Leukemia | 2021
Paradigm shift: combination BET and JAK inhibition in myelofibrosis
Abstract
Myelofibrosis (MF) is a clonal hematologic neoplasm that is characterized by myeloproliferation with bone marrow fibrosis, a pro-inflammatory state, aberrant hematopoietic stem cell (HSC) trafficking with extramedullary hematopoiesis, and potential for clonal evolution to acute myeloid leukemia (AML) [1]. Hyperactivity of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway due to acquisition of somatic driver mutations involving JAK2, CALR, and MPL is central to the pathogenesis of this myeloid malignancy [2]. In addition, constitutive activation of NF-kB in CD34+ MF cells is directly mediated by cell-autonomous downstream consequences of JAKSTAT signaling as well as non-cell-autonomous TNFα driven activation [3]. Aberrant activation of JAK-STAT and NF-kB target gene expression leads to the elaboration of a pathologic proinflammatory state that fuels the disease process. Recognition of this pathobiological feature led to the development and eventual approval of JAK inhibitors (JAKi; ruxolitinib, fedratinib) that are effective in addressing spleen and symptom burden, at the expense of worsening blood counts, but fail to meaningfully alter the natural course of disease for most patients [4, 5]. Despite the significant clinical benefit of JAKi, areas of unmet need remain present and include alleviation of anemia, effective therapy after JAKi failure, and ultimately a disease remission as a goal of therapy. A variety of mechanism-based agents supported by pre-clinical data are under clinical investigation targeting, for example, PI3k, BCL-xL, LSD1, telomerase, and TGF-β [6]. Most of these novel agents have been tested in the setting of ruxolitinib failure which lacks a unified definition but has been associated with a median overall survival (OS) of approximately 12–15 months [7–9]. Agents such as parsaclisib (PI3k inhibitor) and navitoclax (BCL-xL inhibitor) have positive phase 2 data as an add-on strategy for those MF patients with a “suboptimal response” to ruxolitinib treatment in improving spleen and symptom burden [10, 11]. Whereas, bomedemstat (LSD1 inhibitor) has such single-agent data from a phase 1/2 study in patients that have failed and discontinued ruxolitinib treatment [12]. In the same patient population imetelstat (telomerase inhibitor) uniquely has data demonstrating on-target activity and correlation of disease modification with progression-free survival (PFS) and OS benefit [13]. Bromodomain and extraterminal (BET) family proteins are epigenetic reader proteins that bind lysine residues on histone and non-histone proteins and facilitate transcription of gene sets regulated by NF-κB, C-Myc, and TGF-β [14]. BRD 2, 3, 4, and BRDT are members of the BET family proteins and facilitate gene expression through the recruitment of transcription factors and cofactors as well as coordinate activation of RNA polymerase II [15]. BET inhibitors are a novel class of agents that competitively bind the acetylated protein binding bromodomain pocket and interfere with chromatin binding [15]. Elegant pre-clinical work by Kleppe and Levine first demonstrated synergy between JAK and BET inhibition in reducing disease burden in both MPLand JAK2mutated MPN mouse models with resultant prolongation of survival [16]. Interestingly, recent evidence linking BET inhibition to BCL-2 downregulation through BIM is relevant in the context of the concurrent development of navitoclax in MF [17]. BET inhibition, therefore, has a substantial rationale for the treatment of MF as a single agent or in combination with JAKi (Fig. 1). CPI-0610 (pelabresib) is an oral pan BET inhibitor in clinical development [18]. An early signal of clinical activity was seen in the phase 1 portion of the MANIFEST study (NCT02158858) that identified the recommended phase 2 dose of pelabresib as 125 mg daily for 14 days of a 21-day cycle. The ongoing phase 2 portion of the study includes three arms: single-agent pelabresib after ruxolitinib discontinuation (arm 1), add-on of pelabresib to ruxolitinib for those MF patients with a suboptimal response to ruxolitinib (arm 2), and combination therapy of pelabresib and ruxolitinib in JAKi naïve MF patients (arm 3). In all 3 arms significant improvements in spleen and symptom burden, as well as anemia benefits, were recorded [19, 20]. Correlative studies done on samples from patients participating in the MANIFEST study provide evidence for biological modifications that may explain the clinical activity. Based on these findings, the ongoing MANIFEST-2 trial is a randomized, phase 3, double-blind, study of JAKi naïve MF patients pitting ruxolitinib and placebo against ruxolitinib and pelabresib for control of spleen and symptom burden (NCT04603495). Undoubtedly, pelabresib has demonstrated clinical activity of significance, with on-target correlative data suggesting disease biology modification and has inspired the rapid evaluation of several BET inhibitors in MF (Table 1). Although the MANIFEST-2 trial may ultimately prove superiority of the combination over ruxolitinib alone, response duration will be watched with a keen eye. We believe that the real benefit of the combination of ruxolitinib and pelabresib, or any JAKi based combination therapy in the first-line setting, will be the durability of response and the