Klin Padiatr 2016; 228 - A3
DOI: 10.1055/s-0036-1582480

Prognostic impact of IKZF1 deletions in association with vincristine-dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial AIEOP-BFM ALL 95

L Hinze 1, A Möricke 2, G Cario 2, M Zimmermann 1, V Conter 3, M Schrappe 2, M Stanulla 1
  • 1Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
  • 2Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany
  • 3San Gerardo Hospital, Pediatric Clinic, Monza, Italy

Background: Previous studies suggested that patients with IKZF1-deleted acute lymphoblastic leukemia (ALL) may benefit from intensification of conventional maintenance therapy by application of vincristine-steroid pulses (Clappier E, Leukemia 2015; 29: 2154 – 2161). Here, we investigated the impact of additional pulses during maintenance therapy for IKZF1-deleted ALL in a large cohort of intermediate risk patients treated according to the AIEOP-BFM ALL 95 protocol.

Methods: Between April 1995 and December 2000, patients diagnosed with de novo ALL were enrolled in AIEOP-BFM ALL 95 from Austrian, German, Italian and Swiss study centers (Conter V, Lancet 2007; 369:123 – 131). Treatment was stratified in three risk groups: standard (SR), intermediate (IR) and high risk (HR). Risk group definition was as follows: HR, prednisone poor response, and/or no complete remission on day 33, and/or evidence of t(9;22) (or BCR/ABL), and/or evidence of t(4;11) (or MLL/AF4); IR, no HR criteria, and initial WBC 20 × 109/L or more and/or age at diagnosis less than 1 or 6 years or older, and/or T-ALL; SR, no HR criteria, and initial WBC less than 20 × 109/L, and age at diagnosis between 1 and 6 years, and no T-ALL. CNS status was no stratification criterion. Before start of maintenance treatment, patients of the intermediate risk group who were in complete remission were randomly assigned to receive either conventional mercaptopurine and methothrexate chemotherapy or mercaptopurine and methothrexate supplemented with additional pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/ml daily for 7 days) every 10 weeks for six cycles. IKZF1 deletion status in leukemic DNA isolated from initial bone marrow smears was assessed by a multiplex PCR assay (Caye A, Haematologica 2012; 98: 597 – 601).

Results: Out of 655 intermediate risk precursor B cell ALL patients, 80 patients presented with an IKZF1 deletion (12.2%). Forty-three out of these 80 patients were randomly assigned to the standard arm and 37 to the experimental group. As previously described, IKZF1-deletion conferred a worse outcome in the entire intermediate risk group (5-year event free survival (EFS): 0.82 vs. 0.66). In stratified analyses, the 5-year EFS estimates tended to be lower in IKZF1-deleted patients treated according the experimental arm compared to those on standard therapy (0.566 ± 0.08 vs. 0.741 ± 0.07; P = 0.083). This difference was mainly due to a higher cumulative incidence of relapse in the treatment group (0.35± 0.008 vs. 0.26 ± 0.07; P = 0.37). Eleven patients in the control group and 16 in the experimental group suffered from relapses.

Conclusion: Intensification of maintenance therapy with vincristine-steroid pulses for intermediate-risk patients with IKZF1-deleted ALL was not associated with improved outcome on trial AIEOP-BFM ALL 95. Thus, at least on a BFM treatment backbone, pulsed maintenance treatment is not a therapeutic option to improve the dismal outcome of IKZF1-deleted ALL.