Final Results of a Phase II Biomarker-Driven Study of Ruxolitinib in Relapsed and Refractory T-Cell Lymphoma

Moskowitz, Alison J.; Ghione, Paola; Jacobsen, Eric; Ruan, Jia; Schatz, Jonathan H.; Noor, Sarah; Myskowski, Patricia L.; Hancock, Helen; Davey, Theresa; Obadi, Obadi; Onwasigwe, Carlissa; Ganesan, Nivetha; Pomerantz, Lauren; Jarjies, Christine; Kumar, Priyadarshini; Sigler, Allison; Geyer, Mark B.; Noy, Ariela; Straus, David J.; Hollmann, Travis J.; Doğan, Ahmet; Galasso, Natasha; Inghirami, Giorgio; Weinstock, David M.; Horwitz, Steven M.

doi:10.1182/blood-2019-125017

Cited by 24 publications

(15 citation statements)

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“…Toward this end, these discoveries may have an effect on the treatment of these lymphomas. Compounds targeting these vulnerabilities, recently described in some systemic ALCL and other T-cell lymphomas [37,46] should be tested in pre-clinical models, opening the way to the possible design of innovative trials for BIA-ALCL patients and other PTCL subtypes. PDTX are optimal platforms for carrying out pre-clinical studies.…”

Section: Discussionmentioning

confidence: 99%

A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries

Fiore

Cappelli

Zumbo

et al. 2020

Cancers

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Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89_CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89_CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89’s sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches.

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Section: Discussionmentioning

confidence: 99%

A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries

Fiore

Cappelli

Zumbo

et al. 2020

Cancers

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“…A synergistic growth inhibitory effect in NKTCL cell lines was also achieved by a combination of Ruxolitinib with the CDK4/6 inhibitor Ribociclib (LEE011) [ 237 ]. This indicates that Ruxolitinib might not only be efficient in myeloid malignancies, but could also be of therapeutic value for patients with lymphoid malignancies [ 100 , 238 , 239 , 240 , 241 , 242 ]. Clinical trials using Ruxolitinib are ongoing for treatment of different cancer entities, such as HTLV1-associated ATL (NCT01712659), relapsed/refractory ETP-ALL (NCT03613428), relapsed/refractory NK-cell or peripheral T-cell non-Hodgkin Lymphoma (NCT01431209, NCT02974647), and ALL (NCT03117751).…”

Section: When An Immune Cell Becomes Cancerous—hijacking Jakinibs’ Immunosuppressive Side Effects For Treatment Of Nk/t-cell Tumorsmentioning

confidence: 99%

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Klein

Stoiber

Sexl

et al. 2021

Cancers

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The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.

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“…A phase II trial of the JAK2 inhibitor ruxolitinib in R/R PTCL and CTCL reported an ORR of 23%, with responses more frequent in the AITL and Nodal Peripheral T-Cell Lymphoma with TFH Phenotype PTCL-TFH) subtypes [63]. Cerdulatinib is a smallmolecule reversible ATP competitive inhibitor of SYK and JAK family members.…”

Section: Jak/stat and Syk Pathway Inhibitorsmentioning

confidence: 99%

Targeted Approaches to T-Cell Lymphoma

Harrop

Abeyakoon

Weyden

et al. 2021

JPM

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The T-cell lymphomas are a rare group of Non-Hodgkin’s lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an understanding of the various critical pathways in T-cell lymphogenesis and subsequent identification of therapeutic targets has led to a rapid expansion of the previously underwhelming T-cell lymphoma armament. This review aims to provide an up-to-date overview of the current state of targeted therapies in the T-cell lymphomas, including novel antibody-based treatments, small molecule inhibitors and immune-based therapies.

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Final Results of a Phase II Biomarker-Driven Study of Ruxolitinib in Relapsed and Refractory T-Cell Lymphoma

Cited by 24 publications

References 0 publications

A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries

A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Targeted Approaches to T-Cell Lymphoma

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