Rationale for the combination of venetoclax and ibrutinib in T-prolymphocytic leukemia

Kornauth, Christoph; Herbaux, Charles; Boidol, Bernd; Guillemette, Chantal; Caron, Patrick; Mayerhoefer, Marius E.; Poulain, Stéphanie; Tournilhac, Olivier; Pemovska, Tea; Chong, Siew Meng; Kouwe, Emiel van der; Kazianka, Lukas; Hopfinger, Georg; Heintel, Daniel; Jäger, Roland; Raderer, Markus; Jäger, Ulrich; Simonitsch‐Klupp, Ingrid; Sperr, Wolfgang R.; Kubicek, Stefan; Davids, Matthew S.; Staber, Philipp B.

doi:10.3324/haematol.2020.271304

Cited by 8 publications

(9 citation statements)

References 15 publications

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“…For example, positive BCL2 expression as determined via IHC in human peripheral T cell lymphoma not‐otherwise‐specified (PTCL‐NOS) can be seen in 43% to 79.5% of cases, and could be greater in ALK‐negative, compared with ALK‐positive, anaplastic large cell lymphoma 23‐25 . The role of VEN in management of T cell cancers in people is still being defined, though several reports suggest activity in combination with other therapies including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, and histone deacetylase inhibitors 26,27 . Current standard of care treatment for aggressive canine T cell lymphoma involves multiagent maximum tolerated dose chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of canine hematological cancers to BH3 mimetics

Jegatheeson

Cannon

Mansfield

et al. 2022

Veterinary Internal Medicne

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Background Inhibition of antiapoptotic B‐cell lymphoma 2 (BCL2) proteins by small molecule Bcl‐2 homology 3 (BH3) mimetics causes rapid induction of apoptosis of human hematological cancers in vitro and in vivo. Objectives Assess in vitro sensitivity of non‐neoplastic lymphocytes and primary hematological cancer cells from dogs to venetoclax (VEN) or the dual BCL2/ B‐cell lymphoma‐extra‐large (BCLxL) inhibitor, navitoclax (NAV), and evaluate the association between BCL2 protein expression and VEN sensitivity. Animals Nine client‐owned dogs without cancer and 18 client‐owned dogs with hematological cancer. Methods Prospective, nonrandomized noncontrolled study. Lymphocytes isolated from peripheral blood, lymph node, or bone marrow from dogs were incubated with BH3 mimetics for 24 hours. Viable cells were counted using flow cytometry and half maximal effective concentration (EC50) was calculated. BCL2 protein from whole cell lysates was assessed via immunoblots. Results Nodal B and T lymphocytes were more sensitive to VEN than circulating lymphocytes (P = .02). Neoplastic T lymphocytes were sensitive to VEN (mean EC50 ± SD = 0.023 ± 0.018 μM), whereas most non‐indolent B cell cancers were resistant to killing by VEN (mean EC50 ± SD = 288 ± 700 μM). Unclassified leukemias showed variable sensitivity to VEN (mean EC50 ± SD = 0.49 ± 0.66 μM). Detection of BCL2 protein was not associated with VEN sensitivity. Conclusion and Clinical Importance Neoplastic canine T lymphocytes are sensitive to VEN in vitro. Quantification of BCL2 protein alone is insufficient to predict sensitivity to VEN.

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Section: Discussionmentioning

confidence: 99%

Sensitivity of canine hematological cancers to BH3 mimetics

Jegatheeson

Cannon

Mansfield

et al. 2022

Veterinary Internal Medicne

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“… 39 Clinical reports suggest that venetoclax monotherapy is often inadequate to get durable disease control. 84 As demonstrated by dynamic BH3 profiling, inhibitors of histone deacetylase and the JAK/STAT pathway increase apoptotic priming and BCL-2 dependence, strengthening the pro-apoptotic effect of venetoclax in vitro and in vivo . 39 …”

Section: The Anti-apoptotic Map Of Hematologic Malignanciesmentioning

confidence: 97%

“…BCL-xL dependence is usually more pronounced in T-PLL than in CLL, but remains of secondary importance when compared with BCL-2 and MCL-1 dependence (39). Clinical reports suggest that venetoclax monotherapy is often inadequate to get durable disease control (84). As demonstrated by dynamic BH3 profiling, inhibitors of histone deacetylase and JAK/STAT pathway increase apoptotic priming and 12 BCL-2 dependence, strengthening the pro-apoptotic effect of venetoclax in vitro and in vivo (39).…”

Section: T-cell Prolymphocytic Leukemiamentioning

confidence: 99%

The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine

2022

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Mitochondria are critical organelles in the regulation of intrinsic apoptosis. As a general feature of blood cancers, different anti-apoptotic members of the BCL-2 protein family localize at the outer mitochondrial membrane to sequester variable amounts of pro-apoptotic activators, and hence protect cancer cells from death induction. However, the impact of distinct anti-apoptotic members on apoptosis prevention, a concept termed anti-apoptotic dependence, remarkably differs across disease entities. Over the last two decades, several genetic and functional methodologies have been established to uncover the anti-apoptotic dependencies of the majority of blood cancers, inspiring the development of a new class of small molecules called BH3 mimetics. In this review, we highlight the rationale of targeting mitochondrial apoptosis in hematology, and provide a comprehensive map of the antiapoptotic dependencies that are currently guiding novel therapeutic strategies. Cell-extrinsic and intrinsic mechanisms conferring resistance to BH3 mimetics are also examined, with insights on potential strategies to overcome them. We finally discuss how the field of mitochondrial apoptosis might be complemented with other dimensions of precision medicine for more successfully treating ‘highly complex’ hematological malignancies.

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“…Another Phase II clinical trial (NCT03873493) is evaluating the efficacy of ibrutinib in combination with venetoclax in adult patients with R/R T-cell prolymphocytic leukemia (T-PLL). Mechanistically, ITK is required for TCR signaling and CXCR4 signaling, and thus critical for malignant T cell proliferation, differentiation and migration, while preventing anti-tumor immune responses by inhibiting T H 1 CD4 T cell differentiation (49,50,66). Treatment with ibrutinib or knockdown of ITK by siRNA results in reduced ITK phosphorylation and decreased activation of downstream MEK1/2 and AKT, leading to compromised survival and cytokine production as well as migration of PTCL cells (66).…”

Section: Hematological Malignancies Of Myeloid Cells and T Cellsmentioning

confidence: 99%

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

et al. 2021

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The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

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Rationale for the combination of venetoclax and ibrutinib in T-prolymphocytic leukemia

Abstract: Not available.

Cited by 8 publications

References 15 publications

Sensitivity of canine hematological cancers to BH3 mimetics

Sensitivity of canine hematological cancers to BH3 mimetics

The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

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