Advances in management of primary myelofibrosis and polycythaemia vera: Implications in clinical practice

Abstract Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare BCR‐ABL1‐negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence‐based knowledge into routine clinical practice.

thrombosis and haemorrhage, and such complications can also lead to diagnosis. [5,7,[9][10][11] In the current 2022 World Health Organisation (WHO) classification [4] and the International Consensus Classification (ICC) of myeloid neoplasms and acute leukaemias, [12] PV and PMF should be diagnosed by a combination of peripheral blood, BM morphologic and molecular features ( Table 2). In routine practice, diagnosis of PV can be presumptively made based on elevated haemoglobin and haematocrit. Isotopic measurement of the RBC mass can be useful to confirm a true polycythaemia in case of only a small increase in haematocrit, or in a particular context such as splanchnic vein thrombosis. [13,14] It can also be helpful to distinguish 'masked PV' from essential thrombocythaemia (ET) in case of a haematocrit close to the upper limit (in 10-15% of all patients with PV), in the context of splenomegaly or haemodilution. [15] In PMF, the hemogram is usually quite characteristic, with the presence of immature granulocytes, erythroblasts and teardrop cells (dacrocytes). It can also show leucocytosis or leukopenia, as well as thrombocytosis or thrombocytopaenia.
Anaemia is also frequent, with nearly 40% of PMF patients reporting haemoglobin levels < 10 g/dL at diagnosis and nearly one-quarter already transfusion-dependent. [10,16,17] As PMF progresses, it may potentially lead to severe cytopenia due to increase in BM fibrosis. [1] The constitutive activation of the JAK/STAT pathway is a pathogenetic hallmark of all MPNs, with three well-characterised driver mutations in JAK2, CALR and MPL genes. [3,9] JAK2V617F, a valine-tophenylalanine substitution at amino acid position 617 (V617F) in exon 14 of JAK2, is the most prevalent mutation in MPNs, present in > 95% of patients with PV and in approximately 60% of patients with PMF. [3,18] JAK2 exon 12 mutations are also observed in up to 3% of patients with PV. CALR and MPL mutations are present in up to 25% and 8% of patients with PMF, respectively. [3,18]

Our group's practical applications
• Our group starts the diagnostic workup of suspected PMF or PV with a careful clinical examination of signs and symptoms associated with these pathologies such as splenomegaly. • After clinical examination, we perform the following laboratory investigations: • ○Complete blood count to detect elevated haemoglobin and haematocrit in patients with PV and anaemia in patients with PMF.
• ○Peripheral blood smear to detect immature granulocytes, erythroblasts and teardrop cells (dacrocytes) in patients with PMF.
• ○Serum lactate dehydrogenase, which is increased in both PMF and PV.
• ○Serum iron-level measurement, as iron deficiency is a known feature of PV occurring because of accelerated erythropoiesis, and which can mask PV in patients with chronic bleeding.
• Abdominal ultrasound can be used to document and confirm splenomegaly.
• We perform JAK2 molecular testing early on in the diagnostic workup of PV and PMF.
• In clinical practice, BM biopsy is not always performed to diagnose PV. In this perspective, our group reserves BM biopsies for specific situations such as: • ○Masked PV.
• ○If there are atypical features such as marked splenomegaly or a history of splanchnic vein thrombosis.
• We invariably perform a BM biopsy to confirm PMF. However, the benefit/risk balance of BM biopsy should be discussed in TA B L E 2 Diagnostic criteria for polycythaemia vera (PV) and primary myelofibrosis (PMF) [4,12]. • ○Search for a clonality marker in patients with triple-negative PMF.
• ○Guide therapeutic decision-making. Several risk assessment scoring systems have been developed taking into account the clinical, morphologic, cytologic, cytogenetic and/or molecular aspects of PMF (Table 3). There is no consensus regarding the optimal prognostic tool for PMF, and these risk models have never been prospectively validated. [20] The choice of the risk stratification model may vary for each patient, according to available information. [6,21] However, compared to the International Prognostic

