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

Hing, Zachary A.; Mantel, Rose; Beckwith, Kyle A.; Guinn, Daphne; Williams, Erich; Smith, Lisa L.; Williams, Katie; Johnson, Amy J.; Lehman, Amy; Byrd, John C.; Woyach, Jennifer A.; Lapalombella, Rosa

doi:10.1182/blood-2015-01-621391

Cited by 88 publications

(63 citation statements)

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“…Together with the novel anti-CD20 obinutuzumab [152] and other promising agents (the BCL2 inhibitor ABT-199 [153], the XPO1 inhibitor selinexor [154], CD47 agonist [155]), these treatments may exert different pressure on CLL clonal evolution and may modify prognostic stratification and evolutionary trajectories, as evaluated until now.…”

Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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“…37 Similarly, the XPO1/CRM1 inhibitor selinexor has been shown to suppress BTK gene expression and to be effective in cell lines with BTK C481S mutations, as well as an in vivo model of ibrutinib resistance. 38 Certainly there are other agents and pathways with the potential for utility in this group of patients, and further study is needed to identify promising targets.…”

Section: Other Promising Drugs and Targetsmentioning

confidence: 99%

How I manage ibrutinib-refractory chronic lymphocytic leukemia

Woyach

2017

Blood

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The introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia (CLL). Although responses have been durable in the majority of patients, relapses do occur, especially in the high-risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes after ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population. Here, I discuss the diagnosis and management of ibrutinib-refractory CLL. The focus will be on common clinical scenarios that can be mistaken for relapse and how to accurately determine which patients are relapsing. Because there is no established standard of care, I discuss currently available options for standard therapy and existing clinical data. I also discuss new agents with the potential to be effective in patients refractory to ibrutinib. Finally, I discuss strategies for long-term disease control in this patient population.

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“…One patient with Richter's transformation responded to selinexor with a 60% nodal response and subsequently underwent stem cell transplantation. Recently, synergistic activity of selinexor with ibrutinib was demonstrated in a mouse model with CLL and this agent has also demonstrated activity in CLL cells harboring BTK mutations [137].…”

Section: Selinexor (Previously Kpt-330)mentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

134

108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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

Cited by 88 publications

References 14 publications

Chronic lymphocytic leukemia: Time to go past genomics?

Chronic lymphocytic leukemia: Time to go past genomics?

How I manage ibrutinib-refractory chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL)—Then and now

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