XPO1 Mutations May Identify Binet Α Chronic Lymphocytic Leukemia Patients with Shorter Time to First Treatment

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.1743-1743
• Main Authors: Moia, Riccardo, Favini, Chiara, Sagiraju, Sruthi, Spina, Valeria, Bruscaggin, Alessio, Rasi, Silvia, De Paoli, Lorenzo, Deambrogi, Clara, Schipani, Mattia, Kodipad, Ahad Ahmed, Rossi, Davide, Gaidano, Gianluca
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-126054

Background. Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in western countries. CLL is a highly heterogeneous disease; some patients may never require treatment, whereas other relapse early after frontline therapy. In approximately 70% of newly diagnosed cases, CLL presents at an early clinical stage and is managed with a watch & wait strategy. Until now, few clinical and molecular predictors inform on the risk of treatment requirement and the impact of CLL gene mutations is not completely understood. Purpose. We aimed at identifying new molecular markers that may predict early treatment requirement and may help clinicians to better plan the watch & wait strategy in asymptomatic early stage CLL patients. Methods. This study includes 295 Binet A CLL patients referring at our institution who did not require treatment for at least 3 months after diagnosis. Tumor genomic DNA (gDNA) was isolated from peripheral blood mononuclear cells at the time of diagnosis. gDNA was analyzed in the coding exons plus splice sites of the most frequently mutated genes in CLL with a next-generation-sequencing (NGS) approach. NGS analysis was performed on the Illumina MiSeq instrument (coverage >2000x in >80% of the target region). The somatic function of VarScan2 was used for variant calling and a stringent bioinformatic pipeline was developed to protect against the false call of polymorphisms and sequencing errors. A threshold of 5% of variant allele frequency was set for variant calling. The primary endpoint was time to first treatment (TTFT) defined as the timeinterval between the date of CLL diagnosis and the date of first CLL treatment. Statistical analysis was performed using SPSS version 24.0. Results. The median age of the study cohort was 70.8 years old, 136 (46.1%) patients were female, 71 (24.1%) harbored unmutated IGHV genes, 44 (14.9%) had trisomy 12, 12 (4.1%) had 17p deletion, 15 (5.1%) had 11q deletion and 150 (50.8%) had 13q deletion. NGS mutational analysis showed that NOTCH1 was the most frequently mutated gene occurring in 25 (8.5%) patients, followed by ATM in 18 (6.1%), TP53 in 17 (5.8%), MYD88 in 12 (4.1%), SF3B1 in 10 (3.4%), XPO1 in 7 (2.4%), EGR2 in 6 (2.0%), NFKBIE in 4 (1.4%), POT1 in 2 (0.7%), and BIRC3 in 1 (0.3%) patients. After a median follow-up of 9.5 years, 80 (27.1%) patients required treatment. In univariate analysis, molecular characteristics associated with a shorter TTFT were trisomy 12 (HR: 2.42; 95% CI 1.43-4.1