Medical Policy

Policy Num:       11.001.012
Policy Name:     JAK2, MPL, and  CALR, Testing for Myeloproliferative Neoplasms
Policy ID:          [11.001.012]  [Ac / B / M+ / P+]  [2.04.60]

Last Review:      September 23, 2024
Next Review:      September 20, 2025
 

Related Policies: None

JAK2, MPL, and  CALR, Testing for Myeloproliferative Neoplasms

Summary

Description

Somatic (acquired) genetic variants in JAK2, MPL, and CALR genes have been implicated as the underlying molecular genetic drivers for the pathogenesis of myeloproliferative neoplasms (MPN). This evidence review addresses the use of genetic testing for JAK2, MPL, and CALR genes for diagnosis, prognosis, and treatment selection of patients with MPN.

Summary of Evidence

For individuals with a suspected myeloproliferative neoplasm (MPN) who receive genetic testing for JAK2, the evidence includes case series, retrospective studies, meta-analyses, and randomized controlled trials. Relevant outcomes are overall survival (OS), disease-specific survival, test accuracy and validity, and resource utilization. For patients with suspected Ph-negative MPN, JAK2 variants are found in nearly 100% of those with polycythemia vera (PV), 60% to 65% of those with essential thrombocythemia (ET), and 60% to 65% of those with primary myelofibrosis (PMF). In individuals with suspected MPN, a positive genetic test for JAK2 satisfies a major criterion for the International Consensus Classification (2022) and World Health Organization (WHO) 2022 (5th edition) classification for Ph-negative MPNs and eliminates secondary or reactive causes of erythrocytosis and thrombocythemia from the differential diagnosis. The presence of a documented JAK2 variant may aid in the selection of ruxolitinib, a JAK2 inhibitor; ruxolitinib, however, is classified as second-line therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with a suspected MPN who receive genetic testing for MPL, the evidence includes case series and retrospective studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, and resource utilization. For patients with suspected Ph-negative MPN, MPL variants are found in approximately 5% of those with ET and PMF. In individuals with suspected MPN, a positive genetic test for MPL satisfies a major criterion for the International Consensus Classification (2022) and WHO (2022, 5th edition ) classification for ET and PMF and eliminates secondary or reactive causes of thrombocythemia from the differential diagnosis. The goal of ET treatment is to alleviate symptoms and minimize thrombotic events and bleeding irrespective of MPL variant status. For PMF, hematopoietic cell transplantation is the only treatment with curative potential while most other treatment options focus on symptom alleviation. However, in both ET and PMF, establishing the diagnosis through MPL genetic testing does not in and of itself result in changes in management that would be expected to improve the net health outcome. Thus, the clinical utility has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with a suspected MPN who receive genetic testing for CALR, the evidence includes case series and retrospective studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, and resource utilization. For patients with suspected Ph-negative MPN, CALR variants are found in approximately 20% to 25% of those with ET and PMF. For individuals with suspected MPN, a positive genetic test for CALR satisfies a major criterion for the International Consensus Classification (2022) and WHO (2022, 5th edition ) classification for ET and PMF and eliminates secondary or reactive causes of thrombocythemia from the differential diagnosis. The goal of ET treatment is to alleviate symptoms and minimize thrombotic events and bleeding irrespective of CALR variant status. For PMF, hematopoietic cell transplantation is the only treatment with curative potential while most other treatment options focus on symptom alleviation. However, in both ET and PMF, establishing the diagnosis through CALR genetic testing does not result in changes in management that would be expected to improve the net health outcome. Thus, the clinical utility has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Given that genetic testing for MPL and CALR variants is included in the WHO (2022, 5th edition ) and International Consensus Classification (2022) major criteria and the National Comprehensive Cancer Network guidelines (2023 ) for MPNs, MPL, and CALR testing may be consistent with clinical practice in the diagnosis of patients with clinical, laboratory, or pathological findings suggesting ET and PMF.

Objective

The objective of this evidence review is to determine whether genetic testing for JAK2, MPL, and CALR genes improves the net health outcome in individuals with a suspected myeloproliferative neoplasm.

Policy Statements

JAK2 testing may be considered medically necessary in the diagnosis of individuals presenting with clinical, laboratory, or pathologic findings suggesting polycythemia vera, essential thrombocythemia (ET), or primary myelofibrosis (PMF). Based on criteria from the World Health Organization and the International Consensus Classification for diagnosis of PV, documentation of a serum erythropoietin level below the reference range for normal is recommended before JAK2 testing (See Policy Guidelines).

