[Show abstract][Hide abstract] ABSTRACT: Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.
[Show abstract][Hide abstract] ABSTRACT: Blood transfusions can modify host immunity and clinical outcomes in hematological malignancies. One thousand sixty-seven patients with acute myeloid leukemia (AML) were studied for their transfusion dependency at initial presentation and transfusion frequency during induction chemotherapy. Three hundred five patients (29 %) showed initial dependence to red blood cell (RBC) transfusion and 109 (10 %) to platelet transfusion. Transfusion dependency at presentation was associated with a poorer prognosis. Both initial RBC and platelet transfusion needs were associated with lower response rates (P = 0.04 and P = 0.03). Median overall survival (OS) was 10.8 months for patients with RBC need vs 18.8 months for the other patients (P = 0.02) and 6.8 months for patients with platelet transfusion need vs 13.6 months for the others (P = 0.01). Similarly, transfusion intensity during induction therapy influenced negatively treatment outcome. Median transfusion burden per week was 2.5 (range 0-25.7) RBC units and 1.6 (range 0-15.7) platelet concentrates (PCs). Both high RBC and PC transfusion intensities were associated with lower response rates (P = 0.003 and P < 0.0001). Median OS was 9.08 months for patients with RBC transfusions >3/week vs 18.29 months for those with RBC transfusions ≤3/week (P = 0.0003) and 10.75 months for patients with PC transfusions >2/week vs 19.96 months for those with PC ≤2/week (P = 0.0003). RBC and platelet transfusion intensities during induction therapy remained of prognostic value in multivariate analysis. Transfusion need at presentation and the frequency of transfusions during induction chemotherapy appear as strong prognostic factors.
Annals of Hematology 07/2015; 94(11). DOI:10.1007/s00277-015-2456-2 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite remarkable improvements in the treatment of pediatric acute leukemia (AL) over the last decades, relapse still carries a poor prognosis with significant morbidity and mortality. Novel targeted therapies are currently being investigated in an attempt to reduce adverse events and improve survival outcomes. This review summarizes recent data from the literature regarding advances in drug discovery based on biological evidence and the novel targeted drug therapies for childhood AL. Significant challenges still remain for novel drug development in childhood AL. However, first results combined with a large number of new agents currently being investigated are very encouraging. Furthermore, therapeutic advances will depend upon combination strategies using the specific action of each agent and their complementary effects on leukemia cells.
[Show abstract][Hide abstract] ABSTRACT: In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro , 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents.