Zydelig (idelalisib) / Gilead - LARVOL DELTA

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

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

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

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

Evaluation of the Role of AID-Induced Mutagenesis in Resistance to B-Cell Receptor Pathway Inhibitors in Chronic Lymphocytic Leukemia. (PubMed, Curr Issues Mol Biol) - "Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. We conclude that BCR pathway inhibitors enhance AID mutational activity in CLL, but this does not appear to be directly involved in driving drug resistance. AID-targeted loci may nonetheless serve as biomarkers for monitoring genomic instability during treatment and inform further study."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • IRF8

Integrated Transcriptomic and Secretome Proteomic Analysis of Hyperglycemia-Stimulated Endothelial Cells and Screening of Target Compounds. (PubMed, J Vis Exp) - "Furthermore, transcription factor regulation and exemplary molecular docking simulations (e.g., idelalisib with CTCF/BRD4) provided mechanistic hypotheses for experimental validation. In conclusion, this study establishes a reusable multi-omics framework that delineates endothelial pathogenic mechanisms in DKD and nominates repurposable drug candidates, offering a strategic approach for mechanistic and therapeutic discovery."

Journal • Diabetes • Diabetic Nephropathy • Inflammation • Nephrology • Renal Disease • BRD4

The PI3Kδ inhibitor roginolisib (IOA-244) preserves T-cell function and activity. (PubMed, Mol Oncol) - "Furthermore, idelalisib treatment promoted differentiation of conventional CD4+ T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors."

Journal • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD4 • CD8 • PIK3CD

Neurodevelopment in children born to women exposed to pesticides during pregnancy. (PubMed, PLoS One) - "Children's neurodevelopment was evaluated using the International Development and Early Learning Assessment (IDELA), which measures motor skills, literacy, numeracy, social-emotional development, and executive function...Given that exposure data were self-reported, results should be interpreted cautiously. Nevertheless, the study underscores the urgent need for comprehensive risk assessments incorporating objective exposure measurements, particularly in horticultural settings where women of reproductive age represent a substantial proportion of the workforce."

Journal

Financial Toxicity and Quality of Life in Patients Taking Oral Therapy for Hematologic Malignancies (ASH 2023) - "MethodsWe used database query to identify patients at a midwestern, tertiary care, academic medical center who were 18 years or older and were prescribed Enasidenib, Ivosidenib, Venetoclax, Gilteritinib, Midostaurin, Ibrutinib, Acalabrutinib, Imatinib, Nilotinib, Ponatinib, Bosutinib, Duvelisib, or Idelalisib within the past 3 months. Financial stress and hardship were associated with worse satisfaction with QoL and worse experience of SE. Further study should define change in these features over time and interventions to mitigate distress."

Clinical • HEOR • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • CNS Disorders • Depression • Hematological Malignancies • Mood Disorders • Oncology • Oral Cancer • Psychiatry

CaDAnCe-302, a phase 3, open-label, randomized study of BGB-16673 compared with idelalisib + rituximab (R), bendamustine + R, or venetoclax + R re-treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma previously exposed to both a BTK and BCL2 inhibitor (ASH 2025) - P1/2, P3 | "Secondary endpoints include overall survival, PFS in patients with prior exposure to noncovalent BTK inhibitors by IRC, PFS by INV, overall response rate by IRC and INV, rate of partial response with lymphocytosis or higher by IRC and INV, duration of response by IRC and INV, time to next treatment, and safety/tolerability per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Recruitment is ongoing."

Clinical • IO biomarker • P3 data • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Prolymphocytic Leukemia • Richter's Syndrome • Small Lymphocytic Lymphoma

Patient assistance for drug cost sharing: Highlighting the variability across pharmaceutical manufacturers of specialty oral anticancer medications for blood cancers (ASH 2025) - "Two of the three manufacturers that did not offer a PAP had discontinued their free-drug program (idelalisib and duvelisib) whereas one never had a free drug program (revumenib). All SOAMs for blood cancer have copay assistance programs for commercially insured and nearly all directly provide free-drugs for select individuals. However, eligibility by insurance type, income level, and associated documentation requirements vary considerably across manufacturers. Future work needs to evaluate whether this variability results in inequitable access across SOAM agents within same indication."

Clinical • Drug cost • HEOR • Hematological Malignancies • Oncology • Oral Cancer

Integrating oncofertility: Contraceptive guidance in chronic lymphocytic leukemia (ASH 2025) - "BTK inhibitors (e.g ibrutinib) increase thrombotic risk through platelet dysfunction and coagulopathy and may reduce the efficacy of estrogen-containing contraceptives through CYP3A4 induction. Similarly, BCL-2 inhibitors (e.g venetoclax) increase thrombotic risk, particularly when combined with other platelet-function impairing agents, warranting cautious use of estrogen-based contraceptives...Furthermore, conventional chemotherapy (e.g fludarabine, cyclophosphamide) and some target therapies (e.g idelalisib) also present high thrombosis risk and hepatotoxicity, potentially impairing hormonal contraceptive metabolism...On the other hand, immunotherapy agents (e.g rituximab) demonstrate variable thrombosis risks, especially when used in combination therapies... Contraception in women with chronic lymphocytic leukemia (CLL) presents complex challenges requiring individualized care. As many CLL treatments have gonadotoxic and teratogenic properties, it is imperative to..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Long-acting Reversible Contraceptives • Thrombosis • CYP3A4

PI3Kδ inhibition enhances trametinib efficacy by suppressing feedback-activated PI3K/AKT signaling in PTPN11-mutant JMML (ASH 2025) - "These data collectively support thenotion that MEK inhibition relieves feedback inhibition on RAS, resulting in its hyperactivation anddiversion of signaling through bypass pathways such as PI3K/AKT.To counteract compensatory PI3K/AKT activation under MEK inhibition, we tested Trametinib combinedwith Idelalisib, a selective PI3Kδ inhibitor. This dual blockade strategy provides a mechanistic rationale andpreclinical proof-of-concept for combination therapy in PTPN11-mutant JMML, which is historicallyresistant to single-agent MEK inhibitors. These results support future clinical investigation of MEK andPI3Kδ co-inhibition to improve treatment outcomes in this high-risk JMML subgroup."

