Calquence (acalabrutinib) / AstraZeneca - LARVOL DELTA

FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma (FDA) - "On January 16, 2025, the Food and Drug Administration granted traditional approval to acalabrutinib (Calquence, AstraZeneca) with bendamustine and rituximab for adults with previously untreated mantle cell lymphoma (MCL) who are ineligible for autologous hematopoietic stem cell transplantation (HSCT). FDA also granted traditional approval to acalabrutinib as a single agent for adults with previously treated MCL....Efficacy was evaluated in ECHO...a randomized, double-blind, placebo controlled, multicenter trial..."

FDA approval • Project Orbis • Mantle Cell Lymphoma

A Phase 3 Study to Evaluate Efficacy and Safety of Pemivibart, an IgG1 Monoclonal Antibody for Prevention of COVID-19 (CANOPY): Subset Analysis of Participants with Chronic Lymphocytic Leukemia (TCT-ASTCT-CIBMTR 2025) - P3 | "Nine participants (31.0%) were receiving antineoplastic agents including venetoclax (n = 3), acalabrutinib (n =2), and ibrutinib (n = 2). Conclusions : Pemivibart was well tolerated in a subset of adult participants with CLL. No participants developed COVID-19 in the 6 months following administration of pemivibart."

Clinical • P3 data • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Hematological Malignancies • Infectious Disease • Leukemia • Novel Coronavirus Disease • Oncology • Pain • Respiratory Diseases

…Ibrance among next drugs picked by Medicare for price talks (BioPharma Dive) - "Publication of the list kicks off a monthslong process that will feature a series of meetings between drugmakers and the Centers for Medicare and Medicaid Services, which oversees the Medicare insurance program. The negotiations, which drugmakers have opposed vociferously, will yield 'maximum fair prices' that take effect in 2027. Also on the list are Xtandi, Ibrance, Calquence and Pomalyst, blockbuster drugs for cancers of the prostate, breast, blood and bone marrow."

Reimbursement • Breast Cancer • Hematological Malignancies • Prostate Cancer

Acalabrutinib in CNSL (clinicaltrials.gov) - P1/2 | N=49 | Recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Jan 2026 ➔ Jan 2027 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • CNS Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Primary Central Nervous System Lymphoma

Acalabrutinib in Patients With Chronic Lymphocytic Leukemia With Direct Oral Anticoagulation (CICERO) (clinicaltrials.gov) - P=N/A | N=50 | Recruiting | Sponsor: iOMEDICO AG | Trial completion date: Oct 2025 ➔ Mar 2026 | Trial primary completion date: Oct 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

“Extension of indication to include CALQUENCE in combination with venetoclax with or without obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukemia based on interim results from study AMPLIFY (D8221C00001)…as a consequence, sections 4.1, 4.2, 4.4, 4.8, and 5.1 of the SmPC are updated. The Package Leaflet is updated in accordance." (European Medicines Agency) - Pharmacovigilance Risk Assessment Committee (PRAC)-Draft agenda for the meeting on 13 – 16 Jan 2025: “For adoption of PRAC RMP AR, PRAC RMP assessment overview and advice to CHMP”

PRAC • Chronic Lymphocytic Leukemia • Hematological Malignancies • Oncology

ACALLO: Acalabrutinib in CLL and MCL Patients Subjected to Allogeneic Hematopoietic Stem Cell Transplantation (alloSCT) (clinicaltrials.gov) - P2 | N=29 | Completed | Sponsor: Polish Lymphoma Research Group | Active, not recruiting ➔ Completed

Trial completion • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Chronic Lymphocytic Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Transplantation • TP53

Acalabrutinib in High-Risk Chronic Lymphocytic Leukaemia Naïve Patients: An Italian Multicenter Retrospective Observational Real-Life Experience. (PubMed, Hematol Oncol) - No abstract available

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

Novel Mechanisms of Resistance in CLL: Variant BTK Mutations in Second-Generation and Noncovalent BTK Inhibitors. (PubMed, Blood) - "The covalent BTKi ibrutinib, acalabrutinib and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Non-covalent BTKi including pirtobrutinib overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications and consider their impact on clinical trials."

Journal

Differentiation of the chronic lymphocytic leukemia response to ibrutinib and acalabrutinib treatment by single-cell MALDI-TOF MS imaging. (PubMed, J Pharm Biomed Anal) - "In conclusion, single-cell MALDI-TOF mass spectrometry imaging detects differences in the mass spectra of CD19+ lymphocytes treated with two different BTKi. Drug-specific m/z signal clusters can be identified as a chemical fingerprint of the BTKi effect and represent candidates for the therapeutic response biomarkers."

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

HLA-haploidentical allogeneic hematopoietic stem cell transplantation using FluMelTBI conditioning for an elderly patient with fulminant aplastic anemia during treatment for chronic lymphocytic leukemia (PubMed, Rinsho Ketsueki) - "A 66-year-old woman was diagnosed with chronic lymphocytic leukemia (CLL) due to the finding of leukocytosis and started acalabrutinib and obinutuzumab (AO) therapy...One month after the onset of AA, she received HLA-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-SCT) from a daughter using FluMelTBI (fludarabine 180 mg/m2, melphalan 80 mg/m2, total body irradiation 4 Gy) as the conditioning regimen and tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Rapid engraftment was achieved without GVHD or any other serious complications, and CLL has remained in remission. Haplo-SCT using PTCy is considered to be a useful emergency transplantation option for elderly patients with fulminant AA, and more cases are needed to evaluate its safety and efficacy."

