Calquence (acalabrutinib) / AstraZeneca - LARVOL DELTA

Cases and Conversations: Sequencing Strategies in Relapsed and Refractory CLL (ASH 2026) - "Pivotal phase 3 readouts — AMPLIFY (acalabrutinib + venetoclax ± obinutuzumab), CLL17, BRUIN CLL-313/-314 (pirtobrutinib), CELESTIAL-TN (sonrotoclax + zanubrutinib), and MAJIC — have reshaped both the treatment armamentarium and the decision framework around fixed-duration vs continuous therapy. Real-world data show persistent gaps in molecular testing, treatment selection, and toxicity management. This Medical Crossfire® session uses focused didactic primers paired with moderated expert debate to examine the frontline decision points clinicians face every day, with attention to molecular testing, fixed-duration vs continuous therapy, MRD-guided approaches, and proactive AE management."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia

Accelerated Chronic Lymphocytic Leukemia Mimicking Richter Transformation: Diagnostic Pitfall and Response to Acalabrutinib-Based Therapy (SOHO 2026) - "Given the unmutated IGHV status, a Bruton tyrosine kinase inhibitor (BTKi)-based regimen was chosen and obinutuzumab was added for rapid response. This case highlights a clinically significant diagnostic pitfall in which A-CLL closely mimics RT despite high-risk clinical and metabolic features. It underscores that excisional biopsy is essential prior to therapeutic escalation in suspected transformation. Additionally, it demonstrates that FDG PET/CT findings, particularly elevated SUVmax, must be interpreted with caution, as they may be confounded by synchronous malignancies."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Richter's Syndrome • Small Lymphocytic Lymphoma • B2M • IGH • TP53

COMBINED PIRTOBRUTINIB, VENETOCLAX, AND OBINUTUZUMAB IN FIRST-LINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A PHASE 2 TRIAL (EHA 2024) - P2 | "Background: Treatment with combined covalent BTK-inhibitor (cBTKi such as ibrutinib, acalabrutinib, zanubrutinib) withBCL2-inhibitor, venetoclax +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectableMRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report the first results for first-line combined pirtobrutinib, venetoclax, and obinutuzumab in pts with CLL. Avery high rate of bone marrow U-MRD at 10-6 sensitivity was noted at 6-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents."

Clinical • P2 data • Chronic Lymphocytic Leukemia • Febrile Neutropenia • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • TP53

Acalabrutinib, venetoclax and obinutuzumab in relapsed CLL: Final efficacy and ctDNA analysis of the CLL2-BAAG trial. (PubMed, Blood) - P2 | "The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax and obinutuzumab after an optional bendamustine debulking in 45 patients with relapsed/refractory CLL (one patient was excluded from the analysis due to a violation of exclusion criteria). The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. ClinicalTrials.gov Identifier: NCT03787264."

Circulating tumor DNA • Journal • Oncology • IGH • TP53

An international view on the current approaches to frontline chronic lymphocytic leukemia therapy (ASH 2025) - "First-Line Therapy Recommendations: CLL patients with del(17p)/TP53 mutations: For these high-risk patients, the panel strongly favoredcontinuous BTKi therapy, with second-generation BTKis (acalabrutinib, zanubrutinib) preferred due to their more favorable safety profiles...IGHV-unmutated CLL patients without del(17p)/TP53 mutations: While the majority of experts considered patient fitness for this group, recommending continuous BTKi monotherapy for frail patients and venetoclax-based combinations with either a BTKi (acalabrutinib, ibrutinib) or obinutuzumab for fit patients, some emphasized the overall suitability for targeted agents regardless of a traditional fitness assessment, focusing instead on specific comorbidities that might impact tolerability (e.g., cardiac or renal conditions)... This expert panel's insights address the evolving CLL treatment landscape and variable access to novel targeted therapies across LATAM, MEA, APAC, and Russia. It emphasizes that..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Nephrology • IGH • TP53

Combined Pirtobrutinib, Venetoclax, and Obinutuzumab As First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) (ASH 2024) - P2 | "Introduction : Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). Adverse event profile was similar to what was noted in previous studies with these agents. Updated data will be presented."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • TP53

Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Five-year follow-up of ELEVATE-TN. (ASCO 2022) - P3 | "After a 5-y follow-up, efficacy and safety of A+O and A monotherapy were maintained, with significantly longer OS in the A+O arm compared with O+Clb."

Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. (PubMed, N Engl J Med) - P3 | "Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.)."

