Faculty Opinions recommendation of Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.

2017 ◽  
Author(s):  
Varsha Gandhi ◽  
Prithviraj Bose
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Lymphocytic Leukemia

scholarly journals Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

2021 ◽  
Vol 5 (1) ◽  
pp. 334-343
Author(s):  
Sigrid S. Skånland ◽  
Anthony R. Mato
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Targeted Therapies ◽  
Rational Design ◽  
Treatment Options ◽  
Critical Role ◽  
Acquired Resistance ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy

Abstract Insight into the critical role of B-cell receptor signaling for the pathogenesis of chronic lymphocytic leukemia (CLL) led to the development of targeted therapies directed at key regulators of cell survival. Agents targeting B-cell lymphoma-2 protein, Bruton’s tyrosine kinase (BTK), and phosphatidylinositol 3-kinase are approved for treatment of CLL, and have significantly improved the disease management. Nevertheless, acquired resistance to the targeted therapies is a challenge still to be resolved. The mechanisms underlying resistance are becoming clearer, and include secondary mutations within the drug target and activation of bypass pathways. This knowledge has allowed development of strategies to prevent and overcome treatment resistance. Approaches to prevent resistance include targeting bypass mechanisms by combination therapies, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. A rational design of drug sequencing may secure effective treatment options at the relapsed setting. Next-generation inhibitors and bispecific antibodies have the potential to overcome resistance to the BTK inhibitor ibrutinib. Immunotherapy, including chimeric antigen receptor-modified T-cell therapy, is explored for relapsed CLL. Here, recent advances that have contributed to the understanding of resistance to targeted therapies in CLL are discussed. Strategies for managing resistance are reviewed, including translational, real-world, and clinical perspectives.

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

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1336
Author(s):  
Moritz Fürstenau ◽  
Barbara Eichhorst
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
Novel Agents ◽  
New Combination ◽  
Special Focus ◽  
Combination Therapies ◽  
Clinical Resistance ◽  
Btk Inhibitors

The approval of Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib and the Bcl-2 inhibitor venetoclax have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While these novel agents alone or in combination induce long lasting and deep remissions in most patients with CLL, their use may be associated with the development of clinical resistance. In this review, we elucidate the genetic basis of acquired resistance to BTK and Bcl-2 inhibition and present evidence on resistance mechanisms that are not linked to single genomic alterations affecting these target proteins. Strategies to prevent resistance to novel agents are discussed in this review with a special focus on new combination therapies.

scholarly journals BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia

2017 ◽  
Vol 35 (13) ◽  
pp. 1437-1443 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Amy S. Ruppert ◽  
Daphne Guinn ◽  
Amy Lehman ◽  
James S. Blachly ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Lymphocytic Leukemia ◽  
Clinical Relapse ◽  
Resistance Mutations ◽  
Screening Population ◽  
History Of ◽  
Sequential Studies

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

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

Blood ◽  
2020 ◽  
Vol 135 (24) ◽  
pp. 2192-2195 ◽  
Author(s):  
Fabienne Lucas ◽  
Karylin Larkin ◽  
C. Thomas Gregory ◽  
Shelley Orwick ◽  
Tzyy-Jye Doong ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Lymphocytic Leukemia ◽  
Inhibitor Therapy ◽  
Resistance Mutations ◽  
Btk Inhibitor

Lucas et al explored the clonal dynamics of chronic lymphocytic leukemia (CLL) patients following treatment and subsequent acquired resistance to ibrutinib and then venetoclax. They report different patterns of resistance mutations from previously reported changes following venetoclax treatment in the absence of prior BTK inhibitor therapy.

scholarly journals Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1

2022 ◽  
Vol 11 ◽  
Author(s):  
Stefania Fiorcari ◽  
Rossana Maffei ◽  
Claudio Giacinto Atene ◽  
Nicolò Mesini ◽  
Monica Maccaferri ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Lymphocytic Leukemia ◽  
Drug Induced ◽  
Effective Response ◽  
Incurable Disease ◽  
Trisomy 12 ◽  
Leukemic Clone ◽  
Induced Apoptosis ◽  
Interferon Regulatory Factor 4

Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax.

scholarly journals Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia

Blood ◽  
2015 ◽  
Vol 125 (20) ◽  
pp. 3128-3132 ◽  
Author(s):  
Zachary A. Hing ◽  
Rose Mantel ◽  
Kyle A. Beckwith ◽  
Daphne Guinn ◽  
Erich Williams ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Lymphocytic Leukemia ◽  
Key Points

Key Points Selinexor exhibits synergy with ibrutinib in CLL. Selinexor is effective in vitro in ibrutinib-resistant CLL.

scholarly journals An Unusual Case of Prolymphocytic Leukemia Transformation in a Patient With Chronic Lymphocytic Leukemia

