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Prognosis of patients with ABL-class positive B-ALL
AB
CD
Figure 1. Treatment outcome of patients with pediatric ABL-class fusion positive acute lymphoblastic leukemia (ALL). Kaplan-Meier estimates for the whole cohort of 46 cases. (A) Event-free survival (pEFS) and overall survival (pOS) at 5 years (y). (B) Cumulative incidence of relapses (CIR) and of treatment-related mortality (CI- TRM) at 5 years. According to ABL-class fusion subtype, ABL1, PDGFRB, others (ABL2 n=5, CSFR n=2): (C) EFS. (D) OS.
based RNA-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, CA, USA), whole transcriptome or direct panel-based RNA-sequencing.
In both protocols, patient stratification was mainly based on quantitative assessment of minimal residual disease (MRD) using clone-specific immunoglobulin- and T-cell receptor-gene rearrangements by PCR (PCR-MRD) after induction (treatment day 33) and consolidation (day 78) therapy. In AIEOP-BFM ALL 2009, MRD was additionally measured by flow cytometry on treatment day 15 (FCM-MRD).33 The logistics of the AIEOP-BFM ALL studies, cell sample isolation, and MRD marker identification, as well as MRD-based risk stratification of the AIEOP-BFM ALL 2000 study, have been previously reported.8,9 In the AIEOP-BFM ALL 2009 trial, patients were additionally allocated to the high- risk (HR) group, when PCR-MRD was ≥5x10-4 on day 33 and still measurable on day 78 and/or if FCM-MRD at day 15 was ≥10%.
Details on chemotherapy regimens and randomized treatment interventions, as well as HSCT indication, were reported else- where.8,9,34 The study AIEOP-BFM ALL 2000 is registered at www.clinicaltrials.gov by BFM as NCT00430118 and by AIEOP as NCT00613457; the study AIEOP-BFM ALL 2009 is registered as NCT01117441. The analyses were approved by local Institutional Review Boards and informed consent was obtained from the patients and/or guardians in accordance with the Declaration of Helsinki.
Statistical analysis
Event-free survival (EFS) was calculated from diagnosis to first failure, which was defined as death during induction therapy,
resistance, relapse, death in CR, or development of a second malignant neoplasm (SMN). Rates were calculated according to Kaplan-Meier and compared by log-rank test.35,36 Kaplan-Meier plots that compared HSCT with chemotherapy were adjusted to account for the waiting time to transplantation (with a landmark at median time to HSCT). Cumulative incidence of relapse and TRM functions were constructed by the method of Kalbfleisch and Prentice and compared with Gray test.37,38 Proportional differ- ences between patient groups were analyzed by χ2 or Fisher's exact tests.
Results
We identified 46 ABL-class fusion positive cases diag- nosed between October 2000 and August 2018 treated according to AIEOP-BFM ALL 2000 and 2009 protocols.
ABL1 fusions were identified in 15 cases, ABL2 fusions in five cases, CSF1R fusions in three cases, and PDGFRB rearrangements in 23 cases (Online Supplementary Table S1).
Overall, 33 patients received chemotherapy without the addition of any TKI (no-TKI group); a TKI was added on an individual basis and not according to protocol during treatment in 13 cases (TKI group; imatinib in 8 and dasa- tinib in 5 cases) diagnosed between February 2011 and April 2018. In eight of these 13 cases, TKI was introduced at the end of induction or during consolidation therapy, in four during post-consolidation HR-blocks and in one case
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