Management of side effects of BCR/ABL-negative chronic myeloproliferative neoplasm therapies. Focus on anagrelide

Abstract

Although hydroxyurea is considered the first-line cytoreductive therapy in high-risk patients with polycythemia vera or essential thrombocythemia, approximately 20–25% of patients develop resistance or intolerance and they need an alternative therapy. Anagrelide is the treatment of choice in patients with essential thrombocythemia intolerant or with resistance to hydroxyurea. Anagrelide is usually well tolerated. Although there is concern about the increased risk of cardiac side effects, in most cases these are mild, and easily manageable. In this paper, the available evidence about the management of patients with myeloproliferative neoplasms, with a special focus on the side effects of drug therapies is reviewed.

Keywords:

• anagrelide
• BCR/ABL-negative chronic myeloproliferative neoplasms
• essential thrombocythemia
• hydroxyurea
• interferon-α
• Philadelphia-negative chronic myeloproliferative neoplasms
• polycythemia vera
• primary myelofibrosis

Acknowledgement

We would like to thank Dr. Altea Esteve from the University General Hospital of Valencia for providing the images.

Financial & competing interests disclosure

M Antelo received lecture fees and has participated in advisory boards for Shire. J Raya has received honoraria for lectures by Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and performed by Content Ed Net Communications SL and funded by Shire.

Key issues

• Clinical manifestations of Myeloproliferative neoplasms (MPN)

  • – Venous and arterial, thrombosis, and intracranial hemorrhages are the most serious consequences of this entity.

  • – Vascular events, particularly thrombosis and microvascular occlusive symptoms, are the most common clinical manifestations.

  • – Patients with Primary myelofibrosis (PMF) have a shortened survival.

• Risk stratification is mandatory to establish the best approach in every patient

  • – Polycythemia vera (PV): high risk patients include those aged >60 years or with history of thrombosis.

  • – Essential thrombocythemia (ET): high risk patients include those aged >60 years, with history of thrombosis/bleeding events, or with platelet count ≥1500 × 10⁹/l.

• Goals of treatment

  • – In patients with PV and ET, the main goals include reducing the risk of new or recurrence of thrombotic and hemorrhagic events as well as the risk of acute leukemia and post-PV/ET myelofibrosis.

  • – In patients with Primary myelofibrosis (PMF), the main goals include reducing mortality and the risk of leukemic transformation, as well as the treatment of complications.

• Side effects

  • – Toxicity of hydroxyurea is dose dependent and cumulative. Rates of withdrawal range from 8 to 20%. Approximately 20–25% of patients develop resistance or intolerance. Although controversial, some authors, but not all, suggest that hydroxyurea may increase the risk of leukemic transformation.

  • – Anagrelide is not associated with leukemic transformation. Although anagrelide is associated with an increased risk of cardiovascular side effects, the majority of cardiovascular adverse events are mild.

  • – In patients with ET, IFN-α is not currently approved for this use in the majority of countries. Up to 20% of patients have to withdraw treatment due to side effects. No leukemogenic effect has been described.

  • – Ruxolitinib has been approved for the treatment of patients with PV resistant or intolerant to hydroxyurea.

  • – Busulfan and ³²P may be considered in patients with short life expectancy due to their leukemic risk.

• Future perspective

  • – The ideal cytoreductive drug for long-term use in patients with Myeloproliferative neoplasms (MPN) should reduce the risk of thrombosis and hemorrhages, and avoid long-term complications, particularly acute leukemia.

  • – JAK2 inhibitors may be a relevant target for the treatment of these patients.

Notes

IFN: Interferon; ET: Essential thrombocythemia; PV: Polycythemia vera; PMF: Primary myelofibrosis.

Data taken from references 5,13–23,30–32,34,37,55–58,70,91–93.