madman
Super Moderator
JAK2 unmutated erythrocytosis: 2023 update on diagnosis and management
Naseema Gangat, MBBS, Natasha Szuber MD, Ayalew Tefferi, MD
Abstract
Disease Overview: JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities.
Diagnosis: Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening. Initial assessment should also include a gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list.
Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor (EPOR) mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity hemoglobin variants, 2, 3 bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% hemoglobin saturation (p50). The latter include the germline oxygen sensing pathway (HIF2A-PHD2-VHL) and other rare mutations.
Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high-altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo-producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis-stimulating agents, sodium-glucose cotransporter-2 inhibitors).
Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation.
Management: Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non-clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with a frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low-dose aspirin are often advised.
Future directions: Advances in molecular hematology might result in better characterization of “idiopathic erythrocytosis” and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.
Disease Overview
The term “Erythrocytosis” or “Polycythemia” refers to an absolute or relative increase in hemoglobin (Hgb)/hematocrit (Hct) levels from baseline sex- race- and altitude-adjusted normal values.1,2 In 2016, the World Health Organization (WHO) lowered the proposed Hgb and Hct diagnostic thresholds for polycythemia vera (PV) to 16.5 g/dL/49% and 16 g/dL/48% for Caucasian males and females, respectively.3,4,5,6 The lower Hgb/Hct thresholds for PV were introduced to facilitate the diagnosis of masked PV and remain unchanged in the contemporary 2022 International Consensus Classification (ICC) of myeloid neoplasms.7 Unsurprisingly, there has been an unprecedented rise in erythrocytosis referrals to hematology which are frequently triggered by Hgb/Hct levels that exceed thresholds for PV. Although JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis has a higher prevalence than PV, accurate epidemiology has been difficult to ascertain as it represents a spectrum of heterogeneous diseases ranging from hereditary to acquired medical conditions. In a large population-based cohort (n=147 167), the incidence of erythrocytosis ranged from 0.3% to 3.4% based on the application of the WHO 2008 (Hgb/Hct > 18.5g/dl/52%, males and >16.5 g/dl/48%, females) and 2016 (Hgb/Hct > 16.5 g/dl/49%, males and >16 g/dl/48%, females) criteria, respectively; predisposing factors included older age, higher body mass index, history of smoking, hypertension and use of androgens.8 Similarly, in a Canadian study, erythrocytosis was noted in 4.1%/0.35% of males, and 0.35%/0.13% of females, according to WHO 2016 and 2008 thresholds, respectively.9 On the other hand, in a National Health and Nutrition Examination Survey (NHANES) analysis, the overall prevalence of unexplained erythrocytosis was 35.1 per 100,000 population and was significantly higher in older patients aged 50-59 years and 60-69 years, at 128.7 per 100,000 and 102.5 per 100,000, respectively.10
In clinical practice, the diagnostic evaluation of JAK2 unmutated erythrocytosis remains a challenge, and patients are frequently subjected to non-uniform testing.11,12 In a recent single-center study on non-clonal erythrocytosis, additional investigations beyond JAK2 testing were not pursued by the treating hematologist in 58% of patients. 13 On the other hand, in another study, nearly as many secondary erythrocytosis (31%) as PV (39%) patients underwent bone marrow biopsies.14 Similarly, a marked heterogeneity in treatment patterns stems from an unsubstantiated concern for thrombosis, and whether to initiate phlebotomy and desired Hct target, continue to be unresolved issues. 15 In the current review, we provide our contemporary diagnostic and therapeutic approach to known hereditary and acquired entities associated with JAK2 unmutated erythrocytosis.
*Pathogenesis
*Diagnosis
*Diagnostic approach to hereditary erythrocytosis
*Diagnostic approach to acquired erythrocytosis
Management approach
i) General considerations
ii) Role of phlebotomy
iii) Perioperative management
Erythrocytosis associated with high oxygen affinity
i)High oxygen affinity hemoglobin variants
ii) 2,3 bisphosphoglycerate (2, 3 BPG) deficiency
Erythrocytosis associated with germline EPAS1(HIF2A), EGLN1(PHD2), VHL, EPOR variants
i)Germline EPAS1(HIF2A) variants
ii) Germline EGLN1(PHD2) variants
iii) Germline VHL variants (Chuvash polycythemia)
iv) Germline EPOR (EPO receptor) variants
Erythrocytosis associated with cardiopulmonary disease
i) Chronic obstructive pulmonary disease (COPD)
ii) Obstructive sleep apnea (OSA)
iii) Cyanotic congenital heart disease
Erythrocytosis associated with drugs
i) SGLT-2 inhibitor therapy
ii) Testosterone therapy
Erythrocytosis may develop in cis and trans men receiving testosterone therapy. 138,139 The reported prevalence of erythrocytosis (Hct > 50%) in testosterone-treated hypogonadal cis men is variable (5%-66%) with the highest risk associated with injectable compared with trans-dermal testosterone.138-140 Current guidelines generally advise against androgen replacement when Hct is >50% and in patients with Hct > 54%, therapeutic phlebotomy may be implemented, testosterone withheld until Hct is at an acceptable level < 50%, and therapy resumed at a reduced dose.141 142 In a large cohort of trans men (n=1073), receiving testosterone and followed for 20 years, the prevalence of erythrocytosis defined by Hct > 50%, 52%, 54%, was 11%, 3.7%, and 0.5%, respectively.143 Although the largest rise in Hct was seen in the first year, the probability of erythrocytosis increased over time (10% after 1 year and 38% after 10 years), and was associated with smoking, long-acting undecanoate injections, older age, higher body mass index, and pulmonary disease, underscoring the need for regular Hct monitoring and risk factor modification.143 In another study of 519 transgender individuals on testosterone therapy, 20% developed Hct > 50%, testosterone dose was reduced in 42%, and 4.8% underwent phlebotomy, however, thrombosis was documented in only a minority (0.9%) of cases. 144 Although this is discrepant with a recent study in which 5,842 men who received testosterone therapy and developed erythrocytosis (Hct ≥52%) were matched and compared to a cohort having received testosterone but who did not develop erythrocytosis. 145 Interestingly, those with erythrocytosis had a higher risk of major adverse cardiovascular events and venous thromboembolic events (number of outcomes: 301, 5.15%) compared to men who had hematocrit within the normal range (226, 3.87%) while on testosterone (OR 1.35, 95% CI 1.13- 1.61, p <0.001).145 Accordingly, we recommend close Hct monitoring with target Hct < 50% in patients on androgen replacement therapy.