PROGNOSIS AND RISK STRATIFICATION
Scoring System (IPSS) [22] applied at diagnosis only, all other PMF risk models can estimate survival from any point in the disease course.
Given the limited availability of molecular findings in routine clinical practice, dynamic IPSS (DIPSS) [23] and DIPSS-plus [24] remain the most commonly used models for risk stratification and prognostication of PMF, as they are based on easily assessable clinical characteristics and blood counts. [6,21] However, because of the prognostic relevance of the mutational profile in PMF, [25] we favour the use of In patients with PV, age and thrombotic history are the two major risk factors used for risk stratification in clinical practice. Patients aged > 60 years and/or having prior PV-associated arterial or venous thrombosis are considered at "high risk" of thrombosis, whereas those ≤60 years with no PV-associated thrombotic history are categorised as "low risk." [5,11,28] However, it is important to also take into account cardiovascular risk factors (smoking, diabetes mellitus, arterial hypertension, hypercholesterolaemia), the presence of leucocytosis and the symptomatic burden associated with PV to guide risk stratification and subsequent therapeutic management. [11,28,29] 4.1 Our group's practical applications

5
TREATMENT OF PMF

Allogeneic haematopoietic stem cell transplantation (AHSCT)
Currently, AHSCT is the only treatment modality in PMF that offers a potential cure. [9]

Constitutional symptoms
Yes (1) Yes (1) Yes (1) Yes (1) Yes (  Severe anaemia: Hb c Complex karyotype or a single or two abnormalities, including AHSCT in PMF is associated with up to a 50% rate of transplantrelated mortality or severe morbidity (e.g. graft-versus-host disease (GVHD)). [34] The decision of performing AHSCT in patients with PMF is also complicated by the lack of consensus regarding donor type, the optimal source of the stem cell graft, the choice of conditioning regimen and the optimal timing of AHSCT. It is worthy to note that no randomised controlled trials (RCTs) have compared AHSCT with non-transplant treatment strategies, and recommendations guiding transplant decisions are largely based on retrospective analyses and expert opinion. [20] The timing of AHSCT is the most important question in PMF man-

5.3
Treatment of PMF-associated splenomegaly Although these data appear to support pre-transplant use of ruxolitinib, caution is advised. In all three aforementioned trials, [38,49,50] pre-AHSCT ruxolitinib therapy was not beneficial for reducing the incidence of acute or chronic GVHD. Concerns about the safety of ruxolitinib in the pre-AHSCT setting have also been raised. For instance, the JAK ALLO trial reported unusual serious adverse events of ruxolitinib, such as tumour lysis syndrome and cardiogenic shock. [38] Ruxolitinib may also be associated with a cytokine rebound syndrome if rapidly withdrawn. [50] According to ELN/EBMT recommendations, weaning of ruxolitinib starting 5-7 days prior to conditioning should be implemented in an attempt to avoid a cytokine rebound, with ruxolitinib discontinued the day before conditioning. [30] The role of ruxolitinib post-AHSCT for response maintenance remains unclear, with very limited information to guide clinicians. However, ruxolitinib may be considered in patients who relapse after AHSCT to decrease the symptom burden. [32] In patients who are refractory, intolerant to, or ineligible for JAK inhibitors, and who have a massive and symptomatic splenomegaly, splenectomy represents a valuable therapeutic strategy. [33,40]

Our group's practical applications
• We use ruxolitinib for the first-line treatment of splenomegaly in patients with myelofibrosis. • In our practice, we aim to find the optimal balance between efficacy and ruxolitinib-related toxicities such as thrombocytopaenia and anaemia by performing a complete blood count at least every 2 weeks after ruxolitinib initiation and until ruxolitinib doses are stabilised.
• In case of clinical resistance or intolerance to ruxolitinib, we recommend fedratinib for reducing splenomegaly.
• In patients who are refractory, intolerant to, or ineligible for JAK inhibitors, and who have a massive and symptomatic splenomegaly, we perform splenectomy. As asplenism increases the risk of lifethreatening infections from encapsulated organisms, we always vaccinate patients undergoing splenectomy against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
• In patients who have symptomatic splenomegaly and are ineligible for surgical procedures, we opt for splenic irradiation instead of splenectomy. In our practice, we usually monitor the blood count every 2 days in patients treated with splenic irradiation, and we hold irradiation if severe neutropenia (< 0.5×10 9 /L) or thrombocytopaenia (< 20×10 9 /L) is detected.

