Future of Myelofibrosis Treatment is Moving Beyond Just JAK Inhibition

Article

The future of myelofibrosis may include several JAK inhibitor treatment niches as well as combination regimens with JAK inhibition in both the upfront and second-line setting and more, according to John Mascarenhas, MD.

John Mascarenhas, MD

John Mascarenhas, MD

Many exciting new targets and innumerable agents are currently in development to treat patients with myelofibrosis beyond just treatment with JAK inhibition, according to John Mascarenhas, MD. He suggested that the future of myelofibrosis will include several JAK inhibitor treatment niches as well as combination regimens with JAK inhibition in both the upfront and second-line setting, plus agents that may offer overall survival (OS) benefit.1

In a presentation during the 26th Annual International Congress on Hematologic Malignancies, hosted by Physician’s Education Resource®, Mascarenhas, a professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute, detailed the many emerging modalities for treating myelofibrosis, both for patients being treated in the frontline setting and for those who have received prior ruxolitinib (Jakafi) treatment.

Reducing Symptom Burden

Currently, ruxolitinib is standard of care for patients with intermediate- or high-risk myelofibrosis. However, when individual symptoms plague patients, such as anemia and cytopenia, newer agents are also being considered to improve quality of life and survival.

Luspatercept-aamt (Reblozyl) is a recombinant fusion protein that was FDA approved in 2020 to treat anemia in patients with myelodysplastic syndromes.2

In myelofibrosis, luspatercept was investigated in patients requiring red blood cell (RBC) transfusions, whether or not they were also receiving ruxolitinib, in the phase 2 ACE-536-MF-001 trial (NCT03194542). Patients in the study received subcutaneous luspatercept 1.0 mg/kg with titration up to 1.75 mg/kg every 3 weeks for up to 168 days.

In cohorts of patients who had received an RBC transfusion within the past 12 weeks (21 not receiving ruxolitinib, 22 receiving stable doses of ruxolitinib), the investigators found that more patients who were receiving ruxolitinib were able to achieve RBC transfusion independence for at least 12 weeks (27% vs 10%, respectively) and have at least 50% transfusion burden reduction (46% vs 37%) than patients who were not receiving the JAK inhibitor.3

“[It’s a] very well tolerated drug…. It’s like giving an ESA [erythropoiesis-stimulating agent], subcutaneous injection every 3 weeks, minimal toxicity, and when you get a response, it can be quite gratifying, at least in addressing anemia,” commented Mascarenhas. He also noted that the agent is being further explored in the phase 3 INDEPENDENCE trial (NCT04717414) for patients with myelofibrosis who require RBC transfusion and are receiving concomitant JAK inhibition.

Additionally, Mascarenhas referenced pacritinib, a JAK2/IRAK1 inhibitor, which he said was expected to be approved by the FDA the following day for the treatment of patients with myelofibrosis who had mild fibrosis and low platelet counts. “We look forward to the ability to use this drug in our armamentarium of treatment for [patients with] myelofibrosis,” he said.

Novel Therapies Beyond JAK Inhibition

Mascarenhas explained that when patients discontinue treatment with ruxolitinib—and about half have done so by year 3 of treatment4—their survival outcomes are quite poor, with a median survival of about 14 months.5 “This represents an urgent unmet need,” he said.

Among the agents furthest in development, Mascarenhas highlighted pelabresib, imetelstat, navitoclax, parsaclisib, and navtemadlin.

BET Inhibition

BET inhibition has been explored for use in multiple malignancies but has not yet found its niche, according to Mascarenhas, but myelofibrosis could be the exception. Preclinical data show that BET inhibition could be synergistic with JAK inhibition in myelofibrosis, which led to the investigation of pelabresib (CPI-0610) in the MANIFEST trial (NCT02158858). This was a multi-cohort study that looked at the use of the BET inhibition with or without added ruxolitinib in patients who did or did not receive prior JAK inhibition.

In the third cohort of patients who were naïve to JAK inhibition who received pelabresib plus ruxolitinib in the study, the spleen volume response (SVR) at 24 weeks was 72% in patients with intermediate-1 disease by Dynamic International Prognostic Scoring System (DIPSS) criteria, and a 64% SVR rate at 24 weeks for patients with intermediate-2 or high-risk disease. Overall, the SVR rate was 67% (95% CI, 54%-78%). Additionally, 57% (95% CI, 43%-69%) of patients experienced a total symptom score (TSS) improvement of at least 50% and one-third of patients had an improvement in their bone marrow fibrosis.6

Mascarenhas noted that the combination was well tolerated and associated with less myelosuppression than with other drugs in development for myelofibrosis. Only 3% of patients had reported treatment-emergent adverse events (TEAEs) leading to discontinuation from pelabresib, and only 2 grade 5 events were reported of multiorgan failure due to secondary sepsis.

The phase 3 MANIFEST-2 trial (NCT04603495) is an ongoing pivotal, registrational study continuing to look at the use of pelabresib plus ruxolitinib vs ruxolitinib alone in those with primary or secondary myelofibrosis who have not received prior JAK inhibition.

“To me, the most meaningful end point of the study is not necessarily how many patients can get SVR 35%, but rather the durability of response. The longer you can keep people in response with a JAK inhibition, …the higher the response, the better they will do overall,” Mascarenhas said.

BCL-2/BCL-XL Inhibition

Another agent that can improve upon ruxolitinib monotherapy is BCL-2/BCL-XL inhibition with navitoclax, according to Mascarenhas.

