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This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

After normal survival has been achieved in most patients with chronic myeloid leukemia (CML), a new goal for treating CML is survival at good quality of life, with treatment discontinuation in sustained deep molecular response (DMR; MR4 or deeper) and treatment-free remission (TFR). Four tyrosine kinase inhibitors (TKIs) have been approved for first-line therapy: imatinib, dasatinib, nilotinib, bosutinib. Unexpectedly, the outcome of long-term randomized trials has shown that faster response as achieved by higher doses of imatinib, imatinib in combination, or second-generation (2G)-TKIs, does not translate into a survival advantage. Serious and frequent, and in part cumulative long-term toxicities, have led to a reevaluation of the role of 2G-TKIs in first-line therapy. Generic imatinib is the current most cost-effective first-line therapy in the chronic phase. A change of treatment is recommended when intolerance cannot be ameliorated or molecular milestones are not reached. Patient comorbidities and contraindications of all TKIs must be considered. Risk profile at diagnosis should be assessed with the EUTOS score for long-term survival (ELTS). Monitoring of response is by polymerase chain reaction (PCR). Cytogenetics is still required in the case of atypical translocations, atypical transcripts, and additional chromosomal aberrations. TKIs are contraindicated during pregnancy. Since the majority of patients are at risk of lifelong exposure to TKIs, amelioration of chronic low-grade side effects is important.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.

Chronic myeloid leukaemia (CML) was the first neoplastic disease for which knowledge of the genotype led to a rationally designed therapy. As a result of its well known pathophysiology, straightforward diagnosis, well established prognostic factors, and treatment for the cause of disease, CML has been studied to an extent that far exceeds that expected from its frequency, and serves as a model disease for other cancers. Imatinib, an inhibitor of BCR-ABL tyrosine kinase, has revolutionised treatment of this disease, and is now recommended as standard treatment for chronic-phase CML. Interferon alfa is an acceptable alternative treatment in the early chronic phase for patients who do not tolerate imatinib. If imatinib treatment fails, allogeneic stem-cell transplantation, a dose increase of imatinib, or new drugs are recommended. Up to 87% of patients achieve complete cytogenetic remission, therefore we provide guidance for monitoring disease status. Many trials of new drugs and combination therapies that include imatinib are underway.