Results of the European survey on the assessment of deep molecular response in chronic phase CML patients during tyrosine kinase inhibitor therapy (EUREKA registry)

Abstract

Purpose: The advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR-ABL1 transcripts by real-time quantitative PCR every three months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR 4 , MR 4.5 , MR 5) maintain remission after treatment stop, assessment of DMR is crucial. However, systematically collected molecular data, monitored with sensitive standardized assays, are not available outside clinical trials. Methods: Data were collected on the standardized assessment of molecular response in the context of real life practice. BCR-ABL1 transcript levels after >2 years of TKI therapy were evaluated for DMR. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out. Results: Between 2014-2017, 3,377 peripheral blood samples from 1,117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCR-ABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n=197 (6.51%); MMR, n=496 (16.40%); MR 4 , n=685 (22.64%); MR 4.5 , n=937 (30.98%); MR 5 , n=710 (23.47%). With a Cohen's kappa coefficient of 0.708, a substantial agreement between EUTOScertified and local laboratories was shown. Conclusions: Multicenter DMR assessment is feasible in the context of real life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients' molecular response during or after TKI therapy.

Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

“…This was demonstrated in a recent study conducted by the European Treatment and Outcome Study (EUTOS) group in which DMR was measured reliably by local laboratories in Europe, not just the key reference laboratories of individual countries. 53 There are differences of opinion between experts regarding the early molecular response milestone values. Table 1 compares these values between the recent updated ELN recommendations 19 and the National Comprehensive Cancer Network (NCCN) clinical practice guidelines.…”

Standardization of BCR-ABL1 p210 Monitoring: From Nested to Digital PCR

“…Conventional qRT-PCR kits do not have the competence to amplify these sequences. Indeed, MRD monitoring for these patients is still performed only by cytogenetic, FISH analysis, and qualitative nested PCR [5], making it impossible to demonstrate the achievement of a MMR. This limitation decreases the prognostic information and automatically excludes patients showing atypical transcripts from the clinical protocol of treatment discontinuation [5,6].…”

“…Indeed, MRD monitoring for these patients is still performed only by cytogenetic, FISH analysis, and qualitative nested PCR [5], making it impossible to demonstrate the achievement of a MMR. This limitation decreases the prognostic information and automatically excludes patients showing atypical transcripts from the clinical protocol of treatment discontinuation [5,6]. Despite this, Dragani et al described some patients with atypical transcripts who have discontinued TKIs treatment, successfully maintaining the clinical remission [52].…”

“…Cytogenetic analysis or fluorescence in situ hybridization (FISH) are important at diagnosis and until a Complete Cytogenetic Remission (CCyR) is achieved. After the introduction of TKIs, most patients reach a deep molecular response (DMR) that far exceeds the sensitivity of a cytogenetic evaluation [4][5][6]. In this scenario, BCR-ABL1 mRNA levels has become the most important molecular marker for the minimal residual disease (MRD) evaluation, defining the level of molecular remission and guiding clinical decisions, such as therapy changes or discontinuation [7].…”

Definition, Epidemiology, Pathophysiology, and Essential Criteria for Diagnosis of Pediatric Chronic Myeloid Leukemia

“…Up to 5% of patients may harbor atypical BCR-ABL1 transcripts lacking ABL1 exon2 or resulting from atypical BCR breakpoints (see Section 5) [27]. Using routine primer/probe sets may yield a false negative PCR in qualitative or quantitative RT-PCR protocols thus hampering the subsequent assessment of molecular response [106,107].…”