MPL and CALR testing may be considered medically necessary in the diagnosis of individuals presenting with clinical, laboratory, or pathologic findings suggesting ET or PMF.

JAK2, MPL, and CALR testing is considered investigational in all other circumstances including, but not limited to, the following situations:

• Diagnosis of nonclassic forms of myeloproliferative neoplasms (MPNs)

• Molecular phenotyping of individuals with MPNs

• Monitoring, management, or selecting treatment in individuals with MPNs.

Policy Guidelines

Testing Strategy

Individuals suspected to have polycythemia vera (PV) should first be tested for the most common finding, JAK2 V617F. If the testing is negative, further testing to detect other JAK2 tyrosine kinase variants (eg, in exon 12) is warranted.

Individuals suspected to have essential thrombocythemia or primary myelofibrosis should first be tested for JAK2 variants, as noted. If testing is negative, further testing to detect MPL and CALR variants is warranted.

Criteria for Polycythemia Vera Testing

Based on the World Health Organization (WHO) and International Consensus Classification major and minor criteria (see Table PG1), documentation of serum erythropoietin level below the reference range for normal meets a minor criterion for PV. Therefore, serum erythropoietin testing is recommended before JAK2 testing.

Table PG1. World Health Organization 5th Edition and the International Consensus Classification Diagnostic Criteria for Polycythemia Vera

Adapted from Arber et al (2022 ) and Khoury et al (2022).
The diagnosis of polycythemia vera requires the presence of all 3 major criteria or the presence of the first 2 major criteria together with the minor criterion.
^a The World Health Organization 2022 5th edition removed red cell mass as a major criterion since this is not commonly evaluated in clinical practice. The International Consensus Classification still includes increased red blood cell mass as a major criterion.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are rare overlapping blood diseases characterized by the production of 1 or more blood cell lines. The most common forms of MPNs include polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia. A common finding in many MPNs is clonality and a central pathogenic feature in the detection of a somatic (acquired) pathogenic variant in disease-associated genes. Pathogenic variants in disease-associated genes result in constitutively activated tyrosine kinase enzyme or cell surface receptor.

The paradigm for the use of molecular genetics to revolutionize patient management is chronic myeloid leukemia. A unique chromosomal translocation t (9;22), the Philadelphia chromosome (Ph), leads to a unique gene rearrangement (BCR::ABL) creating a fusion gene that encodes for a constitutively active Bcr-abl fusion protein. These findings led to the development of targeted tyrosine kinase inhibitor drug therapy (imatinib) that produces long-lasting remissions. Rarely, patients may show unusual manifestations of nonclassic forms of MPNs, such as chronic myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, or others. Reports have identified JAK2 V617F variants in some of these cases.^1, The remainder of this evidence review focuses only on the non-Ph or Ph-negative MPNs and genetic testing for JAK2, CALR, and MPL.

Diagnosis and monitoring of patients with Ph-negative MPNs have been challenging because many of the laboratory and clinical features of the classic forms of these diseases can be mimicked by other conditions such as reactive or secondary erythrocytosis, thrombocytosis, or myeloid fibrosis. Additionally, these entities can be difficult to distinguish on morphologic bone marrow exam, and diagnosis can be complicated by changing disease patterns: PV and ET can evolve into PMF or undergo a leukemic transformation. A complex set of clinical, pathologic, and biologic criteria was first introduced by the Polycythemia Vera Study Group in 1996^2,3, and by the World Health Organization as a benchmark for diagnosis in 2002^4, and updated in 2008 and 2016.^5,6, In 2022, both the World Health Organization 5th edition and an International Consensus Classification were published.^7,8, Applying these criteria has been challenging because they involve complex diagnostic algorithms, rely on a morphologic assessment of uncertain consistency, and require tests that are not well-standardized or widely available, such as endogenous erythroid colony formation. An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.

Chronic Myeloid Leukemia and Philadelphia Chromosome

Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Classic Myeloproliferative Neoplasms

Varying combinations of these criteria are used to determine whether a patient has PV, ET, or PMF (ie, MPNs that are Ph-negative). An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.

As noted, some diagnostic methods (eg, bone marrow microscopy) are not well-standardized,^9,10,11, and others (eg, endogenous erythroid colony formation) are neither standardized nor widely available.