In the phase 2 REFINE study (NCT03222609), navitoclax was combined with ruxolitinib in patients with relapsed or refractory primary or secondary myelofibrosis, building on preclinical evidence of potential synergy between the classes of agents.

Twenty-seven percent of patients in the study achieved SVR of at least 35% at week 24 and 30% achieved TSS reduction of at least 50% at week 24. Also, 29% had improvement of bone marrow fibrosis of at least 1 grade at any time.7

Grade 3 or higher TEAEs were observed in 85% of patients, most commonly including thrombocytopenia (53%), anemia (32%), and pneumonia (12%).

The combination is being further explored in the randomized phase 3 TRANSFORM studies in patients with myelofibrosis (NCT04472598, NCT04468984) in comparison with ruxolitinib or best available therapy, respectively.

PI3K Inhibition

PI3K inhibition is also being explored for use in combination with ruxolitinib. In a phase 2 trial (NCT02718300), the PI3Kδ inhibitor parsaclisib was combined with ruxolitinib in patients with myelofibrosis who had a suboptimal response to prior ruxolitinib treatment. At 24 weeks, patients with low platelet counts had a median percentage change in spleen volume of –3.9 and 12% achieved spleen reduction of at least 35%, whereas patients with higher platelet counts had a median volume reduction of –10.3 and 3% had reduction of at least 35%.8

“We know that patients with low platelets typically do very poorly with myelofibrosis and represent an unmet need. So you will see now…most trials will try to select out and highlight the outcomes of those patients with low platelets as the field [tries] to develop therapies for this unmet need,” Mascarenhas commented. “But one can appreciate that there is a reduction, at least 35% or greater, [in] 12% of the patients in the low platelet arm that are providing an example of the ability to rescue, with this PI3 kinase inhibitor, spleen responses in this patient population.”

Grade 3/4 toxicities were minimal in this study with few significant differences observed between the low and high platelet count arms, Mascarenhas said.

MDM2 Inhibition

Mascarenhas explained that MDM2 negatively regulates p53, and if it is blocked, it allows for p53 activity and apoptosis of myeloproliferative neoplasm (MPN) cells.

The first-in-class MDM2 inhibitor navtemadlin (KRT-232) was evaluated at varying doses and schedules in a phase 2 study (NCT03662126) of patients with TP53 wild-type primary or secondary myelofibrosis after failure on a JAK inhibitor. The best tolerated dose was considered to be 240 mg for 7 days of a 28-day cycle.

A statistically significant correlation was found in the study between driver gene variant allele frequency (VAF) reduction and SVR. Patients who had a higher SVR also had a higher VAF response (75% in patients achieving SVR ≥35%).9

“We’ve now moved on from just looking at spleen responses and symptom responses to trying to correlate changes in biomarkers with response,” Mascarenhas stated.

Telomerase

Mascarenhas singled out telomerase as an enzyme that is upregulated in MPN hematopoietic stem cells but is not active in somatic cells. He said that telomerase was an attractive therapeutic target that is being explored with treatment with imetelstat.

In a phase 2 study (NCT02426086) of 2 doses of imetelstat in patients with myelofibrosis who were refractory to JAK inhibitor, the first-in-class telomerase inhibitor led to SVR of at least 35% at week 24 in 10% of patients treated with the 9.4 mg/kg dose, and 32% had at least 50% TSS response at week 24. The median OS in the 9.4 mg/kg arm was 29.9 months (95% CI, 22.8-not evaluable),10 “suggesting that one could double the survival in this patient population after ruxolitinib failure,” Mascarenhas said.

Compared with the lower dose, patients treated with the higher dose of imetelstat demonstrated a greater improvement of bone marrow fibrosis and reduction in VAF, both of which was associated with improved survival rates.

The global, randomized phase 3 IMpactMF trial (NCT04576156) is ongoing looking at imetelstat vs best available therapy in patients with myelofibrosis who are refractory to JAK inhibitors. Mascarenhas, who is one of the principal investigators of the study, noted that this is the first and only phase 3 trial in myelofibrosis with OS as a primary end point.

References

1. Mascarenhas J. New Modalities for Treatment of Myelofibrosis. Presented at: 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma; February 23-25, 2022; Miami, FL.

2. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. Updated April 6, 2020. Accessed February 27, 2022. https://bit.ly/3HsJykG

3. Gerds AT, Vannucchi A, Passamonti F, et al. Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) – Updated Data from the Phase 2 ACE-536-MF-001 Study. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 2992. https://bit.ly/3pi9uJq

4. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

5. Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017;130(9):1125-1131. doi:10.1182/blood-2017-05-783225

6. Mascarenhas J, Harrison C, Patriarca A, et al. CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK-Inhibitor-Naïve Myelofibrosis Patients: Update of MANIFEST Phase 2 Study. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 55. https://bit.ly/3sqTeb3

7. Pemmaraju N, Garcia JS, Potluri J, et al. The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis.Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 52. https://bit.ly/3hpmXL2

8. Yacoub A, Borate U, Rampal R, et al. Subgroup Analysis from a Phase 2 Study of the Efficacy and Safety of Parsaclisib, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis (MF). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3647. https://bit.ly/359915F

9. Vachhani 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). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3581. https://bit.ly/3K03v3N

10. Mascarenhas J, Komrokji 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:10.1200/JCO.20.02864

Related Videos
Related Content