Where to Turn for Second-Line Cytoreduction After Hydroxyurea in Polycythemia Vera?

Abstract

The goals of therapy in patients with polycythemia vera (PV) are to improve disease‐related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first‐line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6‐fold increase in mortality and a 6.8‐fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon‐α has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation. Implications for Practice: The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration‐approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low‐dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies.

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

“…Moreover, the BMMSC may infiltrate the tumor microenvironment supporting cancer cell growth, activate mitogen and stress signaling, as well as increase resistance to chemotherapy [19]. Our results indicated that HU effectively reduce BMMSC proliferation with no effect on cell viability, which is in concordance with the notion of that HU acts mainly as a cytostatic agent [1,43].…”

“…HU is a water-soluble antiproliferative agent used in neoplastic and non-neoplastic conditions, such as hematological malignancies, infectious diseases, and dermatology for refractory psoriasis [1]. Mainly, HU arrests cells in the S phase of the cell cycle due to the decrease of dNTPs pools resulting from RNR inhibition and a slowdown of the DNA polymerase movement at replication forks [1,43]. Beyond cancer cells, non-transformed cells are also susceptible to the profound influence of chemotherapy [44,45].…”

Human platelet lysate as validated replacement for animal serum to assess chemosensitivity

“…We chose these agents based on their clinical relevance and on the fact that inducers of ROS and inhibitors of HDACs occur endogenously (Krämer, 2009;Newman and Verdin, 2014) and may hence be differentially contained in FCS and hPL. Hydroxyurea inhibits ribonucleotide reductase and can be used to reduce leukemic cell counts (Eklund et al, 2001;Nazha and Gerds, 2016), imatinib is used to treat BCR-ABL-positive chronic myeloid leukemia (CML) (Lamontanara et al, 2013). HDACi are more and more frequently used for leukemia patients and these agents are being considered for the therapy of further forms of cancer (Ceccacci and Minucci, 2016;Krämer et al, 2014).…”

Recent Progress in Interferon Therapy for Myeloid Malignancies

“…Most CML patients will experience long term responses with tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene and can in many cases be considered functionally cured of their disease (9,11). PV is associated with blood hyperviscosity due to the expansion of the erythrocyte mass, and therefore standard therapy involves blood withdrawal to reduce mass as well as treatment with hydroxyurea, or ruxolitinib (Janus activated kinase 1/2 (JAK1/JAK2) inhibitor) as a second-line chemotherapy option (12,13). PMF can also be treated using JAK2 inhibitors, however this is considered only a symptom relieving measure -PMF is only potentially curable with an allogeneic haematopoietic stem cell transplant (HCT) and is associated with a substantial risk of treatment-related mortality (14).…”

“…Standard therapy for PV involves phlebotomy and cytoreductive drugs (hydroxyurea, busulfan) but recently IFNa and JAK1/2 inhibitors have been examined as potential treatments (102,103). Although busulfan has been effective over long periods (104), resistance to hydroxyurea is associated with increased mortality and progression to more advanced MPNs or secondary AML (13). IFN therapy is an accepted alternative to hydroxyurea or busulfan in PV, and is particularly useful for younger patients or those who are pregnant (105,106).…”