Nonclassic Forms of Myeloproliferative Neoplasms

Although the most common Ph-negative MPNs include what is commonly referred to as classic forms of this disorder (PV, ET, PMF), rarely, patients may show unusual manifestations of nonclassic forms of MPNs, such as chronic myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, or others. Reports have identified JAK2 V617F variants in some of these cases.^1,

Molecular Genetics of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

JAK2 Gene

The JAK2 gene, located on chromosome 9, contains the genetic code for making the Janus kinase 2 (JAK2) protein, a nonreceptor tyrosine kinase. The JAK2 protein is part of the JAK/ signal transducer and activator of transcription (STAT) proteins that are important for the controlled production of blood cells from hematopoietic cells. Somatic (acquired) variants in the JAK2 gene are found in patients with PV, ET, and PMF.^12,

JAK2 V617F Variant

In 2005, 4 separate groups using different modes of discovery and different measurement techniques reported on the presence of a novel somatic (acquired) single nucleotide variant in the conserved autoinhibitory pseudokinase domain of the gene encoding JAK2 protein in patients with classic MPNs. The single nucleotide variant caused a valine-to-phenylalanine substitution at amino acid position 617 (JAK2 V617F) leading to a novel somatic gain-of-function single nucleotide variant that resulted in the loss of autoinhibition of the JAK2 tyrosine kinase. JAK2 V617F is a constitutively activated kinase that recruits and phosphorylates substrate molecules including STAT proteins (so-called JAK-STAT signaling). The result is cell proliferation independent of normal growth factor control.

The JAK2 V617F variant was present in blood and bone marrow from a variable portion of patients with classic BCR-ABL-negative (ie, Ph-negative) MPNs including 65% to 97% of patients with PV, 23% to 57% with ET, and 35% to 56% with PMF (see Table 1). The variant was initially reported to be absent in all normal subjects and patients with secondary erythrocytosis,^{11,1,13,14,15,16,17,18,19,20,21,} although very low levels of cells carrying the variant have been reported in a small subset of healthy individuals.^22,23,

Although almost all studies were retrospective case series and/or cross-sectional studies, and although both the analytic and clinical performances appeared dependent on the laboratory method used to detect the variant, there has been consistency across studies in demonstrating that the JAK2 V617F variant is a highly specific marker for clonal evidence of an MPN.

Table 1. Frequency of the JAK2 V617F Variant in Patients With Classic Philadelphia Chromosome-Negative Myeloproliferative Neoplasm From Case Series

Values are n/N (%).
ET: essential thrombocythemia; MPN: myeloproliferative neoplasm; NR: not reported; PCR: polymerase chain reaction; PMF: primary myelofibrosis; PV: polycythemia vera.
In vivo, mice irradiated and then given transplanted bone marrow cells infected with a retrovirus containing the variant developed a myeloproliferative syndrome.^14,

JAK2 Exon 12 Variants

Scott et al (2007) identified 4 somatic gain-of-function variants in JAK2 exon 12 in 10 of 11 PV patients without the JAK2 V617F variant.^24, Patients with a JAK2 exon 12 variant differed from those with the JAK2 V617F variant, presenting at a younger age with higher hemoglobin levels and lower platelet and white cell counts. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin, and mice treated with transfected bone marrow transplants developed a myeloproliferative syndrome.

Findings have been confirmed by a number of investigators who identified additional variants with similar functional consequences in patients with PV and patients with idiopathic erythrocytosis.^25,26, Based on these findings, it has been concluded that the identification of JAK2 exon 12 variants provides a diagnostic test for JAK2 V617F-negative patients who present with erythrocytosis. Of note, different variants in the same gene appear to have different effects on signaling, resulting in distinct clinical phenotypes.^24,

MPL Gene

The MPL gene, located on chromosome 1, contains the genetic code for making the thrombopoietin receptor, a cell surface protein that stimulates the JAK/STAT signal transduction pathway. The thrombopoietin receptor is critical for the cell growth and division of megakaryocytes, which produce platelets involved in blood clotting. Somatic variants in the MPL gene are associated with ET and PMF.

CALR Gene

The CALR gene, located on chromosome 19, contains the genetic code for making the calreticulin protein, a multifunctional protein located in the endoplasmic reticulum, cytoplasm, and cell surface. The calreticulin protein is thought to play a role in cell growth and division and regulation of gene activity. Somatic variants in the CALR gene are associated with ET and PMF.

