Researchers Outline Novel Treatment Approaches Being Studied in Myelofibrosis

A recent study outlines several treatments being investigated for the treatment of patients with myelofibrosis (MF) and other myeloproliferative neoplasms (MPNs), generally after they have become resistant or intolerant to Janus kinase (JAK) inhibition, a fundamental of MF treatment.

Although it’s undeniable that the treatment of MPNs has been revolutionized with the use of JAK inhibitors like ruxolitinib, these treatments have been shown to have limited disease-modifying effects and have not demonstrated an ability to prevent the progression of polycythemia vera and essential thrombocythemia to MF or leukemic transformation of MPNs.

Addressing these treatment gaps, several treatments are being studied in patients with MF and related neoplasms, typically in those who have being resistant or intolerant to JAK inhibitor treatment.

For example, telomerase inhibitor imetelstat has shown promise, demonstrating a median overall survival (OS) of 19.9 months for patients receiving 4.7 mg/kg and 28.1 months for patients receiving 9.4 mg/kg of the treatment. For the latter group of patients, 25% achieved a 12-week transfusion independence, 43.2% had a bone marrow fibrosis reduction, and 42.1% had a > 25% reduction in driver mutation allele burden.

Targeting bone marrow fibrosis in MF has also shown promise, with anti-SLAMF7 monoclonal antibody elotuzumab inhibiting fibrocyte differentiation in vitro and ameliorating bone marrow fibrosis and splenomegaly induced by romiplostim in humanized mice. The treatment is expected to be studied in patients with JAK2-mutated MF who are not eligible for JAK inhibitor therapy.

Other treatments being studied include:

• Those activating p53 through murine double minute 2 (MDM2) inhibition. Idasanutlin monotherapy or in combination with pegylated interferon alfa has shown promise in preclinical studies and led to the initiation of a phase 1 trial, and MDM2 inhibitor KRT-232 is currently being studied in patients with TP53 wild-type MF that has relapsed after or is refractory to JAK inhibitor therapy.
• Novel epigenetic therapies. The combination of JAK inhibition and bromodomain and extra-terminal (BET) inhibition has shown promise in preclinical models, and results from the MANIFEST trial assessing ruxolitinib in combination and CPI-0610 has also shown promise.
• Those targeting the anti-apoptotic machinery in MF. The combination of ruxolitinib and BH3-mimetic ABT-737 has demonstrated synergy in preclinical MPN models, which also translated into a clinical trial assessing navitoclax, which is the clinical counterpart of ABT-737. This combination will be compared against ruxolitinib and placebo in 2 phase 3 trials.

Widespread use of JAK inhibitors has also put a spotlight on the need for effective treatments for anemia, a frequent adverse event of the therapy, especially in the first 12 to 24 weeks of treatment. There are several treatments in clinical development to address this.

For example, trials assessing the potential of hepcidin mimetics to achieve superior hematocrit control and therefore reduce or eliminate phlebotomy requirements and correct iron deficiency have been initiated. A phase 2 trial of phlebotomy-requiring patients being treated weekly with novel hepcidin mimetic PTG-300 is currently underway.

The clinical development of activin receptor ligand traps has also been closely followed, with luspatercept being studied in a phase 2 trial assessing the anemia response and hemoglobin improvement or red blood cell-transfusion independence.

“One can already foresee a future scenario in which MF patients with more proliferative disease and robust blood counts are treated with ruxolitinib and fedratinib in combination with a BET inhibitor (eg, CPI-0610) or BH3 mimetic (eg, navitoclax) and those with anemia receive either momelotinib or one of the currently approved JAK inhibitors in combination with luspatercept, while those with severe thrombocytopenia at baseline are offered pacritinib,” wrote the researchers.

Reference

Bose P, Masarova L, Verstovsek S. Novel concepts of treatment for patients with myelofibrosis and related neoplasms. Cancers. Published online October 9, 2020. doi:10.3390/cancers12102891