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G. Cario et al.
Table 1. Outcome of BCR-ABL1-like acute lymphoblastic leukemia among different study groups.
Study group
Roberts et al.23
Roberts et al.24
Roberts et al.40
Boer et al.26 Cario et al.41
Protocol
Total therapy XV, Total therapy XVI, P9906 AALL0232, E2993, C19802, C10102 and C10403
Total therapy XV
N. BCR-ABL1(Ph) - like ALL patients/total BCP-ALL
264/1725
40/344
206/1023 Standard-Risk ALL
77/574
46 ABL-class fusion
positive ALL
Outcome (CIR, EFS, OS)
5-years pEFS 58.2±5.3%, 41.0±7.4%, and 24.1±10.5% for children with high-risk ALL, adolescents, and young adults;
5-years pOS 72.8±4.8%, 65.8±7.1%, and 25.8±9.9% for children with high-risk ALL, adolescents, and young adults. Across all age groups OS rates were inferior to those among patients with non–Ph-like ALL (P<0.001 for both comparisons)
5 -years pEFS 90.0% ± 4.7% vs. 88.4% ± 0.9%, P=0.41 in BCR- ABL1–like ALL vs. non-BCR-ABL1–like ALL; 5-years pOS
92.5% ± 4.2% vs. 95.1% ± 1.3%, P=0.41 in BCR-ABL1–like ALL vs. non-BCR-ABL1–like ALL
7-years pEFS 82.4 ± 3.6% vs. 90.7 ± 1.0%, P=0.0022, Ph-like ALL vs. non–Ph-like ALL; 7-years pOS 93.2 ± 2.4% vs. 95.8 ± 0.7%, P=0.14, Ph-like ALL vs. non–Ph-like ALL
8-years pCIR 35% vs. 17%, P=0.07, BCR-ABL1–like ALL vs. non BCR-ABL1–like B-other ALL
5-years pEFS was 49.1±8.9% , 5-years pOS 69.6±7.8% and 5-years
CIR was 25.6±8.2%
COG AALL0331
DCOG ALL-8,
ALL-9, ALL10
COALL 06-97 and COALL 07-03 AIEOP BFM ALL 2000 and
AIEOP BFM ALL 2009
ALL: acute lymphoblastic leukemia; BCP-ALL: B-cell precursor acute lymphoblastic leukemia; CIR: cumulative incidence of relapse; EFS: event-free survival; OS: overall sur- vival.
fier: 03117751), ALL patients with NCI high-risk character- istics or poor early MRD response are screened for ABL- class fusions and JAK pathway mutations. In patients posi- tive for these alterations, dasatinib and ruxolitinib, respec- tively, are given in combination with conventional front- line chemotherapy from the consolidation phase until the end of maintenance therapy.57,62 Patients with NCI standard risk characteristics and early good MRD response are not included because available data on their outcome are very limited.48,52 Other phase I/II trials conducted at the MD Anderson Cancer Center (clinicaltrials.gov identifier: 02420717) are testing dasatinib or low doses of ruxolitinib in combination with hyper-CVAD (cyclophosphamide, vin- cristine, doxorubicin, dexamethasone) in adolescents and adults with relapsed/refractory ALL and ABL-class fusions or CRLF2/JAK mutations, respectively; interim data analy- sis demonstrates the safety of these combinations with lim- ited efficacy.63 A recent phase I trial (clinicaltrials.gov identifier: 03571321) at the University of Chicago and other institu- tions is studying ruxolitinib in combination with the pedi- atric-inspired CALBG 10403 chemotherapy regimen in ado- lescents with newly diagnosed Ph-like ALL harboring CRLF2/JAK alterations, with a planned phase II expansion study if safety is demonstrated.64,65
In Europe, the AIEOP-BFM ALL and ALLTogether study groups are also investigating the addition of innovative or targeted therapy on top of chemotherapy in BCR-ABL1-like ALL. In the AIEOP-BFM ALL 2017 trial (clinicaltrials.gov iden- tifier: 03643276), patients are screened at diagnosis for IKZF1 deletions, which are frequently found in BCR-ABL1- like ALL, and for additional deletions of genes relevant for B-cell development. Those cases defined as IKZF1 plus pos- itive66 with any MRD positivity after induction treatment are randomized to receive the proteasome inhibitor borte- zomib in addition to chemotherapy during consolidation and to receive the bispecific T-cell engager (BiTE) antibody blinatumomab during post-consolidation treatment.
Especially the approach to apply immunotherapy instead of extremely intensive high-risk blocks may be of advantage for ABL-class-fusion positive cases, bearing in mind the high rate of severe treatment-related complications in Ph+ ALL patients treated with high-risk chemotherapy plus TKI. In the ALLTogether study, patients are screened for ABL-class fusions at diagnosis and those positive receive TKI on top of chemotherapy from day 15 of induction onward. In both AIEOP-BFM and ALLTogether studies, these patients have an indication for HSCT in case of poor MRD response. Likewise, the French CALL-F01 protocol (clinicaltrials.gov identifier: 02716233) has been amended in 2018 to bring to RNA sequencing all B-other ALL in case of induction failure or end of induction MRD above or equal to 10-3: these patients are to receive imatinib on top of chemotherapy in the high-risk group. Then, according to subsequent MRD and effective exposure to imatinib, they either continue TKI plus chemotherapy or go to HSCT. A similar approach in the early introduction of a TKI in addi- tion to chemotherapy in ABL-class positive BCP-ALL is planned within the EsPhALL2017/COGAALL1631 protocol (clinicaltrials.gov identifier: 03007147), the first intercontinen- tal collaborative trial for the treatment of pediatric Ph+ ALL involving COG and EsPhALL study groups. In this trial, an amendment is ongoing to extend the eligibility to patients with ABL-class fusion positive BCP-ALL and, thus, treat them with imatinib given early after diagnosis and contin- uously on top of high-risk chemotherapy.
Actually, in pediatric patients there is no clear evidence for superiority of a specific type of TKI. In the COG AALL0622 study, dasatinib (60 mg/m2) was substituted for imatinib (340 mg/m2) on top of the same chemotherapy backbone of the AALL0031 study with no benefit. The same dose of dasatinib was used also in a joint COG/EsPhALL study (BMS CA180372) on top of the EsPhALL therapeutic strategy with preliminary results which appear similar to the contemporary EsPhALL study
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