Frequency of JAK2, CALR, and MPL Somatic Variants in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Philadelphia chromosome-negative MPNs are characterized by their molecular genetic alterations. Table 2 summarizes the driver genes and somatic variants associated with specific Ph-negative MPNs.^27,

Table 2. Frequency of JAK2, CAL4, and MPL Somatic Variants in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Adapted from Cazzola et al (2014).^27,
ET: essential thrombocythemia; indels: insertions and deletions; MPN: myeloproliferative neoplasm; Ph: Philadelphia chromosome; PMF: primary myelofibrosis; PV: polycythemia vera.

A more recent retrospective study of patients observed at the National Research Center for Hematology (Moscow, Russia) from October 2016 to November 2020 assessed the frequency of detection of JAK2 V617F, CALR, and MPL mutations in a Russian cohort of patients with BCR::ABL rearrangement negative (ie, Ph-negative) MPNs.^28, Patients (N=1958) with a diagnosis of ET, PV, PMF, or MPN-unclassified were examined. Table 3 summarizes the driver genes and somatic variants associated with specific Ph-negative MPNs.

Table 3. Frequency of JAK2, CAL4, and MPL Genes in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

ET: essential thrombocythemia; indels: insertions and deletions; MPN: myeloproliferative neoplasm; Ph: Philadelphia chromosome; PMF: primary myelofibrosis; PV: polycythemia vera.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. More than a dozen commercial laboratories currently offer a wide variety of diagnostic procedures for JAK2, CALR, and MPL testing under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in January 2010 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 25, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

JAK2 Testing for a Suspected Myeloproliferative Neoplasm

Clinical Context and Test Purpose

The purpose of JAK2 testing of individuals with a suspected myeloproliferative neoplasm (MPN) is to establish a molecular genetic diagnosis of MPN to inform management decisions.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest includes individuals with a suspected MPN.

Interventions

The test being considered is genetic testing for JAK2.

Comparators

The following practice is currently being used to make decisions about individuals with a suspected MPN: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival, test accuracy, test validity, and resource utilization. The potential beneficial outcomes of primary interest include establishing a molecular genetic diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) to inform management decisions when test results are provided.

The time frame for outcomes measures varies from several months for the improvement of symptoms to long-term survival as a result of disease-related complications.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for JAK2, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Systematic Review

Mejia-Ochoa et al (2019) conducted a systematic review and meta-analysis of the frequency of JAK2, CALR, and MPL in Philadelphia chromosome (Ph)-negative chronic MPNs.^29, Twenty studies reported the frequency of JAK2 V617F in PV, ET, and PMF. The studies were heterogeneous with regard to the diagnostic techniques used and their results. The proportion of patients with JAK2 V617F ranged from 46.7% to 100% in patients with PV, from 31.3% to 72.1% in patients with ET, and from 25.0% to 85.7% in those with PMF.

The World Health Organization (WHO; 2022, 5th edition) criteria and the International Consensus Classification (2022) criteria specifically recommended testing for JAK2 exon 12 variants in patients with suspected PV (presumably in patients who are JAK2 V617F-negative). The criteria suggested testing for JAK2 V617 in patients with ET and MPF.^6,7,8,

Section Summary: Clinically Valid

Evidence of the clinical validity of JAK2 V617F and exon 12 variant testing includes prospective studies and case series and a systematic review of these studies. In PV patients, the proportion of patients with JAK2 V617F ranged from 46.7% to 100% in patients with PV, from 31.3% to 72.1% in patients with ET, and from 25.0% to 85.7% in those with PMF. Additionally, the WHO (2022, 5th edition) and the International Consensus Classification (2022) diagnostic criteria incorporated the JAK2 V617F variants for PV, ET, and PMF and JAK2 exon 12 variants for PV and MPF.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

Testing for JAK2 V617F or JAK2 exon 12 variants has potential clinical utility in several different clinical scenarios:

• Diagnosis of patients with clinical, laboratory, or pathologic findings suggesting classic MPNs (PV, ET, or PMF);

• Phenotyping of disease subtypes in patients with MPNs to establish disease prognosis;

• Identification, selection, and monitoring of treatment.

