Current and emerging therapies

Philadelphia-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematologic malignancies characterized by the abnormal proliferation of blood cells in the bone marrow. MPNs cause significant morbidity in the form of burdensome symptoms, potentially fatal cardiovascular complications, progression to more aggressive disease, and over time, can evolve to acute leukemia.

Although MPNs have diverse characteristics and outcomes, they are driven by shared mutations in JAK2, CALR, and MPL genes, mutations that originate in hematopoietic stem cells (HSC). This is important because HSCs have the ability to regenerate all of the different cell types, including those which are mutated. Developing curative therapies in MPNs would require drugs that target the MPN cell of origin, in this case the mutant HSCs.

Several drugs with various mechanisms have shown clinical efficacy (desired results) in the management of MPN symptoms, i.e., improving enlarged spleen (splenomegaly) and high red or white blood cell counts. Some have additionally shown deep molecular responses, which although controversial, may be considered surrogates for disease-modifying activity.

Currently, however, there is no definitive evidence that any one or combination of these clinical endpoints can reliably predict survival. While these are all important benefits of treatment, we continue in pursuit of treatments capable of reducing disease complications, improving survival, and ideally curing MPNs. This synopsis provides an overview of the current and emerging MPN therapies and their clinical activity.

Conventional therapies such as aspirin, phlebotomy, cytoreductive agents, such as hydroxyurea, and interferon alpha (IFN) have been the mainstay of MPN treatment for decades. Significant advancements have been made in recent years with the development of novel targeted therapies and the recognition of IFN as an important disease-modifying agent.

Although IFN was used for decades in the treatment of PV, ET, and early primary and secondary myelofibrosis (MF), phase 3 randomized trials were only recently conducted. In PV, ropeginterferon alfa-2b treatment was associated with higher clinical, hematological, and molecular responses over hydroxyurea in “high-risk” patients and over phlebotomy alone in “lowrisk” patients. The PROUD-PV study led to the first FDA approval of an IFN for PV in 2021. Although survival was not compared in these randomized studies, retrospective analyses of PROUD-PV and a large single center cohort identified event-free, myelofibrosis-free, and overall survival (OS) benefits with IFN.

The JAK inhibitors were the first targeted agents developed soon after the JAK2V617F driver mutation was identified (2005), now understood to be present in more than 60% of all MPNs. Ruxolitinib, an oral JAK1/JAK2 inhibitor, was the first approved in the U.S. for the treatment of intermediate and high-risk MF after demonstrating significant improvement in symptom burden and spleen volume reduction (SVR), compared to placebo or best available therapy (BAT) in COMFORT-I and II trials, respectively. Analysis of long-term trial data identified an overall survival benefit. In PV, ruxolitinib is a second line treatment. A retrospective study identified its long-term potential for achieving deep, even complete molecular responses coupled with a myelofibrosis-free survival benefit, but further data on its long-term safety and OS benefit in PV are required.

More recently, JAK inhibitors fedratinib and pacritinib were approved for MF by the U.S. Food and Drug Administration (FDA), based on superior SVR to placebo and BAT in the JAKARTA and PERSIST-2 trials, respectively. Because pacritinib is a selective JAK2 and IRAK1 inhibitor with potentially lower likelihood for treatment-induced thrombocytopenia (when platelet counts are too low), the PERSIST-2 trial compared pacritinib to BAT (including ruxolitinb) in thrombocytopenic MF patients.

These positive results led to approval of pacritinib as a first-line treatment of thrombocytopenic MF patients. Retrospective analysis of PERSIST-2 data indicated additional benefit of pacritinib in treatment of anemia, with the hypothesized mechanism being inhibition of the ACVR1 pathway. Lastly, momelotinib is an emerging JAK and ACVR1 inhibitor with positive clinical response, including anemia benefit, shown in the SIMPLIFY-1 and MOMENTUM trials. It is currently in the FDA approval review process.