Clinical • IO biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Novel Coronavirus Disease • Oncology • Respiratory Diseases • IGH • TP53

Rare Intersections: Two Cases Illustrating the Immune Complexity of Chronic Lymphocytic Leukemia Associated With Paraneoplastic Pemphigus With Ocular Involvement and Temozolomide-Induced Autoimmune Cytopenias in Concurrent Lymphoproliferative Disease (SOHO 2026) - "Despite aggressive multimodal immunosuppression (prednisone, cyclosporine, upadacitinib, intravenous methylprednisolone, IVIG, and cyclophosphamide) alongside venetoclax-obinutuzumab, he achieved near-complete MRD-negative remission but developed fulminant corneal melt with uveal prolapse requiring left eye evisceration. Venetoclax was subsequently discontinued due to severe cytopenias, and therapy was transitioned to acalabrutinib to leverage BTK inhibition for both sustained CLL control and its favorable T-cell immunomodulatory properties relevant to PNP pathogenesis. Escalation with a higher dose of upadacitinib and ruxolitinib is under consideration for refractory mucosal disease...Romiplostim was initiated, with rituximab under consideration for refractory thrombocytopenia... Together, these cases demonstrate that CLL is not a passive bystander but an active immunologic substrate that amplifies the risk of severe paraneoplastic syndromes and unmasks autoimmune..."

Clinical • Brain Cancer • Chronic Lymphocytic Leukemia • Glioblastoma • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • IGH • MGMT • RUNX1

Concurrent Hemophagocytosis and Hodgkin Lymphoma–Type Richter Transformation in CLL/SLL: An Incidental Finding With Therapeutic Implications (SOHO 2026) - "Case Presentation: An 85-year-old woman with CLL/SLL with progression on acalabrutinib and currently on venetoclax plus obinutuzumab presented with B symptoms and pancytopenia...HLH-94 protocol was initiated with dexamethasone 10 mg/m2; rising inflammatory markers necessitated age-adjusted etoposide (50 mg/m2)... This case highlights three key points: (1) the importance of pursuing tissue diagnosis despite improving imaging when clinical suspicion for RT is high, (2) the diagnostic value of bone marrow biopsy when lymph node sampling is nondiagnostic, and (3) the role of specialized biomarkers in confirming HLH. CD: cluster of differentiation, CHL: classic Hodgkin lymphoma, CXCL9: C-X-C motif chemokine 9, EBER-ISH: Epstein-Barr virus–encoded RNA in situ hybridization, IL: interleukin, OS: overall survival, PAX5: paired box protein Pax-5, RT: Richter transformation."

Chronic Lymphocytic Leukemia • Classical Hodgkin Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • CD20 • CXCL9 • IL18 • ISG20 • PAX5 • TNFRSF8

Paraneoplastic Pemphigus With Corneal Melt Leading to Evisceration in a Patient With Chronic Lymphocytic Leukemia: Navigating Immunosuppression and Disease Control (SOHO 2026) - "Case Report: A 60-year-old man was diagnosed with immunoglobulin heavy chain variable region (IGHV)-unmutated, TP53 wild-type CLL in 2020 and remained on active surveillance until 5 years later, when progressive PNP prompted initiation of venetoclax-obinutuzumab along with immunosuppression using prednisone, cyclosporine, and upadacitinib...Despite repeated corneal glue applications, methylprednisolone, intravenous immunoglobulins (IVIG), and cyclophosphamide, he developed complete corneal melt with active uveal prolapse and markedly elevated intraocular pressure...Therapy was transitioned to acalabrutinib to leverage Bruton tyrosine kinase (BTK) inhibition for sustained CLL control alongside favorable T-cell immunomodulatory effects relevant to PNP pathogenesis...Escalation to higher dose upadacitinib with the addition of ruxolitinib is under consideration given its broader JAK inhibition profile... This case highlights the catastrophic and underappreciated ocular..."

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

MRD-Driven Time-Limited Therapy of Acalabrutinib and Lenalidomide Plus Rituximab (ALR) or Obinutuzumab (ALO) in Patients with Treatment-Naïve Mantle Cell Lymphoma: Phase 2 Trial Outcomes with MRD and cfDNA Analyses (ASH 2024) - P2 | "The ALO regimen is feasible with encouraging initial safety and efficacy. MRD and cfDNA analyses provide real-time and non-invasive monitoring of molecular response and mutational evolution, which warrants further evaluation in response-adapted strategy (ClinicalTrials.gov - NCT03863184)."

cfDNA • Clinical • P2 data • Anemia • Fatigue • Infectious Disease • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Thrombocytopenia • TP53

The place of acalabrutinib-obinutuzumab combination in the first-line treatment of patients with chronic lymphocytic leukemia. (PubMed, Transl Cancer Res) - No abstract available

