What Long-Term BESREMi Data Show in PV

Dr Rami Komrokji reviews long-term efficacy and safety data in polycythemia vera, highlighting durability of response, phlebotomy reduction, and sustained disease control.

Hello, and welcome.

I'm Rami Komrokji, Vice Chair of Malignant Hematology Department at Moffitt Cancer Center.

Long-term planning is an essential part of treatment in polycythemia vera because PV is chronic myeloproliferative neoplasm and many patients live for years after diagnosis. Treatment decisions need to account not only for initial blood count control, but also for how durable that control is over time. In an international multicenter study with 1545 patients with PV, median survival from diagnosis ranged from 14.1 to 27.6 years, with a median survival of 18.9 years, making durability of response and the ability to remain on treatment especially relevant when selecting first-line therapy.

In this video, we will review BESREMi’s long-term data and discuss what those results show about durability of response, phlebotomy reduction, sustained disease control, and safety and tolerability in polycythemia vera.

Indication

BESREMi is indicated for the treatment of adults with polycythemia vera.

Boxed Warning 

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

Ropeginterferon alfa-2b (BESREMi) is a single-site mono-pegylated interferon and a preferred first-line cytoreductive therapy option for the treatment of both low-risk symptomatic and high-risk PV in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloproliferative Neoplasms.

In BESREMi clinical trials, long-term stability and complete disease control were evaluated to show the treatment’s sustained effectiveness for patients with PV. Complete hematologic response was defined as hematocrit below 45% without phlebotomy in the past 2 months, leukocyte count less than or equal to 10 x 10⁹/L, and platelet count less than or equal to 400 x 10⁹/L.

The results of PEGINVERA, a pivotal trial for BESREMi, demonstrated BESREMi’s long-term durability for hematologic response and composite disease-control outcomes. The PEGINVERA study was a prospective, single-arm trial evaluating the dosing, tolerability, and efficacy of BESREMi over 7.5 years in 51 adult patients with PV.

Eighty percent of patients treated achieved complete hematologic response (CHR with a median duration of this response of 20.8 months).

When the criteria included normal spleen size and absence of thromboembolic events in addition to the CHR criteria, comprehensive disease control was assessed. Sixty-one percent of patients reached comprehensive disease control, with a median duration of 14.3 months.

Over a period of 7.5 years, PEGINVERA has shown that patients with polycythemia vera experienced significant hematologic responses and effective disease control when treated with BESREMi. These results demonstrate that BESREMi can offer durable management of various aspects of PV throughout an extended treatment timeline.

Safety findings from PEGINVERA also add important context. Ninety-five percent of adverse reactions were grade 1 or grade 2, and the most common adverse reaction reported in more than 10% of patients was influenza-like illness. There were no observed cases of acute myeloid leukemia and 1 observed case of myelofibrosis out of 51 patients treated with BESREMi over the 7.5 years.

The most common serious adverse reactions, occurring at a rate of 4% or more, were urinary tract infection, transient ischemic attack, and depression.

Adverse reactions requiring permanent discontinuation in greater than 2% of patients who received BESREMi included depression, arthralgia, fatigue, and general physical health deterioration.

The most common treatment-emergent events reported in the PEGINVERA study over 7.5 years included influenza-like illness, arthralgia, fatigue, and pruritus.

The results of the PROUD-PV and CONTINUATION-PV studies lend additional support for BESREMi as a long-term treatment option for PV. 

The PROUD/CONTINUATION-PV trials assessed the long-term efficacy and safety of BESREMi compared with hydroxyurea in adult patients with PV for 6 years.

In the extension CONTINUATION-PV phase of the study, outcomes at 72 months showed that the proportion of BESREMi-treated patients achieving complete hematologic response was 72.6%, and 81.4% of patients treated with BESREMi required no phlebotomies to maintain hematocrit below 45%. 

Responses to BESREMi increased gradually up to 12 to 24 months and was sustained through 36 months.

Those findings suggest that the effectiveness of BESREMi continues to build during the first 12 to 24 months, and sustained control may then continue over extended follow-up. 

Clinically, the gradual increase in response with BESREMi should be factored in when setting expectations around treatment timelines and when evaluating early versus long-term benefit. The longer response curve also reinforces the importance of staying with treatment long enough to appreciate its full effect.

