Experts Debate Need for New Drugs to Treat Patients with PV and ET

Special ReportsHematologic Malignancies: Polycythemia Vera
Volume 3
Issue 3

Haifa Kathrin Al-Ali, MD, and Carlos Besses, MD, PhD debated the need for new drugs to treat polycythemia vera (PV) and essential thrombocythemia (ET). 

Haifa Kathrin Al-Ali, MD

Though there are currently treatment options available for patients with polycythemia vera (PV) and essential thrombocythemia (ET), they can be associated with adverse effects (AEs) and persisting thrombotic events, according to Haifa Kathrin Al-Ali, MD, of the University Hospital of Leipzig.

During the 2016 European Hematology Association congress in Copenhagen, Al-Ali presented findings to support the opinion that new drugs are needed to treat these diseases. Contrastingly, Carlos Besses, MD, PhD, of Hospital del Mar, Barcelona, presented on the opinion that new drugs are not needed to treat ET and PV.

According to Al-Ali, current treatment guidelines for PV are based on the risk of thrombosis. She said she does not believe the current standard treatment options, such as phlebotomy and hydroxyurea, are able to abolish disease-related thrombotic events.

Al-Ali referenced a recent study1of more than 1,300 patients with PV in which 24.7% of patients who were treated with hydroxyurea and 21.8% of patients who were treated with phlebotomy experienced thrombotic events.

The study also included a group of patients who were treated with a combination of phlebotomy and hydroxyurea. This group showed a thrombotic event rate of 19.3% following treatment.2

“We still have a problem with thrombotic events, even in patients treated with phlebotomy or hydroxyurea,” Al-Ali said.

Al-Ali also pointed to the abundance of symptoms in PV and ET patients as a reason to investigate new drugs for the disease. Patients with PV who are treated with phlebotomy or hydroxyurea experience many AEs, Al-Ali said.

“With the current treatments, I don’t think we are addressing the variety of symptoms these patients are having over decades. Still, there is a need to improve something,” she said.

According to a study3of 890 PV patients treated with hydroxyurea, 9% experienced unacceptable non-hematological toxicities, while another 10% experienced what is called manageable toxicity, Al-Ali said. A study shows that there is also a 20% risk of ET and PV patients developing non-melanoma skin cancer when treated with hydroxyurea, she added.

Al-Ali also discussed pegylated interferon alpha-2a (PEG-IFN-α), which she said is not currently licensed in most European countries. Though the results of a phase III trial are not yet available for PEG-IFN-α, Al-Ali said, initial trials have shown up to a 40% discontinuation rate in patients with PV treated with the drug and up to a 50% discontinuation rate in patients with ET treated with the drug due to AEs.

There have also been trial studies conducted to research anagrelide, Al-Ali said. One-third of the patients in the study who were treated with the drug experienced progressive anemia over several years, in addition to other AEs.4

“We have many of the grade 1 and 2 side effects. Grade 1 and 2 is OK, but I don’t know if it is OK for someone to have palpitations and headaches over years because of the treatment we’re giving,” she said.

In addition, 14.9% of patients in the study treated with anagrelide discountinued the drug due to the disease transforming into myelofibrosis, Al-Ali said.4

Ruxolitinib is now approved for patients with PV, Al-Ali said. The approval of ruxolitinib was based off the RESPONSE trial,5which included patients with PV and ET who had an intolerance of or resistance to hydroxyurea and were experiencing splenomegaly. The findings of the study showed that 38% of patients experienced a reduction in spleen volume. There was also a 60% response in hematocrit levels. Al-Ali said there is also some preliminary evidence that shows that thrombotic events are reduced with ruxolitinib.

“We are still having an unmet medical need in a substantial subgroup of patients with PV and ET and we cannot develop new drugs until we have further clinical research and safety data,” Al-Ali said.

Besses, who argued against the need to investigate new drugs to treat ET and PV, said the classic therapy options, including hydroxyurea, PEG-IFN-α, busulfan, and anagrelide, are adequate options to treat patients with PV or ET.

The goals of treatment, Besses said, are to prevent thrombosis and hemorrhage, control symptoms, and minimize AEs and clonal transformation. To achieve these goals, oncologists classify patients into low risk and high risk, based on the risk of thrombosis.

In PV, Besses said, a study6showed the overall hematological response rate to hydroxyurea was 80% to 90%. In a study of PEG-IFN-α in PV patients,7the complete hematological response rate was 70%.

In a Spanish study of busulfan in 15 PV and 21 ET patients,8including 34 patients that had experienced an intolerance to hydroxyurea and 2 who had experienced a resistance to hydroxyurea, 67% achieved a complete hematological response. Besses said he would recommend busulfan for elderly patients with a short life expectancy.

Besses said in his department at Hospital del Mar, there are approximately 200 PV patients, with two-thirds over 60 years old. In the patients over 60, Besses said his choice for first-line treatment is hydroxyurea and his second-line choice is ruxolitinib.

Among the arguments supporting the viewpoint that the current treatment options are adequate to treat PV and ET patients, Besses said survival rates are close to normal (in ET patients) or slightly reduced (in PV patients) with currently available drugs. Also the frequency of acute transformation is rare (in ET) or low (in PV), and few patients present with severe symptoms.

“The answer to the question ‘do we really need new drugs for ET’ is no, or maybe even not yet,” Besses said. “But the answer to the question ‘do we really need new drugs for PV’ is probably yes.”


  1. Geyer H, Scherber R, Kosiorek, H, et al. Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease.J Clin Oncol.2016;34(2):151-159.
  2. Alvarez-Larrán A, Perez-Encinas M, Ferrer-Marin F, et al. Prevention of Thrombosis in Patients With Polycythemia Treated With Hydroxurea Plus Phlebotomies Or Hydroxurea Alone. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark.
  3. Alvarez-Larrán A, Kerguelen A, Hernandez Boluda J, et al. Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 89 patients with polycythaemia vera.Br J Haematol.2016;172(5):786-793.
  4. Mela Osorio MJ, Ferrari L, Goette NP, et al. Long-term follow-up of essential thrombocythemia patients treated with anagrelide: subgroup analysis according to JAK2/CALR/MPL mutational status.Eur J Haemotol.2016; 96(4):435-442.
  5. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera.N Engl J Med.2015;372(5):426-35.
  6. Alvarez-Larrán A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera.Blood.2012;119(6):1363-1369.
  7. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.J Clin Oncol.2009;27(32):5418-5424.
  8. 8. Alvarez-Larrán A, Martinez Aviles L, Hernandez-Boulda JC, et al. Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea.Ann Hematol.2014;93(12):2037-2043.
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