*Erythrocytosis associated with renal transplant
*Erythrocytosis not otherwise specified (Idiopathic erythrocytosis)
Conclusion
JAK2 unmutated erythrocytosis is an evolving subject that remains diagnostically and therapeutically challenging. Impactful discoveries within the last five years, include mutations in the EPO gene, novel zinc finger domain PHD2 mutations, splicing mutations in VHL, and PIEZO mutations. 56,60,92,93,110 Furthermore, improved molecular characterization of “idiopathic erythrocytosis” cases through expanded and highly sensitive NGS platforms coupled with increased utilization of functional assays is anticipated in the near future.153,94 In the current document we share a practical and comprehensive diagnostic approach to JAK2 unmutated erythrocytosis. Importantly, the prompt and accurate distinction between underlying physiological vs pathological causes of erythrocytosis is crucial, as management is directly impacted by etiology, and incorrect diagnosis may lead to under or over-treatment. In this regard, an individualized management approach is underscored with phlebotomy reserved for symptom control rather than Hct level. Collectively, there is a critical need for prospective controlled studies in order to define optimal management strategies, and new therapies such as HIF2A inhibitors (bezultifan), although mechanistically enticing, require further investigation.
Naseema Gangat, MBBS, Natasha Szuber MD, Ayalew Tefferi, MD
Abstract
Disease Overview: JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities.
Diagnosis: Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening. Initial assessment should also include a gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list.
Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor (EPOR) mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity hemoglobin variants, 2, 3 bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% hemoglobin saturation (p50). The latter include the germline oxygen sensing pathway (HIF2A-PHD2-VHL) and other rare mutations.
Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high-altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo-producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis-stimulating agents, sodium-glucose cotransporter-2 inhibitors).
Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation.
Management: Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non-clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with a frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low-dose aspirin are often advised.
Future directions: Advances in molecular hematology might result in better characterization of “idiopathic erythrocytosis” and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.
Disease Overview
The term “Erythrocytosis” or “Polycythemia” refers to an absolute or relative increase in hemoglobin (Hgb)/hematocrit (Hct) levels from baseline sex- race- and altitude-adjusted normal values.1,2 In 2016, the World Health Organization (WHO) lowered the proposed Hgb and Hct diagnostic thresholds for polycythemia vera (PV) to 16.5 g/dL/49% and 16 g/dL/48% for Caucasian males and females, respectively.3,4,5,6 The lower Hgb/Hct thresholds for PV were introduced to facilitate the diagnosis of masked PV and remain unchanged in the contemporary 2022 International Consensus Classification (ICC) of myeloid neoplasms.7 Unsurprisingly, there has been an unprecedented rise in erythrocytosis referrals to hematology which are frequently triggered by Hgb/Hct levels that exceed thresholds for PV. Although JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis has a higher prevalence than PV, accurate epidemiology has been difficult to ascertain as it represents a spectrum of heterogeneous diseases ranging from hereditary to acquired medical conditions. In a large population-based cohort (n=147 167), the incidence of erythrocytosis ranged from 0.3% to 3.4% based on the application of the WHO 2008 (Hgb/Hct > 18.5g/dl/52%, males and >16.5 g/dl/48%, females) and 2016 (Hgb/Hct > 16.5 g/dl/49%, males and >16 g/dl/48%, females) criteria, respectively; predisposing factors included older age, higher body mass index, history of smoking, hypertension and use of androgens.8 Similarly, in a Canadian study, erythrocytosis was noted in 4.1%/0.35% of males, and 0.35%/0.13% of females, according to WHO 2016 and 2008 thresholds, respectively.9 On the other hand, in a National Health and Nutrition Examination Survey (NHANES) analysis, the overall prevalence of unexplained erythrocytosis was 35.1 per 100,000 population and was significantly higher in older patients aged 50-59 years and 60-69 years, at 128.7 per 100,000 and 102.5 per 100,000, respectively.10
In clinical practice, the diagnostic evaluation of JAK2 unmutated erythrocytosis remains a challenge, and patients are frequently subjected to non-uniform testing.11,12 In a recent single-center study on non-clonal erythrocytosis, additional investigations beyond JAK2 testing were not pursued by the treating hematologist in 58% of patients. 13 On the other hand, in another study, nearly as many secondary erythrocytosis (31%) as PV (39%) patients underwent bone marrow biopsies.14 Similarly, a marked heterogeneity in treatment patterns stems from an unsubstantiated concern for thrombosis, and whether to initiate phlebotomy and desired Hct target, continue to be unresolved issues. 15 In the current review, we provide our contemporary diagnostic and therapeutic approach to known hereditary and acquired entities associated with JAK2 unmutated erythrocytosis.
