How I manage ibrutinib-refractory chronic lymphocytic leukemia

Woyach, Jennifer A.

doi:10.1182/blood-2016-09-693598

Cited by 50 publications

(61 citation statements)

References 32 publications

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“…Despite recent improvements, the management of progressive disease on BCR inhibitors remains challenging (53). The median survival for patients progressing on ibrutinib with CLL is around 2 years, and even shorter for Richter's transformation (10,15,17).…”

Section: Discussionmentioning

confidence: 99%

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia

et al. 2017

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The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity, reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease.

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Section: Discussionmentioning

confidence: 99%

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia

et al. 2017

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“…For example, BTK, which phosphorylates and primes DDX41, interacts within multiple other signaling pathways including TOLL like receptor signaling, pre-B cell proliferation and signaling of chemokine receptors in B cell malignancies [67]. Accordingly, the use of a BTK inhibitor, ibrutinib, has been trialed for various lymphoid malignancies, dramatically changing management and outcome for individuals with chronic lymphocytic leukemia in particular [67,68]. STING agonists are currently in the development phase.…”

Section: Future Handling and Treatment Of Ddx41-associated Myeloid Mamentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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“…In a previous review paper, Woyach reported a case of a patient with chronic lymphocytic leukemia (CLL) who experienced similar symptoms to the ones reported here, such as fatigue and night sweats and without actual evidence of disease progression [8]. Woyach goes on then to recommend minimizing temporary holds and using steroids in patients who experience withdrawal symptoms.…”

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confidence: 99%