2021 ◽  
Vol 9 ◽  
pp. 232470962199076 ◽  
Author(s):  
Stephen Bell ◽  
Natalia Lattanzio ◽  
Julaine Braham ◽  
Victoria Campdesuner ◽  
Qassem Abdelal ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
White Blood Cells ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Surface Protein ◽  
Lymphocytic Leukemia ◽  
Prolymphocytic Leukemia ◽  
First Line Therapy ◽  
Ibrutinib Resistance ◽  
Mature Lymphocyte

B-cell prolymphocytic leukemia (B-PLL) is a rare leukemia characterized by rapidly increasing leukocytosis with splenomegaly and lymphadenopathy. Treatment strategies are largely based on studies of chronic lymphocytic leukemia (CLL). Antibodies against the cell surface protein CD20 are considered to be first-line therapy. A 76-year-old male with known CLL presented 2 weeks after starting chemoimmunotherapy for newly refractory CLL after failing ibrutinib therapy. White blood cell count was elevated at 226.7 × 103/µL. Fluorescent in situ hybridization analysis of a bone marrow specimen showed new development of complex cytogenetics. Flow cytometry revealed B cells appearing slightly dimmer on CD45 and brighter on CD20 compared with typical B-CLL suggestive of less mature lymphocyte forms. The patient was diagnosed with B-PLL and started on obinutuzumab and venetoclax with rapid normalization of white blood cells. This case recapitulates the challenges in diagnosing and treating B-PLL. Ibrutinib resistance is a growing area of study with several proposed mechanisms of acquired resistance. The pathogenesis of B-PLL is not completely understood, although mutations in MYC are presumed to play a role.

Abstract 1097: Mechanisms of primary and acquired resistance to venetoclax in chronic lymphocytic leukemia (CLL)

2021 ◽  
Author(s):  
Ishwarya Murali ◽  
Justin Cha ◽  
Ignaty Leshchiner ◽  
Yanan Kuang ◽  
Kevin Vasquez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Acquired Resistance ◽  
Lymphocytic Leukemia

scholarly journals Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia

2017 ◽  
Vol 9 (1) ◽  
pp. 3-19 ◽  
Author(s):  
Gilad Itchaki ◽  
Jennifer R. Brown
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Therapeutic Option ◽  
Acquired Resistance ◽  
The Elderly ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Toxicity Profile ◽  
First Line ◽  
Heavily Pretreated

Ibrutinib is the first in-class, orally administered, Bruton’s tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib’s unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.

scholarly journals Detection of emerging ibrutinib resistance by flow cytometry in patients with chronic lymphocytic leukemia

2021 ◽  
Author(s):  
Ferenc Takács ◽  
Lili Kotmayer ◽  
Ágnes Czeti ◽  
Gábor Szalóki ◽  
László Tamás ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Lymphocytic Leukemia ◽  
Continuous Treatment ◽  
Clinical Resistance ◽  
Ibrutinib Resistance

Abstract Background: Bruton ’ s tyrosine kinase inhibitor ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Although ibrutinib is a highly effective drug, continuous treatment is required to maintain remission, which may lead to acquired ibrutinib resistance. Early detection of acquired resistance preceding clinical disease progression is an important issue. This is why our aim was to investigate several phenotypic markers on CLL cells to reveal changes in their expression during ibrutinib treatment in sensitive and clinically resistant patients. Materials and methods: In our study 28 (treatment naive, ibrutinib sensitive, clinically ibrutinib resistant) peripheral blood (PB), and 6 paired PB and bone marrow (BM) samples from CLL patients were examined. The expression of several surface markers (CD69, CD184, CD86, CD185, CD27) was assessed by flow cytometry in each sample. Furthermore, the presence of the BTK C481S resistance mutation was tested using digital droplet PCR (ddPCR) in samples from ibrutinib sensitive and resistant cases. In addition, we investigated the changes of CLL cells ’ phenotype during ibrutinib treatment in one patient with acquired ibrutinib resistance. Results: We found that the expression of CD27 decreased during ibrutinib therapy but increased again at the onset of clinical resistance. Expressions of CD69 and CD86 were also elevated at the onset of clinical ibrutinib resistance. Furthermore, the expression of CD86 showed correlation between PB and BM samples. Relapsed cases with high CD86 expression were positive for BTK C481S mutation. In addition, our prospective study showed that the increases in the expression of CD27, CD69 and CD86 were detectable up to several months before the onset of clinical resistance. Conclusion: Our research suggests that the flow cytometric measurements of certain markers, especially CD86, may predict development of ibrutinib resistance, however, confirmatory experiments are still required. Monitoring CD86 expression on peripheral blood CLL cells during ibrutinib treatment may become a potential new method to detect acquired ibrutinib resistance in the near future.

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