Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Abstract

Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

Keywords

myeloproliferative neoplasm - JAK2 signaling - pathophysiology - management

Introduction

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that comprise the Philadelphia-positive chronic myeloid leukemia as well as Philadelphia-negative entities. This review focuses on polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) that belong to the Philadelphia-negative MPNs and will be referred to as MPNs in this review. Other Philadelphia-negative forms such as chronic neutrophilic leukemia, chronic eosinophilic leukemia, and MPN-unclassified are reviewed elsewhere.

Primary myelofibrosis (PMF) develops de novo, but MF can also progress from preexisting PV or ET, then referred to as post-PV or post-ET myelofibrosis (PPV-/PET MF).[1] These MPN subtypes present with characteristic phenotypes: PV with erythrocytosis potentially accompanied by thrombo-/leukocytosis, ET with thrombocytosis, and PMF with bone marrow fibrosis and subsequent cytopenia. They share a propensity for thromboembolic events and bleeding, development of bone marrow fibrosis, and transformation to acute myeloid leukemia (AML). On the molecular level, all three MPN subtypes are characterized by activation of Janus kinase 2 (JAK2) signaling.[2]

Despite the rapidly increasing knowledge regarding pathophysiology and treatment options, there are still unmet clinical needs, especially in MF. Treatment response is lost in 50% of patients after 5 years and survival is limited after stopping therapy.[3] Hence, new therapeutic strategies are urgently needed.

Molecular Pathogenesis of Myeloproliferative Neoplasms

The majority of MPNs harbor a mutation in the pseudokinase domain of JAK2.[4] In a physiologic setting, JAK2 is essential for the proliferation of hematopoietic cells. Ligand binding to hematopoietic cytokine receptors such as erythropoietin (EPOR), thrombopoietin (TPOR or MPL), and GM-CSF receptors induces dimerization and transphosphorylation of the receptor and activation of JAK2, which mediates hematopoietic cytokine signaling. JAK2 activates several signaling pathways promoting proliferation, differentiation, and survival including the signal transducer and activator of transcription (STAT3/5) pathway, the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) signaling pathways.[5] In MPNs, JAK2 signaling is constitutively activated by somatic mutations in JAK2, calreticulin (CALR), or the thrombopoietin receptor MPL leading to dysregulated cell proliferation ([Fig. 1]). These “phenotypic driver mutations” are sufficient to induce MPN features and occur largely mutually exclusive.[6] Rare cases of JAK2 mutant MPN with a concomitant second driver mutation in MPL or CALR have been reported.[7] [8]

Fig 1 Main pathophysiologic mechanisms in myeloproliferative neoplasms (MPNs). MPNs are characterized by constitutive activation of JAK2 signaling promoted by somatic mutations in JAK2, CALR, or MPL (indicated with stars). Activation leads to dimerization and transphosphorylation of the receptor. Consequently, STAT-, MAPK-, or PI3K signaling is activated leading to transcription of genes causing cell proliferation and survival. Created with BioRender.com.

The JAK2 V617F mutation was first described in 2005 as a gain-of-function point mutation.[9] [10] [11] [12] JAK2 V617F is found in 95% of PV patients and 50 to 60% of ET and MF patients. In PV, mutations in exon 12 of JAK2 may also occur at a lower frequency and are associated, although not in all cases, with isolated erythrocytosis and a younger age at diagnosis.[13] MPL mutations are found in 5 to 10% of ET and MF and are absent in PV.[14] [15] In the chaperone protein CALR, more than 35 mutations have been identified, which are located in exon 9 of CALR and most frequently lead to a 52 bp deletion, referred to as type 1 mutation, or a 5 bp insertion, referred to as type 2 mutation.[16] [17] It has been shown that CALR mutations result in the activation of MPL thereby inducing JAK2 signaling.[18] Patients with CALR mutant ET are often diagnosed at younger age and have a more favorable prognosis as compared with JAK2 or MPL mutant MPN, particularly in the case of type 1 CALR mutations.[16] [17] In approximately 10% of ET and MF patients referred to as triple negative MPN, no mutations in JAK2, CALR, or MPL are detected.[19] Triple negativity negatively impacts on prognosis in PMF, while triple negative ET shows mixed pathogenesis with atypical mutations in JAK2 or MPL, very low allele burden of typical mutations, but also inherited mutations.[20]

