib improved progression-free survival and demonstrated favorable tolerability versus investigator's choice of idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; BRUIN-CLL-321, NCT04666038). The introduction of pirtobrutinib as post-cBTKi therapy for patients with CLL/SLL resulted in minimal annual PMPM costs for both Medicare and commercial payers. This finding reflects the low number of eligible patients and is highly influenced by monthly acquisition costs and duration of pirtobrutinib therapy."

Clinical • HEOR • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Small Lymphocytic Lymphoma

PHARMACOLOGICAL MODULATION OF CAR30 AND CAR19 T CELL STEMNESS AND EX VIVO EXPANSION WITH PI3K AND CBP/P300 INHIBITION (EBMT 2026) - "The goal is to analyze the impact of Idelalisib [PI3K inhibitor (PI3Ki), that blocks differentiation] and SGC-CBP30 [inhibitor of CBP/p300 (CBP/p300i), epigenetic expansion promotor] in ex vivo CART anti-CD30 (CAR30T) and CART anti-CD19 (CAR19T) cultures... Combination of CBP/p300i and PI3Ki resulted in a CAR30T-IP with increased expansion, TSCM and in vitro antitumor effect over single agent use. CBP/p300i resulted in a CAR19T-IP with enhanced expansion without T-cell differentiation maintaining antitumor effect. Targeted pharmacological inhibition may contribute to generate enhanced antitumor efficacy CART products."

Preclinical • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • CD4 • CD8

Pirtobrutinib at the Crossroads: Shaping Its Future Role in Chronic Lymphocytic Leukemia (CLL) Care. (PubMed, Eur J Haematol) - "In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for..."

IO biomarker • Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • PLCG2

Clinical Outcomes in Double-Exposed Chronic Lymphocytic Leukemia Patients in Italy. (PubMed, Hematol Oncol) - "Fifty-three patients received treatment after venetoclax: 29/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non-covalent BTKi), 19/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Despite its limitations, this real-world study provides additional insights into double-exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need."

Clinical data • IO biomarker • Journal • B Cell Lymphoma • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Transplantation • BCL2 • TP53

Study on the Mechanism of Post-Chemotherapy Metastasis in Breast Cancer Based on Metabolomics and Development of TCM Metabolic Regulators. (PubMed, Anticancer Agents Med Chem) - "Upregulated phospholipid metabolism is a critical mechanism behind chemotherapy-induced BC metastasis. Combining CMF with phospholipid-targeting agents (idelalisib or EC) offers a promising therapeutic approach to optimize chemotherapy outcomes. These results provide a theoretical foundation for developing novel combination therapies in BC treatment."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor

Systematic Review of Real-World Data on the Effectiveness and Safety Profiles of First-Line Therapies in Chronic Lymphocytic Leukemia. (PubMed, Crit Rev Oncol Hematol) - "Among 1LTT for CLL, IBR has the most extensive and consistent RWD, with results mirroring RCT outcomes. ZAN, ACA and VEN+OBI show promising results based on RWD, however, these data are less extensive but consistent with RCT outcomes. Findings highlight the value of RWD and the need for more robust data on newer agents."

Journal • Real-world evidence • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

PHARMACOLOGICAL MODULATION OF CAR30 AND CAR19 T CELL STEMNESS AND EX VIVO EXPANSION WITH PI3K AND CBP/P300 INHIBITION (EBMT 2026) - "The goal is to analyze the impact of Idelalisib [PI3K inhibitor (PI3Ki), that blocks differentiation] and SGC-CBP30 [inhibitor of CBP/p300 (CBP/p300i), epigenetic expansion promotor] in ex vivo CART anti-CD30 (CAR30T) and CART anti-CD19 (CAR19T) cultures... Combination of CBP/p300i and PI3Ki resulted in a CAR30T-IP with increased expansion, TSCM and in vitro antitumor effect over single agent use. CBP/p300i resulted in a CAR19T-IP with enhanced expansion without T-cell differentiation maintaining antitumor effect. Targeted pharmacological inhibition may contribute to generate enhanced antitumor efficacy CART products."

Preclinical • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • CD4 • CD8

Decoding tamoxifen on idiopathic pulmonary fibrosis: integrating network toxicology and multi-omics. (PubMed, Int J Surg) - "Tamoxifen promotes IPF via miR-432-3p-mediated EGFR suppression, establishing it as a pulmonary toxicant. Integrated network toxicology identifies EGFR as a diagnostic biomarker, highlighting environmental and clinical risks of tamoxifen exposure."

