Polycythemia Vera: Barriers to and Strategies for Optimal Management

Figures & data

Table 1 Summary of Studies Reported in the Literature Regarding Anticoagulant Therapy in MPN

Study	Study Population	Findings
SELECT-D^Citation30 Comparing rivaroxaban versus LMWH	Oncological patients, with 23 lymphoma and 5 MM with DVT and PE	Recurrent TE rate at 6 months 4% in rivaroxaban versus 11% in LMWH arm
Data from the OBENE registry^Citation31 Real-life cohort of DOAC-treated	760 MPN patients	25 (3.3%) were treated with a DOAC, only one case of TE with treatment and 3 major bleeding
Data from real-life experiences in two different American centers^Citation33	133 MPN patients who received DOAC for TE and AF from 1986 to 2021	Recurrent thrombosis of 5.5% (1.5–9.5%) and bleeding of 12.3% (6.4–18.2%) after 1 year. In MVA, high-risk of thrombosis in patients with dabigatran and edoxaban, younger age, and history of thrombosis
MPN-DOACs study^Citation34	442 MPN patients with DOAC indication for AF or VTE	Recurrent thrombosis in 10 cases (2.1% patients’ year) and 22 cases (9.2%)
AVAJAK, NCT05198960	Designed to compare the efficacy of apixaban (2.5mg bd) or rivaroxaban (10mg od) versus aspirin 100mg daily in preventing the occurrence of TE	Ongoing phase 3 recruiting trial

Abbreviations: LMWH, low molecular weight heparin; DVT, deep venous thrombosis; MM, multiple myeloma; TE, thromboembolic event; MPN; myeloproliferative neoplasm; DOAC, direct-acting oral anticoagulants; AF, atrial fibrillation; VTE, venous thromboembolism.

Box 1 ELN 2021 Criteria to Define Intolerance/Resistance to Hydroxycarbamide

Criteria to define the intolerance to hydroxycarbamide (at least one of the following)
Occurrence of grade 3–4 AEs or prolonged grade 2 non-hematological toxicity
Occurrence of haematologic toxicity (Hb <100 g/L, platelet count <100 x 10^9/L, neutrophils <1 x 10^9/L) at the lowest dose to achieve a response
Development of non-melanoma skin cancers
Occurrence of vascular events (defined as clinically relevant bleeding and thrombosis, either venous or arterial)
Criteria to define the resistance/insufficient clinical response to hydroxycarbamide (at least one of the following)
Persistent total symptom score ≥20 or an itching score of 10 for at least 6 consecutive months
Persistent thrombocytosis (platelet count >1000 x10^9/L) and/or microvascular symptoms (eg, erythromelalgia, headaches, tingling)
Symptomatic or progressive splenomegaly (defined as spleen increase by at least 5 cm below the low costal margin in 12 months)
Progressive leukocytosis (defined as an increase of at least 100% if baseline <10 x 10^9/L) and/or persistent leukocytosis (defined if >15 x 10^9/L for consequent 3 months)
Required >6 venesections in a year to attain target Hct <0.45

Abbreviations: Hb, hemoglobin; AE, adverse event; Hct, hematocrit.

Table 2 Available Strategies for Polycythemia Vera Management and Commonly Reported Side Effects with Their Management