Additional gene mutation, known to be prevalent also in other myeloid malignancies such as myelodysplastic syndrome and AML, are frequently detected in MPNs, particularly MF. Most common are mutations in TET2, DNMT3A, ASXL1, EZH2, TP53, IDH1, IDH2, SRSF2, NF1, and NRAS.[17] [21] [22] The presence of the so-called high-molecular-risk (HMR) mutations including ASXL1, EZH2, IDH1, IDH2, and SRSF2, as well as the number of cooccurring nondriver mutations are associated with a worse prognosis.[21] [22] [23] Patients harboring mutations in TP53 are particularly at risk for transformation to AML and also IDH1/2 mutations are enriched in post-MPN AML.[22] [24]

Clinical Presentation of Myeloproliferative Neoplasms

MPNs typically present with cytoses due to the excessive production of mature myeloid blood cells.[1] Erythrocytosis in PV and thrombocytosis in ET, MF, and potentially PV induce rheologic alterations, which can contribute to headaches, impaired vision, or paresthesia. Aquagenic pruritus is a typical feature in PV. Platelets circulating in an activated state further increase the risk of thromboembolic events both in arterial and venous vascular beds. Thromboembolic complications associate particularly with PV and ET but may also occur in MF. Thrombosis in atypical sites such as splanchnic thrombosis, Budd–Chiari syndrome, or cerebral sinus vein thrombosis is characteristic and should trigger the evaluation for an underlying MPN. The risk of bleeding is increased in all three subtypes of MPNs. It relates to extreme thrombocytosis (>1,500 G/L), which leads to acquired von Willebrand syndrome via depletion of unusually large von Willebrand factor multimers, or to thrombocytopenia in MF.

Splenomegaly due to extramedullary hematopoiesis is frequent in MPNs and most pronounced in MF. It can cause abdominal discomfort and early satiety and require therapeutic intervention. Furthermore, MPN patients typically suffer from constitutional symptoms including night sweats, fever, weight loss, and fatigue.[1] They relate to an inflammatory milieu with increased cytokine levels due to activated JAK2 signaling. MF patients present with the highest symptom burden. The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score is a useful tool for standardized monitoring of symptom burden.[25] MF can present as a prefibrotic form with minimal fibrosis, thrombocytosis, and/or leukocytosis or as overt MF with substantial bone marrow fibrosis and progressive cytopenia.[26] [27] Progressive bone marrow failure leads to symptomatic anemia and increased risk for infection and bleeding. Transformation to AML occurs in 10 to 20% of MF patients and is associated with a poor prognosis.[24]

Diagnosis of Myeloproliferative Neoplasms

The suspicion of MPN should be raised upon persistent erythrocytosis, thrombocytosis, or neutrophilia, particularly when causes for reactive cytoses are improbable.[26] Concomitant thromboembolic complications, particularly in atypical sites, make a diagnosis of MPN highly probable. Anemia and/or thrombocytopenia along with myeloid and erythroid precursors in the peripheral blood (leucoerythroblastic blood smear) and tear-drop–shaped red cells or progressive splenomegaly should trigger investigation for MF. Diagnosis is made according to the revised World Health Organization (WHO) criteria based on blood counts, bone marrow morphology, and the presence of a JAK2, CALR, or MPL mutation ([Table 1]).[26] In triple negative MF, extended genetic analyses are suggested to investigate for mutations in ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, or SF3B1 to demonstrate clonality. Typical findings of bone marrow morphology are central to the diagnosis of all three MPN subtypes. Bone marrow biopsy is dispensable for the diagnosis of PV if erythrocytosis is pronounced (hemoglobin 185 g/L/> 165 g/L or hematocrit 55.5%/49.5 in men/women, respectively). However, bone marrow examination is still recommended in these settings to assess bone marrow fibrosis, which is of prognostic relevance.

