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Recommendations from the European LeukemiaNet to address unmet clinical needs in the management of CALR-mutated essential thrombocythemia

Oct 27, 2021
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On May 20, 2020, the Annual Symposium of the European LeukemiaNet (ELN) was held with the aim of identifying unmet needs in myeloproliferative neoplasms. Recommendations regarding the management of essential thrombocythemia (ET) are based on studies that were conducted before the discovery of the CALR mutation. CALR mutations are the second most common genotype and are found in a quarter of patients with ET. Patients with CALR mutations present with different and specific clinical characteristics compared with the most common JAK2 Val617Phe genotype, including differences in symptomatic burden, hematologic values, and risk of thrombosis and bleeding. Therefore, treatment of CALR-mutated ET was considered an unmet clinical need by the ELN and to overcome the uncertainties surrounding treatment, a consensus document with recommendations according to current evidence was proposed.1

A steering committee comprising four ELN members and a panel of 10 experts proposed 51 potential unmet clinical needs in the management of CALR-mutated ET and reached a 90% consensus on 14 recommendations and six solutions. These topics included identifying antiplatelet therapy in low-risk patients, defining extreme thrombocytosis and its management in low-risk patients, indications of cytoreduction and targets of therapy, first-line treatment of choice in patients younger than 60 years, and management of pregnancy.

The ELN recommendations and proposals are summarized in Table 1, and the consensus methods approach is detailed below towards the end of the article.

The report highlighted the need for prospective studies to improve prognostic classification and to guide treatment choice in patients with CALR-mutated ET. In contrast to patients with the JAK2 Val617Phe mutation, prevention of thrombosis is not the primary concern in most patients with a CALR mutation. The main concern in patients with a CALR mutation is thrombocytosis management, particularly if it is accompanied by microvascular symptoms. Another area of focus that warrants further investigation is the efficacy of cytoreductive treatments and a guide to clinical practice. Even with a scarce amount of good scientific evidence on CALR-mutated ET, the experts from the panel were able to reach a >90% high-level consensus and highlight unmet clinical needs and provide recommendations.

Table 1. Recommendations from the ELN and proposals for solutions for each unmet clinical need for CALR-mutated ET*

Antiplatelet therapy in patients at low risk with CALR-mutated ET

Recommendations

Careful observation is a reasonable option for asymptomatic patients with classical low-risk CALR-mutated ET without cardiovascular risk factors, as the incidence of thrombosis is very low.

Antiplatelet therapy with low-dose aspirin (75–100 mg/day) must be considered in patients with classical low risk and cardiovascular risk factors (including active smoking, diabetes, hypertension, hypercholesterolemia, and obesity).

Proposal

A study evaluating the role of antiplatelet treatment and its dosage on the risk of bleeding across ET with a different mutational status, including different CALR subtypes, is warranted.

Definition of extreme thrombocytosis and its management in patients at low risk with CALR-mutated ET

Recommendations

Cytoreduction for patients with classical low risk of developing extreme thrombocytosis (platelet count >1,500 × 10⁹ platelets/L).

Test for acquired von Willebrand disease may be useful if the platelet count is >1,000 × 10⁹ platelets/L or in bleeding events (independently of the platelet count).

Watch and wait without antiplatelet therapy might be an adequate option for asymptomatic patients at low risk with platelets between 1,000–1,500 × 10⁹ platelets/L.

Low-risk symptomatic patients should receive antiplatelet therapy with caution; these patients present with platelet counts of 1,000–1,500 × 10⁹ platelets/L. For these cases, cytoreduction should be considered as an adequate option.

Proposal

A prospective study assessing the accuracy of these recommendations for patients with CALR-mutated ET is needed.

Indications for cytoreduction and targets of therapy

Recommendations

Cytoreduction is indicated in patients with CALR-mutated ET who are >60 years old or have a history of thrombosis or platelet count >1,500 × 10⁹ platelets/L.

The advantage of withholding cytoreduction in patients >60 years without cardiovascular risk factors and no previous incidence of thrombosis (low risk according to IPSET) is unknown.

Platelet count normalization is recommended in patients receiving cytoreduction. However, if this results in toxicity, a lower intensity threshold might be appropriate, particularly in patients without previous thrombosis or bleeding events.

Proposal

Prospective studies are needed to guide clinical practice.

Cytoreductive therapy: First-line choice in young patients (<60 years) and role of peg-IFNα

Recommendations

PEG-IFNα therapy is the preferred option over hydroxycarbamide or anagrelide in young patients with CALR-mutated ET that requires cytoreductive therapy. This recommendation is based on the observed efficacy of interferon from retrospective studies and due to the absence of leukemogenic and teratogenic effects.

A consensus was not achieved in defining the role of hydroxycarbamide and anagrelide therapy in young patients with CALR-mutated ET. This was due to different interpretation by the experts of existing data; some experts favored hydroxycarbamide, and others anagrelide. It was concluded that based on the insufficient evidence regarding efficacy along with the nonconsensus among panelists, that both hydroxycarbamide and anagrelide therapy could be offered to young patients who were ineligible for PEG-IFNα.