Procedure/Treatment	Indications	Side Effects	Management
Venesection	Control of blood viscosity (target <0.45), reducing the associated thrombotic risk	Transient fatigue, light-headedness, vasovagal reaction Iron deficiency	Monitoring ferritin levels and administration of iron supplementation if needed
Low-dose aspirin	Reducing the associated thrombotic risk	Mild gastrointestinal symptoms (indigestion), bleeding events	Considering shift to DOAC (clopidogrel)
Hydroxycarbamide	Cytoreductive treatment to control blood counts and associated hyperviscosity symptoms	Hematological toxicity (high risk of infection, bleeding, fatigue) Gastrointestinal toxicity (gastritis, mucositis, and oral mucosa ulcer) Skin toxicity (ulcer, erythema, skin infiltration, non-melanoma skin cancers) Leukemia transformation	Discontinue HC treatment if intolerance to HC (defined by ELN 2021 criteria)
Interferon(all formulation)	Immune response directed towards neoplastic cells and antiproliferative effect on hematopoietic precursor cells to control blood counts	Flu-like symptoms, fatigue and neuropsychiatric manifestations (low mood, depression)	Discontinue treatment
Ruxolitinib	Inhibition of myeloid proliferation through action on JAK/STAT pathway, used after intolerance/refractory to HC	Hematological toxicities (above all thrombocythemia) Impairment of immune function (increased risk of new or reactivation of latent infections) Non-melanoma skin cancer	Dose based on PLT count. Discontinue in case of grade 3/4 toxicities
Pipobroman, busulfan	Used only in case of high thrombotic and low leukemia progression risks, in case of ineligibility to different treatments	Higher risk of transformation in AML/MDS	Discontinuation and management of the hematological condition

Abbreviations: HC, hydroxycarbamide; PLT, platelets; AML/MDS, acute myeloid leukemia; ELN, European Leukemia Network; DOAC, direct-acting oral anticoagulants.

Table 3 Summary of Ongoing Clinical Phase 1/2 Trial Testing New Molecules in the Setting of PV Patients Intolerant/Refractory to Standard Cytoreductive Treatment Available on https://clinicaltrials.gov/.⁹¹

Trial	Molecule and Mechanism of Action	Aim of the Study	Eligibility Criteria
NCT05558696	Bomedestat, an inhibitor of LSD1, an enzyme involved in increasing cell proliferation and hematopoietic differentiation	Evaluating the safety, tolerability and pharmacodynamic effect of bomedemstat	PV patients who have failed at least one standard cytoreductive therapy
NCT04262141		Assess the dose and haematologic effects of IMG-7289 therapy in PV patients who require platelet, WBC or Hct control	PV patients who failed at least one standard therapy, with a discontinuation time of at least 2–4 weeks
NCT05499013	SLN124, a double-stranded siRNA targeting TMPRSS6 mRNA	Evaluating the safety, tolerability, efficacy, and pharmacokinetic/dynamic effect of SLN124	PV patients who are not receiving any cytoreductive therapy for at least 24 weeks or stable with the ongoing treatment for at least 12 weeks with no planned change in dose
NCT05143957	Sapablursen, a ligand-conjugated antisense (LICA) molecule designed to target the TMPRSS6 gene to modulate the production of hepcidin and subsequent regulation of iron metabolism	Evaluate the efficacy of sapablursen in reducing the frequency of VS and improving QoL	PV patients VS-dependent, with no need for prior cytoreductive discontinuation. If treated, it must have been discontinued at least 12 weeks prior, if it is ongoing, it must be on a stable dose for at least 12 weeks

Abbreviations: PV, polycythemia vera; WBC, white blood cell; QoL, quality of life; TMPRSS6, transmembrane protease, serine 6; siRNA, small interfering ribonucleic acid; Hct, hematocrit; VS, venesection.

Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017–2023. doi:10.1200/JCO.2018.78.8034

 PubMed Web of Science ®Google Scholar

Ianotto JC, Couturier MA, Galinat H, et al. Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms. Int J Hematol. 2017;106(4):517–521. doi:10.1007/S12185-017-2282-5

 PubMed Web of Science ®Google Scholar

How J, Story C, Ren S, et al. Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients. Blood Cancer J. 2021;11(11). doi:10.1038/S41408-021-00566-5

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Barbui T, De Stefano V, Carobbio A, et al. Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients. Leukemia. 2021;35(10):2989. doi:10.1038/S41375-021-01279-1

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ClinicalTrials.gov. Home. Available from: https://clinicaltrials.gov/. Accessed November 23, 2023.

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