Improving Disease Modification and Immune Responses in Myelofibrosis With Pelabresib

Meet the experts

In a recent Between the Lines program, David M. Swoboda, MD, and Andrew Kuykendall, MD, spoke about current treatment strategies and potential advancements that may improve outcomes such as spleen volume reduction in the myelofibrosis field. Swoboda is a hematologist/oncologist at Tampa General Hospital Cancer Institute in Florida. Kuykendall is an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

Swoboda and Kuykendall gave an overview of therapeutic considerations for treating patients with myelofibrosis, which may include a combination of medications, supportive care, and potential stem cell transplantation. Their conversation also highlighted potential clinical improvements that novel JAK inhibitors and other investigational agents such as pelabresib may yield, bringing a specific focus to findings from the phase 3 MANIFEST-2 trial (NCT04603495).¹ Additionally, after reviewing data on biomarkers related to immune responses with these new agents, the panelists then considered the potential next steps that the field may take.

An Overview of Myelofibrosis Characteristics

The program began with an overview of the characteristics and symptoms associated with myelofibrosis and a discussion on currently approved therapies for this population. Swoboda defined myelofibrosis as a type of myeloproliferative neoplasm (MPN), a rare blood cancer associated with abnormal proliferation of at least 1 terminal myeloid cell line. The primary Philadelphia chromosome (Ph)–positive form of MPN is chronic myeloid leukemia (CML), whereas Ph-negative MPNs include polycythemia vera, essential thrombocytopenia (ET), and myelofibrosis.

Specifically, myelofibrosis disrupts production of normal blood cells via fibrosis in the bone marrow; it is more commonly reported in older patients at an average diagnosis age of 65 years. Development of this MPN is associated with JAK activation as well as STAT pathway transducers and activators. Splenomegaly, constipation, impaired bone marrow function, and anemia constitute common symptoms in patients with myelofibrosis.

Swoboda highlighted how this MPN can be categorized as either a primary or secondary disease. Primary myelofibrosis occurs independently of other conditions and is typically related to genetic mutations such as JAK2, CALR, and MPL, whereas secondary disease progresses from other blood disorders.

Current Strategies for Managing Myelofibrosis

The primary objectives of managing myelofibrosis, according to Swoboda, include improving blood cell counts, decreasing the size of the spleen, and alleviating other symptoms via personalized treatment plans. Regarding specific therapeutic strategies, JAK inhibitors appear to be promising in managing symptoms and potentially modifying disease progression, especially among patients with high-risk myelofibrosis.

“If you have a patient who is young and who is healthy enough, the goal is getting them to [undergo] transplant. That’s the only way that we can cure this disease and have sustainable long-term survival in a [patient with] high-risk myelofibrosis,” Swoboda said. “If a patient is at high risk, ideally, you get them to [undergo] transplant. I would say the majority of patients aren’t eligible for transplant. Ultimately, in that setting, you [may] think about [using] JAK inhibitors.”

Currently, available myelofibrosis therapies and their respective FDA approval dates include ruxolitinib (Jakafi) in November 2011,¹ fedratinib (Inrebic) in August 2019,² pacritinib (Vonjo) in February 2022,³ and momelotinib (Ojjaara) in September 2023.⁴ Most of these approvals were based on data from clinical trials assessing spleen volume reduction as a primary end point. Although prior treatment strategies have mainly involved single-agent therapy in myelofibrosis, Swoboda noted that the field has seen growing interest in exploring combination strategies to potentially improve and prolong responses while modifying the natural progression of disease in patients.

“It’s nice that we can focus on patient-reported outcomes and quality of life as primary efficacy end points. That’s probably also a result of the fact that we’re not able to meaningfully [affect] the disease as much as we would like to,” Kuykendall said regarding prior approvals for JAK inhibitors in myelofibrosis. “In a perfect world, these end points would be incorporated into our responses, but we’d love to see more meaningful and durable responses to the underlying disease. That builds upon the rationale for combination therapies.”

As part of modifying disease progression in patients with myelofibrosis, key targets may include the use of therapies that facilitate JAK-STAT pathway inhibition, limit inflammation, target fibrosis, and mitigate clonal hematopoiesis. The panelists highlighted certain obstacles that may interfere with achieving this outcome, such as the involvement of complex disease biology, heterogeneous molecular landscapes, and multiple pathways. Additionally, JAK inhibitors alone can help relieve symptoms but produce limited disease modification.

As part of addressing these barriers, the panelists highlighted a need for better biomarkers to measure disease modification and novel therapeutic approaches that can target several pathways at the same time. The development of combination strategies such as BET inhibitors, telomerase inhibitors, antifibrotic therapies, and immunomodulatory drugs may hold promise in improving outcomes in myelofibrosis. “We don’t have any approved accommodation therapies yet, but the idea of finding these biologically relevant targets will allow us to start to individualize care for specific patient populations as we move forward,” Kuykendall stated.

