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Division of Cancer Medicine
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Prithviraj Bose, MD, has disclosed that he has received consultant/advisor/speaker fees from AbbVie, Blueprint, Bristol Myers Squibb, CTI BioPharma, Incyte, Karyopharm, Novartis, PharmaEssentia, and Sierra Oncology, and funds for research support from Astellas, Blueprint, Bristol Myers Squibb, Cogent, Constellation, CTI Biopharma, Incyte, Ionis, Kartos, NS Pharma, Pfizer, and Promedior.
Division of Hematology
Department of Medicine
Washington University School of Medicine
St Louis, MO
Stephen Oh, MD, PhD, has disclosed that he has received consulting fees from AbbVie, Blueprint, Bristol Myers Squibb, Constellation, CTI Biopharma, Disc Medicine, Geron, Incyte, PharmaEssentia, and Sierra Oncology.
Professor of Medicine
Department of Hematology/Oncology
Northwestern University Feinberg School of Medicine
Brady L. Stein, MD, MHS, has disclosed that he has received consulting fees from Constellation and PharmaEssentia.
This commentary provides expert answers to questions asked at a live symposium on myeloproliferative neoplasms (MPNs). Topics include treatment selection, novel therapeutics, and the molecular testing prior to treatment.
How do you choose treatment for individual patients with myelofibrosis (MF)?
Stephen Oh, MD, PhD:
Treatment options vary based on a patient’s risk category, which can be assessed using various models including inferior petrosal sinus sampling, Dynamic international Prognostic Scoring System, and others. For a patient with low‑risk MF and minimal or no symptoms, observation alone may be appropriate. Patients with more symptoms (even if they are in the low-risk category) are candidates for ruxolitinib or another Janus kinase (JAK) inhibitor. For those patients with higher‑risk disease, allogeneic stem cell transplant can be considered if the patient is an eligible candidate; however, most of our patients are not eligible for transplant, in part because MF tends to be diagnosed in older age, and many older people are more frail or have other comorbidities that limit this therapeutic possibility.
What are some of the most promising investigational strategies in late-stage clinical trial development for MF?
Stephen Oh, MD, PhD:
There are numerous therapeutics in phase III clinical trials for managing patients with MF (Table).
One of the most important drugs being investigated for MF-associated anemia is luspatercept, an erythroid maturation agent already approved for the treatment of anemia in β-thalassemia and myelodysplastic syndrome. Like sotatercept, luspatercept is in the TGF-β superfamily of ligand traps. INDEPENDENCE is an ongoing phase III trial of luspatercept vs placebo in patients with MF who are transfusion dependent and receiving treatment with a JAK inhibitor. The primary endpoint is transfusion independence. Luspatercept has helped improve anemia in other settings and I am optimistic about MF as well.
Momelotinib is an investigational JAK1/JAK2 inhibitor with the potential capacity to improve anemia in a subset of patients with MF, which would be in contrast to currently approved JAK inhibitors. Momelotinib was recently compared with danazol in the phase III MOMENTUM study, which enrolled patients with intermediate-risk to high-risk MF, anemia, symptoms, and previous JAK inhibitor therapy. The primary endpoint was TSS, with secondary endpoints including transfusion independence and splenic response. It appears these endpoints have been reached, and I am optimistic that this drug will be approved in the near future.
Pacritinib is another JAK2 inhibitor that was recently approved by the FDA for patients with intermediate-risk or high-risk MF with a platelet count below 50 x 109/L. Compared with other JAK inhibitors, it causes little myelosuppression, and has shown spleen and symptom benefits even in patients with baseline platelet counts less than 50 x 109/L while keeping their blood counts stable. Pacritinib is still being evaluated in the ongoing phase III PACIFICA study, which is enrolling patients with MF with limited or no prior JAK inhibitor therapy and platelet counts <50 x 109/L.
Ruxolitinib plus parsaclisib
Parsaclisib is a PI3K inhibitor that has been tested in combination with ruxolitinib for the treatment of MF. Results from a phase II study suggested spleen responses and symptom improvements. Two ongoing phase III studies are evaluating the combination of parsaclisib plus ruxolitinib either for initial treatment or in patients previously treated with ruxolitinib (ie, in the “add-on” setting).
