LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone

Jutzi, Jonas S.; Kleppe, Maria; Dias, Jennifer; Staehle, Hans Felix; Shank, Kaitlyn; Teruya‐Feldstein, Julie; Gambheer, Sudheer Madan Mohan; Dierks, Christine; Rienhoff, Hugh Y.; Levine, Ross L.; Pahl, Heike L.

doi:10.1097/hs9.0000000000000054

Cited by 79 publications

(61 citation statements)

References 55 publications

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“…32,86 One promising agent is the orally available LSD1 inhibitor IMG-7289 (bomedemstat) that had shown promising effects in animal models and is currently being tested in a phase I/II study in myelofibrosis patients intolerant of or refractory to ruxolitinib (NCT03136185). 87,88 Preliminary results from this trial showed an SVR in 50% of patients (not defined as ≥35% as in other trials) and ≥50% symptom reduction in 21% of patients. 88 However, it remains to be seen what the final results using more stringent response criteria show before the role of IMG-7289 in the treatment landscape of myelofibrosis can be evaluated.…”

Section: Discussionmentioning

confidence: 75%

<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

Bewersdorf¹,

Jaszczur²,

Afifi³

et al. 2019

CMAR

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Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke's encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.

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Section: Discussionmentioning

confidence: 75%

<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

Bewersdorf¹,

Jaszczur²,

Afifi³

et al. 2019

CMAR

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“…This phase 2 study of IMG in myelofibrosis is continuing to accrue, and a second phase 2 trial to assess efficacy in patients with essential thrombocytosis has also recently opened. In a preclinical model of MPN, synergistic effects were seen with the combination of IMG, with commercially available JAK inhibitor, ruxolitinib, supporting further clinical evaluation of this combination strategy in future MPN patients [32].…”

Section: Expert Opinionmentioning

confidence: 74%

“…In the laboratory, LSD1 inhibition in mouse models of JAK2 mutant MPN significantly enhanced peripheral count, decreased splenomegaly, and reduced inflammatory cytokine levels as well as bone marrow fibrosis consistent with disease control. In addition, a reduction in the allelic burden of mutant JAK2V16F and significantly improved overall survival were observed [32]. Results of a recent phase I/2a study of IMG in patients with high risk or intermediate 2 risk myelofibrosis (MF) confirmed that this drug was well tolerated with only one patient developing a significant adverse effect related to IMG (painful splenomegaly).…”

Section: Expert Opinionmentioning

confidence: 95%

“…In addition, IMG-7289 has also been shown to increase apoptosis and decrease proliferation in SET-2, an AML cell line derived from JAK2V16F mutated patient with post-ET-AML. IMG treatment increased methylation of TP53 (more active in apoptosis than demethylated TP53) and the amount of TP53, increasing levels of p53 upregulated modulator of apoptosis, and decreasing levels of BCL XL [32]. IMG is currently being evaluated with/without ATRA in phase I/II trial in patients with AML and MDS (NCT02842827).…”

Section: Img-7289 (Img)mentioning

confidence: 99%

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What potential is there for LSD1 inhibitors to reach approval for AML?

Pandey

Wang

2019

Expert Opinion on Emerging Drugs

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“…Third, bomedemstat (IMG-7289), an inhibitor of LSD1, an enzyme essential for platelet formation ( 86 ), was recently granted FDA fast-track designation for the treatment of ET patients (NCT04254978). In murine models of MPN, IMG-7289 has shown efficacy in reducing inflammation, splenomegaly and fibrosis, in addition to prolonged survival ( 87 ). IMG-7289 killed Jak2 V617F -mutant cells selectively and synergized with Jak inhibition in pre-clinical MPN mouse models ( 87 ).…”

Section: Therapeutic Targeting Of Soluble Mediators the Malignant Bomentioning

confidence: 99%

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

Jutzi

Mullally

2020

Front. Immunol.

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Philadelphia-negative myeloproliferative neoplasms (MPN) are malignant bone marrow (BM) disorders, typically arising from a single somatically mutated hematopoietic stem cell. The most commonly mutated genes, JAK2 , CALR , and MPL lead to constitutively active JAK-STAT signaling. Common clinical features include myeloproliferation, splenomegaly and constitutional symptoms. This review covers the contributions of cellular components of MPN pathology (e.g., monocytes, megakaryocytes, and mesenchymal stromal cells) as well as cytokines and soluble mediators to the development of myelofibrosis (MF) and highlights recent therapeutic advances. These findings outline the importance of malignant and non-malignant BM constituents to the pathogenesis and treatment of MF.

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LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone

Abstract: Supplemental Digital Content is available in the text

Cited by 79 publications

References 55 publications

<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

<p>Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis</p>

What potential is there for LSD1 inhibitors to reach approval for AML?

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

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