Table 1 Diagnostic criteria according to WHO 2016 classification[26]

Polycythemia vera All three major or Major 1 + 2 and minor	Essential thrombocythemia All four major or Major 1–3 and minor	Primary myelofibrosis All three major and at least one minor
Major criteria
1. Women: hemoglobin > 16.0 g/dL or hematocrit > 48% Men: hemoglobin > 16.5 g/dL or hematocrit > 49% or increased red blood cell mass	1. Platelet count ≥ 450 × 109/L	1. Megakaryocytic proliferation and atypia, with reticulin and/ or collagen fibrosis ≥ grade 2
2. Bone marrow: hypercellularity, trilineage proliferation, pleomorphic mature megakaryocytes	2. Bone marrow: megakaryocyte proliferation with enlarged, mature megakaryocytes with hyperlobulated nuclei, no left shift	2. Not meeting WHO criteria for other myeloid neoplasms
3. JAK2 V617F or JAK2 exon12 mutation	3. Not meeting WHO criteria for other myeloid neoplasms	3. JAK2 or CALR or MPL mutation or presence of another clonal marker or absence of reactive BM reticulin fibrosis
	4. JAK2 or CALR or MPL mutation
Minor criteria
- Subnormal serum erythropoietin level	- Another clonal marker present or - No evidence of reactive thrombocytosis	- Anemia not attributed to comorbid condition - Leucocyte ≥ 11 × 109/L - Palpable splenomegaly - LDH elevation - Leukoerythroblastosis

Diagnosis of ET, which relies on thrombocytosis, typical changes of megakaryopoiesis, and detection of an MPN-typical driver mutation, should be carefully evaluated versus the new entity of prefibrotic MF.[27] Blood, bone marrow, and molecular features are overlapping with ET and the differences in bone marrow morphology, which allow to distinguish ET from prefibrotic MF are subtle. However, proper identification of prefibrotic MF is meaningful, as prognosis is different from ET with a higher risk of progression to overt MF and shorter overall survival.

JAK2 Mutant Clonal Hematopoiesis of Indeterminate Potential

Mutations in DNMT3A, TET2, ASXL1, as well as other mutations frequently seen in myeloid malignancies have also been identified in healthy individuals with normal blood counts. This clonal hematopoiesis of indeterminate potential (CHIP) occurs at increasing frequency at higher age. It has been described as a clonal expansion of hematopoietic cells due to age-related somatic mutations without apparent hematologic malignancy.[28] [29] CHIP is associated with an up to 14-fold risk to develop myeloid neoplasms or cardiovascular complications.[30] [31] Of note, JAK2 V617F is known to occur relatively frequently as CHIP and induces, as in manifest MPNs, chronic inflammatory changes and an increased risk for thromboembolic events.[32] Particularly noticeable is a significantly increased risk of coronary artery disease in JAK2 V617F CHIP as compared with CHIP with DNMT3A, TET2, or ASXL1 mutations.[31] JAK2 mutant MPN can develop from CHIP over time, but currently this findings do not yet translate into clinical recommendations on how to monitor individuals with CHIP.[32]

Therapy of Myeloproliferative Neoplasms

The aims of MPN therapy are prevention of thromboembolic and hemorrhagic complications, symptom alleviation, and prevention of transformation to fibrosis or AML. As PV and ET show an overall high risk of thrombohemorrhagic events, but an overall indolent course with a low rate of transformation to AML, the primary goal is reduction of vascular complications.[1] Allogeneic hematopoietic stem cell transplantation (HSCT), the only therapeutic approach with curative potential, is reserved for patients with higher risk MF. Given the high prevalence of vascular complications in MPNs, addressing cardiovascular risk factors such as smoking habits, dyslipidemia, arterial hypertension, obesity, and diabetes is important.[33]