Emerging therapies in MPNs, primarily MF, now include bromodomain and extra-terminal (BET) inhibitors that target the epigenetic regulators of gene expression, thus changing the level of expression of those target genes. These emerging therapies include CPI-0610, ABBV-744, and INCB054329, in different stages of development for MF and ET. CPI-0610 (pelabresib) is currently in a phase 3 randomized, double-blind, placebo-controlled trial in combination with ruxolitinib as upfront treatment for MF (MANIFEST-2) (NLM, NCT04603495). The phase 2 results showed significant spleen volume reduction, symptom response, anemia benefit, and fibrosis
reversion as monotherapy or in combination with ruxolitinib, in patients who either had never taken a JAK inhibitor, it was not effective, or it stopped working after a time (relapsed/refractory to ruxolitinib).

Other agents in phase 3 studies for myelofibrosis include navitoclax (TRANSFORM-2) (NLM, NCT04468984), imetelstat (IMpactMF) (NLM, NCT04576156), navtemadlin (BOREAS) (NLM, NCT03662126), and luspatercept (INDEPENDENCE)(NLM, NCT04717414).

Navitoclax is a novel BCL-2 and BCL-X inhibitor that also showed significant clinical responses, molecular responses, and fibrosis reversion when added to ruxolitinib in the phase 2 study for patients with relapsed or refractory disease. In a post-hoc analysis, patients who achieved both molecular response and fibrosis reversion on this study had a higher overall survival.

Imetelstat inhibits telomerase, an enzyme crucial for maintaining telomere length in cancer cells. As cancerous cells divide, telomeres, a region of repetitive DNA at the ends of chromosomes, become shorter. Telomerase is increased to prevent this shortening and its associated cancer cell survival. The phase 2 study design was unique in randomizing patients to either of two dose levels of imetelstat and incorporating overall survival as a secondary endpoint. Given the encouraging survival results, the phase 3 was designed with overall survival being the primary endpoint.

Navtemadlin is an inhibitor of the MDM2, an oncoprotein (associated with the growth of cancer cells), and negative regulator of p53, a protein that acts as a tumor suppressor. The study was advanced to phase 3 after preliminary safety and efficacy was established in phase 1b/2 for treatment of p53 wildtype MF, relapsed or refractory to ruxolitinib.

Both imetelstat and navtemadlin were granted fast-track designation by the FDA. Finally, luspatercept is a TGF superfamily ligand trap – which effectively reduces TGF signaling. It is already FDA approved for treatment of patients with transfusion dependent anemia from myelodysplastic syndromes (MDS) and beta thalassemia, an inherited blood disorder characterized by low or dysfunctional hemoglobin. The phase 3 randomized, placebo-controlled trial for MF, combined with a JAK inhibitor, is open to enrollment after results of phase 2 identified safety and notable improvements in anemia and transfusion burden.

Progress made in MF treatment provides an optimistic outlook for ET and PV patients. Beyond conventional cytoreductive treatment for ET, emerging agents in clinical trial include ropeginterferon alfa-2b, pelabresib, and bomedemstat (a lysine-specific demythelase-1 [LSD1] inhibitor). In PV, there is accumulating interest in treatment targeting iron metabolism to normalize erythropoiesis (production of red blood cells) and correct iron deficiency.

Also noteworthy are the profound hematocrit responses, phlebotomy independence rates, and iron normalization in patients treated with rusfertide, which mimics hepcidin, an iron-regulating hormone. Currently in phase 2 clinical trial, the ongoing phase 3 (VERIFY) (NLM, NCT05210790) will determine safety and efficacy of this agent as monotherapy, to replace the need for phlebotomy, or as an add-on to cytoreductive therapy in refractory patients.

While several drugs are in the clinical trial pipeline, there is also a multitude of promising preclinical research examining novel MPN treatments. Immunotherapy approaches, including vaccines and monoclonal antibodies, are high on this list. For CALR mutant MPNs, a clinical trial is highly anticipated for the recently discovered anti-CALR antibody that may selectively target mutant cells including HSCs.

In summary, the treatment landscape for MPNs is rapidly evolving, with a shift towards targeted drugs and combinations that provide improved efficacy and tolerability to current and conventional therapy, as well as disease-modifying activity to improve the overall survival of MPN patients. With several candidate drugs in the investigational pipeline, the outlook for MPN patients is becoming increasingly optimistic, with the potential for improved outcomes and enhanced quality of life.