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

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*

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*

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