Imetelstat is a telomerase inhibitor being investigated for the treatment of patients with MF, particularly those who have relapsed or are refractory to treatment with a JAK inhibitor. IMbark is a randomized phase II study comparing 2 doses of imetelstat in relapsed/refractory, intermediate 2–risk/high-risk MF. Results showed a median overall survival of 29.9 months with the higher dose, and although this trial did not provide a direct comparison to current standards of care, these results suggest that imetelstat could prolong survival in patients with MF. Imetelstat is now being studied in a phase III trial against best available therapy in patients with prior JAK inhibitor failure.
Navtemadlin is an oral small-molecule inhibitor of MDM2. Based on encouraging clinical activity and pharmacodynamic correlates observed in a phase II study in patients with MF that was refractory to or had relapsed after a JAK inhibitor, navtemadlin is now being compared to best available therapy (not including JAK inhibitors) in a phase III trial in patients with prior JAK inhibitor failure.
What data support the approval of ropeginterferon α-2b for the treatment of polycythemia vera?
Brady L. Stein, MD, MHS:
In 2021, ropeginterferon α-2b was FDA approved for the treatment of adults with polycythemia vera (PV). Ropeginterferon is a monopegylated interferon with a longer half-life than standard pegylated interferon. The phase III PROUD-PV study, patients who were cytoreduction naive or pretreated with hydroxyurea for up to 3 years without full response were randomized to ropeginterferon or hydroxyurea. The complete hematologic response rate with reduction of disease burden at 36 months was 53% with ropeginterferon vs 38% with hydroxyurea (P = .044). Of note, the benefit from ropeginterferon was not evident at 1 year, but instead emerged over several years. As such, patients should understand the need for patience with this therapeutic. Of note, thrombosis rates were very low in both arms, even through Year 4. In addition, by 4 years, 67% of patients in the ropeginterferon arm had achieved a molecular response compared with only 26% in the hydroxyurea arm. Thirteen patients in the ropeginterferon arm achieved a variant allele fraction of <1%.
What molecular tests are recommended for patients with MPNs to tailor therapy?
Prithviraj Bose, MD:
Molecular testing remains preliminary in this setting. We have an in‑house panel of 81 genes that we use to assess all newly diagnosed patients with MPNs. I will acknowledge that we are not yet using that information to tailor therapy for PV and essential thrombocythemia (ET). In MF, there is early evidence that this assessment may be helpful. For example, responses to ruxolitinib seem shorter and outcomes are worse in MF with certain nondriver mutations—usually epigenetic and splicing mutations—and response rates to ruxolitinib may be lower in MF with a low JAK2 allele burden. It also appears that pacritinib may have preferential activity in patients with a low JAK2 allele burden. I will emphasize, however, that even in MF, we are not selecting therapy based on next-generation sequencing. All of this is emerging research and not ready for prime time.
How do you approach patients with a of history psychiatric illness who might benefit from interferon therapy?
Brady L. Stein, MD, MHS:
With ropeginterferon, the reported incidence of severe depression is relatively low. Overall, depression affected fewer than 20% of patients in PROUD-PV, with only 5% or less experiencing serious depression. It is certainly something to watch for with interferons as a class, and patients should be carefully selected. If I have a patient who might benefit from peginterferon or ropeginterferon but has a psychiatric history of anxiety or depression, I make sure that they’re cofollowed by a psychiatrist, psychologist, or therapist. This monitoring is important based on that history. Interferon therapy is not indicated for patients with currently uncontrolled anxiety or depression. The presence of autoimmune disease also represents a relative contraindication to the use of interferon.
How often do you use anagrelide in patients with ET, and are you concerned about potentially worsening fibrosis?
Prithviraj Bose, MD:
I don’t use anagrelide very much at all to manage thrombosis risk in patients with ET, and currently have no patients receiving it. I actually use a fair amount of off‑label ruxolitinib in appropriate symptomatic patients following hydroxyurea or interferon.
I’m aware of this concern regarding bone marrow fibrosis and anagrelide. However, I’m not sure whether this is a real effect or what the mechanism might be.
Stephen Oh, MD, PhD:
I think I use anagrelide somewhat more than you do. I also use ruxolitinib in selected patients, in particular, those who have bothersome symptoms that might be improved. The patients I consider for anagrelide are those who have trouble with hydroxyurea, usually due to intolerance.
How have you managed challenges in treating patients with MPNs? Please answer the polling question and join the conversation in the discussion box.