Polycythemia Vera

Low-dose acetyl salicylic acid (ASS) significantly reduces vascular complications in PV and is recommended in all PV patients without contraindications to antiplatelet therapy such as previous bleeding events or acquired von Willebrand syndrome.[34] The question of how completely erythrocytosis needs to be corrected was addressed by the CYTO-PV trial showing clearly lower rates of death from cardiovascular cause or major thrombosis in patients with hematocrit less than 45% as compared with 45 to 50%. Hence, all PV patients should strictly be managed at hematocrit values less than 45%.[35] Furthermore, increasing age and a history of thrombosis are established risk factors for vascular events. Therefore, PV patients older than 60 years and/or with previous thrombosis are considered at high risk and should receive cytoreductive treatment according to the European Leukemia Net (ELN) recommendations.[33] There is growing evidence that leukocytosis could be a risk factor for thrombosis, but to date studies are conflicting.[36] [37] [38]

First-line cytoreductive treatment is usually performed by hydroxyurea (HU). Nevertheless, ELN recommendations advise for the preferential use of pegylated interferon-α rather than HU as first-line cytoreductive therapy in younger patients.[33] Upon intolerance or resistance to HU, pegylated interferon-α or the JAK2 inhibitor ruxolitinib should be used as second-line cytoreductive agents.[39]

Interferon-α is used for the treatment of PV since the 1980s. Pegylation resulted in better tolerability and increased half-life. The ability of interferon-α to reduce clone size and induce molecular remissions makes it a preferred choice, particularly in younger patients, but clone-reducing effects may take time to develop.[40] Recently, Ropeginterferon alfa-2b, a monopegylated isoform of interferon-α was approved in the European Union and Switzerland for first-line cytoreductive therapy of early PV based on the PROUD-PV and CONTINUATION-PV studies.[41] The reduced application frequency of once every 2 weeks may help improve tolerability and adherence. As second-line cytoreductive agents, the JAK1/2 inhibitor ruxolitinib represents a valid option. The RESPONSE study showed effective correction of erythrocytosis, splenomegaly and constitutional symptoms in patients intolerant or resistant to HU, who were treated with ruxolitinib.[42] Also in patients without splenomegaly, ruxolitinib proved to be effective.[43]

Essential Thrombocythemia

In ET, antiplatelet therapy with low-dose ASS is recommended by the ELN guidelines analogous to PV.[33] Studies on the potential of twice-daily ASS for improved prophylactic effects are ongoing.[44] For patients with low-risk ET (<60 years of age without history of thrombosis) positive for a CALR mutation, there is cumulative evidence that they show higher rates of bleeding and should not be exposed to ASS prophylaxis.[45] In patients with platelets greater than 1,000 G/L, acquired von Willebrand syndrome should be ruled out before starting ASS.[33]

The risk for thrombosis in ET has been assessed by the International Prognostic Score of Thrombosis for ET (IPSET-thrombosis). Beyond the classical factors (age and history of thrombosis), this score takes into account the presence of the JAK2 V617F mutation and cardiovascular risk factors stratifying patients into low, intermediate, and high risk.[46] [47] Leukocytosis greater than 11 G/L seems to be an additional risk factor for death and potentially thrombosis.[48] [49] [50]

In ET patients older than 60 years, with a history of a thromboembolic event or a platelet count greater than 1,500 G/L, cytoreductive therapy should be initiated for further risk reduction.

HU and pegylated interferon-α are established as first-line therapies.[33] Conflicting data exist concerning the use of anagrelide. The PT1 study showed more frequent thromboembolic events and bleeding as compared with HU,[51] whereas the ANAHYDRET study found noninferiority of anagrelide compared with HU.[52] Generally, anagrelide should be avoided in patients with cardiovascular risk factors. Recently, an extended release formulation of anagrelide was developed that could offer a more convenient dosing schedule.[53] Ruxolitinib has been tested in ET intolerant or resistant to HU, but so far has not proven beneficial.[54] [55] The ongoing RUXO-BEAT trial evaluates the role of ruxolitinib as first-line therapy in high-risk PV and ET, and results are awaited.

