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Prognosis of patients with ABL-class positive B-ALL
itive cases identified in this study included higher propor- tions of patients aged ten years or older and presenting with hyperleukocytosis (WBC ≥100x109/L). Interestingly, the distribution by age and WBC counts is similar to that of patients with Ph+ ALL included in the EsPhALL stud- ies.15 Poor MRD response at the end of consolidation phase IB (≥5x10-4) was detected in a high proportion of patients with available data (21 of 41, 51%); similar to that of Ph+ ALL patients treated without TKI in the AIEOP- BFM ALL 2000 study, where 22 of 54 (41%) patients had high MRD (≥5x10-4) after consolidation phase.8 Interestingly, in patients who had already been treated with a TKI during consolidation, the majority (6 of 8) had either a low positive or negative EoC-MRD, suggesting a beneficial role of the addition of TKI; however, the low number of TKI-treated patients with EoC-MRD data available does not allow any definitive conclusion to be drawn.
The EFS of the entire cohort was poor, particularly for patients not receiving TKI: <50% at 5 years, very similar to the outcome of Ph+ ALL patients treated in AIEOP-BFM ALL 2000 without TKI.8 This poor outcome was observed even though most patients were treated according to the high-risk schedule and more than half of them underwent HSCT in first CR, a strategy similar to that applied for the cohort of Ph+ ALL patients of the AIEOP-BFM ALL 2000 study.8 Interestingly, the outcome was dismal in patients with WBC ≥100x109/L, as reported also for Ph+ ALL patients treated in the EsPhALL studies.14,15
The impact of HSCT in the cohort reported here is not clear since transplanted patients had an outcome similar to that of patients who were not transplanted. However, patients who received HSCT had worse features, thus, per protocol, an indication for HSCT (and considering the fact that HSCT was associated with a very low rate of relaps- es), one may infer that HSCT might be effective in disease control. HSCT was, however, also associated with high TRM: six out of 25 patients died of TRM.
Only a minority of our patients (13 of 46) received a TKI (either imatinib or dasatinib). It was not given by protocol; it was used in different schedules, basically decided by treating physicians, and generally due to poor response to chemotherapy. Obviously, the identification of the target
lesion had already been achieved during treatment. Of note, most of these patients (9 of 13) also received HSCT, two of them not based on an indication provided by the protocol but on the knowledge of an ABL-class fusion. Although the rate of relapses was low in this small group, their overall outcome was similar to those patients not treated with TKI. Due to the low number of TKI-treated patients, the potentially confounding influence of HSCT and the very short follow up, no conclusions on the bene- fit of the use of TKI can be drawn from this study. However, given also the biological and clinical similarities with the Ph+ ALL, it is plausible that the early and protract- ed administration of TKI on top of chemotherapy might improve treatment response and outcome while reducing the need for HSCT in CR1, as shown for Ph+ ALL.14-18
This study, despite being the largest in this field, is lim- ited by its retrospective nature. The complex interaction of confounding factors, such as case selection bias, strati- fication criteria, chemotherapy intensity, HSCT, and dif- ferent timing/modalities of delivering targeted therapies, do not allow the benefit of a precision medicine approach to be appropriately assessed. There is, therefore, an urgent need for a prospective controlled clinical trial.
To this purpose, it will be crucial to include the early identification of ABL-class fusion ALL cases in the initial diagnostic work-up of patients and to treat them in a properly designed study to investigate the role of TKI and to identify the appropriate chemotherapy backbone. Given the rarity of this clinical entity, this goal can only be pursued by an international collaborative network, like in pediatric Ph+ ALL.
Funding
The project was supported by Grants of Deutsche Krebshilfe, the Madeleine-Schickedanz-Stiftung für Leukämieforschung, the Deutsche Forschungsgemeinschaft (DFG, BE 6555/1-1 and BE 6555/2-1 (GC and AKB)), the Stiftung MHHplus (DSt), the Italian Association for Cancer Research (AIRC) (IG grants to GiC and AB), the Czech Health Research Council - NV15- 30626A (MZ) and the Cancer Australia PdCCRs APP1128727 (for RS and DLW). SI and SE were supported by TRAN- SCALL2 from the Israeli Health Ministry and by the Israeli can- cer association.
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