Pelabresib in MANIFEST-2

The panelists turned their attention to the potential clinical use of pelabresib based on its mechanism of action and data from the MANIFEST-2 trial. Investigators designed pelabresib as an orally available small molecule that inhibits BET proteins, playing a key role in regulating gene transcription. This inhibition may consequently limit BET-associated gene expression that facilitates myelofibrosis pathogenesis, thereby modifying disease progression. By potentially alleviating symptoms and adjusting the course of the disease, pelabresib may enhance clinical outcomes and produce long-term remission or stabilization.

In the phase 3 MANIFEST-2 trial, treatment with pelabresib in combination with ruxolitinib was compared with ruxolitinib alone among patients with myelofibrosis who received no prior therapy with JAK inhibitors. Investigators presented updated findings from MANIFEST-2 at the 2024 American Society of Clinical Oncology Annual Meeting.⁵

A total of 430 patients were randomly assigned 1:1 to receive pelabresib at 125 mg orally once daily (n = 214) or matched placebo (n = 216) on days 1 to 14 plus ruxolitinib at 5 mg orally twice daily on days 1 to 21 of every 3-week cycle. The trial’s primary end point was 35% spleen volume reduction (SVR35) responses at week 24. Secondary end points included absolute changes in total symptoms scores (TSS) at week 24 and 50% or higher reductions in TSS at week 24.

The median age was 66 years (range, 19-84) in the pelabresib/ruxolitinib arm and 66 years (range, 26-88) in the ruxolitinib monotherapy arm. Most patients in each respective arm had primary myelofibrosis (50.0% vs 50.9%), Dynamic International Prognostic Scoring System intermediate-1 disease (59.8% vs 58.8%), JAK2 V617Fmutations (58.4% vs 56.5%), and an ECOG performance status of 0 (50.0% vs 50.5%). Additionally, 3.7% and 0.9% of patients in each arm had transfusion dependence at the time of enrollment.

At week 24, the SVR35 response rate was 65.9% with pelabresib/ruxolitinib compared with 35.2% in the ruxolitinib monotherapy arm, representing a difference of 30.4% (95% CI, 21.6%-39.3%; P < .001). Additionally, data showed a mean spleen volume percentage change of –50.6% (95% CI, –53.2% to –48.0%) and –30.6% (95% CI, –33.7% to –27.5%) in each respective arm.

Based on modified TSS criteria that used a 70-point scale and excluded the fatigue subdomain, the mean change was –15.83 points with pelabresib-based treatment vs –13.73 with ruxolitinib monotherapy, yielding a mean difference of –2.1 (95% CI, –4.04 to –0.15; P = .035). A loss of SVR35 response was reported in 13.4% and 27.8% of patients in each respective arm, and a loss of SVR35 response with more than 25% increase in spleen volume from nadir occurred in 9.3% and 14.8%, respectively.

Reducing the spleen volume may represent a tangible, quantifiable marker of efficacy with myelofibrosis therapy. Based on the improvements in spleen volume reduction with pelabresib plus ruxolitinib, this combination therapy may demonstrate disease-modifying use. “Some of these disease-modifying biomarkers can be challenging to measure in practice, but we’re starting to incorporate some things like durability of response to get a sense for how these things are changing the game,” Kuykendall said.

Per central review in week 24, 38.3% of patients in the pelabresib arm had improvements in reticulin fibrosis by at least 1 grade compared with 25.3% in the ruxolitinib monotherapy arm and 17% and 27.7% of each group had worsening outcomes by at least 1 grade (P = .045). The combination therapy also reduced proinflammatory cytokine levels by a higher margin for all evaluated cytokines, including IL-6, IL-8, and tumor necrosis factor-α. Additionally, pelabresib/ruxolitinib conferred deeper hemoglobin responses and a lower rate of red blood cell transfusion dependence compared with ruxolitinib alone.

Swoboda discussed the value of the data associated with these symptom-related end points, affirming the importance of protecting the quality of life in patients with myelofibrosis. Although he acknowledged that improving outcomes such as responses and survival was ideal, he described how prolonging survival without yielding a good quality of life may raise questions about how beneficial treatment may be.

“We do see a change in the [pelabresib] combination [arm] vs the single-agent [ruxolitinib] when we modify the TSS; it is a significant change,” Swoboda stated. “If we can get—especially in the [patients who are] very symptomatic—a significant improvement in TSS, that is going to be helping our patients and it’s something that we’re going to notice clinically on a day-to-day [basis].”

