Outcome After First Relapse Or Refractory Acute Lymphoblastic Leukemia In Children From 1996 To 2011 – Comparison Of Two Different Treatment Strategies
Authors: Ceppi Francesco , Duval Michel , Laverdiere Caroline , Leclerc Jean-Marie , Delvas Yveline , Cellot Sonia , Teira Pierre , Bittencourt Henrique 
Published: October 2019

Abstract

Introduction
Newly diagnosed acute lymphoblastic leukemia (ALL) has achieved a cure rate of 80-85% in developed countries. Nevertheless, up to 20% of patients still relapse or have a refractory disease. Approximately 50% of these patients are long term survivors. In our institution, the strategy for relapsed patients had changed from hematopoietic stem cell transplantation (HSCT) after reinduction to all patients to a more tailored approach, offering HSCT to patients at high risk of relapse (e.g. those relapsing early after or during treatment) or for those with late marrow relapse with a related donor after a re-induction treatment. The aims of this study was to analyse the results of treatment for children with ALL in first relapse or refractory disease and to compare the outcome based on the strategy of treatment: re-induction followed by HSCT for all patients versus re-induction followed by HSCT or chemotherapy according the risk of relapse.

Patients and Methods
This retrospective study analysed treatment and outcome of children (up to 18 years-old) with a first relapse or refractory ALL treated in a single institution from 1996 until 2011. All patients were previously treated according to DFCI protocol 95, 00 or 05. Two treatment strategies have been used for patients refractory or with marrow relapse. Until 2007, they were all treated with a re-induction treatment (usually the same protocol used as first-line induction) followed by an allogeneic HSCT with a related or unrelated donor once complete remission was attained. Starting from 2007, patients with a late marrow relapse were treated with chemotherapy alone (or with HSCT if an HLA sibling donor was available), and patients refractory or with an early relapse received at least 3 cycles of chemotherapy before HSCT (with a related or unrelated donor), to reduce pre-transplant residual disease.

Results
64 patients had been diagnosed with a first relapse (n=55) or refractory (n=11) ALL whereas 453 patients were diagnosed with ALL during this fifteen years period. At first diagnosis, median WBC was 20 x109/L, 54 (84.5%) patients were B-ALL, 21 (33%) had a positive CNS and 26 (40.5%) had a favourable or a normal karyotype. According to risk stratification at first diagnosis, 26 (40.5%), 30 (47%) and 8 (12.5%) patients were classified as standard, high- and very high risk, respectively. Median ages at relapse diagnosis were 5.9 (range 1.3-17.1) for relapsed and 8.4 (range 1.4-18.4) years for refractory patients. At relapse, median WBC was 6 x109/L and 39 (61%), 14 (22%) and 11 (17%) presented with an isolated marrow, combined and extramedullary (EM) relapse, respectively. Median interval between diagnosis and relapse was 32.5 (range 0.6-135.1) months and 11 (17 %) were classified as refractory, 25 (39%) were classified as early relapse (<36 months from diagnosis to relapse) and 28 (44%) as late relapse (≥ 36 months from diagnosis to relapse). Until 2007, 29 (85 %) patients with marrow relapse received an allogeneic HSCT. After 2007, 14 (70%) received an allo-HSCT and 6 (30%) were treated with chemotherapy after induction. Estimated 3-year event-free survival (EFS) for the whole population was 53% (28% for early and 84% for late relapse [p>0.001]). Before and after 2007, estimated 3-year EFS was respectively 46% and 65% (p=0.3).

Conclusion
Introduction of a more intensive re-induction therapy and the treatment of the late relapse with chemotherapy alone had permitted to improve the survival of children with relapse/refractory leukemia, probably due to a better control of minimal residual disease (MRD). MRD-guided reinduction therapy is currently the standard of care for these patients and new therapeutics approaches are still needed for patients with early relapse.

Disclosures:
No relevant conflicts of interest to declare.