Clinical • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Juvenile Myelomonocytic Leukemia • Leukemia • Thrombocytopenia • PIK3CD • PTPN11

A decade of progress: A comparative analysis of real-world survival in chronic lymphocytic leukemia across therapeutic eras (ASH 2025) - "The ECOG E1912 randomized study demonstratedsuperior overall survival of ibrutinib-based therapy compared to chemoimmunotherapy with fludarabine,cyclophosphamide, and rituximab (FCR)...For these cohorts, 5-year all-cause mortality was comparedbetween the pre-2015 and 2015-2020 groups, and 2-year all-cause mortality was compared between thepre-2015 and post-2020 groups.Second, to directly compare treatment effectiveness, patients who received systemic therapy werestratified into two cohorts based on the class of agent received, irrespective of the treatment date:Chemoimmunotherapy (CIT): Regimens including FCR, BR, Fludarabine with Rituximab,Chlorambucil ± Obinutuzumab, and Alemtuzumab-based treatments.Novel Targeted Therapy: Regimens including covalent BTK inhibitors (Ibrutinib, Acalabrutinib,Zanubrutinib), BCL-2 inhibitor Venetoclax (± Rituximab or Obinutuzumab), and PI3K inhibitors(Idelalisib, Duvelisib).For these treatment-regimen cohorts, 10-year outcomes..."

Clinical • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia

Inhibition of lysine acetyltransferases p300/CBP overcomes BTK inhibitor resistance in a xenograft model of Mantle Cell Lymphoma by suppressing MYC signaling (ASH 2025) - P1/2 | "Thesynergistic effect of p300/CBPi was greater than when combined with PI3K inhibitor (idelalisib) or BCL2inhibitor (venetoclax)...Mean tumor volumes (mm³) at the endpoint were: DMSO, 1314.7; ibrutinib, 949.0; A-485, 1022.8; and combination, 397.2 (all p < 0.001 vs. combination)...No significant weight loss ortoxicity was observed in any treatment group. Western blot analysis of harvested xenograft tumorsshowed that the combination reduced phosphorylation of BTK, AKT, and STAT3, and decreaseddownstream MYC protein expression.Conclusionp300/CBP inhibition overcomes BTKi resistance in MCL primarily by suppressing MYC-driven signaling.These findings provide strong preclinical support for clinical evaluation of BTKi and p300/CBPicombination therapy in patients with BTKi-resistant MCL."

IO biomarker • Preclinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • ANXA5 • CCND1 • IL6 • MYC • PLCG2

Integrated single-cell RNA sequencing and TCR profiling identifies immune drivers of severe early toxicity in CLL patients treated with idelalisib (ASH 2025) - "PI3K inhibitors, such as idelalisib and duvelisib, have demonstrated efficacy in relapsed/refractory chroniclymphocytic leukemia (CLL) but severe autoimmune toxicities limit their clinical use. This aligns with prior findings that CD4+ Tcells reprogram metabolism and promote Th17 responses via HIF-1α and GLUT1 in rheumatoid arthritis,an autoimmune disease.Overall, our findings suggest idelalisib-induced toxicity develops in patients with a predisposed immunemicroenvironment with sustained higher clonal diversity and metabolic-immune dysregulation, leading tothe expansion of CD8+ and CD4+ T cell clones with TH17/TH1 polarization, cytotoxicity, and migratoryphenotypes. These insights into PI3Kδ inhibitor-induced toxicity may suggest potential targets to mitigateadverse effects."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immunology • Inflammatory Arthritis • Leukemia • Rheumatoid Arthritis • Rheumatology • Transplant Rejection • ACLY • BACH2 • CD4 • CD8 • CXCR3 • EGR1 • FOXP3 • GZMB • HIF1A • IFNG • IFNGR1 • IL7R • IRF1 • JAK2 • LDHA • MTHFD2 • PIK3CD • PRF1 • RAC2 • SLC2A1 • STAT1 • TBX21 • TMSB4X • ZEB1

Population-Based Registry Data over 15 Years Suggests Comparable Overall Survival for CLL Patients Treated with Chemoimmunotherapy and Targeted Therapies As First-Line Treatments (ASH 2024) - "The first-line treatments with CT included chlorambucil (Chl) 60.8%, fludarabine ± cyclophosphamide (FC) 32.6%, and bendamustine (Ben) 6.6%. CIT included FC/FCM (mitoxantrone) with a CD20 antibody (ab) 52.1%, Ben with a CD20 ab 16.6%, Chl with a CD20 ab 27.2%, alemtuzumab ± CT 2.0%, and other regimens 4.0%. TT included acalabrutinib ± Obinutuzumab (O) 29.7%, ibrutinib ± rituximab (R) 36.4%, venetoclax ± O or ibrutinib 26.1%, idelalisib ± R 3.6%, and zanubrutinib 3.6%...In this population-based registry study, it was shown that only around a third of patients with CLL required treatment, and there was no OS advantage from initiating patients on targeted therapy as a first line compared to chemoimmunotherapy followed by targeted therapy upon relapse. This concept should be validated in prospective trials."

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