Dr Kremyanskaya on the Use of Cytoreductive Measures in PV and ET

Marina Kremyanskaya, MD, PhD, assistant professor, medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai; medical director, inpatient oncology unit, The Mount Sinai Hospital, discusses disease and patient characteristics that influence the choice between hydroxyurea and interferon therapy for patients with polycythemia vera (PV) or essential thrombocythemia (ET).

Typically, both hydroxyurea and interferons are effective cytoreductive measures in patients with PV or ET, Kremyanskaya says. During individual patient assessment, clinicians consider factors such as comorbidities, age, and therapeutic goals, Kremyanskaya explains. For instance, hydroxyurea is often the optimal treatment option in older patients with newly diagnosed, high-risk disease requiring cytoreductive therapy, Kremyanskaya notes. The favorable characteristics of this agent include its limited toxicity profile that leads to high tolerability, as well as the ease of tailoring the dosage of hydroxyurea according to individual patient needs, according to Kremyanskaya. Although hydroxyurea is not universally effective, it often serves as a prudent initial therapeutic approach, Kremyanskaya emphasizes.

Conversely, younger patients who are concerned about issues such as disease progression and infertility may find interferons to be a more suitable treatment option, Kremyanskaya says. Interferons are hypothesized to have disease-modifying effects in both PV and ET. Although definitive evidence of this ability is still emerging, many oncologists still consider interferons to be a viable therapeutic avenue for younger patients, Kremyanskaya explains.

In the future, patients with chronic myeloproliferative neoplasms need more effective therapies, Kremyanskaya emphasizes. Although PV and ET are commonly considered earlier-stage malignancies, they are associated with high morbidity, mortality, and symptom burden, Kremyanskaya notes. Improved treatment approaches for these patients, with a focus on disease modification, may stop disease progression in many patients and could lead to cures, Kremyanskaya concludes.

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Marina Kremyanskaya, MD, PhD, discusses disease and patient characteristics that influence the choice between hydroxyurea and interferon therapy for patients with polycythemia vera or essential thrombocythemia. 

Marina Kremyanskaya, MD, PhD, assistant professor, medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses the safety profile and future implications of rusfertide (PTG-300) in the treatment of patients with phlebotomy-dependent polycythemia vera (PV), as seen in the phase 2 REVIVE trial (NCT04057040).

The REVIVE trial evaluated rusfertide vs placebo in patients with PV requiring phlebotomy. At the 2023 EHA Congress, REVIVE investigators presented data from this open-label, dose-escalation study, which showed that treatment with rusfertide led to significantly higher efficacy compared with placebo in this patient population.

Rusfertide was very well tolerated in the study, and most patients were able to remain on rusfertide treatment for the duration of the study, Kremyanskaya begins. Notably, some patients remained on the study for over 2.5 years by the time of data read out, Kremyanskaya adds. The REVIVE investigators reported that the major adverse effects (AEs) observed with rusfertide were grades 1 and 2, with the most common AE being injection site reactions, she notes.

In the phase 2 trial, rusfertide was given as a subcutaneous injection once weekly, and patients were able to self-administer the treatment, Kremyanskaya expands. As reported, most patients experienced low-grade injection site reactions that were typically limited and improved over time, Kremyanskaya emphasizes. Moreover, most patients did not need to discontinue the study because of injection site reactions, and no grade 4 or 5 AEs were reported. Overall, this drug is well tolerated in patients with PV, she says.

Now, the worldwide, randomized, placebo-controlled, phase 3 VERIFY trial (NCT05210790) is enrolling patients, Kremyanskaya continues. This study will provide investigators with more information about the efficacy of rusfertide in both controlling hematocrit levels and improving patient symptoms, she says. Overall, the VERIFY investigators are looking forward to completing enrollment and analyzing the data from this phase 3 study, she concludes.

Marina Kremyanskaya, MD, PhD, discusses the safety profile and future implications of rusfertide in the treatment of patients with phlebotomy-dependent polycythemia vera, as seen in the phase 2 REVIVE trial.

Dr Kremyanskaya on the Safety of Rusfertide in Phlebotomy-Dependent PV

Marina Kremyanskaya, MD, PhD, assistant professor, medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses the potential advantages of using rusfertide (PTG-300) to treat patients with phlebotomy-dependent polycythemia vera (PV), as seen in the phase 2 REVIVE trial (NCT04057040).

At the 2023 EHA Congress, investigators presented data from the phase 2 open-label, dose-escalation REVIVE trial. The potential advantage that rusfertide offers to patients with PV is that it could eliminate phlebotomy requirements for patients who are heavily dependent on phlebotomies, Kremyanskaya begins. In particular, rusfertide could make a difference in the treatment of patients who do not tolerate phlebotomies well, and in those who are symptomatic from the multiple phlebotomies they are undergoing, she explains. Notably, Kremyanskaya believes that an additional benefit is that rusfertide can be and is often given as an additional agent to the PV-directed therapy that a patient is already on.