Treatment of PMF-associated anaemia
Anaemia in PMF is generally multifactorial, and patients should be evaluated for bleeding, haemolysis, nutritional deficiencies (e.g. iron, vitamin B12, folate) and other remediable causes. [54] Available (off-label) drugs for the management of anaemia in PMF include erythropoiesis-stimulating agents (ESAs) such as epoetin and darbepoetin, corticosteroids (e.g. prednisone) and androgens (e.g. danazol). [35] Unfortunately, their efficacy is often limited and short-lived.
Nearly all patients with PMF-associated anaemia will eventually become transfusion-dependent, requiring chronic RBC transfusions that may improve symptoms and quality of life. [54,56] Complications of chronic RBC transfusions, however, include iron overload, cardiac insufficiency and alloimmunisation. [56] In patients with transfusiondependent anaemia and iron overload, iron chelation therapy is the main approach to prevent iron-induced organ damage. [35,54] Splenectomy may exceptionally be indicated for palliative control of persistent anaemia. [54] It improves anaemia and thrombocytopaenia by allowing for sequestered blood cells to enter the peripheral circulation. [40] However, splenectomy is associated with significant morbidity and mortality, with the most common complications being bleeding, infection and thrombosis. [56,57] There are also several promising agents for improving PMF-

TREATMENT OF PV
Management of PV is primarily guided by the risk for thromboembolic events (Figure 2), but also the chronicity of the disease and the long-term risk of haematological transformation to SMF or acute F I G U R E 2 Risk-stratified treatment algorithm of polycythaemia vera (PV). Hct, haematocrit.
leukaemia. [61] Low-risk patients (aged ≤60 years with no history of thrombosis) should be treated with low-dose aspirin (75-100 mg/day) and phlebotomy. [11] Phlebotomy should begin as soon as possible after the diagnosis of PV. In the induction phase, the phlebotomy regimen should consider a person's weight and should remove 300-450 mL of blood weekly or twice weekly until target haematocrit < 45% is achieved. [28] During the maintenance phase, phlebotomy intervals should be determined by measuring haematocrit levels monthly in the first 6 months and then every 1-2 months thereafter. [62] High-risk patients (aged > 60 years and/or history of thrombosis) should receive, in addition to phlebotomy and low-dose aspirin, cytoreductive therapy with hydroxyurea or pegylated interferon alpha, with the latter recommended in patients aged < 60 years and in women who desire pregnancy. [18,[63][64][65][66] Recently, the ELN proposed that cytoreductive therapy with interferon alpha should be considered in specific clinical subgroups of low-risk patients with PV, especially in cases of intolerance to phlebotomy, progressive splenomegaly (increase by > 5 cm in the past year), persistent leucocytosis or thrombocytosis, or high symptom burden (e.g. severe pruritus). [29] Both low-risk and high-risk patients should be managed aggressively for cardiovascular risk factors, such as hypertension, hypercholesterolaemia, diabetes mellitus and smoking, as they also contribute to thrombotic risk in PV. [11,28] Based on its efficacy in controlling blood counts and preventing thrombosis, ease of administration, lower cost, wider availability and favourable toxicity profile, hydroxyurea, administered orally at a starting dose of 500 mg twice daily, is the most frequently used first-line cytoreductive drug in PV. [11,63,64,66] However, hydroxyurea is contraindicated in pregnancy, and is hence recommended to be stopped 3 months prior to intended conception. [11] By contrast, pegylated interferon is generally considered to be safe in pregnancy, and is therefore the preferred cytoreductive drug for young women of reproductive age. [66,67] Although hydroxyurea is a manageable and well-tolerated drug, during the course of disease, a quarter of patients with PV become resistant (12%) or intolerant (13%) to hydroxyurea. [68] Resistance to hydroxyurea therapy is an important adverse prognostic factor, associated with a sixfold increased risk of death and a sevenfold increased risk of progression to myelofibrosis or transformation to acute leukaemia. [68] Second-line cytoreductive therapy for PV includes pegylated interferon as a substitute for hydroxyurea and hydroxyurea for pegylated interferon. [11,28,66]  Other than ruxolitinib, pipobroman is approved in France as secondline therapy following the failure of hydroxyurea, but is preferentially used in elderly patients due its leukemogenic potential. [61,66] In 2021, ropeginterferon alpha-2b, a long-acting, mono-pegylated proline-interferon alpha-2b, became the first and only approved interferon for PV that patients can take regardless of their treatment history. The efficacy and safety of ropeginterferon alpha-2b versus hydroxyurea were demonstrated in the phase III PROUD-PV trial and its extension study, CONTINUATION-PV, conducted in patients with early-stage PV and no history of cytoreductive treatment or < 3 years of prior hydroxyurea treatment. [70,71] At 36 months, ropeginterferon alpha-2b resulted in a 71% haematologic response rate (defined as haematocrit < 45% with no phlebotomy in the past 3 months, platelet count < 400×10 9 /L and leucocyte count < 10×10 9 /L) compared to 51% for hydroxyurea (p = 0.012). [70,71] The phase II low-PV RCT has also recently shown that supplementing phlebotomy with ropeginterferon alpha-2b is safe and effective in steadily maintaining haematocrit values < 45% in 127 low-risk patients with PV. [72] Compared to phlebotomy and low-dose aspirin (standard arm), the addition of ropeginterferon alpha-2b was associated with a 84% haematological response rate (defined as haematocrit < 45% without disease pro- Overall, these data underscore the need for improved treatments to help alleviate common and problematic symptoms associated with PV. Of note, our group always offers sperm cryopreservation to male patients wishing to preserve their fertility before starting treatment for any MPN including PV and PMF.

