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Clinical Trial
. 2021 Jan;8(1):e55-e66.
doi: 10.1016/S2352-3026(20)30353-7. Epub 2020 Dec 22.

Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study

Monique L den Boer  1 , Gunnar Cario  2 , Anthony V Moorman  3 , Judith M Boer  1 , Hester A de Groot-Kruseman  1 , Marta Fiocco  4 , Gabriele Escherich  5 , Toshihiko Imamura  6 , Allen Yeoh  7 , Rosemary Sutton  8 , Luciano Dalla-Pozza  8 , Nobutaka Kiyokawa  9 , Martin Schrappe  2 , Kathryn G Roberts  10 , Charles G Mullighan  10 , Stephen P Hunger  11 , Ajay Vora  12 , Andishe Attarbaschi  13 , Marketa Zaliova  14 , Sara Elitzur  15 , Giovanni Cazzaniga  16 , Andrea Biondi  16 , Mignon L Loh  17 , Rob Pieters  18 ; Ponte di Legno Childhood ALL Working Group
Affiliations
Clinical Trial

Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study

Monique L den Boer et al. Lancet Haematol. 2021 Jan.

Erratum in

Abstract

Background: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era.

Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model.

Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups.

Interpretation: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia.

Funding: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.

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Conflict of interest statement

Declaration of interest

MLdB, AVM, HAdGK, JMB, MF, GE, TI, AY, RS, LDP, NK, KGR, AV, AA, MZ, SE, GCazzaniga, AB, MLL and RP declare no competing interests. GCario reports personal fees from Jazz Pharmaceuticals and Novartis outside the submitted work. SPH reports personal fees from Novartis, Amgen, and other from Amgen, outside the submitted work. CGM reports personal fees from Illumina and grants from Loxo Oncology during the conduct of the study, and grants from Abbvie and Pfizer and personal fees from Amgen outside the submitted work. MS reports grants from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis during the conduct of the study, and personal fees from SHIRE, Servier, and JazzPharma outside the submitted work.

Figures

Figure 1:
Figure 1:. Cohort overview
The diagram shows the distribution of pre-TKI ABL class patients collected by the different study groups and the number of patients with information on prednisone response, end of induction minimal residual disease, stem cell transplant in first complete remission and IKZF1 deletion.
Figure 2:
Figure 2:. Outcome characteristics of children with ABL-class B-ALL in the pre-TKI era
(A) CIR curve of 119 ABL-class patients, excluding 3 early death cases (left panel) and per ABL fusion type (right panel), Gray’s test p=0.82. (B) EFS curve of 122 ABL-class patients (left panel) and per ABL fusion type (right panel), log-rank p=0.059. *ABL2-fusion versus remaining ABL-class: HR 2.40, 95%CI 0.95–6.10, Cox p-value 0.064. (C) OS curve of 122 ABL-class patients (left panel) and per ABL fusion type (right panel), log-rank p=0.0030. **ABL2-fusion versus remaining ABL-class: HR 4.90, 95%CI 1.84–13.03, Cox p-value 0.0015. Color code ABL fusions: ABL1, blue; ABL2, orange; CSF1R, green; PDGFRB, red; n=number of patients in the analysis, r=relapse, e=event, d=death.
Figure 2:
Figure 2:. Outcome characteristics of children with ABL-class B-ALL in the pre-TKI era
(A) CIR curve of 119 ABL-class patients, excluding 3 early death cases (left panel) and per ABL fusion type (right panel), Gray’s test p=0.82. (B) EFS curve of 122 ABL-class patients (left panel) and per ABL fusion type (right panel), log-rank p=0.059. *ABL2-fusion versus remaining ABL-class: HR 2.40, 95%CI 0.95–6.10, Cox p-value 0.064. (C) OS curve of 122 ABL-class patients (left panel) and per ABL fusion type (right panel), log-rank p=0.0030. **ABL2-fusion versus remaining ABL-class: HR 4.90, 95%CI 1.84–13.03, Cox p-value 0.0015. Color code ABL fusions: ABL1, blue; ABL2, orange; CSF1R, green; PDGFRB, red; n=number of patients in the analysis, r=relapse, e=event, d=death.
Figure 3:
Figure 3:. Minimal residual disease levels at the end of induction therapy in children with ABL-class B-ALL
(A) Absolute MRD levels at the end of induction (EOI) per ABL-class type. The red line indicates the median value per ABL-class type. Kruskal Wallis p<0.0001. ABL1 and CSF1R MRD EOI levels are lower than those of ABL2 (p=0.044 and p=0.041, respectively) and PDGFRB cases (p<0.0001 and p=0.0010, respectively). (B) Event-free survival of ABL-class cases according to MRD EOI levels. MRD EOI <1×10−2, n= 32, blue line, 5-year EFS 81.9% (95%CI 68.7–97.7) and MRD EOI ≥1×10−2, n=61, red line, 5-year EFS 44.7% (95%CI 33.2–60.4), log-rank P=0.0023. Cox proportional HR 3.34, 95% CI 1.47–7.60, p=0.0039. (C) Cumulative incidence of relapse according to MRD EOI levels. MRD EOI levels <1×10−2, n=32, blue, 5-year CIR 18.1% (SD 7.5) and MRD EOI levels ≥1×10−2, n=60, red, 5-year CIR 41.1% (SD 7.0), Gray’s test p=0.10.
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Comment in

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