Treatment With JAK2 Inhibitors

Due to the strong epidemiologic and biologic literature linking JAK2 pathway variants to the occurrence of MPNs, there has been considerable recent attention on using JAK2 as a molecular target for drug discovery. In preclinical and early clinical studies, a number of promising JAK2 inhibitors have been identified, and reports have suggested that some are useful in symptom relief.^30, Many patients with these diseases have good responses to cytotoxic drugs, and the natural course of the disease, particularly for PV and ET, can be quite indolent. Considerable studies will be required to sort through the safety and efficacy of these new treatments before they enter routine clinical use. Several early-phase and preliminary treatment trials evaluating the safety and efficacy of tyrosine kinase inhibitors in patients with JAK2 V617F-positive MPNs have been reported.^31,32,33, It also has been noted that benefits from tyrosine kinase therapy may not be specific for JAK2 V617F-positive MPNs but may be observed in wild-type disease as well.^34,

In 2011, ruxolitinib (a JAK kinase inhibitor) was approved by the U.S. Food and Drug Administration for the treatment of intermediate- and high-risk myelofibrosis (including PMF, post-PV myelofibrosis, and post-ET myelofibrosis) based on results from 2 RCTs. One, a double-blind RCT by Verstovsek et al (2012) assessing patients with intermediate- to high-risk myelofibrosis, randomized participants to twice-daily oral ruxolitinib (n=155) or to placebo (n=154) and followed them for 76 weeks (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment [COMFORT-I]).^35, The primary outcome (≥35% reduction in spleen volume at or after 24 weeks) was observed in 41.9% of patients treated with ruxolitinib compared with 0.7% in the placebo group (p<.001). At the prospectively defined data cutoff of 32 weeks, there were 10 (6.5%) deaths in the ruxolitinib group and 14 (9.1%) deaths in the placebo group (Kaplan-Meier method, p=.33). With 4 additional months of follow-up (median, 51 weeks total follow-up), there were 13 (8.4%) total deaths in the ruxolitinib group and 24 (15.6%) total deaths in the placebo group (Kaplan-Meier method, p=.04). Myelofibrosis symptom score at 24 weeks improved 45.9% from baseline in patients who received ruxolitinib and 5.3% in placebo patients. Discontinuations due to adverse events were similar in the ruxolitinib (11%) and placebo (10.6%) groups. In a post hoc subgroup analysis of patients with the JAK2 V617F variant, mean changes in spleen volume at 24 weeks were -34.6% in the ruxolitinib group and +8.1% in the placebo group; in patients without the variant, mean changes in spleen volume were -23.8% and +8.4%, respectively. Changes in total symptom score at 24 weeks in patients with the JAK2 V617F variant were -52.6% in the ruxolitinib group and +42.8% in the placebo group (higher scores indicate more severe symptoms); in patients without the variant, changes in total symptom score were -28.1% and +37.2%, respectively.

A second trial by Harrison et al (2012) reached similar conclusions (COMFORT-II).^36, Patients with intermediate- or high-risk PMF, post-PV myelofibrosis, or post-ET myelofibrosis received oral ruxolitinib (n=146) or best available therapy (n=73). No differences in OS were observed between the 2 groups at 48 weeks. Twenty-eight percent of patients in the ruxolitinib group had at least a 35% reduction in spleen volume at 48 weeks compared with 0% in the control group (p<.001). In the JAK2 V617F-positive subgroup, the incidence of spleen reduction was 33% in the ruxolitinib group and 0% in the control group; in the JAK2 V617F-negative subgroup, the incidence of spleen reduction was 14% in the ruxolitinib group and 0% in controls. In the ruxolitinib group, patients had an improved overall quality of life and a reduction in myelofibrosis symptoms compared with no benefit to the control group. Serious adverse events were similar between groups: anemia occurred in 5% of patients in the ruxolitinib group and 4% of the control group, pneumonia occurred in 1% of the ruxolitinib group and 5% of the control group, and 8% of patients in the ruxolitinib group and 5% in the control group discontinued treatment.

