Efficacy and Safety of Tirabrutinib and Idelalisib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia

Kutsch, Nadine; Pallasch, Christian P.; Decker, Thomas; Hebart, Holger; Chow, Kai Uwe; Graeven, Ullrich; Kisro, Jens; Kroeber, Alexander; Tausch, Eugen; Fischer, Kirsten; Fink, Anna‐Maria; Wendtner, Clemens‐Martin; Ritgen, Matthias; Stilgenbauer, Stephan; Zhang, Danjie; Li, Biao; Jürgensmeier, Juliane M.; Rajakumaraswamy, Nishanthan; Bhargava, Pankaj; Hallek, Michael; Eichhorst, Barbara

doi:10.1097/hs9.0000000000000729

Cited by 3 publications

(2 citation statements)

References 15 publications

(34 reference statements)

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“…[20,43] Kinase inhibitors, such as idelalisib (PI3K𝛿) and ibrutinib (BTK), in combination with OBN, are currently being evaluated in clinical trials as secondline therapies. [44,45] Finally, "CHOP" is a chemotherapy program consisting of a DNA alkylating agent, a topoisomerase inhibitor, and a microtubule depolymerization inhibitor. CHOP, administered in combination with the anti-CD20 mAb, RTX, is a commonly used program in the treatment of many B cell hematological malignancies.…”

Section: Discussionmentioning

confidence: 99%

Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors

Gambles,

Sborov,

Shami

et al. 2023

Macromolecular Bioscience

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Drug‐Free Macromolecular Therapeutics (DFMT) utilizes modified monoclonal antibodies (or antibody fragments) to generate antigen‐crosslinking induced apoptosis in target cells. DFMT is a two‐component system containing a morpholino oligonucleotide (MORF1) modified antibody (Ab‐MORF1) and human serum albumin conjugated with multiple copies of complementary morpholino oligonucleotide (MORF2), (HSA‐(MORF2)x). The two components recognize each other via Watson‐Crick base pairing complementation of their respective MORFs. One HSA‐(MORF2)x molecule can hybridize with multiple Ab‐MORF1 molecules on the cell surface, thus serving as the therapeutic crosslink‐inducing mechanism of action. Herein, we examined various anti‐neoplastic agents in combination with the anti‐CD20 Obinutuzumab (OBN)‐based DFMT system. We examined three different classes of chemotherapies: DNA alkylating agents; proliferation pathway inhibitors; and DNA replication inhibitors. We utilized Chou‐Talalay combination index mathematics to determine which drugs engaged synergistically with OBN‐based DFMT. We determined that OBN‐based DFMT synergizes with topoisomerase inhibitors and DNA nucleotide analogues but is antagonistic with proliferation pathway inhibitors. We performed cell mechanism experiments to analyze points of synergism or antagonism by investigating Ca2+ influx, mitochondrial health, lysosomal stability, and cell cycle arrest. Finally, we demonstrated the synergistic drug combinatorial effects of OBN‐based DFMT with etoposide in vivo using a human xenograft non‐Hodgkin's lymphoma mouse model.This article is protected by copyright. All rights reserved

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Section: Discussionmentioning

confidence: 99%

Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors

Gambles,

Sborov,

Shami

et al. 2023

Macromolecular Bioscience

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“…Initial data shows high efficacy and tolerability in relapsed CLL patients treated with a combination of tirabrutinib, idelalisib and obinutuzumab with an ORR of 93.3% (95% CI, 80.5-98.8%), and a 24-month PFS and OS of 80.6% (90% CI, 41.1%–94.9%) and 96.7% (90% CI, 83.9%–99.3%), respectively. Serious treatment-emerged adverse events were experienced in 36.7% ( 92 ).…”

Section: Bcr-mediated Downstream Signaling In Cllmentioning

confidence: 99%

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

Schmid,

Hobeika

2024

Front. Oncol.

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B cell antigen receptor (BCR) signaling is a key driver of growth and survival in both normal and malignant B cells. Several lines of evidence support an important pathogenic role of the BCR in chronic lymphocytic leukemia (CLL). The significant improvement of CLL patients’ survival with the use of various BCR pathway targeting inhibitors, supports a crucial involvement of BCR signaling in the pathogenesis of CLL. Although the treatment landscape of CLL has significantly evolved in recent years, no agent has clearly demonstrated efficacy in patients with treatment-refractory CLL in the long run. To identify new drug targets and mechanisms of drug action in neoplastic B cells, a detailed understanding of the molecular mechanisms of leukemic transformation as well as CLL cell survival is required. In the last decades, studies of genetically modified CLL mouse models in line with CLL patient studies provided a variety of exciting data about BCR and BCR-associated kinases in their role in CLL pathogenesis as well as disease progression. BCR surface expression was identified as a particularly important factor regulating CLL cell survival. Also, BCR-associated kinases were shown to provide a crosstalk of the CLL cells with their tumor microenvironment, which highlights the significance of the cells’ milieu in the assessment of disease progression and treatment. In this review, we summarize the major findings of recent CLL mouse as well as patient studies in regard to the BCR signalosome and discuss its relevance in the clinics.

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Next Generation BTK Inhibitors in CLL: Evolving Challenges and New Opportunities

Frustaci

Deodato

Zamprogna

et al. 2023

Cancers

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Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL.

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Efficacy and Safety of Tirabrutinib and Idelalisib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia

Abstract: The study is registered under the ClinicalTrials.gov identifier NCT02968563.

Cited by 3 publications

References 15 publications

Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors

Obinutuzumab‐Based Drug‐Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia

Next Generation BTK Inhibitors in CLL: Evolving Challenges and New Opportunities

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