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Genomic landscape of B-other ALL
Table 1. Early response to treatment of B-other acute lymphoblastic leukemia patients stratified by DUX4r.
Total B-other DUX4r ALL non-DUX4r ALL (n=110) (n=30) (n=80)
n(%) n(%) n(%)
P
DUX4r vs. non-DUX4r
0.005
0.04
0.04
0.03
1Good: <1000 leukemic blood blasts/μL on treatment day (d) 8; poor: ≥1000/μL. 2Minimal residual disease (MRD) at d15 of treatment measured by flow cytometry (FC).3MRD measured by polymerase chain reaction (PCR). n: number; TP: time point; TP1: treatment day 33; TP2: treatment day 78. 4Standard risk (SR), medium risk (MR), high risk (HR); for definitions see Online Supplementary Methods. P-value by Fisher exact test. 5Patients died before TP2 or no MRD target; neg.: negative; pos.: positive (any positive value); NA: not applicable/not available. Unknown values are not considered for percentage and statistics.
Prednisone response1 Good
Poor
FC MRD d152
<10%
≥10%
NA 5 2 3
102 (93%) 8 (7%)
24 (80%) 6 (20%)
78 (98%) 2 (2%)
86 (82%) 19 (18%)
19 (68%) 9 (32%)
67 (87%) 10 (13%)
PCR MRD3
TP1 + TP2 neg.
Other
TP1 ≥10-3 + TP2 pos. or TP2 ≥10-3
NA 45 1 3
Final risk group4
28 (26%) 56 (53%) 22 (21%)
3 (10%) 17 (59%) 9 (31%)
25 (32%) 39 (51%) 13 (17%)
SR 25 (23%)
MR 52 (49%)
HR 30 (28%)
NA 35 1 2
the BCR-ABL1-like phenotype12 or may coincide with the ETV6-RUNX1-like phenotype.11 Moreover, it has been demonstrated that the definition of BCR-ABL1-like ALL varies significantly among studies;12 this likely results from the limited specificity of BCR-ABL1-associated gene expression signature. Thus, not only a complex genetic and gene expression characterization but also a hierarchi- cal approach is needed in order to classify BCP-ALL into non-overlapping subsets.
In parallel to aberrations that define subtypes, a wide range of additional genetic aberrations has been identified. Among them, two groups of aberrations have already become therapeutically relevant either as novel prognostic factors or as therapy targets. The first group is represented by IKZF1 gene deletion (IKZF1del) and IKZF1plus deletion pattern. IKZF1del was repeatedly shown to confer a high- er risk of relapse9,13-15 and is used in therapy adjustment algorithms in some contemporary treatment protocols (clinicaltrials.gov identifier: 03020030; DCOG ALL1116). However, the Italian Association of Pediatric Hematology and Oncology-Berlin-Frankfurt-Muenster (AIEOP-BFM) study group has recently shown that IKZF1plus, defined by a combination of IKZF1del with other aberrations (dele- tions of CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion), confers a significantly higher risk of relapse compared to IKZF1del alone, and the newly defined IKZF1plus pattern will be used to improve risk pre- diction accuracy in the upcoming BFM ALL protocol.17 The second group of therapeutically relevant aberrations largely comprises aberrations affecting genes encoding kinases, cytokine receptors and signaling regulators, resulting in activation of kinase signaling10,18-23 (“kinase aberrations”). These aberrations occur especially, but not
exclusively, in BCR-ABL1-like ALL. A wide range of kinase aberrations has already been described, and novel ones still continue to be reported. These aberrations vary by type (gene fusions/juxtapositions, copy number changes, mutations) and frequency; CRLF2, NRAS or KRAS lesions are relatively common and occur in various ALL subtypes,2,6,24-27 while, for example, fusions involving ABL1, ABL2, EPOR, PDGFRB or JAK2 are less frequent and occur predominantly in BCR-ABL1-like ALL.28-30 Two functional classes of aberrations, ABL-class and JAK/STAT-class, are currently used for targeted ALL therapy in some ongoing clinical trials (clinicaltrials.gov identifiers: 03117751, 02883049, 03020030).
The ongoing translation of these genetic findings into treatment is bringing new diagnostic demands and a dilemma as to which genetic methods should be incor- porated into diagnostic algorithms and how this should be achieved. In order to explore this, well-defined con- secutive cohorts need to be analyzed to assess the real incidence of various ALL subtypes and genetic aberra- tions. Unfortunately, so far, such data have been very scarce, and virtually all the published cohorts were in some way selected, enriched, biased, or not analyzed completely.
Here, we present a genetic study of all pediatric B-other ALL cases consecutively diagnosed and uniformly treated in the Czech Republic over the last seven years. We per- formed this study to facilitate the use of optimal treatment strategies by extending and refining diagnostic algorithms, and to assess the feasibility and the benefits of introducing genome-wide technologies into routine diagnostics. A fur- ther study aim was to determine unbiased population fre- quencies of known ALL subtypes derived from B-other
haematologica | 2019; 104(7)
3 (10%) 13 (45%) 13 (45%)
22 (28%) 39 (50%) 17 (22%)
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