The treatment of myelofibrosis is undergoing a significant evolution, with emerging therapies and innovative combination strategies offering new hope for patients. Experts in the field are exploring novel agents and refining treatment approaches to address the complex challenges of this rare blood cancer.
Novel Therapies in Myelofibrosis
Several new therapies are showing promise in the treatment of myelofibrosis. Luspatercept, a TGF beta superfamily-targeting agent already approved for myelodysplastic syndromes (MDS), is being investigated in the INDEPENDENCE trial for its potential to address anemia in myelofibrosis patients. According to Dr. Firas El Chaer from the University of Virginia Comprehensive Cancer Center, positive outcomes from this study could lead to wider adoption of luspatercept in combination with JAK inhibitors that can cause anemia.
Nuvisertib (TP-3654), a Pim-1 kinase inhibitor, is also generating excitement. Early phase 1 studies presented by Dr. Lindsay A. M. Rein from Duke University Medical Center, show interesting data on symptom improvement in relapsed/refractory myelofibrosis patients. Nuvisertib is being explored in combination with both ruxolitinib and momelotinib, potentially offering new strategies for patients who have not responded well to existing treatments.
Pelabresib, a BET inhibitor, has demonstrated encouraging results in combination with ruxolitinib. Dr. Raajit K. Rampal from Memorial Sloan Kettering Cancer Center, highlighted data presented at ASH, showing that the combination of pelabresib and ruxolitinib leads to more persistent benefits and deeper symptom responses compared to ruxolitinib alone. Specifically, week 48 data indicated that loss of response occurred to a greater extent with ruxolitinib alone versus the combination, suggesting a sustained benefit over time. In the phase 3 MANIFEST-2 trial, the combination of pelabresib and ruxolitinib achieved a spleen volume reduction (SVR35) response rate of 65.9% at week 24, compared to 35.2% with ruxolitinib alone (p < .001).
Addressing Anemia in Myelofibrosis
Anemia is a common and challenging complication of myelofibrosis. Imetelstat, a telomerase inhibitor recently approved for MDS, is now being investigated in the IMbark phase 2 study for its potential to reduce symptoms and improve anemia in myelofibrosis patients. However, its use requires careful monitoring due to potential side effects such as neutropenia and thrombocytopenia.
Another agent, DISC-0974, an anti-hemojuvelin monoclonal antibody, is in early-phase trials and shows promise in improving transfusion dependency and anemia. It inhibits the hepcidin signaling pathway and could be used as an add-on to JAK inhibitors.
Momelotinib, a JAK inhibitor approved by the FDA in September 2023 for intermediate- or high-risk myelofibrosis with anemia, has shown promise in improving spleen volume and disease-related symptoms without exacerbating anemia or thrombocytopenia. Clinical trial data, including the MOMENTUM trial, demonstrated that 25% of patients on momelotinib achieved a Myelofibrosis Symptom Assessment Form v4.0 TSS reduction of at least 50% vs 9% on danazol (p < .01).
Combination Strategies and Biomarkers
Combination therapies are gaining traction as a means to improve outcomes in myelofibrosis. Andrew Kuykendall, MD, from Moffitt Cancer Center, emphasized the importance of identifying appropriate endpoints and biomarkers to assess disease modification in these combination approaches. Novel agents like navtemadlin, an MDM2 inhibitor, are being studied in trials such as the BOREAS and POIESIS studies, with correlative data presented at ASH highlighting the need for better biomarkers to monitor treatment response.
Emerging Targets and Future Directions
Researchers are also exploring novel targets such as calreticulin. There are currently two drugs in phase 1 trials that target calreticulin, showing specific effects on CALR mutant cells. These drugs could potentially offer a more targeted approach, similar to rituximab in other hematologic malignancies.
Furthermore, new JAK inhibitors, including type 2 JAK inhibitors and selective JAK inhibitors targeting the V617F mutation, are in clinical trials. These agents aim to improve the therapeutic index and reduce off-target effects, potentially leading to better outcomes for patients.
LSD1 inhibition with bomedemstat is also being investigated across the spectrum of myeloproliferative neoplasms (MPNs), showing potential in essential thrombocythemia and polycythemia vera. This approach raises questions about when to intervene in the course of these diseases.
As the field advances, there is a growing emphasis on refining endpoints and understanding the long-term benefits of these therapies. Experts stress the importance of enrolling patients in clinical trials to further develop and optimize treatment strategies for myelofibrosis.