Often, the dose of a cytoreductive agent, such as an interferon or hydroxyurea, cannot be increased because patients cannot tolerate the higher dose. However, these patients still require phlebotomies and may still besymptomatic, Kremyanskaya expands. Therefore, the use of rusfertide given as an additional agent to the PV-directed therapy that a patient is already receiving may be effective, she emphasizes. Accordingly, in the future, rusfertide may be an additional agent for patients who derive some benefit from cytoreductive therapy but do not completely respond to this therapy, as well as for patients who do not tolerate phlebotomies well, Kremyanskaya notes.

Treatment with rusfertide could free these patients from being dependent on frequent follow-up visits to an institution and worrying about their blood counts, and in turn lead to significant improvements in their levels of independence and in their quality of life, Kremyanskaya concludes.

Marina Kremyanskaya, MD, PhD, discusses the potential advantages of using rusfertide to treat patients with phlebotomy-dependent polycythemia vera, as seen in the phase 2 REVIVE trial.


Dr Kremyanskaya on the Promise of Rusfertide in Phlebotomy-Dependent PV

Marina Kremyanskaya, MD, PhD, assistant professor, medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses the rationale for investigating rusfertide (PTG-300) in the phase 2 REVIVE trial (NCT04057040) for patients with phlebotomy-dependent polycythemia vera (PV).

The standard of care for PV in patients who display uncontrolled erythrocytosis has historically been therapeutic phlebotomy, Kremyanskaya begins, adding that this is done to maintain a hematocrit level of less than 45%. Notably, if a patient is considered to have high-risk disease, they will be treated with therapeutic phlebotomy, as well as with cytoreductive therapies, she notes. In comparison, some patients who are considered low risk are treated with cytoreductive therapy if they are symptomatic or cannot undergo phlebotomies, Kremyanskaya says.

Investigators continue to develop rusfertide, a hepcidin mimetic, for the treatment of PV, Kremyanskaya expands. A hepcidin mimetic is a hormone peptide produced by the liver that controls erythrocytosis and hematologic malignancies, she says. Rusfertide was developed on the hypothesis that hepcidin can be used as a controller of erythrocytosis, which can then be considered a chemical phlebotomy or areplacement for phlebotomy in this patient population, Kremyanskaya emphasizes.

Notably, some patients with PV become iron deficient because of phlebotomies, she adds. This is important because symptoms of PV are related to iron deficiency and the inflammatory nature of the myeloproliferative neoplasm, Kremyanskaya continues. In REVIVE, when patients received rusfertide, the dose was up titrated to get them to the goal hematocrit level of less than 45%, and several patients were able to maintain that dose, Kremyanskaya says. Overall, these patients now may not need a therapeutic phlebotomy, as many reported feeling better and had improvements in their systemic symptoms following treatment, Kremyanskaya concludes.

Marina Kremyanskaya, MD, PhD, discusses the rationale for investigating rusfertide in the phase 2 REVIVE trial for patients with phlebotomy-dependent polycythemia vera.


Dr Kremyanskaya on the Rationale for Investigating Rusfertide in Phlebotomy-Dependent PV

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses key efficacy data for rusfertide (PTG-300) in the phase 2 REVIVE trial (NCT04057040) of phlebotomy-dependent polycythemia vera.

Polycythemia vera is a specific type of erythrocytosis that also features systemic symptoms and a high risk of thromboembolic and/or cardiovascular (CV) complications. High levels of the iron-regulator hepcidin have been implicated in uncontrolled red blood cell formation.

The REVIVE trial compared the ability of the first-in-class hepcidin mimetic rusfertide vs placebo to control erythrocytosis in patients with polycythemia vera who had previously received 3 or more phlebotomies in 28 weeks with or without concurrent cytoreductive therapy. The trial was composed of a dose-finding stage (part 1), blinded randomized withdrawal (part 2), and an open-label extension portion (part 3).

Patients in part 1 received a weekly subcutaneous dose of rusfertide that was individually adjusted to achieve a hematocrit level below 45% (range, 10 mg-120 mg). In part 2, patients were randomized to continue rusfertide or to receive placebo. The study's primary end point was efficacy as characterized by the proportion of responders in part 2, Kremyanskaya says. Responses were achieved if patients had a hematocrit level below 45% without phlebotomy eligibility, did not receive therapeutic phlebotomy, and had completed 12 weeks of treatment, she explains.

Results from the randomized withdrawal phase were presented at the 2023 EHA Congress and demonstrated that rusfertide produced a significantly higher percentage of responders vs placebo, Kremyanskaya reports. These percentages were 69.2% (n = 18/26) with rusfertide vs 18.5% (n = 5/27) with placebo. Additionally, most patients on the study had low ferretin levels at baseline, indicating iron deficiency, Kremyanskaya states. After treatment with rusfertide, ferretin levels were normalized and maintained for many of these patients, she says.

Analysis of symptom improvement was based on data from part 1, as the majority of patients in the placebo arm of part 2 discontinued treatment prior to the 12-week mark, Kremyanskaya continues. Rusfertide treatment significantly improved the rate and severity of problems with concentration, itching, fatigue, and inactivity, which tend to be moderate or severe at baseline. Regarding safety, the agent was generally well tolerated, Kremyanskaya concludes.