The limitations of CONTINUATION-PV included that it was initially designed as a single-arm extension of PROUD-PV. The second arm with hydroxyurea or best available treatment was subsequently added for comparison, resulting in a study entry gap of approximately 21 weeks.

A post hoc analysis of PROUD/CONTINUATION-PV showed that BESREMi was associated with improved probability of event-free survival versus standard treatment, with events defined as thromboembolic events, disease progression, or death. Median probability of event-free survival was not reached, and the analysis was not prespecified.

Safety data from PEGINVERA and PROUD/CONTINUATION-PV also support BESREMi as a long-term treatment option for polycythemia vera. 

In the PROUD/CONTINUATION-PV trials, the proportion of patients with serious adverse events, grade 3 or higher adverse events, and major thromboembolic adverse events was similar between the 2 treatment groups.

Eight percent of BESREMi-treated patients discontinued treatment due to drug-related toxicity compared to 4% of patients in the hydroxyurea group.

The most common adverse events reported in more than 10% of patients treated with BESREMi included hematologic side effects, liver function abnormalities, fatigue, headache, arthralgia, and dizziness.

Treatment-related serious adverse events occurred in 2% of the patients in the BESREMi group and 4% of the patients in the hydroxyurea group. The most frequently reported grade 3 and grade 4 treatment-related adverse events were increase in gamma-glutamyltransferase and increase in alanine aminotransferase in the BESREMi group, and leukopenia and thrombocytopenia in the hydroxyurea group.

Viewed together, BESREMi’s long-term efficacy and safety data showing durable hematologic response, reduced phlebotomy requirements, sustained benefit, and a favorable tolerability profile support its use as a treatment approach focused on sustained disease control over time, not only short-term count correction.

INDICATION 

BESREMi is indicated for the treatment of adults with polycythemia vera. 

IMPORTANT SAFETY INFORMATION 

WARNING: RISK OF SERIOUS DISORDERS 

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.  

CONTRAINDICATIONS 

• Existence of or history of severe depression, suicidal ideation, or suicide attempt 

• Hypersensitivity to interferons or any inactive ingredients 

• Moderate or severe hepatic impairment 

• History or presence of active serious or untreated autoimmune disease 

• History of transplantation and receiving immunosuppressant agents 

WARNINGS AND PRECAUTIONS 

• Depression and Suicide: Closely monitor patients for any symptoms of psychiatric disorders and, if needed, consider psychiatric consultation and treatment or dosage modifications as listed in the full prescribing information. 

• Endocrine Toxicity: Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease. Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi. 

• Cardiovascular Toxicity: Patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease or recent stroke or myocardial infarction. 

• Decreased Peripheral Blood Counts: Monitor complete blood counts at baseline, during titration, and every 3-6 months during the maintenance phase. 

• Pancreatitis/Colitis/Pulmonary Toxicity: Interrupt BESREMi treatment in patients with possible pancreatitis, colitis, or pulmonary toxicity and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis or who show signs or symptoms of serious ulcerative or hemorrhagic colitis, or who develop pulmonary infiltrates or pulmonary function impairment. 

• Ophthalmologic Toxicity: Advise patients to have eye examinations before and during treatment. Discontinue BESREMi in patients who develop new or worsening eye disorders. 

• Hyperlipidemia/Hepatotoxicity/Renal Toxicity: Monitor serum triglycerides, liver enzymes, hepatic function, and serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi in patients with persistently marked elevated triglycerides, evidence of hepatic decompensation, or if renal impairment develops during treatment. 

• Dental and Periodontal Toxicity: Patients should have good oral hygiene and regular dental examinations. 

• Dermatologic Toxicity: Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs. 

• Driving and Operating Machinery: BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence, or hallucination during BESREMi therapy should avoid driving or using machinery. 

• Embryo-Fetal Toxicity: Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman. Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose. Advise women not to breastfeed during treatment and for 8 weeks after the final dose. 

ADVERSE REACTIONS 

The most common adverse reactions reported in >40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain. 

DRUG INTERACTIONS 

Patients on BESREMi who are receiving concomitant drugs which are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification. Avoid use with myelosuppressive agents, narcotics, hypnotics, or sedatives, and monitor patients receiving the combination for effects of excessive CNS toxicity. 

To report SUSPECTED ADVERSE REACTIONS, contact PharmaEssentia at 1-800-999-2449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 

Please see full Prescribing Information, including Boxed Warning at besremihcp.com.