Myelofibrosis

Therapy of MF includes symptom-directed supportive measures, disease-modifying treatments, and allogeneic HSCT.[56] In contrast to PV and ET, risk stratification is not primarily focused on thrombohemorrhagic risk, but on overall outcome. Prognostication schemes have been continuously refined given the recent progress of insight into molecular factors in MF. Particularly, mutations with prognostic significance have been added to current stratification schemes and improve prognostication.[17] [22] While the dynamic international scoring systems (DIPSS and DIPSS-plus) rely on clinical factors, blood counts, and cytogenetics, the more recent mutation-enhanced international prognostic scoring system for transplant-age patients (MIPSS-70 and MIPSS-70 plus) and genetically inspired prognostic scoring system (GIPSS) take into account a patient's mutational profile ([Table 2]).[57] [58] [59] [60] [61]

Table 2 Prognostic scores in myelofibrosis

	DIPPS[57]	DIPSS-plus[58]		MIPSS70[59]		MIPSS70+ version 2.0[60]
Clinical features	Age > 65 y		1
	Constitutional symptoms				1	Constitutional symptoms	2
	Hemoglobin < 10 g/dL		2	Hemoglobin < 10 g/dL	1	Hemoglobin < 8 g/dL (women), < 9 g/dL (men)	2
						Hemoglobin 8–9.9 g/dL (women), 9–10.9 g/dL (men)	1
	Leukocytes > 25 G/L		1	Leukocytes > 25 G/L	2
	Blasts in peripheral blood > 1%		1	Blasts in peripheral blood > 2%			1
		Transfusion dependency	1
		Thrombocytes < 100 G/L	1	Thrombocytes < 100 G/L	2
Karyotype		Unfavorable karyotype[a]	1			Unfavorable karyotype[c]	3
						VHR karyotype[c]	4
Fibrosis				Fibrosis grade 2 or 3	1
Mutations				No CALR type 1 mutation	1	No CALR type 1 mutation	2
				HMR mutation[b]	1	HMR mutation[d]	2
				2 or more HMR mutations	2	2 or more HMR mutations	3
Interpretation ( median survival in years )
Very low						0 (NR)
Low	0 (NR)	0 (15.4)		0–1 (27.7)		1–2 (16.4)
Intermediate-1	1–2 (14.2)	1 (6.5)		Intermediate 2–4 (7.1)		Intermediate 3–4 (7.7)
Intermediate-2	3–4 (4.0)	2–3 (2.9)
High	5–6 (1.5)	4–6 (1.3)		5–12 (2.3)		5–8 (4.1)
Very high						≥ 9 (1.8)

Abbreviations: HMR, high molecular risk; LDH, lactate dehydrogenase; NR, not reached.

^a Complex, +8, −7/7q-, i(17q), −5/5q-, 12p-, inv(3), or 11q23 rearrangement.

^b ASXL1, EZH2, SRSF2, IDH1/2.

^c “Very high risk (VHR)”—single/multiple abnormalities of −7, i(17q), inv(3)/3q21, 12p −/12p11.2, 11q −/11q23, or other autosomal trisomies not including +8/+ 9 (e.g., +21, +19); “favorable”—normal karyotype or sole abnormalities of 13q − , +9, 20q − , chromosome 1 translocation/duplication or sex chromosome abnormality including -Y; “unfavorable”—all other abnormalities.[60]

^d ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 Q157.

In patients with low or intermediate-I risk MF, management is primarily symptom-oriented.[33] MF-associated anemia can be treated with erythropoietin-stimulating agents if endogenous erythropoietin is low (<125 IU/L). Androgens such as danazol may also be used except upon prostate or liver disease.[62] Immunomodulators such as pomalidomide with or without steroids represent an additional approach to counteract anemia without concomitant polyneuropathy. Patients not responding or not eligible to one of those therapies should be supported by red blood cell transfusions.[33]

