KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on ...adults treated in recent protocols, and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of comutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in 3 consecutive trials from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%; P = .001) and OS (28.1% vs 60.7%; P = .006) rates. Next, we analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements and KMT2A genomic fusion as markers. In approximately one-third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. In contrast, KMT2A-based MRD was highly reliable and strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR, 7.1%; OS, 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.
Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute ...lymphoblastic leukemias (T-ALL; TLX1/3
) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1
and TLX3
T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes.
We compared TLX1
and TLX3
adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (
) and
l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples.
We show that TLX1
patients expressed low levels of
when compared with TLX3
and TLX-negative patients, due to epigenetic silencing of
by both DNA methylation and a decrease of active histone marks. Promoter methylation of the
gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally,
promoter methylation was an independent prognostic factor for both event-free survival HR, 0.42; 95% confidence interval (CI), 0.24-0.71;
= 0.001 and overall survival (HR, 0.40; 95% CI, 0.23-0.70;
= 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (
= 0.012).
We conclude that
methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.
Adults with relapsed or refractory B‐precursor acute lymphoblastic leukaemia (R/R BCP‐ALL) have very poor outcome. Blinatumomab as single agent has shown activity in R/R BCP‐ALL. We aimed to assess ...the activity of blinatumomab in concomitant association with intensive chemotherapy. Seventeen patients with R/R BCP‐ALL were treated with combination of blinatumomab and VANDA (etoposide, cytarabine, mitoxantrone, dexamethasone and asparaginase) regimen. Complete remission (CR) was achieved in 14/17 patient (82%) and 11/17 (65%) were transplanted. One‐year leukaemia‐free survival was 58.8% for the whole cohort and 90.9% for transplanted patients. These preliminary data suggest that the VANDA‐blinatumomab salvage regimen leads to a very high rate of CR and HSCT in suitable patients.
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