The Frequency and Impact of IKZF1 Deletions on Minimal Residual Disease in Adult Ph-Negative B-Cell Acute Lymphoblastic Leukemia Patients Treated in Russian Acute Lymphoblastic Leukemia Study

Background: The incidence of IKZF1 gene deletions is approximately 20 % in adult patients with BCR-ABL1- negative B-cell acute lymphoblastic leukemia (BCR-ABL1-neg ALL). These mutations are associated with poor prognosis. Minimal residual disease (MRD) positivity at postinduction time increases incidence of relapse. IKZF1 gene deletions are frequently associated with MRD measured at the end of induction using flow cytometric techniques.

Aim: To evaluate the frequency and impact of IKZF1 deletions on minimal residual disease in adult patients with d e novo BCR-ABL1-neg B-cell ALL.

Patients and methods: The study included 41 adult patients (median age 28, range 17-56; m:f=15:26 ) with newly diagnosed BCR-ABL1-neg B-cell ALL, who were enrolled in Russian acute lymphoblastic leukemia study [ClinicalTrials.gov public site; NCT01193933] since Feb 2010 till March 2017. Intragenic deletions of IKZF1 were detected using breakpoint-specific fluorescent multiplex polymerase chain reaction according to the procedure described by [Aurelie Caye et al, Haematologica, 2013]. DNA for PCR was extracted from leukemia cells of frozen bone marrow samples. MRD analysis was assessed at day 70 (postinduction time) in bone marrow aspirate by multiparameter flow cytometry with using of monoclonal antibodies: CD19 APC, CD10 PE, CD34 PE-Cy7, CD45 PerCP, CD20 APC-H7, CD38 FITC, CD58 FITC. MRD measurements were performed for 17 patients since March 2015 till March 2017.

Results: The IKZF1 gene deletions were detected in 9 (21%) of 41 patients with BCR-ABL1- neg ALL (5 cases with del 4-7 (55%), 2 - del 2-7 (22 %), 1 - del of 2-8 (11%) and in 1 patient all types of deletions were determined (del 4-7, del 4-8, del 2-7, del 2-8). The median follow-up time in 41 patients was 22 months (range: 1,8-91 month). 4 patients died of the disease (10%) and 2 of infections, 35 patients are alive. MRD data were available for 17 patients, of whom 8 were with IKZF1 mutations. Notably, all the patients with IKZF1 mutations had MRD positive status at day 70, patients without mutations had MRD positivity in 2 cases only (22%), р=0,0011.

Conclusion: The frequency of IKZF1 gene deletions in patients with BCR-ABL1- neg ALL was 21%. The IKZF1 gene deletions in leukemic cells found before treatment are associated with MRD persistency after induction therapy.

Figure

View largeDownload slide

Figure

View largeDownload slide

Close modal