Our group's practical applications
• Although therapeutic phlebotomy is the mainstay of controlling erythrocytosis, with a target haematocrit < 45%, it can exacerbate iron deficiency, which may cause thrombocytosis and additional symptoms. However, since the aim of therapeutic phlebotomy is to induce iron deficiency such that RBC production becomes limited, we usually do not prescribe iron supplementation. • Our group usually reserves cytoreductive therapy (hydroxyurea or pegylated interferon alpha) for patients with high-risk PV, and for low-risk patients in the following situations: • ○Presence of symptomatic or progressive splenomegaly.
• We prescribe ruxolitinib as second-line therapy for PV patients intolerant of or resistant to hydroxyurea. A switch to pegylated interferon may also be an option for some patients.
• For the management of PV-associated symptoms, we favour the use of ruxolitinib, antihistamines, aprepitant, antidepressants or interferon-α to treat pruritus. To help minimise erythromelalgia and migraines, we offer aspirin. There is also a multitude of therapeutic management issues affecting the care of patients with PMF and PV. In PV, current therapeutic decisions are based on predictive clinical variables, such as age and history of thrombosis, without considering the disease itself and its symptomatic burden. Other issues related to the therapeutic management of PV include impaired quality of life from frequent phlebotomy, ineffective reduction of PV-associated symptoms and a high rate (25%) of intolerance or resistance to hydroxyurea front-line therapy. [68] Pegylated interferon alpha is an attractive treatment, as it can alter the natural history of PV by targeting the mutant clone and preventing clonal evolution that underlies disease progression. It has also shown efficacy and safety in both low-risk and high-risk PV. [70,72] In PMF, the only potentially curative treatment is AHSCT, but it is associated with important morbidity and mortality, with no consensus regarding the optimal AHSCT protocol and the timing of transplant. Moreover, although the JAK inhibitor ruxolitinib has clearly enriched the therapeutic armamentarium for PMF, patients can develop ruxolitinib-refractory disease requiring alternative therapeutic approaches. [40] Other critical questions in the management of patients with PMF include pre-AHSCT management of marked splenomegaly and management of blast phase disease. [33] Given the enhanced understanding of molecular genetics of PMF and PV, many emerging mechanistic-based targeted therapeutic agents have been evaluated in the last years for both diseases.

DISCUSSION
Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2V617F cell growth, seems to be a promising novel drug for PV. [77] Navitoclax (a novel anti-apoptotic B-cell leukaemia 2  inhibitor), imetelstat (a telomerase inhibitor) and pelabresib (a BET inhibitor) might have disease-modifying effects in patients with PMF.
[ [78][79][80] Overall, given the complexity of PMF and PV management and the heterogeneity of the two diseases highlighted in this critical review, we strongly believe that all patients with PMF and PV should be managed by multidisciplinary teams, with close collaboration between different healthcare professionals including biologists, haematologists, pathologists and oncologists.

AUTHOR CONTRIBUTION
All authors contributed to the collection of information and evidence, wrote the original draft and reviewed and edited the final draft. Jean-Jacques Kiladjian coordinated this work.

ACKNOWLEDGEMENTS
The authors would like to thank Thomas Rohban, MD, and Magalie El Hajj, PharmD, from Partner 4 Health (Paris, France), for providing medical writing support in accordance with Good Publication Practice (GPP3) guidelines.

FUNDING INFORMATION
This project was funded by Novartis France.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analysed.