Best of Heme 2025: Updates in Myeloproliferative Neoplasms with Dr Pemmaraju
Presented by:
Naveen Pemmaraju, MD | MD Anderson Cancer Center
Conference:
Best of Heme 2025 | Vail, Colorado
Introduction
In his presentation at the 2025 Best of Heme conference in Vail Colorado, Dr Naveen Pemmaraju noted "We are about to enter into a new golden era of MPNs, and you've been sleeping on it." The myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that can evolve into life-threatening cancers, but Dr Pemmaraju emphasized that recent therapeutic advancements are revolutionizing MPN care, targeting novel mechanisms of action that go beyond the traditional Janus Kinase (JAK) inhibitors.
Polycythemia Vera (PV): Past, Present, and Future
Dr Pemmaraju first reviewed the traditional standards of care for polycythemia vera (PV), noting the importance of diagnosis and for distinguishing PV from secondary polycythemia causes such as sleep apnea, smoking, and renal cell carcinoma. While traditional therapies have relied on hydroxyurea, interferon (including pegylated interferons), phlebotomy, and baby aspirin, Dr Pemmaraju highlighted several recent FDA approvals and emerging therapies. Ropeginterferon alfa-2b, a long-acting interferon shown to provide durable hematologic and molecular responses in PV, was FDA approved 2021. In addition, Ruxolitinib, a JAK1/2 inhibitor, was shown to be effective in hydroxyurea-resistant and/or intolerant PV patients. Dr Pemmaraju also noted Rusfertide (PTG-300), a hepcidin mimetic currently under development, which is designed to reduce iron absorption and mitigate erythrocytosis. In the phase II REVIVE study, this agent reduced phlebotomy dependency and provided durable control over hematocrit. As such he noted the ongoing VERIFY (Phase III) trial, which is aiming for FDA approval for this agent.
“For the first time, we have a drug [Rusfertide] that can potentially replace phlebotomy entirely in PV management.”
Essential Thrombocythemia (ET): A Shifting Landscape
Dr Pemmaraju noted a shifting landscape of treatment for essential thrombocytopenia with agents such as Ropeginterferon and bomedemstat (LSD1 inhibitor) helping to advance treatment beyond traditional hydroxyurea and anagrelide. In addition, he noted the addition of new KIT inhibitors such as avapritinib and bezuclastinib which are being investigated for systemic mastocytosis and 8p11 myeloid/lymphoid neoplasms.
Myelofibrosis (MF): Moving Beyond JAK Inhibitors
For primary myelofibrosis, Dr Pemmaraju noted the current standard of care with four approved Janus Kinase (JAK) inhibitors, Ruxolitinib (RUX), a JAK1/2 inhibitor, currently approved for intermediate/high-risk MF, Fedratinib (a dual JAK2, FLT3 inhibitor) as an alternative for RUX-resistant MF, Pacritinib (a dual JAK2/ACVR1 inhibitor), currently approved for MF patients with platelets <50K, and Momelotinib (a JAK1/2 inhibitor, ACVR1 target) the first MF therapy addressing anemia (FDA approved in 2023).
“JAK inhibitors have changed the game, but they do not cure MF. The only curative option remains allogeneic stem cell transplant.”
Dr Pemmaraju also noted several novel combination strategies under investigation, designed to advance treatment for MF beyond JAK inhibitors. These include RUX in combination with BCL-2 inhibitors such as Navitoclax, in combination with BET inhibitors such as Pelabresib, in combination with XPO1 inhibitors such as Selinexor, and in combination with MDM2 inhibitors such as Navtemadlin. While these combinations have in some cases led to promising outcomes such as reducing spleen size and symptom burden, overall symptom control remains a major challenge in combination trials, and several combinations have failed to meet FDA approval.
“We’re losing good drugs because we haven’t changed our endpoints. It’s time to rethink what ‘success’ means in myelofibrosis trials.”
Looking toward the future of MF treatment, Dr Pemmaraju emphasized the potential for disease modification with some agents as well as immunotherapy approaches. Some of the emerging targets he noted, beyond JAK inhibition, include telomerase inhibition with agents such as Imetelstat currently in phase III clinical trials, T-regulatory (Treg) cell-based therapies, including a novel approach using umbilical cord-derived Tregs to restore immune equilibrium, and MDM2 Inhibition with agents like Navtemadlin, which could be potentially effective for patients with JAK-refractory MF.
“For the first time, immunotherapy is entering the MPN space. We are seeing real signals of disease modification.”
Dr Pemmaraju also highlighted the potential for expanding the MPN landscape to the rarer subtypes and the expanded use of targeted therapies. For example, for patients having 8p11 syndrome and other myeloid neoplasms driven by fibroblast growth factor receptor 1 (FGFR1), he noted the potential for targeted therapies like Pemigatinib, an FGFR1 inhibitor which is currently FDA approved showing high response rates, and Olverembatinib, a dual FGFR1 and BCR-ABL inhibitor, which has shown promising activity in clinical trials.
“The rare diseases we once ignored are finally getting targeted therapies. We must keep pushing for drug development in underserved populations.”
For patients with JAK2 and CALR mutations, Dr Pemmaraju also noted the potential for targeted therapies such as AJI-11095, a Type II JAK2 inhibitor, targeting the inactive conformation of JAK2, INCB160058, a JAK2 V617F-selective agent, the first mutant-specific JAK2 inhibitor, as well as CALR-directed therapies, including monoclonal antibodies, bispecific antibodies, and CAR-T therapies.
Changing Definitions of Treatment Success in MPN
In the final portion of his presentation, Dr Pemmaraju called for a paradigm shift in clinical trial endpoints for MPN. He noted that, historically, trials have focused on endpoints such as spleen size and symptom reduction, however, he emphasized that true disease modification requires new measures of success, including overall survival (OS), event-free survival (EFS), rates of transformation to AML, transfusion independence, molecular remission (JAK2/CALR burden reduction), and improvements in bone marrow fibrosis. As a closing thought, Dr. Pemmaraju encouraged oncologists to enroll patients in clinical trials to continue to advance the field.
“We are at an inflection point in MPN care. The way we measure success must evolve alongside our therapies.”
Key Takeaways
✔ In Polycythemia Vera, Dr Pemmaraju noted that Rusfertide and ropeginterferon are helping to redefine treatment goals.
✔ For Essential Thrombocythemia, Bomedemstat and other novel inhibitors may offer non-cytotoxic options for patients.
✔ In Myelofibrosis, Dr Pemmaraju cited four currently approved JAK inhibitors, although novel combinations and immunotherapies are helping to expand the treatment landscape.
✔ For the Rare MPNs, targeted therapies like pemigatinib and olverembatinib are helping patients achieve deep molecular responses.
✔ In terms of future directions, Dr Pemmaraju cites the JAK2 and CALR mutant-specific inhibitors, cellular therapies, and a revised definition of treatment success in MPNs.
Speaker Disclosure Information: Dr. Pemmaraju reported no relevant disclosures for this presentation.
You can see the full presentation by Dr Pemmaraju at the 2025 Best of Hematology conference, beginning at the 23:45 mark here.