Activity of the Janus kinase inhibitor ruxolitinib in chronic lymphocytic leukemia: results of a phase II trial

Spaner, David; Wang, Guizhei; McCaw, Lindsay; Li, Yanmei; Disperati, Patricia; Cussen, Mary-Ann; Shi, Yonghong

doi:10.3324/haematol.2015.135418

Cited by 30 publications

(72 citation statements)

References 15 publications

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“…Importantly, several JAK inhibitors are either approved or being tested in clinical trials for the treatment of several conditions associated with DS –albeit in the typical population–, including myeloproliferative, inflammatory and autoimmune disorders, as well as leukemia (Padron et al, 2016; Spaner et al, 2016; Tefferi et al, 2011; Quintás-Cardama et al, 2010; Shi et al, 2014; Keystone et al, 2015; Jabbari et al, 2015). It should be noted, however, that the dose limiting toxicities of JAK inhibitors, like ruxolitinib, are anemia and thrombocytopenia (McKeage, 2015; Plosker, 2015).…”

Section: Discussionmentioning

confidence: 99%

Trisomy 21 consistently activates the interferon response

Sullivan¹,

Lewis²,

Hill³

et al. 2016

eLife

268

261

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Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.DOI: http://dx.doi.org/10.7554/eLife.16220.001

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Section: Discussionmentioning

confidence: 99%

Trisomy 21 consistently activates the interferon response

Sullivan¹,

Lewis²,

Hill³

et al. 2016

eLife

268

261

View full text Add to dashboard Cite

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“…1D) were undertaken due to the importance of this transcription factor in CLL biology (Tomic et al, 2011; Li et al, 2015; Spaner et al, 2016). STAT3 phosphorylation in response to TLR7- and IL2-signaling involves autocrine production of IL10 (Spaner et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

“…STAT3 is phosphorylated by a number of cytokines including IL6 and type 1 interferons (IFNs) following activation of CLL cells by IL2 and resiquimod (Tomic et al, 2011; Li et al, 2015; Spaner et al, 2016) but we focused first on IL10. Surprisingly, IL10 in culture supernatants measured by ELISAs after 48 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

et al. 2017

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Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6 ± 10.4 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the “watch-and-wait” phase of management.

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“…Importantly, these effects could be reversed following JAK1/3 inhibition by tofacitinib(7). Intriguingly the JAK inhibitor ruxolitinib (n=13), decreased lymphadenopathy and increased lymphocytosis in CLL patients(22), suggesting a role for JAK-inhibition in regulating egress or preventing influx of tumor cell into the lymph node. These effects appeared transient and for that reason the authors hypothesized that a combination of ruxolitinib with BCR-kinase inhibitors may achieve superior results(22).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, results from a phase II clinical trial using the JAK1/2 inhibitor ruxolitinib in 13 CLL patients showed rapid but transient decreases in lymphadenopathy and increased lymphocytosis(22). Together these data highlight a potential strategy for simultaneous inhibition of Syk and JAK in CLL.…”

Section: Introductionmentioning

confidence: 99%

The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia

Blunt

Koehrer

Dobson

et al. 2017

Clinical Cancer Research

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Purpose B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients. Experimental Design PBMCs from CLL patients were treated with cerdulatinib alone or in combination with venetoclax. Cell death, chemokine and cell signalling assay were performed and analysed by flow cytometry, immunoblotting, Q-PCR and ELISA as indicated. Results At concentrations achievable in patients, cerdulatinib inhibited BCR- and IL-4-induced downstream signalling in CLL cells using multiple read-outs and prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production. Cerdulatinib induced apoptosis of CLL cells, in a time- and concentration-dependent manner, and particularly in IGHV unmutated samples with greater BCR-signalling capacity and response to IL-4, or samples expressing higher levels of sIgM, CD49d+ or ZAP70+. Cerdulatinib overcame anti-IgM, IL-4/CD40L or NLC-mediated protection by preventing upregulation of MCL-1- and BCL-XL, however BCL-2 expression was unaffected. Furthermore in samples treated with IL-4/CD40L, cerdulatinib synergised with venetoclax in vitro to induce greater apoptosis than either drug alone. Conclusion Cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax, with the potential to target critical survival pathways in this currently incurable disease.

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Activity of the Janus kinase inhibitor ruxolitinib in chronic lymphocytic leukemia: results of a phase II trial

Cited by 30 publications

References 15 publications

Trisomy 21 consistently activates the interferon response

Trisomy 21 consistently activates the interferon response

Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia

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