The Molecular Response at 3 Months, Measured Using a Genxpert Platform, Predicts Further Outcomes in Chronic Myeloid Patients, but the Cutoff Differs from the 10% Cutoff Commonly Used with the EUTOS Method
Authors: García Gutiérrez Valentín , Gómez-Casares María Teresa , Puerta Jose Manuel , Alonso Juan Manuel , Osorio Santiago , Hernández-Boluda Juan Carlos , Collado Rosa , Ramirez Maria Jose , Ibañez Fatima , Martin Maria Luisa , Rodriguez Juan Diego , Martinez-Laperche Carolina , Gomez Montse , Fiallo Viviana , Sara Redondo , Rodriguez Alicia , Ruiz Concepcion , Steegmann Juan Luis , Jiménez-Velasco Antonio 
Published: October 2019

Abstract
Backgroung: In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels ≤10% measured using conventional RQ-PCR (IS) have consistently been correlated with further outcomes. Monitoring molecular responses using the Xpert BCR-ABL1 MonitorTM PCR system has demonstrated an optimal correlation with standardized RT-qPCR (IS), however, it is not known whether both methods are also equivalent when measuring BCR-ABL1 levels higher than 10%. We previously showed how the cutoff of 10% was not correlate with subsequent responses when using Xpert BCR-ABL1 in a cohort of 125 consecutive CML patients treated with imatinib (58%) and second generation TKI (2GTKI) (42%) as frontline treatment. By contrast, by using a receiver operating characteristic curve, a new cutoff of 1.5% was correlated with probabilities to achieve complete cytogenetic response (CCR) and major molecular response (MMR. The aim of this study is to validate the new cutoff of 1.5% at 3 months in patients treated with second generation 2GTKI.
Methods: We have studied 57 new consecutive CML-CP patients treated 2GTKI from from Andalusian CML Group Registry. BCR-ABL1 transcript quantification was performed using the automated method Xpert BCR-ABL1 Monitor™, Cepheid, aligned to the 0.1% BCR-ABL1 ratio according to the standards of the World Health Organization. The samples were not centrally collected. All analyses were performed on an intention-to-treat basis unless otherwise stated. The proportions of patients who achieved MMR and CCyR after first-line treatment for 1 year and the response at 3 months were compared by applying Pearson's chi-square test or Fisher's exact test The study was approved by the Ethics Committee.
Results: The median age at diagnosed was 48 years (18-74). The ratio of men to women was 59/41, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median follow up was 38 months (3-56). First-line treatment consisted of nilotinib and dasatinib in 58% and 42% of patients, respectively. Overall, the probability of achieving CCyR and MMR at 12 months was 92% (48/52) and 82% (39/47), respectively. Ten patients (17%) required treatment changes as a result of resistance (n=3), not achieving MMR (n=3) or intolerance (n=4). No patients progressed to advanced phases, and only 1 patient died during follow-up (not CML related). The overall median value of BCR-ABL1 at 3 months was 0.16%. Consistent with the original cohort of patients treated with first-line 2GTKI, all patients achieved a BCR-ABL1 level ≤10% at 3 months; therefore, this cutoff did not predict further evolution. We classified this new cohort based on the new cutoff observed in the primary population (BCR-ABL1 level at 3 months ≤1.5%); 77% of patients achieved BCR-ABL1 levels ≤1.5%, whereas 23% of patients did not. This cutoff also predicted the probability to obtain MMR by 12 months (91% vs. 44% (p=0.025).
Conclusions: We have shown that when using the current version of GeneXpert, a BCR-ABL1cutoff of 10% at 3 months may underestimate the probability of not achieving an ulterior optimal response. We have shown that a new cutoff of 1.5% at 3 months can better identify patients with lower risk to achieve an optimal response at 12 months. This information should be taken into considerations when using this practical and widespread platform to monitor CML patients.

Disclosures
García Gutiérrez: Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ramirez:Bristol-Myers-Squibb: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria. Steegmann:BMS: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group; Ariad: Honoraria, Other: Research funding for the Spanish CML Group.