Journal • Breast Cancer • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • MIR432

DZ2024B0002: A Phase 3 Study of DZD8586 versus Investigators Choice in r/r CLL/SLL (clinicaltrialsregister.eu) - P2/3 | N=55 | Recruiting | Sponsor: Dizal (Jiangsu) Pharmaceutical Co. Ltd.

New P2/3 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • BCL2

Pharmacological Modulation with PI3K and CBP/P300 Inhibition Enhances ex vivo Expansion and Enrichment of CAR30 Memory Stem T Cells (EHA-EBMT-CART 2026) - "Idelalisib [PI3K inhibitor (PI3Ki)] blocks T-cell differentiation (Lampson, B.L. et al ., 2016)...CBP/p300i enhanced expansion without further T-cell differentiation maintaining antitumor cytotoxicity. CBP/p300i and PI3Ki combination resulted in an IP with increased CAR30-T SCM and in vitro antitumor effect."

Preclinical • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • CD4 • CD8

EFFICACY OF PEMBROLIZUMAB MONOTHERAPY AND IN COMBINATION WITH BCR INHIBITORS FOR RICHTER TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (EHA 2024) - "Sixteen patients went on to receive a BCR kinase inhibitor (ibrutinib [n=15], idelalisib [n=1]) in combinationwith pembrolizumab, after SD or PD on pembrolizumab monotherapy. This expanded analysis confirmed that pembrolizumab has modest single agent activity in RT. Combinationtherapy with pembrolizumab and a BCR kinase inhibitor is associated with increased efficacy (ORR >60%),similar to other reports. These results support further investigation of immune checkpoint inhibitor-basedcombination therapy in RT."

Clinical • Combination therapy • IO biomarker • Monotherapy • Anemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Pulmonary Disease • Richter's Syndrome • Thrombocytopenia • TP53

BRUIN CLL-321: Randomized Phase III Trial of Pirtobrutinib Versus Idelalisib Plus Rituximab (IdelaR) or Bendamustine Plus Rituximab (BR) in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (ASH 2024) - P3 | "Methods : Eligible CLL/SLL pts previously treated with cBTKi were randomized 1 : 1 to receive pirtobrutinib monotherapy (200mg QD) or IC of IdelaR or BR and stratified by prior use of venetoclax and del(17p) status. Summary/Conclusion : BRUIN CLL-321 is the first randomized study conducted exclusively in cBTKi pretreated CLL/SLL pts. In this heavily pretreated patient population with poor prognosis, pirtobrutinib treatment led to a significant improvement in PFS compared to IC, along with a more favorable safety profile."

Clinical • P3 data • Anemia • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases • Small Lymphocytic Lymphoma • IGH • TP53

High Karyotypic Complexity and Translocations Are Adverse Prognostic Features in Patients with Chronic Lymphocytic Leukemia without TP53 Aberrations Treated with Venetoclax-Based Time-Limited Combinations (ASH 2022) - "Studies on the prognostic impact of CKT with targeted agents are not only heterogeneous in size and methodologies but also conflicting, with reports on both negative impact (venetoclax [ven] + rituximab [RVe] and ibrutinib monotherapy) and no impact (ven + obinutuzumab [GVe], ven + ibrutinib, idelalisib + rituximab) on progression-free (PFS) and overall survival (OS). In pts lacking TP53 aberrations, hCKT (≥5 CA) but not iCKT (3-4 CA) was associated with shorter PFS following treatment with time-limited ven combinations. While this study confirms the adverse impact of CKT with CIT, it identifies hCKT as an adverse prognostic factor in the context of ven-based combination treatment in CLL. Presence of translocations was associated with inferior PFS in all treatment arms."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • IL2 • TP53

PATIENT REPORTED OUTCOMES FROM BRUIN CLL-321: PHASE 3 TRIAL COMPARING PIRTOBRUTINIB TO IDELALISIB/RITUXIMAB OR BENDAMUSTINE/RITUXIMAB IN COVALENT BTKi PRETREATED CLL/SLL (ICML 2025) - "These analyses suggest a meaningful and clinically relevant improvement in CLL/SLL-related symptoms, physical functioning, and fatigue at most assessments between baseline and Week 25 in the pirtobrutinib group compared to IdelaR/BR. Most PRO assessments met clinically meaningful thresholds, and for those that did not there remained a consistent directional difference in favor of pirtobrutinib, suggesting a consistent benefit in terms of PF, CLL/SLL-related symptoms, and fatigue versus IdealR/BR. Keyword: chronic lymphocytic leukemia (CLL)"

Clinical • P3 data • Patient reported outcomes • Chronic Lymphocytic Leukemia • Lymphoma • Small Lymphocytic Lymphoma

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor-Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). (PubMed, J Clin Oncol) - "Pirtobrutinib improved PFS and TTNT, and demonstrated favorable tolerability, versus IdelaR/BR in exclusively cBTKi pretreated patients with CLL/SLL."