*Pathogenesis
*Diagnosis
*Diagnostic approach to hereditary erythrocytosis
*Diagnostic approach to acquired erythrocytosis
Management approach
i) General considerations
ii) Role of phlebotomy
iii) Perioperative management
Erythrocytosis associated with high oxygen affinity
i)High oxygen affinity hemoglobin variants
ii) 2,3 bisphosphoglycerate (2, 3 BPG) deficiency
Erythrocytosis associated with germline EPAS1(HIF2A), EGLN1(PHD2), VHL, EPOR variants
i)Germline EPAS1(HIF2A) variants
ii) Germline EGLN1(PHD2) variants
iii) Germline VHL variants (Chuvash polycythemia)
iv) Germline EPOR (EPO receptor) variants
Erythrocytosis associated with cardiopulmonary disease
i) Chronic obstructive pulmonary disease (COPD)
ii) Obstructive sleep apnea (OSA)
iii) Cyanotic congenital heart disease
Erythrocytosis associated with drugs
i) SGLT-2 inhibitor therapy
ii) Testosterone therapy
Erythrocytosis may develop in cis and trans men receiving testosterone therapy. 138,139 The reported prevalence of erythrocytosis (Hct > 50%) in testosterone-treated hypogonadal cis men is variable (5%-66%) with the highest risk associated with injectable compared with trans-dermal testosterone.138-140 Current guidelines generally advise against androgen replacement when Hct is >50% and in patients with Hct > 54%, therapeutic phlebotomy may be implemented, testosterone withheld until Hct is at an acceptable level < 50%, and therapy resumed at a reduced dose.141 142 In a large cohort of trans men (n=1073), receiving testosterone and followed for 20 years, the prevalence of erythrocytosis defined by Hct > 50%, 52%, 54%, was 11%, 3.7%, and 0.5%, respectively.143 Although the largest rise in Hct was seen in the first year, the probability of erythrocytosis increased over time (10% after 1 year and 38% after 10 years), and was associated with smoking, long-acting undecanoate injections, older age, higher body mass index, and pulmonary disease, underscoring the need for regular Hct monitoring and risk factor modification.143 In another study of 519 transgender individuals on testosterone therapy, 20% developed Hct > 50%, testosterone dose was reduced in 42%, and 4.8% underwent phlebotomy, however, thrombosis was documented in only a minority (0.9%) of cases. 144 Although this is discrepant with a recent study in which 5,842 men who received testosterone therapy and developed erythrocytosis (Hct ≥52%) were matched and compared to a cohort having received testosterone but who did not develop erythrocytosis. 145 Interestingly, those with erythrocytosis had a higher risk of major adverse cardiovascular events and venous thromboembolic events (number of outcomes: 301, 5.15%) compared to men who had hematocrit within the normal range (226, 3.87%) while on testosterone (OR 1.35, 95% CI 1.13- 1.61, p <0.001).145 Accordingly, we recommend close Hct monitoring with target Hct < 50% in patients on androgen replacement therapy.
*Erythrocytosis associated with renal transplant
*Erythrocytosis not otherwise specified (Idiopathic erythrocytosis)
Conclusion
JAK2 unmutated erythrocytosis is an evolving subject that remains diagnostically and therapeutically challenging. Impactful discoveries within the last five years, include mutations in the EPO gene, novel zinc finger domain PHD2 mutations, splicing mutations in VHL, and PIEZO mutations. 56,60,92,93,110 Furthermore, improved molecular characterization of “idiopathic erythrocytosis” cases through expanded and highly sensitive NGS platforms coupled with increased utilization of functional assays is anticipated in the near future.153,94 In the current document we share a practical and comprehensive diagnostic approach to JAK2 unmutated erythrocytosis. Importantly, the prompt and accurate distinction between underlying physiological vs pathological causes of erythrocytosis is crucial, as management is directly impacted by etiology, and incorrect diagnosis may lead to under or over-treatment. In this regard, an individualized management approach is underscored with phlebotomy reserved for symptom control rather than Hct level. Collectively, there is a critical need for prospective controlled studies in order to define optimal management strategies, and new therapies such as HIF2A inhibitors (bezultifan), although mechanistically enticing, require further investigation.
