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Final results of the GIMEMA LAL1509 for Ph+ ALL
Figure 3. Cumulative incidence of relapse. CI: Confidence Interval; CHR: complete hematologic remission; yrs: years.
Single nucleotide polymorphism array analysis was car- ried out at presentation in 39 cases; the most frequent aber- rations were deletions of IKZF1 (84.6%), PAX5 (38.5%), CDKN2A/B (33.3%), MLLT3 (33.3%), JAK2 (28.2%) and RB1 (28.2%). Furthermore, in a small fraction of patients (four of 37; 10.8%) a deletion involving MEF2C was identi- fied.
Disease-free survival and overall survival
At a median follow up of 57.4 months, the DFS was 47.2% (95% CI: 35.6.0-72.6) (Figure 4A), with a median DFS of 30.4 months, and the OS was 56.3% (95% CI: 44.5-71.3), with a median OS not reached (Figure 4B). A better, though not significant, DFS was observed in patients who obtained a CMR at day +85, compared to cases with a MRD positiv- ity (70% vs. 42%, P=0.08) (Figure 5A). The observed DFS prolongation in CMR patients did not translate into a statis- tically significant advantage in OS, even though better sur- vival was observed (70% vs. 52.9%, P=0.27) (Figure 5B). This is probably related to the number of patients and because of the efficacy of consolidation treatments in induc- ing MRD negativity. DFS was also evaluated on the basis of the fusion protein and the presence of additional copy num- ber evolution (CNA). There were no significant differences in DFS between BCR-ABL1 p190+ patients compared to p210+ and/or p190/p210+ cases (49.7% vs. 41.7%, P=0.4). Likewise, OS was superimposable among the two subsets (56% vs. 44.2%, P=0.9, not shown).
At variance, the presence of additional CNA cases with the co-occurrence of IKZF1 plus CDKN2A/B and/or PAX5 (IKZF1 plus) at presentation had a strong impact on DFS and OS had a significantly worse DFS and OS than cases with no alterations and/or with IKZF1 deletions only: 0% versus 60% (P=0.0008) and 20% versus 69.5% (P=0.0068) at 60 months (Figure 6). Importantly, the presence of IKZF1 dele- tions alone did not affect DFS. Unfortunately, as also report- ed by Pfeifer and colleagues,26 the negative prognostic impact was also not abrogated when adjusted by transplant
Table 2. Number and types of serious adverse events occurred during the protocol.
Serious adverse events
Gastrointestinal system
Nervous system
Serous effusions Infectious diseases Cardiologic toxicity General disorders
Graft versus host disease
Total number of events (N=8)
4
2 2 5 1 3 1
Events related to dasatinib or chemotherapy
2
1 2 0 0 1 0
allocation. In addition, patients with IKZF1 plus CDKN2A/B or PAX5 deletions showed a significantly increased CIR (P=0.0031) i.e., all patients harboring these alterations relapsed within 24 months from induction therapy. Patients carrying a MEF2C deletion appeared to have a better DFS as opposed to patients without it (80% vs. 39.6%, P=0.12).23 Finally, allo-SCT, evaluated in a Cox model by a time-depen- dent covariate, did not impact on OS and DFS survival.
Univariate and multivariate survival analyses
Several factors (age, sex, WBC count, type of fusion pro- tein, additional genetic lesions, etc.) were investigated in univariate analysis to establish their impact on DFS: patients who achieved a CMR after induction, showed a better, though non-significant, DFS, also in multivariate analysis (P=0.07). The co-occurrence of IKZF1 deletions plus CDKN2A/B or PAX5 deletions was the only significant factor associated with a worse DFS (P=0.0008) in our cohort of patients. Along the same line, IKZF1 deletions plus CDKN2A/B or PAX5 were the only significant factors impacting on OS in both univariate (P=0.01) and multivari- ate analysis (P=0.005).
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