A follow-up to the COMFORT-I trial, published by Verstovsek et al (2015), provided data on a median 3-year follow-up.^37, At a median of 149 weeks (range, 19 to 175 weeks), 77 (49.7%) of the 155 patients originally randomized to ruxolitinib were still receiving therapy. One hundred eleven of 154 patients who originally received placebo crossed over to receive ruxolitinib, and, of these, 57 (51.4%) were still receiving the drug. Of the patients originally randomized to therapy, discontinuation rates were 21% at 1 year, 35% at 2 years, and 51% at year 3. Reasons for discontinuing ruxolitinib were disease progress (23.1%), adverse events (19.2%), death (19.2%), and withdrawal of consent (15.4%). The initial primary outcome measure of this study was a reduction in spleen volume, and, in this follow-up study, reductions in spleen size were durable with longer-term treatment. The mean percentage change from baseline was -31.6% at week 24 and -34.1% at week 144. Of patients initially randomized to ruxolitinib, 91 (59%) of 155 patients achieved a 35% or more reduction in spleen volume at any time during study follow-up. The probability of maintaining this same reduction for at least 132 weeks was 0.53, and more than 80% of patients maintained a reduction of at least 10%. Regarding OS, 42 patients randomized to ruxolitinib died while 54 in the placebo group died. With a median follow-up of 149 weeks for both the ruxolitinib and placebo groups, the hazard ratio for OS favored patients in the ruxolitinib arm (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; p=.067). Anemia and thrombocytopenia were the most common adverse hematologic events and were highest during the first 6 months of therapy, both of which subsequently increased to a new steady state. The most common nonhematologic adverse events, which occurred more commonly in the ruxolitinib group, were ecchymosis (18.7%), dizziness (14.8%), and headache (14.8%). Additionally, more patients treated with the study drug developed urinary tract infections and herpes zoster, although the incidence of these infections did not increase with the length of therapy. All herpes zoster infections were grade 1 or 2, and no other opportunistic infections were identified during follow-up. Four new cases of acute myeloid leukemia were reported since the first analysis published in 2012, 2 in patients originally randomized to ruxolitinib and 2 in the placebo arm, for a total of 8 cases since the study began. The rate of leukemic transformation per person-year of ruxolitinib exposure was 0.0121 per person-year and 0.0233 per person-year in patients originally randomized to ruxolitinib or placebo, respectively.

Although identification of a drug producing long-term remission (like imatinib in chronic myeloid leukemia) is the ultimate goal, discovery likely will be complicated by the complexity of molecular processes occurring in patients with these other MPNs and the fact that JAK2 V617F alone does not appear to be a unique or absolutely necessary event in many patients with these diseases. The role of the JAK2 V617F variant in selecting or monitoring patients for new treatments or residual neoplasia remains undefined.

Section Summary: Clinically Useful

Evidence for the clinical utility of JAK2 testing includes meta-analyses, retrospective studies, and RCTs. Evidence for JAK2 testing for phenotyping and monitoring provides conflicting results. However, the presence of JAK2 V617F or JAK2 exon 12 variants is considered a major criterion for the diagnosis of PV, ET, and PMF. JAK2 V617F and JAK2 exon 12 testing allow secondary or reactive erythrocytosis or thrombocytosis to be differentiated from PV, ET, and PMF.

For individuals with a suspected myeloproliferative neoplasm (MPN) who receive genetic testing for JAK2, the evidence includes case series, retrospective studies, meta-analyses, and randomized controlled trials. Relevant outcomes are overall survival (OS), disease-specific survival, test accuracy and validity, and resource utilization. For patients with suspected Ph-negative MPN, JAK2 variants are found in nearly 100% of those with polycythemia vera (PV), 60% to 65% of those with essential thrombocythemia (ET), and 60% to 65% of those with primary myelofibrosis (PMF). In individuals with suspected MPN, a positive genetic test for JAK2 satisfies a major criterion for the International Consensus Classification (2022) and World Health Organization (WHO) 2022 (5th edition) classification for Ph-negative MPNs and eliminates secondary or reactive causes of erythrocytosis and thrombocythemia from the differential diagnosis. The presence of a documented JAK2 variant may aid in the selection of ruxolitinib, a JAK2 inhibitor; ruxolitinib, however, is classified as second-line therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

MPL Testing for a Suspected Myeloproliferative Neoplasm

Clinical Context and Test Purpose

The purpose of MPL testing of individuals with a suspected MPN is to establish a molecular genetic diagnosis of MPN to inform management decisions.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest includes individuals with a suspected MPN.

Interventions

The test being considered is genetic testing for MPL.

Comparators

The following practice is currently being used to make decisions about treating individuals with a suspected MPN: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are OS, disease-specific survival, test accuracy, test validity, and resource utilization. The potential beneficial outcomes of primary interest include establishing a molecular genetic diagnosis of ET or PMF to inform management decisions when test results are positive.

The time frame for outcomes measures varies from several months for the improvement of symptoms to long-term survival as a result of disease-related complications.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for MPL, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Systematic Review

Mejia-Ochoa et al (2019) conducted a systematic review and meta-analysis of the frequency of JAK2, CALR, and MPL in Ph-negative chronic MPNs.^29, Across 14 studies, the frequency of the MPL variant was 0% in PV, and ranged from 0.9% to 12.5% in ET, and from 0% to 17.1% in PMF. The studies were heterogeneous with regard to the diagnostic techniques used and their results.