Disclosures: Dr Kremyanskaya reported receiving honoraria and being on the advisory board for Protagonist Therapeutics, Inc.

Marina Kremyanskaya, MD, PhD, discusses key efficacy data for rusfertide in the phase 2 REVIVE trial of phlebotomy-dependent polycythemia vera.



Dr Kremyanskaya on the Efficacy of Rusfertide in Phlebotomy-Dependent Polycythemia Vera

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses the next steps of the phase 1/2 MANIFEST trial (NCT02158858) in myelofibrosis.

Updated findings from arm 1 of the MANIFEST trial demonstrated clinical and exploratory activity with the oral small molecule inhibitor of bromodomain 1/2 of BET proteins, pelabresib in patients with advanced myelofibrosis who were refractory to, ineligible for, or intolerant of ruxolitinib (Jakafi). 

The trial is ongoing, and patients are still being enrolled to arm 1 of the study, Kremyanskaya says. Therefore, additional efficacy data will emerge, as well as findings from centrally-reviewed bone marrow samples regarding fibrosis and bone marrow pathology.

Additionally, the MANIFEST trial led to the development of the phase 3 MANIFEST-2 trial (NCT04603495) in which patients with JAK inhibitor–naïve myelofibrosis will be randomized 1:1 to receive ruxolitinib plus pelabresib vs ruxolitinib plus placebo. The results will determine whether combining pelabresib with ruxolitinib can induce longer and deeper responses compared with single-agent therapy, Kremyanskaya concludes.

Marina Kremyanskaya, MD, PhD, discusses the next steps of the phase 1/2 MANIFEST trial in myelofibrosis. 



Dr. Kremyanskaya on the Next Steps of the MANIFEST Trial in Myelofibrosis 

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical Oncology, Icahn School of Medicine, Mount Sinai, medical director, Inpatient Oncology Unit, The Mount Sinai Hospital, discusses the design of the phase 1/2 MANIFEST trial (NCT02158858) in myelofibrosis.

Pelabresib is an investigational oral small molecule inhibitor of bromodomain 1/2 of BET proteins, Kremyanskaya says. During the 2021 ASH Annual Meeting and Exposition, updated findings from arm 1 of the MANIFEST trial were presented. The results demonstrated clinical and exploratory activity with pelabresib in patients with advanced myelofibrosis who were refractory to, ineligible for, or intolerant of ruxolitinib (Jakafi). 

In addition to arm 1, the trial is evaluating pelabresib in combination with ruxolitinib as first-line treatment for JAK inhibitor–naïve patients with myelofibrosis and as a second-line add-on treatment for patients who had a suboptimal response to or progression on ruxolitinib, Kremyanskaya concludes.

Marina Kremyanskaya, MD, PhD, discusses the design of the phase 1/2 MANIFEST trial in myelofibrosis.  



Dr. Kremyanskaya on the Design of the MANIFEST Trial in Myelofibrosis  

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical oncology at Mount Sinai Hospital, discusses the goals of the phase II MANIFEST trial examining the efficacy of CPI-0610 in patients with myelofibrosis.

A phase II clinical trial examined the efficacy of the selective and potent oral small molecule BET inhibitor CPI-0610 as monotherapy or in combination with ruxolitinib (Jakafi) in patients with myelofibrosis, says Kremyanskaya. Arm 1 of the study examined single-agent CPI-0610 in patients no longer on ruxolitinib. In arm 2 of the study, CPI-0610 was added to ruxolitinib in patients already receiving the JAK/STAT inhibitor for at least 6 months.

In the study, investigators are looking for the typical responses patients with myelofibrosis have. Patients with this disease tend to have anemia and splenomegaly; therefore, a focus of the study was to look for improvement in splenomegaly with the treatment. Another parameter of the trial is improvement in bone marrow fibrosis as a marker of the disease process itself and then other blood counts, such as thrombocytopenia, adds Kremyanskaya.

Marina Kremyanskaya, MD, PhD, discusses the goals of the phase II MANIFEST trial examining the efficacy of CPI-0610 in patients with myelofibrosis.

Dr. Kremyanskaya on MANIFEST Trial With CPI-0610 in Myelofibrosis

Marina Kremyanskaya, MD, PhD, assistant professor of medicine, hematology, and medical oncology at Mount Sinai Hospital, discusses unmet needs in myelofibrosis.

Myelofibrosis is a rare disease and there is not as much awareness about this malignancy, according to Kremyanskaya. When patients are diagnosed with myelofibrosis, they can have physically and emotionally adverse events. There are few treatment options available to them currently, according to Kremyanskaya.

There is a huge unmet need for new therapies in the second- or third-line setting for these patients after they fail approved therapies, or for specific patient populations, such as patients who experience anemia, says Kremyanskaya. These patients need therapies that target different mechanisms of action and work differently, concludes Kremyanskaya.

Marina Kremyanskaya, MD, PhD, discusses unmet needs in myelofibrosis.

Marina Kremyanskaya, MD, PhD

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