Children with TEL/AML1-Positive Acute Lymphoblastic Leukemia (ALL) and Favorable Presenting Features May Benefit from the Use of Vincristine-Dexamethasone (VCR-DXM) Pulses on Top of Antimetabolite-Based Continuation Therapy.
Authors: Rizzari Carmelo , Cazzaniga Giovanni , Valsecchi Maria Grazia , Silvestri Daniela , Conter Valentino , Aricò Maurizio , Barisone Elena , Casale Fiorina , De Rossi Giulio , Locatelli Franco , Lo Nigro Luca , Messina Chiara , Micalizzi Concetta , Pession Andrea , Parasole Rosanna , Rondelli Roberto , Santoro Nicola , Testi Anna Maria , Basso Giuseppe , Masera Giuseppe , Biondi Andrea 
Published: April 2020

Abstract
Introduction: In 1995 the International BFM Study Group study started an intergroup study for patients at intermediate risk (IR) who were randomized to receive or not VCR-DXM pulses during the antimetabolite-based continuation therapy. The AIEOP participated in this study and treated, in addition, with the same protocol also patients with more favorable presenting features (see methods) if their DNA Index was &lt; 1.16 or ≥1.60. Approximately 40% of these patients present the TEL/AML1 fusion gene, associated with t(12;21)(p13;q22), which is the most common gene rearrangement in pediatric ALL (approximately 25% of all cases). Relapses in these patients occur usually late and may depend on the intensity of the chemotherapy regimens adopted.
Aim: To evaluate the impact of VCR-DXM pulses on top of antimetabolite continuation therapy in patients presenting with TEL-AML1 positive ALL and no other high risk features, treated in the AIEOP ALL 95 protocol.
Patients and Methods: The subgroup ALL children evaluated in this study had the following features: age 1–5 years, non-T immunophenotype, WBC count &lt; 20,000/cmm, absence of t(9;22) or t(4;11) translocations, &lt; 1,000 blasts/cmm in peripheral blood after 7 days of prednisone therapy and one intrathecal dose of MTX on day 1, complete remission after induction phase (protocol IA), DNA Index &lt; 1.16 or ≥1.60. Patients were treated with the BFM-based AIEOP ALL 95, which includes protocols I, M, and II; at the beginning of continuation phase patients were randomized to receive (ARM P) or not (Arm NoP) 6 pulses (q 10 weeks) of VCR (1.5 mg/sqm weekly x 2) and DXM (6 mg/sqm daily x 7 days) on top of conventional 6-MP (50 mg/sqm daily) and MTX (20 mg/sqm weekly) continuation therapy. Analysis of treatment effect (DFS: time from randomization to relapse or death in CR) was performed according to intention to treat. The presence of the TEL-AML1 fusion gene was studied by using standard RT-PCR.
Results: Out of the 211 patients who were randomized either in the Arm P (n= 107) or NoP (n=104), 88 (42%) were positive for the TEL-AML1 (43 were randomized to Arm P and 45 to Arm NP) and 123 (58%) were negative (64 were randomized to Arm P and 59 to arm NoP). With a median follow-up of 4.7 yrs, the 7-year DFS (SE) was similar in the two arms for the overall cohort and for the TEL-AML1-negative subgroup, while in the TEL-AML1 positive subgroup DFS was 92.8 (4.0) vs 77.9 (6.6) (p=0.06) in arms P and NoP, respectively.
Conclusion: These data suggest that children with TEL-AML1-positive ALL treated according to a BFM-based intensive chemotherapy schedule, may benefit from the addition of VCR-DXM pulses during the antimetabolite based continuation therapy.