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Risk of Therapy-Related Myeloid Neoplasms in Patients With Chronic Lymphocytic Leukemia Treated With BTK Inhibitors: A Retrospective Multicenter Analysis Using the TriNetX Database (SOHO 2026) - "Adult patients with CLL treated with ibrutinib, acalabrutinib, or zanubrutinib were included. Patients with prior chemoimmunotherapy exposure, including fludarabine/cyclophosphamide, FCR, bendamustine/rituximab, and obinutuzumab/chlorambucil, were excluded to better isolate the long-term effects of BTKi therapy... In this large real-world TriNetX analysis of patients with CLL treated with BTK inhibitors and without prior chemoimmunotherapy exposure, therapy-related myeloid neoplasms were uncommon but increased over longer follow-up. MDS was the most frequent secondary myeloid neoplasm, followed by AML. The underlying immune dysregulation inherent to CLL, including impaired immune surveillance and defective T-cell function, may also contribute to the development of secondary malignancies in this population."

Retrospective data • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

Early Chemorefractory Progression in TP53-Deleted Chronic Lymphocytic Leukemia: A Case Highlighting the Need for Targeted Therapy (SOHO 2026) - "The patient initially received 2 cycles of rituximab-bendamustine, followed by 1 cycle of R-CHOP because of ongoing clinical concern for active disease...Based on the patient's molecular profile and resistance to conventional therapy, treatment with acalabrutinib plus obinutuzumab was planned... A 66-year-old man was diagnosed with CLL based on peripheral blood immunophenotyping showing a typical clonal B-cell population positive for CD19, CD5, and CD23, with weak CD20 expression and kappa light-chain restriction. Serum immunofixation also demonstrated a kappa monoclonal band. Cytogenetic evaluation with FISH revealed 17p13.1 (TP53) deletion in all analyzed cells, indicating a veryhigh-risk disease profile."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD20 • CD5 • FCER2 • TP53

CLL16: A Phase-3-trial of Acalabrutinib, Obinutuzumab & Venetoclax Compared to Obinutuzumab and Venetoclax in Previously Untreated Patients With High Risk CLL (clinicaltrials.gov) - P3 | N=202 | Recruiting | Sponsor: German CLL Study Group | N=650 ➔ 202

Enrollment change • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2 • IGH • TP53

Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for Treatment for Patients with Richter Transformation (ASH 2021) - P2 | "Previous therapy for CLL included ibrutinib, n=4; chlorambucil + OBIN and then acalabrutinib, n=1; BR, n=1; one pt had no prior therapy for CLL)...R/R RT (n=1) : One pt (58-year-old male) with previously untreated CLL (unmutated IGHV, del(17p), TP53 mutation, NOTCH1 mutation) developed RT and received R-CHOP for 3 cycles with no response... Treatment with combined VEN, OBIN and atezolizumab leads to high rates of remission in pts with previously untreated RT; all 7 pts achieved a remission and 3 pts proceeded to allo-SCT. With the limitation of small numbers, these results are encouraging in relation to combined ibrutinib plus nivolumab in previously untreated RT (7/14, 50% response rate; Jain, ASH 2018). Enrollment in the trial continues and updated data will be presented at the ASH meeting."

Checkpoint inhibition • Clinical • IO biomarker • Bone Marrow Transplantation • Diabetes • Diffuse Large B Cell Lymphoma • Lung Cancer • Melanoma • Metabolic Disorders • Oncology • Pancreatitis • Richter's Syndrome • Solid Tumor • Transplantation • IGH • NOTCH1 • TP53

Acalabrutinib Monotherapy vs Investigator's Choice of Treatment in Patients With CL Leukaemia and Heart Failure (clinicaltrials.gov) - P4 | N=60 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2030 ➔ Sep 2032 | Trial primary completion date: Aug 2030 ➔ Sep 2032

Monotherapy • Trial completion date • Trial primary completion date • Cardiovascular • Chronic Lymphocytic Leukemia • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Leukemia • Oncology

Consensus-Based Ranking of Determinants for Frontline Therapy Selection in Chronic Lymphocytic Leukemia: A Conjoint Analysis. (PubMed, Crit Rev Oncol Hematol) - "Furthermore, five commonly used regimens (ibrutinib, acalabrutinib, zanubrutinib, ibrutinib-venetoclax, venetoclax-obinutuzumab) were comparatively ranked according to their ability to accomplish each goal. Integrating conjoint analysis enables quantitative weighting of determinants and prioritization of treatment options beyond conventional categorical algorithms. The model supports evidence-based, individualized treatment strategies for CLL in clinical practice."

