JAK inhibitors (JAKis) play a central role in the treatment of myeloproliferative neoplasms (MPNs), including myelofibrosis (MF). At present, four JAKis are FDA-approved for MF – ruxolitinib, fedratinib, pacritinib, and momelotinib.¹ Although these agents are highly effective in controlling symptom burden and improving splenomegaly in patients, they have limited anti-clonal effect and do not alter the natural history of the disease. This means that many patients still experience disease progression with long-term use, and there is a need for novel agents with disease-modifying effects to improve their long-term outcomes.² A variety of targeted therapies are being developed and explored in this setting, either as monotherapy or in combination with a JAKi.²

Telomerase inhibition has emerged as a potential therapeutic strategy in MF due to the role of the holoenzyme telomerase in maintaining the proliferative capacity of malignant hematopoietic stem cells (HSCs).³ Imetelstat, a telomerase inhibitor, has been evaluated in clinical trials for its efficacy in treating MF. In an initial pilot study (NCT01731951) involving 33 patients with intermediate-2 or high-risk MF, imetelstat induced complete or partial remissions in 21% of participants, with some achieving a molecular response and experiencing reversal of bone marrow fibrosis.³ A subsequent larger clinical trial, the Phase II IMbark study (NCT02426086), assessed imetelstat’s impact on spleen volume, symptom response, and overall survival (OS) in patients refractory to a JAKi. Modest spleen and symptom responses were observed in the trial, and the findings suggested a potential survival benefit, particularly in patients receiving the higher dose of 9.4 mg/kg.⁴

The ongoing Phase III IMpactMF (NCT04576156) study is now evaluating imetelstat further, comparing this agent with best available therapy (BAT). Additionally, the Phase III IMproveMF study (NCT04576156) is investigating a combination of imetelstat with ruxolitinib in patients with a suboptimal response to ruxolitinib monotherapy. At the 66th ASH Annual Meeting and Exposition in San Diego, CA, John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai, New York, NY, highlighted that ‘preclinical data suggest the two [agents] can synergize nicely together’ and shared preliminary data from the dose escalation portion of the trial. These early findings suggest that the combination can be administered in patients with no significant safety concerns or dose-limiting toxicities (DLTs).

In MF, overexpression of murine double minute 2 (MDM2), a negative regulator of the tumor suppressor p53, contributes to the proliferation of malignant HSCs. Inhibiting MDM2 aims to restore p53 function, promoting apoptosis of these TP53 wild-type CD34+ MF cells.⁵ Navtemadlin, an oral MDM2 inhibitor, has been investigated for its potential therapeutic benefits in the Phase III BOREAS trial (NCT03662126), which compared the agent with BAT in patients with relapsed/refractory (R/R) MF. At week 24, 15% of patients receiving navtemadlin achieved a ≥35% reduction in spleen volume (SVR35) versus 5% in the BAT group (p=0.08), and 24% experienced a ≥50% reduction in total symptom score (TSS50) compared with 12% in the BAT arm (p=0.05).⁵ At ASH 2024, Prithviraj Bose, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, commented on the findings of BOREAS and stated that navtemadlin appears to ‘profoundly affect a number of biomarkers that we think are markers of disease modification in myelofibrosis’.

As mentioned by Dr Bose, the development of navtemadlin continues with the Phase III POIESIS trial (NCT06479135). Dr Bose shares more details about the trial, including its unique trial design, in which JAKi-naïve patients are randomized to receive ruxolitinib or placebo, and following this, those who demonstrate a suboptimal response to ruxolitinib treatment are randomized to navtemadlin plus ruxolitinib or navtemadlin plus placebo.

Bromodomain and extraterminal domain (BET) proteins are epigenetic regulators that influence the expression of genes involved in inflammation and hematopoiesis.⁶ In MF, aberrant BET protein activity contributes to disease pathogenesis by promoting pro-inflammatory cytokine production and abnormal megakaryocyte proliferation.⁶ Hence, the inhibition of BET proteins aims to mitigate these pathological processes and have a disease-modifying effect in MF. ​

Pelabresib is an investigational oral BET inhibitor that has been evaluated in the Phase II MANIFEST trial (NCT02158858) alone and in combination with ruxolitinib. In JAKi-naïve patients, the combination of pelabresib plus ruxolitinib resulted in durable improvements in splenomegaly and symptoms. At the week 24 cut-off, 68% of this patient cohort achieved SVR35 and 56% achieved TSS50.⁶

Recently, the primary analysis of the randomized Phase III MANIFEST-2 trial (NCT04603495) was published, evaluating the safety and efficacy of pelabresib plus ruxolitinib versus placebo plus ruxolitinib in JAKi-naïve MF.⁷ The study met its primary endpoint, with the combination therapy showing a statistically significant improvement in the proportion of patients achieving SVR35 at week 24 (65.9% versus 35.2% in the control arm; p<0.001). Although the TSS50 endpoint was not met, there were trends towards a symptom improvement benefit with the combination therapy.⁷ Additionally, the combination was well-tolerated, with no new safety signals identified. ​

Collectively, these data point towards the potential use of pelabresib combined with ruxolitinib to enhance therapeutic outcomes by targeting both inflammatory and proliferative components of the disease. Last year, we spoke to Lucia Masarova, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, at the 1st Annual MPN Workshop of the Carolinas in Asheville, NC, to gain valuable insight into the promise of BET inhibition for treating MF. Dr Masarova highlighted the encouraging findings with pelabresib to date, and emphasized the ‘need to move beyond single agent JAK inhibition’.