Proposal

An observational, multicenter, retrospective or prospective study that explores the efficacy of current cytoreductive agents (hydroxycarbamide, anagrelide, and PEG-IFNα) as frontline therapy for CALR-mutated ET is needed.

Management of pregnancy in patients with CALR-mutated ET

Recommendations

Treatment algorithms for high-risk pregnancies should not be changed according to genotype.

Aspirin should be recommended for all patients throughout pregnancy, unless specifically contraindicated. At approximately 34 weeks of gestation, aspirin is typically switched to low-molecular-weight heparin to avoid severe bleeding during delivery.

Post-partum thromboprophylaxis with 6 weeks of low-molecular-weight heparin should be offered to all patients.

Proposals

A retrospective study that defines risk classification, patients’ genotype, and treatment paradigm is needed.

Additionally, a prospective study that assesses von Willebrand factor (antigen and functional activity during early pregnancy and at 14–16 weeks’ gestation) and outlines the rates of acquired von Willebrand disease is also warranted. This study needs to specifically describe the outcomes according to genotype, therapy, and acquired von Willebrand disease, with a special focus on bleeding events (spontaneous or associated with obstetrical procedures or childbirth).

ELN, European LeukemiaNet; ET, essential thrombocythemia; IPSET, international prognostic score for thrombosis in ET; PEG-IFNα, pegylated interferon alfa.
*Adapted from Alvarez-Larrán et al.1

Methods

A total of 51 topics were proposed as potential unmet clinical needs in the management of CALR-mutated ET by the expert panel. These topics were categorized into seven categories: pathogenesis, diagnosis, prognosis, indications of cytoreduction and targets of therapy, antiplatelet therapy, cytoreductive therapy, and management of pregnancy. These topics were then scored on a scale from 0 (resolved or not relevant) to 5 (constituted a relevant unmet clinical need). Topics with a total score of >45 points and a mean or median value of ≥4.5 points were selected.

Evidence review

The steering committee reviewed the available data on the selected unmet clinical needs, outlined a recommendation of management, and proposed studies for resolving these needs.

  • Step 1: A widespread search on PubMed of randomized clinical trials, meta-analyses, systematic reviews, retrospective studies, and real-world-based studies published from 1975 to May 31, 2021
  • Step 2: Expert opinions for each of the debated issues
  • Step 3: Searches were refined to target highly debated issues or those that needed to be updated

The expert panel reviewed references and summaries of evidence on the selected topics and then provided additional evidence for each statement.

Consensus approach

All statements by the steering committee underwent a consensus process according to the Delphi consensus protocols. It was based on the expert panel responses from a questionnaire. Each expert was asked to provide their agreement or disagreement to each suggestion and to suggest amendments. Consensus was reached when 90% of the panelists agreed with a statement. Statements that reached a consensus between 70–90% were altered and resubmitted until a consensus was reached. The recommendations that did not reach at least 70% consensus were cancelled. The final 90% agreement reached by the consensus are included in this summary.

Results

Selection of unmet clinical needs in CALR-mutated ET

Assessment of general aspects in the management of CALR-mutated ET to identify potential unmet clinical needs can be seen in Table 2. Indication of cytoreduction, targets of therapy, antiplatelet therapy, and cytoreductive therapy achieved the highest scores and were selected for further revision.

Table 2. Identification of expert panelists and scoring of potential unmet clinical needs*

Characteristic

Total score

Mean (SD)

Median (IQR)

Pathogenesis

25

2.50 (1.65)

3 (1–4)

Diagnosis

27

2.45 (1.51)

2 (1–4)

Prognosis

38

3.45 (1.37)

4 (2–5)

Indications of cytoreduction

50

4.55 (0.52)

5 (4–5)

Targets of therapy

48

4.36 (0.81)

5 (4–5)

Antiplatelet therapy

48

4.36 (0.92)

5 (4–5)

Cytoreductive therapy

50

4.55 (0.52)

5 (4–5)

Management of pregnancy

43

3.91 (0.94)

4 (3–5)

*Adapted from Alvarez-Larrán et al.1
Topics identified by the steering committee as unmet clinical needs to be reviewed.

Management of extreme thrombocytosis had the highest score among all the topics in the risk stratification. The expert panel considered antiplatelet therapy in low-risk patients and as first-line treatment choice for young patients (<60 years) in need of cytoreduction as the most relevant unmet clinical needs. Moreover, the management of extreme thrombocytosis and identifying the role of antiplatelet therapy during pregnancy were regarded as highly relevant. On this basis, the topics below were selected as unmet clinical needs:

  • antiplatelet therapy in patients at low risk with emphasis on the type of mutation (Type 1 vs Type 2)
  • definition of extreme thrombocytosis and its management in patients at low risk
  • indications of cytoreduction and targets of therapy
  • cytoreductive therapy as the first line of choice in young patients and role of pegylated interferon alfa (PEG-IFNα)
  • management of pregnancy in CALR-mutated ET

  1. Alvarez-Larrán A, Sant'Antonio E, Harrison C, et al. Unmet clinical needs in the management of CALR-mutated essential thrombocythaemia: A consensus-based proposal from the European LeukemiaNet. Lancet Haematol. 2021;8(9):E658-E665. DOI: 1016/S2352-3026(21)00204-0

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