Journal • Review • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • TP53

Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease (ASH 2022) - P2 | "The efficacy of ibrutinib plus VO in such pts is encouraging, but cardiac and infectious toxicities (tox) are common. Low rates of cardiac and infectious tox were observed. Our data support continued investigation of the MRD-guided, time-limited AVO triplet."

Clinical • IO biomarker • P2 data • Anemia • Cardiovascular • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Disorders • Hodgkin Lymphoma • Hypertension • Infectious Disease • Musculoskeletal Pain • Neutropenia • Novel Coronavirus Disease • Oncology • Pain • Pneumonia • Respiratory Diseases • Richter's Syndrome • Thrombocytopenia • BCL2 • IGH • TP53

Temporal Trends in Cardiovascular Toxicity With Second-Generation Bruton Tyrosine Kinase Inhibitors: Acalabrutinib vs Zanubrutinib (SOHO 2026) - "Background: The second-generation Bruton tyrosine kinase inhibitors (BTKi) acalabrutinib and zanubrutinib were designed to reduce the off-target cardiotoxicity of ibrutinib...Propensity score matching (1:1) balanced age, race, sex, CKD, diabetes, obesity, COPD, smoking, alcohol use, anticoagulant and antiplatelet use, concomitant CLL therapy (venetoclax, rituximab, obinutuzumab), and baseline hemoglobin and platelet counts... Zanubrutinib was associated with numerically higher rates of hypertension, whereas acalabrutinib showed significantly higher long-term risks of AF/flutter and major adverse cardiovascular events. These findings highlight the importance of individualized treatment selection, particularly in patients with underlying cardiac comorbidities. Prospective head-to-head studies are needed to validate these real-world observations."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Efficacy of 2nd-line treatment in CLL after venetoclax-based 1st-line treatment: Results from the GAIA/CLL13 trial (ASH 2025) - "We reportefficacy outcomes for 177 patients receiving 2nd-line treatment after prior reporting of progression in theGAIA/CLL13 trial.In the GAIA/CLL13 trial, 926 physically fit patients with CLL and without TP53 aberration were randomizedbetween 1st-line treatment with chemoimmunotherapy (CIT, n=229), rituximab-venetoclax (RV, n=237),obinutuzumab-venetoclax (GV, n=229), and GV-ibrutinib (GIV, n=231)...The 13 patients with progression as Richter's transformation received R-CHOP-like therapy(n=8), ABVD-like therapy (n=2), brentuximab, rituximab-venetoclax or allogeneic stem cell transplant (n=1each).For patients who had received CIT in 1st-line treatment, 1 received CIT again, 34 received BTK inhibitor-based, 22 received venetoclax-based, and 5 received venetoclax + BTK inhibitor therapy...The majority received acalabrutinib + venetoclax (AV, n=24); 2 received AV +obinutuzumab as 2nd-line treatment.The 2-year TFS2 rate was 21.4% for CIT, 76.6% for BTK inhibitor-based,..."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Immunology • Leukemia • Rare Diseases • Richter's Syndrome • CD20 • TP53

BTK Inhibitors Are Associated With Significantly Lower Hospitalization and Reduced Cardiovascular Morbidity Compared With Venetoclax-Based Regimens in CLL/SLL: A Propensity Score-Matched, Real-World Analysis (SOHO 2026) - " Using the TriNetX Research Network (111 health care organizations), we identified adults with CLL/SLL diagnosed between January 2016 and December 2023 who received BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib; n = 8661) or venetoclax-based regimens (venetoclax ± rituximab or obinutuzumab; n = 9823). In this large, propensity score-matched, real-world analysis, BTKi-based therapy was associated with significantly lower all-cause hospitalization, mortality, heart failure, and coronary artery disease compared with venetoclax-based regimens in patients with CLL/SLL. These findings highlight important real-world differences in health care utilization and cardiovascular outcomes that may inform treatment selection in this population."

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

MRD-driven Initial Therapy of Acalabrutinib and Lenalidomide plus Rituximab (ALR) or Obinutuzumab (ALO) for Mantle Cell Lymphoma. (PubMed, Blood Adv) - P2 | "Longitudinal cfDNA analysis in ALR revealed clonal evolution during response and progression. This safe and active regimen is feasible as a time-limited initial therapy for MCL patients and warrants further evaluation in response-adapted strategy."

Journal • Fatigue • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Neutropenia • Thrombocytopenia • TP53

Pirtobrutinib Monotherapy for First-Line Chronic Lymphocytic Leukemia: A Non-Anchored Indirect Comparison Using Reconstructed Patient-Level Data. (PubMed, Hematol Rep) - "Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696-1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066-1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684-3.1240) versus acalabrutinib plus obinutuzumab... This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL."

Journal • Monotherapy • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology