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Prognosis of patients with ABL-class positive B-ALL
had higher white blood cell counts at diagnosis (WBC), with a statistically significant difference for NCI-HR fea- tures (P<0.0001 each) (Table 1). ABL-class fusion positive cases had a significantly worse response to treatment compared to the entire B-ALL 2000 cohort: prednisone poor response (PPR) was observed in 50% versus 5.6% of patients with data available, high MRD level (≥5x10-4) after induction treatment (EoI) in 71.4% versus 19.2% and after consolidation (EoC) in 51.2% versus 5.1% of cases with data available. There are, however, differences by type of ABL-class fusion: the majority of PDGFRB-fusion positive cases with data available showed a PPR (17 of 23, 73.9%), high EoI-MRD (20 of 21, 95.2% with data avail- able) as well as high EoC-MRD (15 of 20, 75% with data available). In contrast, in ABL1-class positive cases, PPR (2 of 14, 14.3%), high EoI-MRD (6 of 15, 40.0%), and high EoC-MRD (2 of 14, 14.3%) were observed much less fre- quently (Table 1). Of note, we observed a favorable MRD response (MRD negative or low-positive) at EoC in 5 of 6 ABL-class positive cases with MRD data available in whom a TKI was added to chemotherapy before EoC (three had an ABL1-fusion and two had a PDGFRB-fusion).
For the entire cohort of 46 cases, 5-year EFS was 49.1+8.9% and 5-year OS 69.6+7.8%; CIR was 25.6+8.2% (9 events) and TRM 20.8+6.8% (8 events) (Figure 1A and B). Six of the nine patients with leukemia relapse in first CR were successfully treated subsequently and are in long-term CR. One case was resistant to treat- ment (resistance defined as blast persistence after three HR blocks) and two presented with SMN after HSCT (one thyroid cancer and one lymphoma), both patients with SMN were treated successfully. Details of the events are shown in Table 2.
No significant differences in 5-year EFS and 5-year OS were observed comparing the ABL-class subgroups ABL1-fusions, PDGFRB-fusions and other fusions (5 ABL2 and 3 CSFR1 fusions) (Figure 1C and D). Interestingly, the ABL1-fusion positive group, which showed a better treat- ment sensitivity as compared to the PDGFRB-fusion posi- tive group, had a higher frequency of relapses (5 of 15 patients vs. 3 of 23); of note HSCT was performed only in 2 of 15 ABL1-fusion positive cases versus 17 of 23 PDGFRB-fusion positive cases (Online Supplementary Figure S2A-C).
Patients treated with TKI had worse features (12 of 13
AB
Figure 2. Treatment outcome of patients with pediatric ABL-class fusion positive acute lymphoblastic leukemia (ALL) according to treatment without or with tyro- sine kinase inhibitor (TKI). Kaplan-Meier estimates comparing patients treated without TKI (no-TKI) and with TKI (TKI) are shown. (A) Event-free survival (EFS) at 5 years (y). (B) Overall survival (OS) at 5 years.
Table 2. Distribution of events according to tyrosine kinase inhibitor (TKI) treatment.
Total No TKI1 TKI n(%) n(%) n(%)
All cases
Resistant2 Relapses3
After chemotherapy
After HSCT6 Death in induction Death in CR7
After chemotherapy After HSCT
SMN8
46 (100.0)
1 (2.2) 9 (19.6) 6 (13.0) 3 (6.5) 1 (2.2) 7 (15.2) 1 (2.2) 6 (13.0) 2 (4.4)
33 (100.0)
1 (3.0) 8 (24.2)4 6 (18.1) 2 (6.1) 0
5 (15.2) 0
5 (15.2) 2 (6.1)
13 (100.0)
0
1 (7.7)5 0
1 (7.7) 1 (7.7) 2 (15.4) 1 (7.7) 1 (7.7) 0
ALL: acute lymphoblastic leukemia. 1TKI: tyrosine kinase inhibitor. 2Resistant patients are those who did not achieve complete remission (CR) by end of the third high-risk (HR) block of chemotherapy. 3Relapses: 5 cases ABL1 fusion positive (pos.), 3 cases PDGFRB fusion pos., 1 case CSF1R fusion pos. 4No-TKI relapses: after chemotherapy: 1 very early, 3 early, 2 very late (both RCSD11-ABL1 pos.), after hematopoietic stem cell transplantation (HSCT): 4 months and 17 months after HSCT. 5TKI relapse: 1 case 9 months post HSCT. 6HSCT. 7CR: complete remission. 8SMN: second malignant neoplasms: 1 case with post-transplant lymphoma, 1 case with thyroid cancer after HSCT.
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