Page 65 - Haematologica Vol. 110 - January 2025

ARTICLE - Real-life study on 421 adult Ph-neg ALL treated with LAL1913 program D. Lazzarotto et al.
This observational study was approved by the Ethics Com- mittee of Friuli Venezia Giulia, Italy (ethical approval number CEUR-2022-Os-03) and conducted in accordance with the Declaration of Helsinki (revised 2008).
Treatment protocol
All patients were treated according to the GIMEMA LAL1913 protocol as described by Bassan et al. and detailed in Online Supplementary Table S1.1 Antibiotic, antimycotic and anti- viral prophylaxis, and pegaspargase toxicity management were administered according to the policy of each center. Treatment-related toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Measurable residual disease analysis
sion for OS and DFS.
Simon-Makuch plot was used to assess the time-depen- dent effects of HSCT and Mantel-Byar test was used for comparison of survival curves.
The same descriptive statistics were used to compare the characteristics of the real-life and the LAL1913 clinical trial populations. To compare OS and DFS, a subclass matching propensity score was performed (5 quantile classes) con- sidering the following variables: age, sex, risk, lineage, and transplant. All 602 observations were matched, and the real-life data were weighted according to subclassification. Propensity score estimates were calculated using a logistic regression model. A summary of the characteristics of the patients in the propensity score matching is reported in Online Supplementary Table S2.
P<0.05 was considered statistically significant.
Results
Patients’ characteristics
The main characteristics of the 421 patients are summa- rized in Table 1. Median age was 42 years (range 18-80) and was significantly lower in T-ALL/LL patients (38.5 vs. 45, P=0.0009); 23% (N=97) were older than 55 years, 52.5% (N=221) had B-ALL, and 12% (N=50) had LL (of which N=45 were T-lineage, P<0.0001).
The median white blood cell (WBC) count was significantly higher in T-ALL (P<0.0001), as was also the involvement of lymph nodes and mediastinum (42% and 47% of patients, respectively). Central nervous system (CNS) involvement was documented in 9% (N=37) of patients at disease onset (more frequently in T-ALL/LL: 12.5% vs. 5%, P=0.0149).
As for cytogenetics / genetics (evaluable in 81% of patients, N=342), 15 patients had a KMT2A;11q23 rearrangement, 45 had other adverse karyotypes, while a t(1;19)/TCF3::PBX1 translocation was detected in 5 patients and a hyperdip- loidy in 15. The Philadelphia-like signature was not routinely tested (see Methods).
Overall, 49% of patients were standard risk (SR), 10% high risk (HR), and 41% very high risk (VHR). T-ALL/LL patients more frequently displayed VHR features (52% vs. 30% of B-ALL/LL, P<0.0001).
The median follow-up of the entire population was 24.6 months. At the last follow-up, 306 patients (73%) were alive (251/306 [82%] in CR1) and 115 (27%) had died (64/115 [56%] due to underlying disease; 24/115 [21%] due to transplant-re- lated mortality; 9/115 [8%] deaths during induction; 5/115 [4%] deaths in CR during subsequent courses of chemotherapy; 13/115 [11%] due to other causes).
Treatment and response
All 421 patients received the first course of therapy (C1) and 358 (85%) of them were able to continue the treatment up to the third course (C3). Prior to C3 we recorded 15 deaths,
Measurable residual disease analysis was carried out on bone marrow samples through real-time quantitative polymerase chain reaction (RTq-PCR) for immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements following the EuroMRD guidelines11 in 3 reference laboratories (as in the GIMEMA LAL1913 trial) or locally through multiparameter flow cytom- etry (MFC) targeting leukemia-associated immunophenotype in patients lacking suitable molecular probes. Similarly to the GIMEMA LAL1913 trial, data on MRD were collected at 4 specific timepoints: end of induction week 4 (TP1), week 10 (end of course 3, TP2), week 16 (end of course 5, TP3), and week 22 (end of course 7, TP4). Patients with low positive (<10-4) or negative TP2-3 and negative TP4 (or negative TP2- 3 when TP4 was missing) were defined as MRD-negative (MRD-neg), while those with TP2-3 ≥10-4 and/or positive TP4 were defined as MRD-positive (MRD-pos), according to the LAL1913 clinical trial.
Statistical analysis
The comparison between baseline characteristics among subgroups was obtained using Fisher’s exact or χ2 test for categorical variables, Student t test for normally distrib- uted variables, and Mann-Whitney test for non-normally distributed variables. Logistic regression was used to study variables influencing the achievement of MRD-negativity at TP2. Median follow-up time was calculated among survivors and was last updated in June 2023.
The response evaluation criteria are reported in the On- line Supplementary Appendix. OS was calculated from the date of diagnosis to the date of the last follow-up or to the date of death from any cause. DFS was calculated from the date of achieving first CR to the date of the last follow-up, relapse or death from any cause. DFS stratifi- cation for MRD followed the definition for MRD-neg and MRD-pos described above using the available timepoints for each patient. OS and DFS were estimated according to the Kaplan-Meier method and the differences between groups were compared with the log-rank test. Univariate and multivariate analyses were carried out by Cox regres-
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