In the pelabresib/ruxolitinib and ruxolitinib monotherapy arms, respectively, investigators reported any-grade treatment-emergent adverse effects [TEAEs; 96.7% vs 96.7%], grade 3 or higher TEAEs [49.1% vs 57.0%], serious AEs [29.7% vs 29.4%], and toxicity resulting in death [2.4% vs 2.8%]. Rates of TEAEs associated with dose discontinuation, reduction, and interruptions for pelabresib were 12.3%, 32.5%, and 32.1%, respectively; the corresponding rates for placebo were 7.5%, 29.0%, and 22.9%.

Hematologic toxicity generally consisted of anemia or hemoglobin level decreases, with any-grade events occurring in 44.8% of the pelabresib/ruxolitinib arm vs 55.1% of the ruxolitinib monotherapy arm. Additionally, common nonhematologic AEs in each arm included any-grade thrombocytopenia or platelet count decreases (52.8% vs 37.4%), diarrhea (23.1% vs 18.7%), dysgeusia (18.4% vs 3.7%), constipation (18.4% vs 24.3%), and nausea (14.2% vs 15.0%).

Molecular Insights in Pelabresib Responses and Next Steps

Swoboda and Kuykendall then highlighted findings from an immunophenotypic analysis study presented at the European Hematology Association 2024 Hybrid Congress evaluating how pelabresib may affect immune responses in patients with MPN.⁶ Investigators of this study also aimed to identify additional potentially targetable pathways that may enhance the agent’s efficacy in this population.

Patients were categorized based on whether they had a response to pelabresib, and their immune profiles were assessed before and after treatment. Across this study population, patients had disease types including ET, CML, or MPN not otherwise specified.

Results showed that patients with a response had an immune landscape that was comparable with that of healthy donors at baseline and after the completion of therapy. Among patients without a response, investigators noted a distinct immune profile characterized by monocyte changes such as decreased CD14 and CD4 expression, heightened CD16 and chemokine receptors, and the presence of CXCR3 expression.

Overall, findings showed persistent elevation of innate immunity and profibrotic pathways in the monocytes of patients without a response to pelabresib, suggesting that transforming growth factor β (TGF-β) and galectin may be worthwhile therapeutic targets. Additionally, a more exhausted phenotype was associated with CD4-positive and CD8-positive T cells among patients without a response, supporting the possibility of supplementing pelabresib with immune checkpoint inhibitors to reinstate an effective immune response against a malignant clone.

Based on these results, Kuykendall noted how treatments like pelabresib, which fall outside the realm of immunotherapy, are dependent on a healthy and nonexhausted immune system for yielding efficacy among patients with MPN. He considered how this dynamic could be applied to clinical practice.

“Does this mean we need to be initiating some of these therapies early on when patients have as attacked an immune system as possible? Classically, you could think about some sort of additional combination therapy with immune-acting agents or TGF-β inhibitors,” he noted. “How do you identify which patients would derive benefit from those combinations?”

Additionally, although data from trials such as MAINFEST-2 suggest that patients with the best spleen responses may live the longest, Kuykendall expressed uncertainty about whether spleen volume reduction should be a primary target in myelofibrosis or whether it should serve as a surrogate end point. He described how more work was needed to determine the specific factors that constituted a meaningful spleen response.

Regarding other potential next steps, Swoboda highlighted how combination therapies may be key to making further progress in the field. He described how combining pelabresib with agents such as momelotinib or pacritinib may “be interesting to see in the future” and mentioned the possibility of using triplet therapies in this population.

“It’s nice that this has been a field that’s evolved a lot in the last couple [of] years, and [it] seems [like it’s] about to explode. It’s a good time for providers to have more tools for their [patients with] myelofibrosis,” Swoboda concluded.

References

1. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008-3014. doi:10.1158/1078-0432.CCR-11-3145
2. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed October 7, 2024. https://tinyurl.com/cbyb737w
3. CTI BioPharma announces FDA accelerated approval of VONJO (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. News release. CTI BioPharma Corp. February 28, 2022. Accessed October 7, 2024. https://tinyurl.com/5djbru2w
4. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GSK plc. September 15, 2024. Accessed October 7, 2024. https://tinyurl.com/yrrxpeyv
5. Rampal R, Grosicki S, Chraniuk D, et al. Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naïve patients with myelofibrosis. J Clin Oncol. 2024;42(suppl 16):6502. doi:10.1200/JCO.2024.42.16_suppl.6502
6. Ejarque RA, Dos Reis RA, Cadman-Davies L, et al. Immunophenotypic analysis of patients with myeloproliferative neoplasms receiving therapy with the BET inhibitor pelabresib. Abstract presented at: European Hematology Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract P1016.