Novel Agents in Chronic Lymphocytic Leukemia: New Combination Therapies and Strategies to Overcome Resistance

Resistance to Acalabrutinib in CLL Is Mediated Primarily By BTK Mutations

(2020) Jennifer Woyach et al.   BLOOD

Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax

(2020) Piers Blombery et al.   BLOOD

AMG-176, an Mcl-1 antagonist, shows preclinical efficacy in chronic lymphocytic leukemia

(2020) Xue Yi et al.   CLINICAL CANCER RESEARCH

Novel BCL2 mutations in venetoclax-resistant, ibrutinib-resistant CLL patients with BTK/PLCG2 mutations

(2020) Fabienne Lucas et al.   BLOOD

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK inhibition as an Effective Strategy

(2020) Anthony R. Mato et al.   CLINICAL CANCER RESEARCH

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

(2020) Paolo Ghia et al.   JOURNAL OF CLINICAL ONCOLOGY

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial

(2020) Jeff P Sharman et al.   LANCET

A RANDOMIZED PHASE 3 TRIAL OF ZANUBRUTINIB VERSUS IBRUTINIB IN SYMPTOMATIC WALDENSTRÖM MACROGLOBULINEMIA:THE ASPEN STUDY

(2020) Constantine S. Tam et al.   BLOOD

Changes in Bcl-2 members in response to ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL

(2020) Marco Vincent Haselager et al.   BLOOD

Treatment of Chronic Lymphocytic Leukemia

(2020) Jan A. Burger   NEW ENGLAND JOURNAL OF MEDICINE

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

(2020) B. Eichhorst et al.   ANNALS OF ONCOLOGY

Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

(2020) Carsten Utoft Niemann et al.   BLOOD

Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia

(2020) Kerry A. Rogers et al.   JOURNAL OF CLINICAL ONCOLOGY

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial

(2020) Othman Al-Sawaf et al.   LANCET ONCOLOGY

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma

(2020) Constantine S. Tam et al.   Blood Advances

HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model

(2020) Kamira Maharaj et al.   Frontiers in Immunology

Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with B-cell receptor inhibitors: results of a phase 2 study

(2019) Farrukh T. Awan et al.   LEUKEMIA & LYMPHOMA

Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial

(2019) Loretta J Nastoupil et al.   Lancet Haematology

Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas

(2019) Yonghui Sun et al.   LEUKEMIA

Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables

(2019) Andrew W. Roberts et al.   BLOOD

IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia

(2019) Annika Scheffold et al.   BLOOD

Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia

(2019) Eugen Tausch et al.   HAEMATOLOGICA

Ibrutinib and Venetoclax for First-Line Treatment of CLL

(2019) Nitin Jain et al.   NEW ENGLAND JOURNAL OF MEDICINE

Prevalence of BTK and PLCG2 mutations in a real‑life CLL cohort still on ibrutinib after three years: a FILO group study

(2019) Anne Quinquenel et al.   BLOOD

Phase 1 study of selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

(2019) Constantine Si Lun Tam et al.   BLOOD

Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study

(2019) Peter Hillmen et al.   JOURNAL OF CLINICAL ONCOLOGY

Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia

(2019) Tait D. Shanafelt et al.   NEW ENGLAND JOURNAL OF MEDICINE

Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions

(2019) Kirsten Fischer et al.   NEW ENGLAND JOURNAL OF MEDICINE

Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

(2019) Richard W. Birkinshaw et al.   Nature Communications

Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia

(2019) Yun Chen et al.   BLOOD

Ublituximab and Umbralisib in Relapsed/ Refractory B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

(2019) Matthew Lunning et al.   BLOOD

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

(2019) Romain Guièze et al.   CANCER CELL

Duobody-CD3xCD20 Induces Potent Anti-Tumor Activity in Malignant Lymph Node B Cells from Patients with DLBCL, FL and MCL Ex Vivo, Irrespective of Prior Treatment with CD20 Monoclonal Antibodies

(2019) Hilma J Van Der Horst et al.   BLOOD

A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Entospletinib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

(2019) Nadine Kutsch et al.   BLOOD

Ongoing Results of a Phase 1B/2 Dose-Escalation and Cohort-Expansion Study of the Selective, Noncovalent, Reversible Bruton'S Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Cell Malignancies

(2019) John N. Allan et al.   BLOOD

High Surface IgM Levels Associate with Shorter Response Duration and Bypass of the BTK Blockade during Ibrutinib Therapy in CLL Patients

(2019) Giorgia Chiodin et al.   BLOOD

Sequential and combination treatments with novel agents in chronic lymphocytic leukemia

(2019) Moritz Fürstenau et al.   HAEMATOLOGICA

Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia (Comment to Tausch et al.)

(2019) Jonathan Weiss et al.   HAEMATOLOGICA

Response to Comment by Jonathan Weiss et al.

