Poor Prognosis in Children with ABL-Class Fusion Positive B-Cell Acute Lymphoblastic Leukemia Treated According to AIEOP-BFM Protocols
Authors: Cario Gunnar , Leoni Veronica , Conter Valentino , Attarbaschi Andishe , Zaliova Marketa , Sramkova Lucie , Cazzaniga Giovanni , Fazio Grazia , Sutton Rosemary , Elitzur Sarah , Izraeli Shai , Lauten Melchior , Locatelli Franco , Basso Giuseppe , Buldini Barbara , Bergmann Anke K , Lentes Jana , Steinemann Doris , Gohring Gudrun , Schlegelberger Brigitte , Haas Oskar A , Schewe Denis Martin , Buchmann Swantje , Moericke Anja , White Deborah L. , Revesz Tamas , Stanulla Martin , Mann Georg , Bodmer Nicole , Arad-Cohen Nira , Zuna Jan , Valsecchi Maria Grazia , Zimmermann Martin , Schrappe Martin , Biondi Andrea 
Published: November 2019

ABL-class fusions other than BCR-ABL1 (or Ph+) are found in 2-3% of precursor B-cell acute lymphoblastic leukemia (pB-ALL) in children and adolescents. Occasional reports suggest that this rare ALL subtype has a poor prognosis and patients can benefit from treatment with tyrosine kinase inhibitors (TKIs).

Aim of this retrospective study is to investigate the presenting features, treatment response and outcome in ABL-class fusion positive cases identified within large cohorts of patients treated in AIEOP-BFM ALL trials.

This retrospective survey of ABL-class fusion positive pB-ALL other than Ph+ ALL was performed in patients aged 1-17 years at the diagnosis, treated from October 2000 to August 2018 according to the AIEOP-BFM (Associazione-Italiana- di- Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols in Austria, Australia, Czech Republic, Germany, Israel, Italy and Switzerland. While ABL-class fusions screening was not required by protocols, it was performed in some patients, according to centers' policies, usually after poor early treatment response.

Overall, 46 ABL-class fusion positive cases with ABL1 fusions (N=15), ABL2 fusions (N=5), CSF1R fusions (N=3) and PDGFRB rearrangements (N=23) were identified. Compared with other pB-ALL children and adolescents, the ABL-class fusion positive cases presented with higher proportions of patients aged 10 years or older (52.2 vs. 22.2, P&lt; .0001), hyperleukocytosis (WBC ≥100x109/l, 41.3 vs. 6.3, P&lt; .0001), or poor minimal residual disease (MRD) response (&gt;5x10-4 levels were observed in 65.2% vs. 18%, P&lt; .0001 of patients after induction treatment phase IA and in 45.7% vs. 4.8%, P&lt; .0001 after consolidation phase IB). For the entire cohort of 46 cases, the 5-year probability of event-free survival (EFS) was 49.1+8.9% and that of overall survival (OS) 69.6+7.8%; the cumulative incidence of relapse (CI) was 25.6+8.2% and treatment-related mortality 20.8+6.8%.

Although not prescribed by the protocols, 13 patients received a TKI during different phases of treatment (TKI group), by choice of treating physicians, generally due to poor early treatment response. Eight TKI patients with high MRD levels at the end of induction phase IA received the TKI during consolidation phase IB, and six of them achieved either a low positive or negative MRD level at the end of consolidation phase IB. Nine of the 13 patients treated with TKIs underwent hematopoietic stem cell transplantation (HSCT) and only 1/9 (TKI+HSCT) relapsed.

Thirty-three cases did not receive any TKI (no-TKI group) and eight of them relapsed; 6/17 patients treated with chemotherapy only, versus only 2/16 who underwent HSCT.

Overall, 25 patients underwent HSCT, and of them 3 relapsed and 6 died of treatment-related complications.

In patients with a WBC higher or lower than 100x109/L, the 5-year EFS was 36.8+12.7% vs. 59.9+11.6%, respectively (P= .21), and the 5-year OS was significantly lower in patients with a high WBC (48.8+12.9% vs. 87.4+6.8%, P= .036). This difference was more pronounced in the no-TKI group with a 5-year EFS 27.8+13.6% vs 61.8+12.7%, (P= .07), and an OS of 36.7+14.6% vs 94.4+5.4%, respectively (P= .0015).

Presenting features, treatment response and outcome in this cohort of ABL-class fusion positive patients are markedly similar to those of patients with Ph+ ALL included in the EsPhALL studies. Our results suggest that TKIs and HSCT may be beneficial in reducing the risk of relapse. Thus there is an urgent need for large international cooperative controlled studies to investigate the impact of TKI, in combination with an appropriate chemotherapy backbone and the role of HSCT. To this purpose, an early identification of patients with ABL-class fusion positive acute lymphoblastic leukemia will be necessary.

Disclosures

Izraeli: sightdx: Consultancy; novartis: Honoraria; prime oncology: Speakers Bureau. Locatelli:Miltenyi: Honoraria; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria.