Novel therapeutics in myeloproliferative neoplasms

Venugopal, Sangeetha; Mascarenhas, John

doi:10.1186/s13045-020-00995-y

Cited by 37 publications

(22 citation statements)

References 95 publications

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“…Indeed, FYN-TRAF3IP2 -dependent lymphoma cells display exquisite sensitivity to the BCL-X L , BCL2 and BCL-W (encoded by Bcl2l2 ) inhibitor ABT-263. ABT-263 is in clinical development for the treatment of myelofibrosis 44 . Thrombocytopenia is the most important side effect of BCL-X L inhibition, but is manageable with appropriate dosing.…”

Section: Discussionmentioning

confidence: 99%

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

et al. 2021

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Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

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Section: Discussionmentioning

confidence: 99%

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

et al. 2021

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“…Though ruxolitinib changed the landscape of MPN management and outlook, there are unmet needs to develop novel drugs or more effective therapeutic strategies for MPN patients. Novel JAK pathway inhibitors are under investigation as well [ 160 , 161 ]. Combination of ruxolitinib with azacitidine and with pelabresib (CPI-0610, a BET inhibitor) is being studied for advanced MPNs [ 162 ].…”

Section: Discussionmentioning

confidence: 99%

Novel agents and regimens for hematological malignancies: recent updates from 2020 ASH annual meeting

Hou

et al. 2021

J Hematol Oncol

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Antibodies and chimeric antigen receptor-engineered T cells (CAR-T) are increasingly used for cancer immunotherapy. Small molecule inhibitors targeting cellular oncoproteins and enzymes such as BCR-ABL, JAK2, Bruton tyrosine kinase, FLT3, BCL-2, IDH1, IDH2, are biomarker-driven chemotherapy-free agents approved for several major hematological malignancies. LOXO-305, asciminib, “off-the-shelf” universal CAR-T cells and BCMA-directed immunotherapeutics as well as data from clinical trials on many novel agents and regimens were updated at the 2020 American Society of Hematology (ASH) Annual Meeting. Major developments and updates for the therapy of hematological malignancies were delineated at the recent Winter Symposium and New York Oncology Forum from the Chinese American Hematologist and Oncologist Network (CAHON.org). This study summarized the latest updates on novel agents and regimens for hematological malignancies from the 2020 ASH annual meeting.

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“…The survival advantage observed in RUX‐again patients highlights the role of appropriate treatment strategies and ruxolitinib use in outcomes. Other JAK2 inhibitors and alternative drugs are currently under clinical investigation and may soon broaden the therapeutic scenario of MF further 35 . Future real‐world evidence will possibly clarify whether the use of ruxolitinib rechallenge will be reduced or abandoned with the advent of new treatments in clinical practice and what criteria should be used to select a patient for one treatment or another.…”

Section: Discussionmentioning

confidence: 99%

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome

Palandri

Tiribelli

Breccia³

et al. 2021

Cancer

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BACKGROUND After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS The authors performed a subanalysis of an observational, retrospective study (RUX‐MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX‐again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX‐stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX‐again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P < .001) and a high Total Symptom Score (TSS; P < .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose > 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX‐again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX‐again patients (P = .004). CONCLUSIONS Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.

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Novel therapeutics in myeloproliferative neoplasms

Cited by 37 publications

References 95 publications

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

Novel agents and regimens for hematological malignancies: recent updates from 2020 ASH annual meeting

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome

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