(2019) Eugen Tausch et al.   HAEMATOLOGICA

Inhibition of bromodomain and extra‐terminal proteins increases sensitivity to venetoclax in chronic lymphocytic leukaemia

(2019) Giovanna Carrà et al.   JOURNAL OF CELLULAR AND MOLECULAR MEDICINE

The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment

(2019) Ekaterina Kim et al.   LEUKEMIA

A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity

(2019) Sajid Khan et al.   NATURE MEDICINE

Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation

(2018) Alexandru D. Buhimschi et al.   BIOCHEMISTRY

A CD19/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era

(2018) Hannah R. Robinson et al.   BLOOD

High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: Integrating molecular and cellular therapies

(2018) Peter Dreger et al.   BLOOD

Non-covalent inhibition of C481S Bruton’s tyrosine kinase by GDC-0853: a new treatment strategy for ibrutinib resistant CLL

(2018) Sean D. Reiff et al.   BLOOD

BTKCys481Serdrives ibrutinib resistance via ERK1/2 and protects BTKwild-typeMYD88-mutated cells by a paracrine mechanism

(2018) Jiaji G. Chen et al.   BLOOD

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL

(2018) Michael Hallek et al.   BLOOD

Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia

(2018) Michael Y. Choi et al.   Cell Stem Cell

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

(2018) Stephan Stilgenbauer et al.   JOURNAL OF CLINICAL ONCOLOGY

Chronic lymphocytic leukaemia

(2018) Michael Hallek et al.   LANCET

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial

(2018) Jeffrey A Jones et al.   LANCET ONCOLOGY

Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

(2018) John F. Seymour et al.   NEW ENGLAND JOURNAL OF MEDICINE

Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia

(2018) Carmen D. Herling et al.   Nature Communications

Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia

(2018) Susan M. O’Brien et al.   JAMA Oncology

Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial

(2018) Paula Cramer et al.   LANCET ONCOLOGY

Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity

(2018) Ryan S. Soderquist et al.   Nature Communications

The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation

(2018) Sean D. Reiff et al.   Cancer Discovery

Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL

(2018) Kamil Bojarczuk et al.   BLOOD

The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

(2018) Ian W. Flinn et al.   BLOOD

Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients.

(2018) Samantha Drennan et al.   CLINICAL CANCER RESEARCH

Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies

(2018) Greg P. Coffey et al.   CLINICAL CANCER RESEARCH

Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study

(2018) Arnon P. Kater et al.   JOURNAL OF CLINICAL ONCOLOGY

Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

(2018) Rishu Agarwal et al.   NATURE MEDICINE

Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL

(2018) Jennifer A. Woyach et al.   NEW ENGLAND JOURNAL OF MEDICINE

Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

(2018) Adriana E. Tron et al.   Nature Communications

Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia

(2018) Piers Blombery et al.   Cancer Discovery

Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications

(2017) Emerence Crompot et al.   HAEMATOLOGICA

BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia

(2017) Jennifer A. Woyach et al.   JOURNAL OF CLINICAL ONCOLOGY

PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment

(2017) D Jones et al.   LEUKEMIA

Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1

(2017) A Cosson et al.   LEUKEMIA

Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia

(2017) J Deng et al.   LEUKEMIA

Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells

(2017) M K Hasan et al.   LEUKEMIA

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment

(2017) A Paulus et al.   Blood Cancer Journal

Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment

(2017) Ailin Guo et al.   Oncotarget

Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition

(2017) Joyoti Dey et al.   Scientific Reports

Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications

(2017) Emerence Crompot et al.   HAEMATOLOGICA

Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation

(2016) Mohamed A. Kharfan-Dabaja et al.   BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION

The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism

(2016) M. A. Anderson et al.   BLOOD

Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study

(2016) Stephan Stilgenbauer et al.   LANCET ONCOLOGY

Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models

(2016) E. A. Punnoose et al.   MOLECULAR CANCER THERAPEUTICS

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia

(2016) Andrew W. Roberts et al.   NEW ENGLAND JOURNAL OF MEDICINE

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

(2016) John C. Byrd et al.   NEW ENGLAND JOURNAL OF MEDICINE

Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

(2016) Jan A. Burger et al.   Nature Communications

Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL

(2016) Shruti Sharma et al.   Oncotarget

Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia

(2016) Stefania Fiorcari et al.   Oncotarget

Nurse-like cells promote CLL survival through LFA-3/CD2 interactions

(2016) Frédéric Boissard et al.   Oncotarget

Hypermorphic mutation of phospholipase C,  2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation

(2015) T.-M. Liu et al.   BLOOD

Treatment with Ibrutinib Inhibits BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo

(2015) S. E. M. Herman et al.   CLINICAL CANCER RESEARCH

Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia

(2015) F. Cervantes-Gomez et al.   CLINICAL CANCER RESEARCH

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

(2015) Jan A. Burger et al.   NEW ENGLAND JOURNAL OF MEDICINE

MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies

(2015) G S Choudhary et al.   Cell Death & Disease

Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients

(2015) F Boissard et al.   Blood Cancer Journal

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma

(2015) David Chiron et al.   Oncotarget

PKC-  as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

(2014) D. El-Gamal et al.   BLOOD

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

(2014) Dejan Juric et al.   NATURE

Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib

(2014) Jennifer A. Woyach et al.   NEW ENGLAND JOURNAL OF MEDICINE

Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia

(2014) John C. Byrd et al.   NEW ENGLAND JOURNAL OF MEDICINE

Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

(2014) Richard R. Furman et al.   NEW ENGLAND JOURNAL OF MEDICINE

TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial

(2013) P. Dreger et al.   BLOOD

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

(2013) Andrew J Souers et al.   NATURE MEDICINE

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

(2013) John C. Byrd et al.   NEW ENGLAND JOURNAL OF MEDICINE

Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer

(2013) L-Y Huw et al.   Oncogenesis

The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia

(2012) M. F. M. de Rooij et al.   BLOOD

An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737

(2011) S. Al-harbi et al.   BLOOD

Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial

(2010) P. Dreger et al.   BLOOD