Investigational Agents for JAKi-Refractory Myelofibrosis

John O. Mascarenhas, MD

JAK inhibitors (JAKis) have an undeniable role in the first- and second-line treatment of myeloproliferative neoplasms (MPNs). But after JAKis, promising novel mechanisms may be implemented to improve patient outcomes.¹ 

During the 14th International Congress on Myeloproliferative Neoplasms, John O. Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancer and Myeloid Disorders at the Tisch Cancer Institute, discussed 3 targeted therapies for patients with MPNs; navtemadlin (AMG-232), imetelstat (MYF3001), and bomedemstat (IMG-7289).

Navtemadlin

Results from a phase 2 study (NCT03662126) indicate that navtemadlin may have a disease-modifying effect in myelofibrosis (MF).²

“This is an MDS inhibitor. It belongs to a class of drugs that bind MDM2, and MDM2 is upregulated in MPNs, and the MDM2 negatively regulates wildtype p53. If you interrupt that interaction, you turn on a p53 pathway that [causes] the downstream effects that lead to cell death and senescence” explained Mascarenhas, during his presentation.¹

The phase 2 study assessed 111 patients with relapsed or refractory (R/R) MF of which 108 had 1 or more driver mutation, and 75 had 1 or more mutation in an HMR gene. Further, driver mutations in JAK2 were reported in 73% of patients, CALR were found in 19%, and MPL were found in 12%.

Navtemadlin demonstrated spleen response that were associated with reductions of MPN-driver mutation burden, decreased peripheral CD34+ cell counts, improvements in bone marrow fibrosis scores, and reduction in TNFα. Results specifically showed that a best driver gene reduction ≥ 20% was observed in 34% of the patients with mutations in driver genes and HMR variant allele fraction (VAF) reductions. Twenty-nine percent of those patients showed a complete VAF reduction. The reduction in driver allele VAF at any time on study was significantly associated withsystemic vascular resistance (SVR). Reportedly, ≥ 20% of patients had SVR responses vs < 20% decrease in driver VAFs (32% vs 5%; P = .0072).

According to Mascarenhas, navtemadlin was introduced to the clinic after early data, and hematologists/oncologists have encountered serious toxicity, specifically gastrointestinal (GI) toxicity. Because of the safety/tolerability profile of navtemadlin, other agents in the same class may offer better results, explained Mascarenhas. One example is the telomerase inhibitor, imetelstat (MYF1001), which has less GI toxicity.

Imetelstat

Imetelstat is a first-in-class agent that has been shown to be competitive compared with other drug in its class. Because the telomerase enzyme is highly upregulated in cancerous progenitor cells, treatment with an agent like imetelstat can allow continued and uncontrolled proliferation, according to Mascarenhas.¹

Research has shown that disease modification with a telomerase inhibitor can improve survival.1 According to Mascarenhas, such an agent leads to dose-dependent fibrosis improvement, and fibrosis improvement correlates with a loner median overall survival (OS). Moreover, telomerase inhibition is associated with at least a 20% reduction in VAF, which can also prolong OS, Mascarenhas explained.¹

In a phase 2 study (NCT02426086), imetelstat showed clinical benefit in symptom response rate in the refractory MF population. The safety of profile of the agent at the 4.7 mg/kg once every 3-week dose level was acceptable in the poor-risk population.³

In the 107 patients treated with imetelstat in the study, the median OS was 29.9 months. There was a bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. As Mascarenhas alluded to during his explanation of telomerase inhibition, fibrosis improvement and VAF reduction in the phase 2 study correlated with OS. Regarding safety, the most common adverse events (AEs) in both treatment arms were grade 3 or 4 cytopenia. All AEs in the study were reversible.

Bomedemstat

Although LSD1 inhibition is no longer a popular treatment strategy, Mascarenhas explained that due to its mechanism of action, there is rationale and a window of opportunity to capitalize on the target. One LSD1 inhibitor showing promise is bomedemstat (IMG- 7289).¹

Phase 2 data (NCT03136185) show that bomedemstat administered once daily is safe and improves symptom burden, spleen size, and anemia in patients with advanced MF. The study investigated this agent in 89 patients who had a median age of 68 years (range, 35-88) and were predominantly male (52%). The majority of patients in the study had high-risk disease (40%).⁴

At 24 weeks, 89% of patients had a reduction in total symptom score with a mean change of -36%. Thirty-nine of those patients had a ≥ 50% reduction. Among the 27 patients who were evaluable for SVR, 78% had a reduction in spleen volume from baseline with a mean SVR of -4, and 37% of them showed ≥ 20% SVR.

Safety results showed that diarrhea and dysgeusia (28% each) were the most common non-hematologic AEs reported by patients in the study. Serious cases of thrombocytopenia were observed during the study. The results showed no new safety signals or dose-limiting toxicities related to bomedemstat. Further, there were no treatment-related deaths during the study.

“The future will include multiple JAK inhibitor niches. Combination therapy approaches, upfront, and second-line therapy have been showing new and novel agents that can use after a JAKi failure. I think our goal should focus on its survival benefits. We need to move on beyond slated symptoms and start improving survival in patients with this disease,” Mascarenhas concluded.

_REFERENCES:

_{1. Mascarenhas J. Promising new MPN treatments. Presented at: 14th International Congress on Myeloproliferative Neoplasms; October 27-28, 2022; Brooklyn, NY.}

_{2. Vachani P, Lange A, Delgado RG, et al. Potential disease-modifying activity of navtemadlin (KRT-232), a first-in-class mdm2 inhibitor, correlates with clinical benefits in relapsed/refractory myelofibrosis (MF). Blood. 2021;138(suppl 1):3581. doi:10.1182/blood-2021-147543}

_{3. Mascarenhas J, Konrokji RS, Palandri F, et al. Randomized, single-blind, multicenter phase ii study of two doses of imetelstat in relapsed or refractory myelofibrosis. J Clin Oncol. 2021;39(26): 2881-2892. doi:0.1200/JCO.20.02864}

_{4. Gill H, Yacoub A, Pettit KM, et al. A phase 2 study of the LSD1 inhibitor IMG-7289 (bomedemstat) for the treatment of advanced myelofibrosis. Blood. 2021;138(suppl ):139. doi:10.1182/blood-2021-148682}