Survey Reveals Importance of Precise PV Treatment Guidelines and Research

Giuseppe Alberto Palumbo, MD, PhD

Heterogeneous patterns of polycythemia vera (PV) management indicate the need for continued research in this disease and increased guideline specificity across treatment centers in Italy, according to survey results from a study investigating routine treatment patterns used in patients with PV.¹

The survey collected variable responses regarding PV treatment approaches for low-risk patients, leukocytosis definition, splenomegaly, hydroxyurea discontinuation or interruption, and ruxolitinib (Jakafi) use.

According to a 2020 study compiling updates in PV diagnosis, risk-stratification, and management, the current first-line PV treatment recommendations stratify patients based on risk.2 Low-risk patients, defined as those aged 60 years or younger with no history of thrombotic events, are usually treated with phlebotomy and aspirin. High-risk patients, defined as those aged over 60 years and/or those with a history of thrombosis, are generally treated with aspirin, phlebotomy, and cytoreductive therapy, typically hydroxyurea. In patients with PV who are resistant or intolerant to hydroxyurea, ruxolitinib, approved by the FDA in 2014 in this population, is an effective second-line option.

“Determining the impact of these changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management,” lead study author, Giuseppe Alberto Palumbo, MD, PhD, of the University of Catania in Italy, and colleagues, wrote in a paper of the data, which was published in the European Journal of Haematology.¹

This study, conducted by the MPN Lab, surveyed 60 participants in Italy, 48 (80.0%) hematologists and 12 (20.0%) transfusion specialists, to determine how they manage PV. The survey, which was carried out between June and September 2021, consisted of 19 closed-answer questions that were collected anonymously by an external agency. All survey participants, which included the study authors themselves, had direct experience with managing PV.

Two of the survey questions were about the treatment of low-risk patients. When asked which low-risk patients should be considered for cytoreduction, 71.7% and 76.7% of participants replied that progressive leukocytosis and massive thrombocytosis, respectively, were driving criteria. Other cited driving criteria included progressive splenomegaly in the absence of myelofibrosis progression (66.7%), excessive number of phlebotomies (55.0%), and persistent symptoms despite good disease control with phlebotomies (53.3%). When asked which low-risk patients requiring cytoreduction should receive interferon-alpha (IFN-α) instead of hydroxyurea or other cytoreductive therapies, 73.3% of responders indicated that they considered the patient’s desire for maternity/paternity, 26.7% indicated that any patient without a contraindication to IFN-α should receive that agent, 40.0% indicated that patients age 40 years or younger should receive IFN-α, and 25.0% indicated that patients age 60 years or younger should receive IFN-α.

In total, 56.7% of participants replied that they assessed leukocytosis differently according to patient smoking habits. In non-smokers, 23.1% of these participants defined leukocytosis as a white blood cell (WBC) count of over 15 x 109/L, 64.7% used a WBC count of over 15 x 109/L confirmed after 6 months of follow-up, 2.9% used a WBC count of over 20 x 109/L, and 11.8% used a WBC count of over 20 x 109/L after 6 months of follow-up.

In smokers, 11.8% of these participants defined leukocytosis as a WBC count of over 15 x 109/L, 14.7% used a WBC count of over 15 x 109/L confirmed after 6 months of follow-up, 14.7% used a WBC count of over 20 x 109/L, and 58.8% used a WBC count of over 20 x 109/L after 6 months of follow-up. Of the participants who did not consider smoking habits when assessing patients for leukocytosis, 23.1% defined leukocytosis as a WBC count of over 15 x 109/L, 38.5% used a WBC count of over 15 x 109/L confirmed after 6 months of follow-up, 19.2% used a WBC of over 20 x 109/L, and 19.2% used a WBC of over 20 x 109/L confirmed after 6 months of follow-up.

Participants were able to provide more than 1 response when asked to define splenomegaly and excessive phlebotomies. Regarding the definition of clinically meaningful splenomegaly, 58.3% reported considering the presence of splenomegaly-related symptoms, regardless of spleen size, and 25% of all responders chose this option alone. Additionally, 36.7%, 28.3%, and 13.3% of participants reported considering the presence of a palpable spleen at over 5 cm, 10 cm, and 15 cm BLCM, respectively, regardless of symptoms. Forty-two percent of participants indicated that they define splenomegaly by palpation alone.

Regarding the definition of excessive phlebotomies, 61.7% of responders reported that any number of phlebotomies were excessive if they were not well tolerated, 50.0% considered over 1 a month excessive, 30.0% considered any number excessive when associated with clinically significant iron deficiency, and 28.3% considered more than 1 every 2 months excessive.

When asked which toxicities participants considered tolerable for hydroxyurea continuation in fit patients, 41.7%, 38.3%, 33.3%, 33.3%, and 21.7% replied with alopecia, gastrointestinal toxicity, development of non-melanoma skin cancers and keratosis, cytopenia, and development of aphthosis and leg ulcers, respectively.

When asked which lack of responses participants considered tolerable for hydroxyurea continuation in fit patients, 43.3%, 40.0%, 38.3%, 31.7%, and 20.0% replied with persistent splenomegaly without myelofibrosis evolution, persistent leukocytosis, persistent thrombocytosis, an excessive number of phlebotomies, and persistent symptoms, respectively. Additionally, 43.3% of responders noted that they typically administer hydroxyurea at a dose of 2g per day before switching to second-line therapy in patients with no toxicities.

Regarding which hydroxyurea-intolerant patients the participants considered preferable candidates for ruxolitinib instead of other cytoreductive agents, 80.0% cited those who developed aphthosis or leg ulcers. Other responses included those with gastrointestinal toxicity (46.7%), those with non-melanoma skin cancers or keratosis (45.0%), and those with cytopenia (41.7%).

Regarding which disease aspects made hydroxyurea-refractory patients preferable candidates for ruxolitinib over other cytoreductive agents, 80.0% cited persistent splenomegaly without myelofibrosis evolution, 70.0% considered persistent symptoms, 35.0% considered persistent thrombosis, and 28.3% considered persistent leukocytosis.

When the participants were asked about ruxolitinib use, 45.0% responded that there were specific clinical situations in which they do not feel confident using ruxolitinib. The reasons these responders cited were a history of recurrent herpes zoster or other clinically meaningful infections (31.7%), concurrent or active solid tumors (20.0%), latent tuberculosis requiring prophylaxis (18.3%), recurrent non-melanoma skin cancer (16.7%), age over 80 years (8.3%), multiple concomitant therapies (8.3%), and therapy with direct oral anticoagulants (6.7%). Additionally, 60.0% of all participants indicated that they withdraw ruxolitinib in patients with severe infections.

Regarding vaccines in patients receiving cytoreduction, 65.0% of responders replied that they never consider cytoreductive therapy a vaccine contraindication, 33.3% replied that they do consider cytoreductive therapy a contraindication for all attenuated vaccines, and 1.7% replied that they consider cytoreductive therapy a contraindication for all vaccines.

This survey did not ask about JAK2 V617F variant allele frequency, as participants included those from smaller centers that do not routinely assess allelic burden. Additionally, this survey included few questions about ropeginterferon alfa-2b-njft (Besremi) and did not include questions about iron deficiency in PV. Other limitations of this survey include the small number of participants and the potential for self-selection bias.

“Educational programs could be of value in improving the consistency of treatment of PV,” the study authors concluded.

References

1. Palumbo GA, Breccia M, Baratè C, et al. Management of polycythemia vera: a survey of treatment patterns in Italy. Eur J Haematol. 2023;110(2):161-167. doi:10.1111/ejh.13889
2. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12):1599-1613. doi:10.1002/ajh.26008