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G. Cario et al.
without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoi- etic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).
Introduction
Continuous optimization of risk-adapted multi-agent treatment has led to excellent curative rates in the majori- ty of children and adolescents suffering from acute lym- phoblastic leukemia (ALL).1-9 However, the progress in ALL subtype classification according to the nature of spe- cific sentinel genetic aberrations identified molecular ALL subgroups like low-hypodiploid, KMT2A-rearranged or BCR-ABL1 positive precursor-B-ALL (B-ALL) with distinct biological and clinical characteristics associated with poor outcome. Intensive chemotherapy, including allogeneic hematopoietic stem cell transplantation (HSCT) for some of these patients, is associated with severe toxicity and long-term sequelae.
In this context, one of the first ALL genetic aberrations identified was the gene fusion BCR-ABL1 resulting from the chromosomal translocation t(9;22) (generating the so- called Philadelphia chromosome), translated into the BCR- ABL1 fusion protein, a constitutively active tyrosine kinase, which can be inhibited by tyrosine kinase inhibitors (TKI). This is an excellent example for a success- ful molecular treatment target: the addition of the first- generation TKI imatinib to intensive chemotherapy back- bone has led, in fact, to a significant improvement of out- come in children with Philadelphia chromosome positive ALL (Ph+ ALL) with cure rates of 60-70%.10-18 The Children’s Oncology Group (COG) studies showed a clear advantage in Ph+ ALL from continuous protracted expo- sure to TKI combined with chemotherapy, challenging the indications to transplant for all patients with Ph+ ALL.16-18 COG results were confirmed by the European intergroup study group for treatment of Ph+ ALL (EsPhALL) in the EsPhALL2004 and the subsequent EsPhALL2010 studies, showing that intensive chemotherapy combined with imatinib given continuously from induction phase allows a remarkable reduction in the rate of HSCT, without affecting outcome.13-15 However, these trials also demon- strated that the combination of chemotherapy and ima- tinib is associated with a high rate of treatment-related toxicity and mortality.
In the last decade, different tyrosine kinase gene fusions other than BCR-ABL1 have been identified which are sen- sitive to TKI similar as BCR-ABL1. These so called ABL- class fusions typically comprise rearrangements of the ABL1, ABL2, PDGFRB and CSF1R genes, each of which can have different fusion partner genes. ABL-class fusion positive B-ALL subtypes other than BCR-ABL1 have been identified showing a gene expression profile largely simi- lar to that of Ph+ ALL. Therefore, they are included in the BCR-ABL1-/Ph-like-ALL group recognized as a provisional entity in the 2016 World Health Organization classifica- tion of myeloid neoplasms and acute leukemia although they only make up a minor proportion of patients in this
new category. Whereas BCR-ABL1-/Ph-like-ALL accounts for 15-20% of all pediatric B-ALL, the frequency of ABL- class fusion positive B-ALL is estimated to be about 2-3% which is similar to the frequency of BCR-ABL1 pos. ALL.19- 21 BCR-ABL1-/Ph-like ALL is associated with other high- risk clinical features, such as older age, elevated white blood cell (WBC) count at diagnosis, high rates of end- induction minimal residual disease (MRD), as well as increased risk of induction failure and of leukemia relapse.22-28
Data on the ABL-class fusion positive ALL other than Ph+ ALL are rare and are limited to anecdotal case reports. In this study, we retrospectively analyzed clinical charac- teristics and outcome of ABL-class fusion positive cases treated based on contemporary MRD-based protocols of the Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster (AIEOP-BFM ALL study group. The aim was to provide a comprehensive picture of current outcome of these cases without the addition of a TKI to chemotherapy, and to get first data on those cases in which a TKI was added to chemotherapy. It should serve as a basis on which to decide whether the addition of a TKI to chemotherapy may be beneficial, when taking into account the risk of a relevant increase of toxicity and treatment-related mortality (TRM).
Methods
Patients and diagnostics
This retrospective survey of ABL-class fusion positive B-ALL other than Ph+ ALL was performed in patients aged 1-17 years, treated from October 2000 to August 2018 according to the AIEOP-BFM ALL 2000 and 2009 protocols in Centers in Austria, Australia, Czech Republic, Germany, Israel, Italy, and Switzerland.
Routine diagnostics was performed according to national stan- dards based on protocol requirements.8,9,29-31 Diagnosis of ALL was made when 25% or more lymphoblastic cells were present cyto- morphologically in the bone marrow. Flow-cytometry immunophenotyping was performed based on the AIEOP-BFM consensus guidelines.29 Complete remission (CR) was defined as the absence of physical signs of leukemia or detectable leukemia cells on blood smears, a bone marrow with active hematopoiesis and <5% blasts, and morphologically normal cerebrospinal fluid. Presence of ETV6-RUNX1, BCR-ABL1 and KMT2A-AFF1 fusion transcripts was screened as previously described.8,9
ABL-class fusions screening, not required by protocols, was per- formed in a minority of patients according to the policy of individ- ual centers or due to poor response to treatment. Methods used included fluorescence in situ hybridization (FISH, e.g. using probes by Cytocell®, Cambridge, UK), multiplex or singleplex reverse- transcription polymerase chain reaction (PCR),32 array compara- tive genomic hybridization (CGH) (Agilent Technologies, Waldbronn, Germany) with subsequent confirmation by panel-
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haematologica | 2020; 105(7)