Journal • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Chronic Lymphocytic Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Neutropenia • Oncology • Transplantation

Real-world Study of Acalabrutinib (clinicaltrials.gov) - P=N/A | N=200 | Enrolling by invitation | Sponsor: Ruijin Hospital

New trial • Chronic Lymphocytic Leukemia

SAKK 38/19: Assessing a CtDNA and PET-oriented Therapy in Patients with DLBCL a Multicenter, Open-label, Phase II Trial. (clinicaltrials.gov) - P2 | N=260 | Active, not recruiting | Sponsor: Swiss Group for Clinical Cancer Research | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

AVO Therapy Found Effective and Well Tolerated in High-Risk CLL (Hematology Advisor) - P2 | N=72 | NCT03580928 | "The research team enrolled 72 patients with CLL between August 2, 2018, and November 30, 2022, including 45 with a TP53 aberration. They were administered acalabrutinib, obinutuzumab, and venetoclax sequentially and then in combination for 15 cycles....The results revealed that the AVO combination therapy was highly active in all participants, with 42% of patients with the TP53 aberration achieving the primary end point of complete response (CR) with BM-uMRD at cycle 16. The best rate of CR with BM-uMRD for patients with the TP53 aberration was 58%. The results have been sustained, with 70% of patients with the TP53 aberration achieving 4-year progression-free survival. Overall, 24% of patients on combination AVO therapy experienced a serious adverse event of grade 3 or higher."

P2 data • Chronic Lymphocytic Leukemia

Benefit VA: A Randomized Phase II Study Of Bruton Tyrosine Kinase Inhibitor With Or Without Venetoclax In Veterans With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (clinicaltrials.gov) - P2 | N=100 | Not yet recruiting | Sponsor: VA Office of Research and Development | Initiation date: Jan 2025 ➔ Apr 2025

Trial initiation date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

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

Relative Efficacy of Systemic Treatments for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: A Network Meta-Analysis According to 17p Deletion/TP53 Mutations (ASH 2024) - "Ibrutinib was used as reference treatment.Results : Twelve trials involving 4,437 patients and 13 treatment options were included in the meta-analysis : three Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, and zanubrutinib), two BTK inhibitors combined with other treatments (ibrutinib plus rituximab plus bendamustine [RB] and ibrutinib plus rituximab), two phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib and duvelisib), three PI3K inhibitors combined with other treatments (idelalisib plus ofatumumab, idelalisib plus RB, idelalisib plus rituximab), three anti-CD20-based treatment (RB, ofatumumab, and rituximab), and one BCL-2 inhibitor (venetoclax plus rituximab). In the 17p deletion/TP53 mutation subgroup, zanubrutinib demonstrated the most favorable efficacy (HR 0.52, 95% CI 0.31-0.88 versus ibrutinib) with the highest SUCRA value (97%). For patients without these mutations, venetoclax plus rituximab was the most effective (HR 0.49, 95% CI..."

IO biomarker • Retrospective data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

Acalabrutinib for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (clinicaltrials.gov) - P2 | N=61 | Not yet recruiting | Sponsor: Ohio State University Comprehensive Cancer Center

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

CLL-Frail: Efficacy of Acalabrutinib in Very Old or Frail Patients with Treatment-naïve or Relapsed/Refractory CLL (clinicaltrials.gov) - P2 | N=53 | Active, not recruiting | Sponsor: German CLL Study Group | Trial completion date: Dec 2024 ➔ May 2025 | Trial primary completion date: Jul 2023 ➔ May 2025

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

17-BI-1206-02: A Study of BI-1206 in Combination With Rituximab With or Without Acalabrutinib in Subjects With Indolent B-Cell NHL (clinicaltrials.gov) - P1/2 | N=140 | Recruiting | Sponsor: BioInvent International AB | N=98 ➔ 140 | Trial completion date: Sep 2025 ➔ Sep 2026 | Trial primary completion date: Sep 2025 ➔ Sep 2026

Enrollment change • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • CRP

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=650 | Recruiting | Sponsor: German CLL Study Group | Trial completion date: Feb 2027 ➔ May 2028 | Trial primary completion date: May 2026 ➔ May 2028

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2 • TP53

Acalabrutinib and Obinutuzumab for Chronic Lymphocytic Leukemia Complicated With Peripheral Neuropathy. (PubMed, Cureus) - "Acalabrutinib and obinutuzumab were administered, and his symptoms gradually improved. Hence, acalabrutinib and obinutuzumab may have been active in patients with CLL complicated by peripheral neuropathy."

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

Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia. (PubMed, Elife) - "Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. Here, we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W."

Journal • Chronic Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Immunology • Leukemia • Multiple Sclerosis • Oncology

Prospective Randomized Phase 2 Study of Acalabrutinib + Obinutuzumab or Venetoclax in Previously Untreated CLL (ASH 2024) - P2 | "The addition of venetoclax (Thompson Leukemia 2023) and obinutuzumab (Rawstron ASH 2018) in patients already receiving ibrutinib led to deep responses in two separate studies. This single center phase 2 study will determine the rate of bone marrow uMRD after 6 cycles of delayed treatment with AO or AV started after 12 cycles of A monotherapy. The results are expected to add information on the delayed combination approach as well as choice of combination agent."

Clinical • IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • TP53

The Cardiovascular Outcomes Difference between Acalabrutinib and Zanubrutinib: A Retrospective Cohort Study Using Real-World Data (ASH 2024) - "They have demonstrated lower cardiotoxicity compared to first-generation BTK inhibitor ibrutinib. The risks of new-onset hypertension, ventricular arrhythmia, myocardial infarction, new-onset heart failure, conduction block, and stroke were similar between the two groups. Further studies with long-term follow-up data will be valuable for evaluating the safety of next-generation BTK inhibitors."

Real-world • Real-world evidence • Retrospective data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Myocardial Infarction • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma