In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile

William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia

Targeting RUNX1 in acute myeloid leukemia : preclinical innovations and therapeutic implications

Introduction: RUNX1 is an essential transcription factor for normal and malignant hematopoiesis. RUNX1 forms a heterodimeric complex with CBFB. Germline mutations and somatic alterations (i.e. translocations, mutations and abnormal expression) are frequently associated with acute myeloid leukemia (AML) with RUNX1 mutations conferring unfavorable prognosis. Therefore, RUNX1 constitutes a potential innovative and interesting therapeutic target. In this review, we discuss recent therapeutic advances of RUNX1 targeting in AML.Areas covered: Firstly, we cover the clinical basis for RUNX1 targeting. We have subdivided recent therapeutic approaches either by common biochemical pathways or by similar pharmacological targets. Genome editing of RUNX1 induces anti-leukemic effects; however, off-target events prohibit clinical use. Several molecules inhibit the interaction between RUNX1/CBFB and control AML development and progression. BET protein antagonists target RUNX1 (i.e. specific BET inhibitors, BRD4 shRNRA, proteolysis targeting chimeras (PROTAC) or expression-mimickers). All these molecules improve survival in mutant RUNX1 AML preclinical models.Expert opinion: Some of these novel molecules have shown encouraging anti-leukemic potency at the preclinical stage. A better understanding of RUNX1 function in AML development and progression and its key downstream pathways, may result in more precise and more efficient RUNX1 targeting therapies

The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia

Childhood acute lymphoblastic leukemia (ALL) consists of various subtypes that respond differently to cytotoxic drugs and therefore have a markedly different clinical outcome. We used microarrays to investigate, in 190 children with ALL at initial diagnosis, whether 70 key apoptosis genes were differentially expressed between leukemic subgroups defined by lineage, genetic subtype, in vitro drug resistance, and clinical outcome. The expression of 44 of 70 genes was significantly different in T-versus B-lineage ALL, 22 genes differed in hyperdiploid versus nonhyperdiploid, 16 in TEL-AML1-positive versus-negative, and 13 in E2A-rearranged versus germ-line B-lineage ALL. Expression of MCL1 and DAPK1 was significantly associated with prednisolone sensitivity, whereas BCL2L13, HRK, and TNF were related to L-asparaginase resistance. BCL2L13 overexpression was also associated with unfavorable clinical outcome (P < .001). Multivariate analysis including known risk factors revealed that BCL2L13 expression was an independent prognostic factor (P = .011)

Expression of the outcome predictor in acute leukemia 1 (OPAL1) gene is not an independent prognostic factor in patients treated according to COALL or St Jude protocols

New prognostic factors may result in better risk classification and improved treatment of children with acute lymphoblastic leukemia (ALL). Recently, high expression of a gene named OPAL1 (outcome predictor in acute leukemia) was reported to be associated with favorable prognosis in ALL. Therefore, we investigated whether OPAL1 expression was of prognostic importance in 2 independent cohorts of children with ALL treated on Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)–92/97 (n = 180) and St Jude Total 13 protocols (n = 257). We observed a consistently higher (2.8-fold) expression of OPAL1 in TEL-AML1–positive ALL compared with TEL-AML1–negative ALL in both cohorts, but higher OPAL1 expression was not consistently associated with other favorable prognostic indicators such as age and white blood cell count, or ALL genetic subtype. Lower OPAL1 expression was also not associated with increased in vitro drug resistance. Multivariate analyses including known risk factors showed that OPAL1 expression was not independently related to prognosis in either the COALL or St Jude cohorts. In conclusion, OPAL1 expression may not be an independent prognostic feature in childhood ALL, and its previously reported prognostic impact appears to be treatment dependent

Clofarabine Improves Relapse-Free Survival of Acute Myeloid Leukemia in Younger Adults with Micro-Complex Karyotype

International audienceAcute myeloid leukemia (AML) encompasses heterogeneous entities with dismal outcomes. Intermediate and unfavorable-risk AML represent the most difficult-to-treat entities. We recently reported the benefit of the clofarabine-based consolidation (CLARA) regimen compared to the standard high-dose cytarabine (HDAC) regimen in younger AML patients. Here, we aimed at assessing the clinical significance of single-nucleotide polymorphism (SNP)-array alterations and their interactions with chemotherapy regimens. A SNP-array was successfully performed in 187 out of the 221 intent-to-treat patients (CLARA arm: n = 92 patients, HDAC arm: n = 95 patients). The CLARA regimen did not significantly improve relapse-free survival (RFS) among patients who displayed a complex karyotype when compared to the HDAC regimen (4-year RFS (4y-RFS): 36.4% vs. 18.8%, respectively; p = 0.134). Defining micro-complex karyotypes from at least four SNP-array lesions enabled us to refine and enlarge the subset of adverse patients. In such patients, the CLARA regimen significantly improved RFS compared to the HDAC regimen (4y-RFS: 44.4% vs. 13.8%, respectively; p = 0.004). From our study cohort, 8% of patients displayed TP53 mutations, which were associated with an impaired RFS (4y-RFS: 20.0% vs 43.7%; p = 0.029). In a multivariate analysis, micro-complex karyotypes remained the sole poor prognostic factor in the HDAC arm (hazard ratio (HR) = 2.324 (95% confidence interval (CI) = 1.337-4.041), p = 0.003). The SNP array represents a powerful and reproductive approach to refine adverse AML patients that may benefit from alternative consolidation regimens