Management of Waldenström macroglobulinemia in 2020

Castillo, Jorge J.; Treon, Steven P.

doi:10.1182/hematology.2020000121

Cited by 27 publications

(20 citation statements)

References 49 publications

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“…Based on these data, ibrutinib and other BTK inhibitors have become the preferred CLL treatment to date. A similar development has taken place in Waldenström's macroglobulinemia, WM (14).…”

Section: Introductionsupporting

confidence: 55%

“…The C481 mutants are not exclusively seen during ibrutinib treatment, they are also found in patients treated with other irreversible BTKi that target C481, namely acalabrutinib ( 57 ) and zanubrutinib ( 58 ). Furthermore, resistance mutations not only appear in CLL, but also in MCL ( 59 ), marginal zone leukemia (MZL) ( 60 ) and Waldenström’s macroglobulinemia ( 14 , 61 ).…”

Section: Resistance Mutations Predominantly Affect Btkmentioning

confidence: 99%

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Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the BTK gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic BTK driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.

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Section: Introductionsupporting

confidence: 55%

Section: Resistance Mutations Predominantly Affect Btkmentioning

confidence: 99%

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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“…Importantly, a multinational phase I/II study demonstrated the efficacy of acalabrutinib in ibrutinibintolerant CLL patients, verifying its reduced toxicities compared to ibrutinib (Isaac and Mato, 2020). Clinical trials have also shown the efficacy of acalabrutinib monotherapy in patients with WM (Castillo et al, 2020a;Castillo and Treon, 2020;Owen et al, 2020), which bodes well for additional FDA approval of acalabrutinib in the treatment of WM. A number of ongoing clinical trials are evaluating the effects of acalabrutinib, as monotherapy or in combination therapies with other regimens, in patients with DLBCL (monotherapy or in combination with R-CHOP, KRT-232 or vistusertib), FL (in combination with rituximab or pembrolizumab), MZL (in combination with tafasitamab), MM (monotherapy or in combination with dexamethasone), B-ALL (in combination with ACP-319), posttransplant LPD (in combination with rituximab), PCNSL and SCNSL (in combination with durvalumab) 1 .…”

Section: Introductionmentioning

confidence: 80%

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

Zhu

Gokhale

Jung

et al. 2021

Front. Cell Dev. Biol.

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The clinical success of the two BTK inhibitors, ibrutinib and acalabrutinib, represents a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) and has also revolutionized the treatment options for other B cell malignancies. Increasing evidence indicates that in addition to their direct effects on B lymphocytes, both BTK inhibitors also directly impact the homeostasis, phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL patients. In this review, we attempt to provide an overview on the overlapping and differential effects of ibrutinib and acalabrutinib on specific receptor signaling pathways in different immune cell subsets other than B cells, including T cells, NK cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells, dendritic cells, osteoclasts, mast cells and platelets. The shared and distinct effects of ibrutinib versus acalabrutinib are mediated through BTK-dependent and BTK-independent mechanisms, respectively. Such immunomodulatory effects of the two drugs have fueled myriad explorations of their repurposing opportunities for the treatment of a wide variety of other human diseases involving immune dysregulation.

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“…A recent study shows that overexpression of CXCR4 in CD8+ T-cells redirects them to CXCR12+ cells in the BM vascular niche and promotes their memory differentiation and anti-tumor response ( Khan et al, 2018 ). Instead, use of CXCR4-targeting agents holds promise for treatment of the patients with B-cell lymphomas including WM ( Castillo and Treon, 2020 ). Chemotherapeutic agent, such as ibrutinib that targets B-cell receptor signaling and is used in the treatment of certain B-cell lymphomas could also interfere with the interaction of tumor cells with the BM niche.…”

Section: Clinical Relevancementioning

confidence: 99%

Role of the Bone Marrow Niche in Supporting the Pathogenesis of Lymphoid Malignancies

Jalali

Ansell

2021

Front. Cell Dev. Biol.

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While the bone marrow (BM) microenvironment is the primary location for nurturing the multipotent hematopoietic stem cells and developing the blood cells of either myeloid or lymphoid origin under normal physiological conditions, it could provide a supportive milieu for the proliferation of blood cancer cells. In fact, the multiple and complex direct cell-to-cell or indirect soluble factors-mediated interactions taking place among the BM cells of different origins are shown to play a significant role in tumorigenesis of hematological cancers. In the current review, we focus on lymphoid malignancies and highlight the novel insights surrounding the role of both cellular as well as non-cellular BM compartments in modulating hematopoiesis and promoting growth and proliferation of cancer cells across a variety of aggressive and indolent lymphoid malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia. We also discuss the mechanisms of potential intervention and discuss their therapeutic impact in clinical settings.

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Management of Waldenström macroglobulinemia in 2020

Cited by 27 publications

References 49 publications

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

Role of the Bone Marrow Niche in Supporting the Pathogenesis of Lymphoid Malignancies

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