Symptomatic splenomegaly, which is a frequent problem in MF, generally responds well to JAK1/2 inhibitor treatment (e.g., by ruxolitinib), which is approved for intermediate- and high-risk patients based on the COMFORT trials.[63] [64] [65] HU represents an alternative option with response in approximately 40% of patients.[66] Splenic irradiation or splenectomy is increasingly infrequently used. Particularly splenectomy should be reserved for refractory patients given a high perioperative risk. JAK1/2 inhibition with ruxolitinib is effective in reducing constitutional symptoms, an effect which may relate particularly to the JAK1 inhibition positively impacting on the inflammatory milieu in MF.[67] As ruxolitinib is inhibiting not only mutated but also unmutated JAK2, benefits can be expected regardless of the JAK2 mutational status and CALR or MPL mutant as well as triple negative MF patients also represent candidates for ruxolitinib therapy.[68]

Although ruxolitinib is generally well tolerated, anemia and thrombocytopenia are frequent given that normal hematopoiesis is inhibited. Anemia can be treated with supportive measures. Furthermore, varicella zoster virus reactivation is observed more frequently in patients treated with ruxolitinib. There are data raising concern regarding higher incidences of malignant B-cell lymphoma in patients receiving ruxolitinib; however, only patients with preexistent B-cell clone were affected.[69] Those patients should be regularly screened for lymphoma. Attention must be paid to a possible withdrawal reaction including respiratory distress syndrome upon abrupt discontinuation of the drug. The risk of severe withdrawal syndrome can be reduced but not completely avoided by tapering ruxolitinib.[70] However, specific guidance on tapering regimens is currently lacking. The concurrent use of corticosteroids and/or HU might be beneficial.[71]

Allogeneic HSCT represents the only curative therapeutic approach in MF to date and is currently recommended by the ELN and the European Society for Blood and Marrow Transplantation for patients with high-risk or intermediate-2-risk MF.[72] In intermediate-1-risk patients, evaluation of allogeneic HSCT is advised if additional adverse factors are present including transfusion dependence, poor-risk cytogenetics, triple negativity for driver mutations, or the presence of an ASXL1 mutation. Thanks to the introduction of reduced intensity conditioning regimes and the continued improvement of supportive measures, allogeneic HSCT has become increasingly available for elderly patients.[72]

Given the substantial symptom burden and limited overall survival of higher risk forms of MF, patients with MF are in urgent need for improved therapeutic options. Additional JAK2 inhibitors, combination therapies with ruxolitinib, as well as therapeutic options addressing new targets are currently in development.[4] Fedratinib, a JAK2 inhibitor with additional activity toward FLT3, was approved by the U.S. Food and Drug Administration for intermediate- and high-risk MF in 2019 and approval in Europe and Switzerland is awaited. Fedratinib effectively reduces splenomegaly and symptom burden in both treatment-naive patients and patients resistant or intolerant to ruxolitinib.[73] [74] The potential adverse event of Wernicke's encephalopathy led to a clinical hold of the JAKARTA phase 3 studies, but was subsequently attributed to poor nutrition status of the respective patients without clear association with fedratinib.[75] However, thiamin levels should be regularly checked in patients on fedratinib. The JAK1/2 inhibitor momelotinib evaluated by the SIMPLIFY phase 3 studies and currently under evaluation in the MOMENTUM trial showed beneficial effects not only for control of splenomegaly and constitutional symptoms, but also seems to improve anemia due to inhibition of hepatic hepcidin production.[76] The JAK2/FLT3 inhibitor pacritinib currently in phase 3 studies seems to have advantageous profile for patients with thrombocytopenia.[77] Apart from novel JAK2 inhibitors, several combination therapy approaches with ruxolitinib (e.g., with Bcl2/Bcl-xL inhibition) are in clinical development and novel therapeutic targets are also being addressed such as telomerase inhibition.[78] [79] [80] These novel approaches in development are reviewed in detail elsewhere.

Based on the rapid progress in the molecular understanding of MPNs in the last years, it is the goal and hope that new innovative approaches for therapy will emerge from this insight and soon will become beneficial for MPN patients.

Conflict of Interest

F.C.Z. holds shares in Novartis. S.C.M. has consulted for and received honoraria from Celgene/BMS and Novartis.

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Publication History

Received: 04 February 2021

Accepted: 17 March 2021

Article published online:
30 June 2021