Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell disorders, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). At the 29th European Hematology Association (EHA) Annual Meeting held in Madrid, Spain, from June 13 to 16, 2024, notable advancements were made in MPN research. Oncology Frontier-Hematology Frontier invited Professor Minghui Duan from the Department of Hematology, Peking Union Medical College Hospital, to introduce and provide an in-depth review of two significant studies on myelofibrosis treatment. We hope Professor Duan's insights will help us understand the research progress in this field and provide important references for future research and treatment.

Study Overview

S221 – Safety and Efficacy of PELABRESIB Combined with RUXOLITINIB in Patients with Myelofibrosis: Latest Data from the Phase III MANIFEST-2 Study

Background

Myelofibrosis (MF) is characterized by bone marrow fibrosis (BMF), anemia, splenomegaly, and MF-related symptoms. Pelabresib (PELA) is an investigational oral small molecule designed to inhibit BET proteins and reduce BET-mediated gene expression involved in MF pathogenesis. MANIFEST-2 (NCT04603495) is a global, randomized, double-blind, controlled Phase III study investigating the efficacy and safety of PELA combined with Ruxolitinib (PELA+RUX) versus placebo combined with Ruxolitinib (PBO+RUX) in JAK inhibitor (JAKi)-naïve MF patients.

Objective

To report the latest efficacy and safety results from the MANIFEST-2 study.

Methods

Eligible patients had DIPSS scores ≥INT-1 risk, platelet counts ≥100 × 10^9/L, spleen volumes ≥450 cm^3, ≥2 symptoms with an average score ≥3 or a total symptom score (TSS) ≥10 (MFSAF v4.0), peripheral blasts <5%, and ECOG PS ≤2. Patients were randomized 1:1 to receive PELA or PBO (once daily for 14 out of 21 days) combined with RUX (twice daily continuously). The primary endpoint was ≥35% reduction in spleen volume at week 24 (SVR35). Key secondary endpoints included absolute change in TSS at week 24 and ≥50% reduction in TSS from baseline (TSS50). Other endpoints included hemoglobin (Hb) response (≥1.5 g/dL increase without transfusions in the first 12 weeks), RBC transfusion frequency, BMF, and safety. Informed consent was obtained from all enrolled patients.

Results

As of August 31, 2023, 430 patients were randomized. At week 24, the SVR35 response was 65.9% (141/214) in the PELA+RUX group versus 35.2% (76/216) in the PBO+RUX group (P<0.001). The proportion of patients achieving SVR35 at any time was 80.4% (172/214) versus 50.0% (108/216); 80% (137/172) versus 63% (68/108) at week 12; and 83.7% (144/172) versus 79.6% (86/108) maintained response at cutoff. The mean (SE) absolute change in TSS was -15.99 (1.028) versus -14.05 (0.986) (P=0.0545), with TSS50 response at week 24 of 52.3% (112/214) versus 46.3% (100/216) (P=0.216). The proportion of patients with dual SVR35 and TSS50 responses was about twice as high (40.2% [86/214] in the PELA+RUX group vs. 18.5% [40/216] in the PBO+RUX group). In anemic patients (baseline Hb <10 g/dL), Hb response was 16.4% (11/67) versus 14.1% (10/71). RBC transfusion requirements in the first 24 weeks were 30.8% (66/214) versus 39.8% (86/216). Significant BMF improvement (≥1 grade) at week 24 was observed in 38.5% (40/104) versus 24.2% (24/99) (OR 2.09 [1.14-3.93]). Among 426 patients evaluated for safety, common treatment-emergent adverse events (TEAEs; ≥20%) in the PELA+RUX versus PBO+RUX groups included anemia (43.9% vs. 55.6% [grade 3 or higher, 23.1% vs. 36.4%]), thrombocytopenia (32.1% vs. 23.4% [9% vs. 5.6%]), decreased platelet count (20.8% vs. 15.9% [4.2% vs. 0.9%]), and diarrhea (23.1% vs. 18.7% [0.5% vs. 1.4%]). Mean (SD) time to any TEAE was 23.05 (45.61) days versus 28.23 (46.84) days. More results will be presented at the conference.

Conclusion

In JAKi-naïve MF patients, PELA+RUX significantly and durably reduced spleen volume, decreased TSS, and improved anemia and BMF at week 24 compared to PBO+RUX, addressing four major MF disease characteristics. The results support a potential shift in MF treatment paradigms to PELA+RUX combination therapy. Pelabresib development was partially funded by the Leukemia and Lymphoma Society. CH and JM contributed equally to this manuscript.

S222 – Efficacy and Safety of Navitoclax Combined with Ruxolitinib Versus Ruxolitinib Plus Placebo in Treatment-Naïve Myelofibrosis Patients: Results from the Phase III TRANSFORM-1 Study

Background

Janus kinase inhibitors (JAKis) provide spleen volume reduction (SVR) and symptom improvement for MF patients, but their impact on disease biology is limited, highlighting the need for new treatments. Navitoclax (NAV) is an oral inhibitor of BCL-2 family proteins BCL-XL, BCL-2, and BCL-W. Combined with Ruxolitinib (RUX), NAV has shown significant activity in reducing gene VAF and improving response depth in MF patients. This study presents updated data from the ongoing Phase III TRANSFORM-1 study (NCT04472598).

