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G. Cario et al.
AB
Figure 3. Treatment outcome of patients with pediatric ABL-class fusion positive acute lymphoblastic leukemia (ALL) according to white blood cell count at diag- nosis (WBC). Kaplan-Meier estimates comparing patients with WBC <100x109/L and patients with WBC equal or >100x109/L are shown. (A) Event-free survival (pEFS) at 5 years. (B) Overall survival (pOS) at 5 years.
were HR vs. 24 of 33 in no-TKI treated patients) and the majority of them underwent HSCT (9 of 13 vs. 16 of 33); their 5-year EFS and 5-year-OS did not differ significantly compared with the no-TKI group: EFS no-TKI 47.7+10.0%, TKI 62.9+5.4%, P=0.98; OS no-TKI 70.9+9.0%, TKI 75.5+12.3%, P=0.64 (Figure 2A and B). Whereas TRM was similar in both groups, only one out of 13 cases of the TKI patients relapsed versus 8 of 33 of no-TKI cases (Online Supplementary Figure S3A and B). Of note, there were four late occurring events in the no-TKI group: two SMN after HSCT and two late relapses in ZMIZ1-ABL1 positive patients not transplanted.
No significant difference in outcome between patients treated with or without HSCT were seen: 5-year EFS was 47.9+11.4% versus 55.0+15.5%, P=0.35; 5-year OS 66.7+10.5% versus 84.0+10.6%, P=0.22) (Online Supplementary Figure S4A and B). However, analyzing the events in more detail, it is remarkable that the majority of events in HSCT-treated patients (n=25) were non-relapse events (TRM=6, SMN=2, relapses=3) whereas in patients not transplanted (n= 21) relapses predominated (TRM=1, relapses=6) (Table 2). In those patients who were not treated with TKI, the CIR and TRM rate in transplanted versus not transplanted cases were 13.2+9.3% versus 43.8+17.8%, P=0.06 (CIR) and 32.3+12.4% versus 0.0%, P=0.034 (TRM) (Online Supplementary Figure S4C and D).
Analysis by MRD showed a 5-year EFS of 40.4±11.4% in EoI-MRD≥5x10-4 versus 76.2±14.8% in EoI MRD<5x10-4, P=0.11) (Online Supplementary Figure S5A); CIR was similar in both MRD groups (27.3+11.2% vs. 23.8+15.9%, P=0.74), while TRM in patients with EoI-MRD≥5x10-4 was 25.4+9.4% versus 0.0% in EoI MRD<5x10-4 (P=0.1) (Online Supplementary Figure S5B). By EoC-MRD, 5-year EFS in cases with an MRD≥5x10-4 was 46.2+12.1% versus 56.7+15.4% in those with MRD<5x10-4, P=0.31. However, it should be considered that 19 of 21 patients with EoC-MRD≥5x10-4 received HSCT versus only three of 20 patients with MRD<5x10-4 (Online Supplementary Figure S6).
We also analyzed the outcome of patients with a WBC higher or less than 100x109/L: 5-year EFS was 36.8+12.7% versus 59.9+11.6%, respectively, P=0.21, while 5-year OS was significantly lower in patients with a WBC >100x109/L (48.8+12.9% vs. 87.4+6.8%, P=0.036). This
difference was more pronounced in the no-TKI group with a 5-year EFS 27.8+13.6% versus 61.8+12.7%, P=0.07 and an OS of 36.7+14.6% versus 94.4+5.4%, respectively, P=0.0015) (Figure 3A and B).
Discussion
The improvement in genetic diagnostics has allowed the identification of rare ALL subgroups with specific clin- ical characteristics and target lesions. In this context, ABL- class fusion positive B-ALL other than Ph+ ALL constitutes a challenging entity, which is estimated to represent about 2-3% of childhood ALL. The frequency is reported in the context of the BCR-ABL1-/Ph-like ALL, which is higher in adolescents and associated with higher risk features and a worse outcome as compared to the non-BCR-ABL1-/Ph- like ALL patients.20,21,23,26 First protocols based on “precision medicine” have been designed to identify and treat ALL patients with drugs specific for targetable lesions given in addition to standard chemotherapy (e.g. St Jude Total XVII (NCT03117751) and AALL1131(NCT02883049)). Within the BCR-ABL1-/Ph-like ALL group, it is suggested that patients with ABL-class fusion positive ALL might benefit from the addition of TKI to chemotherapy. However, besides the above mentioned on-going trials, no con- trolled studies have been conducted in this field so far, and the published data on the role of TKI for this subgroup is restricted to case reports.21,39,40
We report here the largest series of ABL-class fusion positive cases, treated according to two consecutive AIEOP-BFM ALL protocols with a stratification mostly based on MRD response. Screening for ABL-class rearrangements was not required by the protocols and was often done retrospectively in the frame of research projects, thus, no conclusions on incidence can be drawn from this retrospective study. Likewise, due to the selec- tion in screening policy, the outcome data need to be inter- preted with great caution. Nevertheless, the cohort described here provides interesting information and clear- ly shows the urgent need for prospective co-operative clinical studies.
When compared with other B-ALL patients recruited in the AIEOP-BFM ALL protocols, the ABL-class fusion pos-
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haematologica | 2020; 105(7)