A significant proportion of patients with chronic myeloid leukemia and suboptimal response according to European Leukemia Net criteria have excellent prognosis without treatment change

Abstract

Background. The Recommendations of the European Leukemia Net (ELN) have become an essential tool in the management and prognosis of patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). However, the definition of suboptimal response remains under discussion. Methods. We used conventional cytogenetics for the detection of clonal changes in Ph-positive and negative clones. RT-PCR and sequencing were carried out on peripheral blood leukocytes to detect the type of BCR-ABL1 transcript. The BCR-ABL1 mutational status was assessed using sequencing of RT-PCR products. High performance capillary electrophoresis for determination of imatinib (IMA) plasma concentration was used. Results. A retrospective study of 110 patients diagnosed with chronic-phase (CP) CML treated with IMA or 2 nd generation TKIs in the years 2000-2009 focused on analysis of patients with suboptimal response according to ELN criteria. 40 patients were administered IMA as first-line therapy and 70 had been pretreated with interferon-alpha (IFN-α) with or without Ara-C and/or hydroxyurea (HU) for a median 12 months (range, 1-92 months). After adjusting for the ELN criteria, major molecular response (MMR) was achieved after median 34 and 39 months in 66.7% and 41.7% of patients after the first and second-line IMA therapy with suboptimal response defined as lack of achievement of MMR at the 18 th month of treatment, respectively. In comparison to patients with optimal response, patients with suboptimal response did not show significant differences in overall survival (OS) or progression-free survival (PFS). Cytogenetic assays demonstrated additional chromosome abnormalities (ACAs): chromosome 8 trisomy in a Ph-negative clone during the IMA treatment (in 1 case) and der(9q) in Ph-positive clone (in 2 cases); in patients receiving first-line IMA only chromosome 8 trisomy was observed which was associated with myelodysplastic syndrome -this was the only case where hematopoietic stem cell transplantation (HSCT) was performed. During the treatment with IMA in both subgroups no regulatory mutations in the ABL kinase domain were confirmed. Conclusion. We believe that the category of suboptimal response should be redefined or withdrawn from the ELN 2009 recommendations for management of CML patients treated with TKIs. Patients with suboptimal response who have no additional risks (additional cytogenetic abnormalities or BCR-ABL1 regulatory mutations) may remain on IMA treatment while patients with these risks should be switched to the 2 nd generation TKIs.

Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches

“…Therefore, monitoring of additional changes such as ACAs is useful for identifying patients at higher risk of treatment failure (Oehler, 2013). Definition of CML according to hematologic, cytogenetic, and molecular changes can be useful in predicting treatment responses and in organizing guidelines for CML treatment, especially in the chronic phase (Rohon et al, 2013).…”

Critical appraisal of European LeukemiaNet (ELN) 2013 recommendations for the management of chronic myeloid leukemia: is it early for a warning?

“…Mainly because of the need for more evidence, especially for an early treatment change, ELN recommended patients with warning signs to be monitored more stringently given the assumption that they would achieve an inadequate treatment response and consequently result in a poor outcome [2]. This has motivated several investigators to conduct studies challenging the validity of the ELN recommendations, and Rohon et al [4] tested the clinical significance of suboptimal response according to the 2009 ELN recommendations in a retrospective analysis, which included 110 patients with both early and late CML-CP. Although the number of patients in that study was relatively small, the authors showed that patients with optimal and suboptimal responses had similar outcomes, and all patients with suboptimal response eventually achieved complete CyR (CCyR) if they were kept on receiving imatinib.…”

“…Although the number of patients in that study was relatively small, the authors showed that patients with optimal and suboptimal responses had similar outcomes, and all patients with suboptimal response eventually achieved complete CyR (CCyR) if they were kept on receiving imatinib. Furthermore, they stated that patients with suboptimal response clearly form a heterogeneous group of which a significant proportion show characteristics that correspond to patients with optimal response [4].…”