The WHO (2022, 5th edition) and International Consensus Classification (2022) criteria specifically cited testing MPL exon 10 variants in patients with ET and PMF. The criteria included testing for MPL exon 10 variants in patients with ET and PMF.^6,8,7,

Section Summary: Clinically Valid

Evidence of the clinical validity of MPL exon 10 variant testing includes case series. The frequency of the MPL variant was 0% in PV, and ranged from 0.9% to 12.5% in ET, and from 0% to 17.1% in PMF. In ET and PMF patients, the WHO (2022, 5th edition) and International Consensus Classification (2022) incorporated MPL exon 10 variants as a major criterion for the diagnosis of ET and PMF.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Testing for MPL exon 10 variants has potential clinical utility in several different clinical scenarios:

• Diagnosis of patients with clinical, laboratory, or pathologic findings suggesting classic ET or PMF;

• Phenotyping of disease subtypes in patients with ET and PMF to establish disease prognosis.

No RCTs were identified that used the results of MPL exon 10 variant testing to guide treatment and management decisions. Additionally, there is no change in management that would be expected to improve the net health outcome

Section Summary: Clinically Useful

Direct evidence for the clinical utility of MPL testing is lacking. While MPL exon 10 testing has potential utility in diagnosing ET and PMF using the WHO (2022, 5th edition) and International Consensus Classification (2022) major criteria for MPNs and excluding reactive or secondary causes of thrombocytosis, there is no change in management that would be expected to improve the net health outcome. Thus, the clinical utility has not been established. Given that genetic testing for MPL is included in the WHO (2022, 5th edition) and International Consensus Classification (2022) major criteria and the National Comprehensive Cancer Network guideline for MPNs (2024 ), MPL testing may be consistent with clinical practice in the diagnosis of patients with clinical, laboratory, or pathological findings suggesting ET and PMF.

For individuals with a suspected MPN who receive genetic testing for MPL, the evidence includes case series and retrospective studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, and resource utilization. For patients with suspected Ph-negative MPN, MPL variants are found in approximately 5% of those with ET and PMF. In individuals with suspected MPN, a positive genetic test for MPL satisfies a major criterion for the International Consensus Classification (2022) and WHO (2022, 5th edition ) classification for ET and PMF and eliminates secondary or reactive causes of thrombocythemia from the differential diagnosis. The goal of ET treatment is to alleviate symptoms and minimize thrombotic events and bleeding irrespective of MPL variant status. For PMF, hematopoietic cell transplantation is the only treatment with curative potential while most other treatment options focus on symptom alleviation. However, in both ET and PMF, establishing the diagnosis through MPL genetic testing does not in and of itself result in changes in management that would be expected to improve the net health outcome. Thus, the clinical utility has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

CALR Testing for a Suspected Myeloproliferative Neoplasm

Clinical Context and Test Purpose

The purpose of CALR testing of individuals with a suspected MPN is to establish a molecular genetic diagnosis of MPN to inform management decisions.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest includes individuals with a suspected MPN.

Interventions

The test being considered is genetic testing for CALR.

Comparators

The following practice is currently being used to make decisions about individuals with a suspected MPN: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are OS, disease-specific survival, test accuracy, test validity, and resource utilization. The potential beneficial outcomes of primary interest include establishing a molecular genetic diagnosis of ET or PMF to inform management decisions when test results are positive.

The time frame for outcomes measures varies from several months for the improvement of symptoms to long-term survival as a result of disease-related complications.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for CALR, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Systematic Review

Mejia-Ochoa et al (2019) conducted a systematic review and meta-analysis of the frequency of JAK2, CALR, and MPL in Ph-negative chronic MPNs.^29, Thirteen studies reported the frequency of the CALR variant in PV, ET, and PMF. The studies were heterogeneous with regard to the diagnostic techniques used and their results. The frequency of the CALR variant was 0% in patients with PV, 12.6% to 50.0% in ET, and 10% to 100% in PMF.

Section Summary: Clinically Valid

Evidence of the clinical validity of CALR variant testing includes retrospective studies, case series, and a systematic review of these studies. The frequency of the CALR variant was 0% in patients with PV, 12.6% to 50.0% in ET, and 10% to 100% in PMF.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Testing for CALR exon 9 variants has potential clinical utility in several different clinical scenarios:

• Diagnosis of patients with clinical, laboratory, or pathologic findings suggesting classic ET or PMF;

• Phenotyping of disease subtypes in patients with ET and PMF to establish disease prognosis.

However, establishing the diagnosis through CALR genetic testing does not result in changes in management that would be expected to improve net health outcome.