Objective

To evaluate the long-term efficacy and safety of NAV+RUX versus placebo (PBO)+RUX in JAKi-naïve adult MF patients.

Methods

TRANSFORM-1 enrolled JAKi-naïve adult MF patients with DIPSS+ intermediate-2 (INT-2) or high-risk, measurable splenomegaly, and ECOG scores ≤2. Patients received PBO or NAV, starting at 200 mg/day (if platelet [PLT] >150×10^9/L) or 100 mg increasing to 200 mg/day (if PLT ≤150×10^9/L), and RUX at label doses. The primary endpoint was ≥35% spleen volume reduction at week 24 (SVR35W24). Key secondary endpoints included mean change in TSS at week 24, SVR35 at any time during study treatment, anemia response per IWG criteria during study treatment, and patient-reported outcomes (PROs) for fatigue (PROMIS Fatigue SF 7a) and physical function (EORTC QLQ-C30). Exploratory endpoints included response in high molecular risk (HMR) patients (ASXL1, SRSF2, EZH2, IDH1/2, U2AF1 p.Q157 mutations) and change in driver gene (JAK2, CALR, MPL) VAF from baseline. The proportion of patients with ≥10-point TSS improvement (clinically meaningful change threshold) was also assessed.

Results

As of September 28, 2023, 252 patients were enrolled with a mean follow-up of 20.3 months (range 0.0–35.3); patients were randomized 1:1 to NAV+RUX (n=125) or PBO+RUX (n=127). Demographics were similar between groups, with over 80% INT-2 risk and nearly 50% HMR mutations. The primary endpoint was met: 63% (79/125) of NAV+RUX patients achieved SVR35W24 versus 32% (40/127) in the PBO+RUX group (P<0.0001). Similar trends were observed for SVR35 at any time: 77% (96/125) versus 43% (55/127). Other endpoints included: SVR35W24 in HMR patients (59% [35/59] vs. 41% [22/54]), anemia response (34% [43/125] vs. 28% [35/127]), and VAF reduction (≥20% at any time) (57% [67/118] vs. 42% [51/121]). Mean TSS change and ≥10-point TSS improvement at week 24 showed no significant differences between groups. Fatigue and physical function changes at week 24 were numerically comparable. Most common AEs (>30%) in the NAV+RUX group included thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs occurred in 28% of NAV+RUX patients versus 38% of PBO+RUX patients.

Conclusion

In JAKi-naïve MF patients, NAV+RUX achieved twice the SVR35W24 improvement compared to PBO+RUX, despite adverse prognostic factors. Consistent SVR35 trends favoring NAV+RUX were observed across subgroups. NAV+RUX also showed higher rates of anemia response and VAF reduction. PRO endpoints indicated similar impacts on symptoms and physical function. Serious AEs were lower in the NAV+RUX group. No new safety signals were observed.

Expert Commentary

Professor Minghui Duan: Primary myelofibrosis (PMF, including post-PV and post-ET MF) is a severe hematologic disorder with no cure outside allogeneic hematopoietic stem cell transplantation (AHSCT), which is limited to a small subset of patients due to age, post-transplant complications, and lack of suitable donors. Most patients cannot be cured and eventually deteriorate until death. Symptom management is thus crucial. MPN symptoms are complex, and a treatment’s benefit in one area may exacerbate others; for example, Ruxolitinib reduces spleen size but can worsen anemia and thrombocytopenia.

JAK inhibitors like Ruxolitinib significantly improve PMF symptoms but have limited efficacy, with about 40% achieving SVR35, and efficacy wanes in 3-5 years. Patients who discontinue Ruxolitinib due to various reasons have a poor prognosis, with a median survival of about 14 months and heavy symptom burdens. While AHSCT may cure some MF patients, most deteriorate without it. New JAKis, like Momelotinib, alleviate anemia while reducing spleen size, improving quality of life and reducing medical costs. Fedratinib is suitable for patients with lower platelet counts. However, none surpass Ruxolitinib in spleen reduction or overall survival (OS).

Current challenges include understanding JAKi resistance mechanisms. Research suggests other pathways (BCL-2, BET, PI3K, XPO-1) play roles in PMF pathogenesis and resistance, leading to combination therapies with JAKis. Early studies and clinical trials show promise, with several combinations entering Phase III trials. These EHA studies present two key combination therapies, showing significant benefits and supporting PELA+RUX as a frontline treatment for INT-2 and high-risk MF patients.

The MANIFEST-2 and TRANSFORM-1 studies signify the beginning of the “Ruxolitinib + X” treatment era, offering new hope for high-risk MF patients. However, both focus on high-risk patients with short follow-up. Long-term efficacy and high treatment costs remain challenges, potentially limiting patient access.

Future directions include combining current treatments with interferons or Selinexor, earlier intervention, and pursuing long-term survival or early molecular response as treatment goals.