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Final results of the GIMEMA LAL1509 for Ph+ ALL
Mutational screening was performed in relapsed cases depend- ing on material availability by Sanger sequencing (Online Supplementary Materials and Methods).
Copy number aberrations analysis was performed on diagnostic samples by Cytoscan arrays, as previously described.23
Statistical analysis
Survival was estimated using the Kaplan-Meier Product Limit. Differences in OS and DFS were evaluated by means of the Log- Rank test in univariate analysis and by the Cox regression model in multivariate analysis, after assessment of proportionality of haz- ards. The role of allo-SCT on DFS was evaluated in the Cox regres- sion model by means of a time-dependent covariate. All analyses were performed using the SAS system software (version 9.4). All tests were two-sided, accepting P≤0.05 as statistically significant. Study data were collected and managed using REDCap24,25 elec- tronic data capture tools hosted at the GIMEMA Foundation.
Results
Patients
From July 2011 to October 2013, 60 patients with de novo Ph+ ALL were enrolled in the GIMEMA LAL1509 trial. Thirty-four patients were males and 26 females. Median age at presentation was 41.9 years (range, 18.7-59.1). The median white blood cell count (WBC) at diagnosis was 12.4x109/L (range, 1.4-178). A BCR-ABL1 p190 fusion tran- script was detected in 33 patients (55%), a BCR-ABL1 p210 fusion transcript in 18 (30%), while 9 patients (15%) were positive for both transcripts; p210 and p190/p210 were grouped together for all statistical analyses. The median fol- low-up was 57.4 months (range, 4.2-75.6) (Table 1).
Hematologic response during and after induction
After the steroid pre-phase, 38 of 60 patients (63%) showed a PB blast reduction of ≥75%. All patients achieved CHR by day +57, 51 patients (85%) by day +22. By the end of the induction (day +85), all 60 patients were evaluable for response: 58 patients (97%) were in CHR, while two patients showed a disease progression between day +57 and day +85, both of these were p210-positive.
Minimal residual disease monitoring during and at the end of induction
Molecular analysis showed that transcript levels rapidly and constantly decreased during the induction phase. The rate of transcript reduction was highly significant (P<0.0001) between the onset of the disease and day +22, between days +22 and +45, and between days +57 and +85. Importantly, a significantly greater clearance was observed in BCR-ABL1 p190 (n=33) versus p190/210 and p210 (n=27) cases at every time point of MRD evaluation (P=0.0032, P=0.0031, P=0.0016, P=0.007 at days +22, +45, +57 and +85, respectively) (Figure 2A).
At the end of the induction, CMR was obtained in 11 patients (18.3%). In these patients, the rate of BCR-ABL1 transcript clearance was significantly higher at every point of MRD evaluation since day +22 (Figure 2B).
Post-remission treatment and response
Figure 1 summarizes the patients’ disposition. Of the 11 patients who were in CMR at the end of induction, seven continued with dasatinib: four remain in CHR and CMR after 64, 54, 55 and 53 months (one patient was allografted
Table 1. Patients’ characteristics Patients’ characteristics
Median age at diagnosis (range)
Sex M
F
Median WBC count at diagnosis (range)
Type of fusion transcript p190
p210*
p190/p210*
Median FU (range)
N=60
41.9 years (18.7-59.1)
34 (56.6%)
26 (43.3%) 12.4x109/L (1.4-178)
33 (55%) 18 (30%) 9 (16%)
57.4 months (4.2-75.6)
*Considered together for subsequent analyses: M: male; F: female; WBC: white blood cell count; FU: follow-up.
after 6 months of dasatinib administration), one experi- enced a hematologic relapse, one experienced a molecular recurrence and one patient died of transplant-related com- plications, performed after 6 months of dasatinib mainte- nance while in CHR and CMR. The remaining four patients stopped dasatinib maintenance: two due to a molecular relapse (BCR-ABL1 T315I mutation was detected in one) and were both allografted, and one patients for a protocol violation due to a medical decision (i.e., transplant alloca- tion within 6 months); all three patients are in CHR after 57, 58 and 60 months. Finally, one patient went off-study for non-compliance.
The 47 patients who were in CHR but not in CMR at the end of induction were evaluated for allo-SCT eligibility. According to protocol guidelines, 25 of 47 patients were considered eligible for the procedure. Seventeen patients were transplanted, 11 after a consolidation cycle with clo- farabine plus cyclophosphamide and of these, six patients obtained CMR. Eight patients did not undergo an allo-SCT due to: i) one case of patient’s refusal, ii) a documented hematologic or extramedullary relapse in four cases, iii) an unforeseen unavailability of the donor in one case and iv) a medical decision in two cases (one major protocol viola- tion). The remaining 22 of 47 patients were considered inel- igible for transplant: 20 patients underwent at least one cycle of clofarabine-cyclophosphamide and 13 received both cycles, with six patients obtaining CMR, while two patients went off protocol prior to consolidation treatment due to a major violation. After the second cycle of clofara- bine-cyclophosphamide, 11 of 13 patients started mainte- nance with dasatinib. Five patients, initially deemed ineligi- ble for transplant, could undergo the procedure after one cycle of consolidation chemotherapy: in two cases for a medical decision, in one case because of the presence of the BCR-ABL1 T315I mutation and in two cases for dasatinib interruption (hematologic toxicity in one and patient’s deci- sion in the other). Overall, 22 patients underwent an allo- SCT and after the procedure 12 patients restarted dasatinib as maintenance treatment. After allo-SCT, five patients were persistently MRD-positive and two of them went off treatment due to the emergence of the BCR-ABL1 T315I mutation and for a medical decision, respectively, whereas the others restarted treatment with dasatinib. Thirteen patients were MRD-negative after the transplant and in nine patients dasatinib was restarted: i) in three patients dasatinib was administered for the planned 6 months; ii) in one patient for 5 months; iii) in one patient for 3 months; iv) in two patients for 2 and 1 months each.
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