Other BET inhibitors are also in development for MF, such as OPN-2853. This agent is being evaluated in combination with ruxolitinib in the PROMise study (ISRCTN12451433). At ASH 2024, we heard the interim results of this trial from Adam Mead, MA, BM, BCh, MRCP, FRCPath, PhD, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Dr Mead stated that ‘very encouraging signals of efficacy’ have been observed with the combination thus far.

In MF, the overexpression of anti-apoptotic proteins B-cell lymphoma–2 (BCL-2) and BCL-extra large (BCL-xL) contributes to the survival and proliferation of malignant HSCs. Navitoclax, a dual inhibitor of BCL-2 and BCL-xL, restores apoptotic processes to promote apoptosis of the malignant cell population. This agent has been investigated in combination with ruxolitinib in the Phase II REFINE trial (NCT03222609), and demonstrated durable responses and early signs of disease modification in patients with MF with suboptimal ruxolitinib response.⁸ Building on these findings, the Phase III TRANSFORM-1 trial (NCT04472598) evaluated the combination of navitoclax and ruxolitinib in JAKi-naïve patients with MF. The study met its primary endpoint, showing a significantly higher SVR35 at week 24 compared to placebo plus ruxolitinib (63.2% versus 31.5%, respectively, p<0.0001).⁹ Similarly, the Phase III TRANSFORM-2 trial (NCT04468984) is assessing this combination in patients who have relapsed or are refractory to JAKis.¹⁰

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that plays a crucial role in regulating HSC differentiation and proliferation.¹¹ In MF, aberrant LSD1 activity contributes to the disease’s pathogenesis by sustaining malignant HSC function and promoting ineffective hematopoiesis. Inhibiting LSD1 aims to restore normal differentiation pathways, thereby reducing the proliferation of malignant cells and ameliorating disease symptoms.¹¹ Bomedemstat is an irreversible LSD1 inhibitor and is the most widely studied agent in this drug class in MPNs. In a Phase II study (NCT03136185) involving patients with advanced MF, the agent was generally well tolerated and demonstrated improvements in symptom burden and reductions in anemia and bone marrow fibrosis.¹² Following this, a Phase II study (NCT05569538) combining bomedemstat with ruxolitinib is actively recruiting.¹³

The phosphoinositide 3-kinase (PI3K) pathway is integral to cell survival, proliferation, and differentiation. Inhibiting PI3K in MF has been proposed to restore sensitivity to treatments like ruxolitinib and suppress malignant cell proliferation.¹⁴ ​A Phase I study evaluated umbralisib, a selective PI3Kδ inhibitor, in combination with ruxolitinib in patients who had a suboptimal response or lost response to ruxolitinib monotherapy. The combination was well-tolerated and showed promising clinical activity. ¹⁴ Additionally, a Phase II study (NCT02718300) investigated parsaclisib, another PI3Kδ inhibitor, as add-on therapy to ruxolitinib in patients with suboptimal response to optimized ruxolitinib therapy. The combination led to reductions in spleen volume and improvements in symptom scores, suggesting enhanced therapeutic benefits.¹⁵ Abdulraheem Yacoub, MD, University of Kansas Medical Center, Kansas City, KS, shared the findings at the 1st Annual MPN Workshop of the Carolinas, highlighting that, although the results of this trial were encouraging, subsequent Phase III studies did not meet their primary endpoints.

Cellular therapies, including CAR T-cell therapy and regulatory T-cell (Treg) therapy, are being explored as innovative treatments for MF.¹⁶ In MF, mutations in the calreticulin (CALR) gene are common, and researchers are developing CAR T-cells to target mutant CALR (mutCALR). At ASH 2024, we heard from Alex Rampotas, MBBS, MRCP, University College London, London, UK, and Zoë Wong, BSc, University of Oxford, Oxford, UK, who have focused their efforts on this. Their preclinical studies have demonstrated that these engineered CAR T-cells can effectively eliminate CALR-mutant cells in vitro and in vivo, suggesting a potential targeted treatment strategy for patients harboring mutCALR.

Additionally, Treg therapies are being investigated to modulate the immune environment in MF. The Phase Ib LIMBER-TREG108 trial (NCT05423691) is evaluating CK0804, an allogeneic CXCR4-enriched Treg cell therapy, as an adjunct to ruxolitinib in patients with a suboptimal response to ruxolitinib alone.¹⁷ This approach aims to enhance therapeutic efficacy by leveraging the immunomodulatory properties of Treg cells, and at ASH 2024, Dr Masarova shared the findings of the trial, including insights from an extensive longitudinal analysis of cytokines in patients on the study. This uncovered ‘an excellent correlation between responders and upregulation of anti-inflammatory cytokines’.

A range of other agents with various targets are in development and under investigation for MF, both in the pre-clinical and clinical stages. These include the histone deacetylase 4 (HDAC4) inhibitor tasquinimod, which will be explored in a Phase II trial (NCT06327100) for patients with primary MF (PMF), post-polycythemia vera MF (post-PV MF), or post-essential thrombocythemia MF (post-ET MF).¹⁸ A Phase I/II, multicenter dose-escalation study (NCT04176198) is currently enrolling and will assess the safety, tolerability, and pharmacokinetics of nuvisertib, a PIM-1 kinase inhibitor, in patients with intermediate or high-risk primary or secondary MF.¹⁹ Finally, the RSK inhibitor PMD-026, which is currently in Phase II development for breast cancer, has shown activity in preclinical models of myeloid malignancies, including MPNs.²⁰ Stephen Oh, MD, PhD, Washington University School of Medicine, St. Louis, MO, provided insight into this work at ASH 2024.

In conclusion, numerous promising avenues for the treatment of MF are being explored and evaluated to move the field beyond single-agent JAKi therapy. These strategies address the complex pathophysiology of MF and may offer novel therapeutic options for patients with limited alternatives.

References

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