The goals of treatment and management for ET are to alleviate symptoms and minimize complications of the disease such as thrombotic events and bleeding, though establishing the diagnosis does not lead to preventive management. For PMF, hematopoietic cell transplantation is the only treatment with curative potential while most other treatment options focus on alleviation of symptoms.

Section Summary: Clinically Useful

Direct evidence for the clinical utility of CALR testing is lacking. While CALR exon 9 testing has potential clinical utility in diagnosing ET and PMF using the WHO (2022, 5th edition) and International Consensus Classification (2022) major criteria for MPNs and excluding reactive or secondary causes of thrombocytosis, there is no change in management that would be expected to improve net health outcome. Thus, the clinical utility has not been established. Given that genetic testing for CALR is included in the WHO (2022, 5th edition) and International Consensus Classification (2022) major criteria and the National Comprehensive Cancer Network guideline (2024 ) for MPNs, CALR testing may be consistent with clinical practice in the diagnosis of patients with clinical, laboratory, or pathological findings suggesting ET and PMF.

For individuals with a suspected MPN who receive genetic testing for CALR, the evidence includes case series and retrospective studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, and resource utilization. For patients with suspected Ph-negative MPN, CALR variants are found in approximately 20% to 25% of those with ET and PMF. For individuals with suspected MPN, a positive genetic test for CALR satisfies a major criterion for the International Consensus Classification (2022) and WHO (2022, 5th edition) classification for ET and PMF and eliminates secondary or reactive causes of thrombocythemia from the differential diagnosis. The goal of ET treatment is to alleviate symptoms and minimize thrombotic events and bleeding irrespective of CALR variant status. For PMF, hematopoietic cell transplantation is the only treatment with curative potential while most other treatment options focus on symptom alleviation. However, in both ET and PMF, establishing the diagnosis through CALR genetic testing does not result in changes in management that would be expected to improve the net health outcome. Thus, the clinical utility has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

World Health Organization

The 2022 (5th edition) World Health Organization (WHO) major criteria for myeloproliferative neoplasms (MPNs) are unchanged from the 2016 (4th edition) criteria and are as follows^6,7,:

• Polycythemia vera (PV): " Presence of JAK2, V617F, or JAK2 exon 12 mutation"

• Essential thrombocythemia (ET): " Presence of JAK2, CALR, or MPL mutation"

• Primary myelofibrosis (PMF): " Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of reactive myelofibrosis."

International Consensus Classification

In 2022, an international clinical advisory committee endorsed by the Society for Hematopathology (SH) and the European Association for Haematopathology (EAHP) published a new classification schema for myeloid neoplasms and acute leukemias.^8, Many of the clinical advisory committee authors were authors on the 2016 (4th edition) of the WHO criteria, but the International Consensus Classification was developed independently of the WHO. The gene-related major criteria for MPNs are as follows:

• PV: "Presence of JAK2 V617F or JAK2 exon 12 mutation"

• ET: "JAK2, CALR, or MPL mutation"

• PMF: "JAK2, CALR, or MPL mutation or presence of another clonal marker or absence of reactive bone marrow reticulin fibrosis"

For PV, it is recommended to use highly sensitive assays for JAK2 V617F (sensitivity level, <1%); in negative cases, searching for noncanonical or atypical JAK2 mutations in exons 12 to 15 can be considered. For ET and MPF, it is recommended to use highly sensitive assays for JAK2 V617F (sensitivity level , <1%) and CALR and MPL (sensitivity level, 1% to 3%); in negative cases, a search for noncanonical JAK2 and MPL mutations can be considered. Other clonal markers that can be assessed in MPF include mutations associated with myeloid neoplasms (eg, ASXL1, EZH2, IDH1, IDH2, SF3B1, SRSF2, and TET2 mutations).

National Comprehensive Cancer Network

The National Comprehensive Cancer Network published guidelines (v.1.2024 ) on the workup, diagnosis, and treatment of suspected MPNs.^38, For patients with suspicion of MPNs, the guidelines recommend "molecular testing (blood or bone marrow) for JAK2 V617F mutation; if negative, test for CALR and MPL mutations (for patients with ET and MF) and JAK2 Exon 12 mutations (for patients with PV); or molecular testing using multigene NGS [next-generation sequencing] panel that includes JAK2, CALR, and MPL. Once an MPN diagnosis is confirmed, NGS is recommended for mutational prognostication."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in June 2024 did not identify any ongoing or unpublished trials that would likely influence this review.

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