t(12;21)/ETV6-RUNX1 Confers a Specific Pattern of In Vivo Sensitivity to Treatments in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Trials 58881 and 58951 of the EORTC Children Leukemia Group

Background

In childhood BCP-ALL, the presence of t(12;21)/ETV6-RUNX1 defines one of the most prevalent oncogenic subgroup and is usually associated with a favorable outcome. Nevertheless, an excellent prognosis has not been reported by all collaborative groups, suggesting that the outcome of ETV6-RUNX1 patients (pts) could be influenced by the treatment. To address this issue, the long-term outcome of ETV6-RUNX1pts was investigated into the EORTC 58881 and 58951 studies, with particular attention to the effect of the randomized treatments.

Methods

The 58881 study (1989-1998) used a BFM backbone without cranial irradiation, and aimed to compare E-Coli (Medac®) Asparaginase (A'ase) with Erwinia A'ase and to assess the value of 6-Mercaptopurine (6-MP) i.v. (1 g/m²/month) when added to classic maintenance. The subsequent 58951 study (1999-2008) used the best arm of the trial 58881, i.e. E-Coli A'ase and classic maintenance. The aims of this study were to compare dexamethasone (Dexa) (6 mg/m²/day) with prednisone (Pred) (60 mg/m²/day) during induction and maintenance; to evaluate increased number of A'ase administrations (24 vs 12) for non-very high risk pts; and to assess the value of vincristine/corticosteroid pulses during maintenance for average risk pts.

Detection of ETV6-RUNX1 by FISH and/or RT-PCR was centralized. Pts less than 1 year (yr) or with t(9;22)/BCR-ABLwere excluded from the analysis.

Results

An ETV6-RUNX1 was evidenced in 104/363 (28%) and 380/1493 (27%) newly diagnosed BCP-ALL pts enrolled in the 58881 and 58951 trial respectively. A majority of ETV6-RUNX1 pts were below the age of 10 yrs (93.3% in 58881 and 91.3% in 58951).

The median follow-up was 11.8 yrs for the 58881 and 6.7 yrs for the 58951. In both studies, the 10-yr event-free-survival (EFS) rate was significantly higher for ETV6-RUNX1pts than for all BCP-ALL pts (82.5% vs 74.9% in 58881 and 90.8% vs 82.7% in 58951), and was similar to the 10-yr EFS of hyperdiploid pts. Noteworthy, very few EFS events were observed during treatment period or after 6 yrs from diagnosis.

The main prognostic factors of the ETV6-RUNX1 subgroup in both studies were the white blood cell count (WBC) and the response to prephase.

As shown in the table below, the analysis of the relationship between treatment modalities and outcome revealed that the in vivo drug sensitivity of ETV6-RUNX1 ALL was distinct from that of other BCP-ALL.

In this subgroup, the benefit of a more potent A'ase (58881) or of intensified A'ase administrations (58951) was less pronounced as compared to other pts, and 6-MP i.v. during maintenance was particularly deleterious. Moreover, the overall benefit of vincristine/corticosteroid pulses was not observed in ETV6-RUNX1 average risk group pts, who already had an outstanding outcome. By contrast, the use of Dexa in place of Pred significantly improved the 10-yr EFS of ETV6-RUNX1pts (95.0% vs 87.2%, hazard ratio (HR)=0.44, 95% CI 0.20-0.96) whereas no difference was observed in the remaining population (HR=1.01, 95% CI 0.77-1.33) (test for interaction: p=0.04).

	58881				58951
	All (n=363)	ETV6-RUNX1 (n=104)	Hyperdiploid (n=102)	Others1 (n=155)	All (n=1493)	ETV6-RUNX1 (n=380)	Hyperdiploid (n=484)	Others1 (n=619)
10-yr EFS rates
All pts	74.9%	82.5%	83.3%	65.2%	82.7%	90.8%	88.4%	73.2%
Pred ² (n=745)					81.8%	87.2%	88.8%	73.0%
Dexa ² (n=748)					83.6%	95.0%	88.0%	73.5%
Medac A'ase 2,3 (n=320)	76.6%	83.2%	88.6%	65.7%
Other A'ase 2,3 (n=43)	62.8%	78.6%	50.0%	60.0%
10-yr disease-free-survival rates
Short A'ase 4 (n=607)					83.5%	91.2%	90.1%	72.4%
Long A'ase 4 (n=622)					87.0%	94.8%	88.2%	80.7%
No 6-MP iv 2,5 (n=96)	85.4%	100%	90.9%	72.5%
6-MP iv 2,5 (n=94)	72.3%	70.6%	78.6%	68.8%
No Pulse 5,6 (n=148)					87.5%	96.1%	88.5%	71.1%
Pulse 5,6 (n=153)					82.8%	95.1%	91.3%	82.3%

¹ Others, MLL rearrangements excluded
² All risk groups
³ Pts randomized or not for A'ase
⁴ Non-very high risk pts
⁵ Pts who started maintenance
⁶Average risk pts

Conclusions

Within the EORTC 58881 and 58951 trials, the use of Dexa rather than Pred allowed to further improved the long-term outcome for ETV6-RUNX1 pts. Our data also show that this excellent outcome can be jeopardized by slight changes in therapy, such as the addition of 6-MP i.v. to classic maintenance. Together, these results stress the importance of analyzing homogeneous oncogenetic subgroups when comparing different therapeutic schemes, to unmask specific drug effects that could be hidden when analyzing the whole group of patients.