Profiles of interferon-gamma and interleukin-2 in patients after allogeneic hematopoietic stem cell transplantation

BACKGROUND Allogeneic hematopoietic stem cell transplantation(allo-HSCT)may be related to the occurrence of complications,including graft-versus-host disease(GvHD)and infections.The pathogenesis of acute GvHD is connected with T lymphocytes,which identify alloantigens on host's antigen-presenting cells,activate production of interferon-gamma(IFN-gamma)and interleukin-2(IL-2),and act on the immune effector cells and damage tissues and organs.AIM The aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT.METHODS We enrolled 62 patients,i.e.,30(48%)male and 32(52%)female subjects[median age 49.5(19-68)years],after allo-HSCT from siblings(n=12)or unrelated donors(n=50)due to acute myeloid leukemia with myeloablative conditioning(n=26;42%)and with non-myeloablative conditioning(n=36;58%).All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting.Blood samples were collected pre-transplant before and after(on day-1)the conditioning therapy and on days+2,+4,+6,+10,+20,and+30 after allo-HSCT.Serum levels of IL-2 and IFNgamma were determined using ELISA.RESULTS Patients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection.Group I included patients with neither acute GvHD nor infections[n=15(24%)],group II consisted of patients with infections without acute GvHD[n=17(27%)],group III was comprised of patients with acute GvHD without infections[n=9(15%)],and group IV included patients with both acute GvHD and infections[n=21(34%)].IFN-gamma concentrations were higher in Group II than in other groups on days+20(P=0.014)and+30(P=0.008).Post-hoc tests showed lower concentrations of IFN-gamma on day+30 in groups I(P=0.039)and IV(P=0.017)compared to group II.The levels of IL-2 were mostly undetectable.CONCLUSION Serum levels of IFN-gamma following allo-HSCT progressively escalate.High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD.Serum concentrations of IL-2 in most patients are undetectable.

Inhibition of FLT3:A Prototype for Molecular Targeted Therapy in Acute Myeloid Leukemia

Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AML diagnosis was dependent on morphology,aided initially only by cytochemistry.Unlike acute lymphoblastic leukemia(ALL),immunophenotyping offered little in the diagnosis of AML,at least during the 1970s and 1980s.The advent of reliable cytogenetics changed the entire prognostic outlook of AML.With karyotypic analysis,different groups of AML could be classified and stratified for various therapies.Unique mutational profiling was a major advance in further categorizing AML patients,aided by the immunophenotypic identification of antigenic markers on the cells.All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease(MRD)—became crucial for the management of AML patients.The efficacy of MRD has rapidly progressed in the past decade,from a specificity of 103 with immunophenotyping to 104 with polymerase chain reaction(PCR),which is only appropriate for some patients with AML,and finally to 105 or even 106 cells with the extraordinary sensitivity of next-generation sequencing(NGS).All of these advances have promoted the concept of personalized medicine,which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes.Responses can be predicted and measured accurately.Such targeted agents have now become a cornerstone in the management of AML,increasing effi-cacy and dramatically reducing toxicity.The focus of this review is on one of the most well-studied targeted agents in AML:the FMS-like tyrosine kinase 3(FLT3)inhibitors,which have impacted the prognostication and therapeutics of AML.This review selectively discusses the FLT3 inhibitors in detail,as a model for the other burgeoning targeted agents that have already been approved,as well as those that are currently in development.

Antitumoral effects of cannabis in Notch1-mutated T-cell acute lymphoblastic leukemia

Dear Editor,In T-cell acute lymphoblastic leukemia(T-ALL),an aggressive hematologic cancer with poor clinical outcomes,more than 50%of cases show NOTCH1-driven transformation[1].The NOTCH1 receptor signaling pathway is activated through a series of proteolytic cleavages,ultimately causing the release of the active intracellular domain(NICD),which translocates to the nucleus where it promotes transcription of target genes involved in cell growth.The importance of NOTCH1 mutations in T-ALL has generated great interest in the development of anti-NOTCH1 targeted therapies.A new and promising emerging field in cancer treatment is medical cannabis.Accumulating evidence suggests the direct effects of cannabis on tumor progression in cell lines and animal models[2].Cannabis,and its unique secondary metabolites,known as phytocannabinoids,directly affect the propagation of cancer cells by modulating key cellsignaling pathways[3].We have previously demonstrated that different cannabis extracts,each containing a unique composition of metabolites,selectively impaired the survival of cancer cell lines depending on amatch between the chemical composition of the extract and the characteristics of the specific cancer cell line[4].In the present work,we set out to investigate whether cannabis extracts with unique phytocannabinoid profiles can selectively facilitate antitumor effects in T-ALL cells that harbor a Notch1 mutation.