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S. Chiaretti et al.
Table 6. Summary of univariate and multivariate analyses for event-free survival, considering clinically relevant variables and molecular prognostic markers.
Univariate analysis for EFS
Multivariate analysis for EFS HR (95%CI) P
Ph-like vs. non-Ph-like Age
WBC
Plt
Hb
F vs. M
No SR vs. SR
HSCT vs. No HSCT as a time dependendent covariate
IKZF1+ CDKN2A/2B and/or
PAX5 vs. IKZF1-only/WT
Cell cycle genes deletion vs. WT RAS clonal vs. WT/M subclonal JAK/STAT clonal vs. WT/M subclonal
HR (95%CI)
2.6 (1.3-5.19)
1.03 (1.01-1.05) 1.005 (0.999-1.010) 0.993 (0.986-0.999) 0.81 (0.69-0.94) 0.78 (0.41-1.5) 1.89 (0.97-3.67) 1.04 (0.35-3.10)
1.73 (0.76-3.98)
0.967 (0.451-2.069)
0.604 (0.269-1.358)
0.85 (0.26-2.82)
P
0.007
0.004 0.074 0.023 0.006 0.455 0.062 0.939
0.193
0.93
0.222
0.796
2.3 (1.124-4.92)
1.04 (1.015-1.067)
0.023
0.002
0.782 (0.649-0.943) 0.01
EFS: event-free survival; Ph-like: Philadelphia-like; WBC: white blood cell; Plt: platelet; Hb: hemoglobin; F: female; M: male; SR: standard risk; WT: wild-type; HSCT: allogeneic stem cell transplant; WT/M: wild-type/mutated; OR: odds ratio; CI: Confidence Interval.
Figure 2. Survival curves of Philadelphia-like (Ph-like) and non-Ph-like patients. event-free survival and disease-free survival.
that proved positive with the BCR/ABL1 predictor. The validity and reproducibility of the BCR-ABL1-like predictor has been externally validated by other institutions and from external samples in Europe, showing an overall con- cordance with other tools (FISH and NGS) of 88%.29
With regards to the relationship between the Ph-like sta- tus, MRD response and outcome, we showed that Ph-like ALL patients have a higher risk of CR failure: in fact, 74.1% of Ph-like ALL and 91.4% non-Ph-like achieved a CR. This difference was neither detected in the intensive GMALL trials 06/99 and 07/03 – in which all patients achieved a CR, albeit with a short duration -,6 nor in the
hyper-CVAD-based protocols or the augmented BFM reg- imen administered at MDACC.19
More importantly, our study allowed to correlate the Ph-like status with MRD, that is presently regarded as the most important prognostic marker in ALL management. In fact, this analysis showed that in the GIMEMA LAL1913 protocol, at all TP analyzed, the percentage of MRD-positive patients was significantly higher in the Ph- like ALL subset than in non-Ph-like cases. This difference was particularly evident at TP2 (HSCT decisional point), when 52.9% of Ph-like and only 20% of non-Ph-like cases were MRD-positive. Indeed, when both clinically relevant
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