Journal • P3 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Final Analysis of the Prospective Multicenter CLL2-Give Trial of Obinutuzumab (GA101, G), Ibrutinib (I), and Venetoclax (Ve) in Untreated Patients with CLL with 17p Deletion/TP53 Mutation (ASH 2022) - "Subsequent treatments were administered in 4 pts (1 pt with 3 therapies: venetoclax, idelalisib/rituximab, ibrutinib; obinutuzumab (n=1); acalabrutinib/venetoclax/obinutuzumab (n=2)). Most common cardiac disorder of any grade was atrial fibrillation in 14.6% of pts. Conclusion The CLL2-GIVe regimen is a potent and promising fixed-duration, first-line treatment for pts with high-risk CLL with a manageable safety profile worthy of further exploration in phase 3 studies."

Clinical • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Congestive Heart Failure • Gastroenterology • Gastrointestinal Disorder • Heart Failure • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Novel Coronavirus Disease • Oncology • Ovarian Cancer • Respiratory Diseases • Richter's Syndrome • Solid Tumor • Thrombocytopenia • IGH • TP53

Acalabrutinib versus rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia: ASCEND results at 4 years of follow-up. (ASCO 2022) - P3 | "At ~4 years of follow-up, acala maintained efficacy compared with standard-of-care regimens and a consistent tolerability profile in R/R CLL."

Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Oncology • IGH

REAL-WORLD OUTCOME OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED WITH BTK INHIBITORS (BTKI): A SUBGROUP ANALYSIS OF OVER 1100 PATIENTS ENROLLED INTO THE GIMEMA CLL2121 STUDY (EHA 2024) - P=N/A | "852 pts were treated with ibrutinib-based therapies (534 1L, 318 2+L), 278 with acalabrutinib (2111L, 67 2+L), 23 with zanubrutinib (14 1L, 9 2+L), and 6 with pirtobrutinib (1 1L, 5 2+L)...Next line treatment afterthe BTKi was venetoclax-based combinations (62%), covalent BTKi (11%), idelalisib+/-rituximab (9%),chemoimmunotherapy (8%), anti-CD20 monoclonal antibodies (2%), pirtobrutinib (1%), and other (8%)... This real world study conducted on a large cohort of pts with CLL/SLL in Italy shows a high proportion of ptsdiscontinuing BTKi due to toxicity or progression, with a shorter TTNT in TN vs R/R pts, suggesting a lowerthreshold to switch treatment in clinical practice. BTKi discontinuation is a turning point in the disease history,that portends a short overall survival, with limited salvage options, being mainly venetoclax as also in ourseries. Additional analysis on an extended cohort will be presented at the meeting."

Clinical • IO biomarker • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • IGH

A Phase 2 Study of Zanubrutinib and Venetoclax (ZV) in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) (ASH 2024) - P2 | "One pt had prior therapy with ibrutinib and venetoclax (double-exposed), another pt had prior ibrutinib and acalabrutinib which were stopped due to intolerance, and two had prior idelalisib. Conclusions Fixed-duration combination therapy with ZV is active and well-tolerated in R/R CLL, including in pts with previous exposure to targeted agents. This study is actively accruing, and larger numbers of pts with longer follow-up will help further improve our understanding of the potential benefits of this regimen in R/R CLL."

P2 data • Atrial Fibrillation • B Cell Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • Febrile Neutropenia • Hematological Disorders • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Oncology • Septic Shock • Thrombocytopenia • BCL2 • IGH • NOTCH1 • SF3B1 • TP53

Poriferast-5-en-3β-ol improves pelvic inflammatory disease via reducing GADD45A-induced inflammation. (PubMed, J Reprod Immunol) - "GADD45A is a central inflammatory regulator in PID. DZY and Poriferast-5-en-3β-ol attenuate inflammation by targeting GADD45A, providing new mechanistic and therapeutic insights for PID."

Journal • Gynecology • Infectious Disease • Infertility • Inflammation • Sexual Disorders • GADD45A • IL1B