Fever supports CD8+ effector T cell responses by promoting mitochondrial translation.

Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study.

Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, PGray = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], PGray = .34 [per protocol analysis]; historical control: 22 ± 4%, PGray = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.

Guía de práctica médica leucemia crónica en personas de 15 años y más / Chronic leukemia medical practice guide in people aged 15 years and over

Generar recomendaciones basadas en la mejor evidencia disponible acerca del manejo de personas de 15 años y más con Leucemia crónica. Personas de 15 años y más con Leucemia crónica que reciben atención en el nivel secundario y terciario de salud en el sector público y privado de salud.

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment.

Acute leukemias with adverse prognostic features carry a high relapse rate without allogeneic stem cell transplantation (allo-SCT). Allo-SCT has a high morbidity and is precluded for many patients because of advanced age or comorbidities. Postremission therapies with reduced toxicities are urgently needed. The murine acute leukemia model C1498 was used to study the efficacy of an intravenously administered vaccine consisting of irradiated leukemia cells loaded with the natural killer T (NKT)-cell agonist α-galactosylceramide (α-GalCer). Prophylactically, the vaccine was highly effective at preventing leukemia development through the downstream activities of activated NKT cells, which were dependent on splenic langerin(+)CD8α(+) dendritic cells and which led to stimulation of antileukemia CD4(+) and CD8(+) T cells. However, hosts with established leukemia received no protective benefit from the vaccine, despite inducing NKT-cell activation. Established leukemia was associated with increases in regulatory T cells and myeloid-derived suppressor cells, and the leukemic cells themselves were highly suppressive in vitro. Although this suppressive environment impaired both effector arms of the immune response, CD4(+) T-cell responses were more severely affected. When cytarabine chemotherapy was administered prior to vaccination, all animals in remission posttherapy were protected against rechallenge with viable leukemia cells.

Treatment with GM-CSF secreting myeloid leukemia cell vaccine prior to autologous-BMT improves the survival of leukemia-challenged mice.

Vaccination with irradiated autologous tumor cells, engineered to secrete granulocyte macrophage-colony stimulating factor (GM-CSF) (GM tumor), can generate potent antitumor effects when combined with autologous bone marrow transplantation (BMT). That notwithstanding, the post-BMT milieu, characterized by marked cytopenia, can pose a challenge to the implementation of vaccine immunotherapies. To bypass this problem, partial post-BMT immune reconstitution has been allowed to develop prior to vaccination. However, delaying vaccination can also potentially allow the expansion of residual tumor cells. Other approaches have used reinfusion of "primed" autologous lymphocytes and multiple administrations of GM tumor cells, which required the processing of large amounts of tumor. Utilizing the MMB3.19 murine myeloid leukemia model, we tested whether a single dose of GM tumor cells, 7 days prior to syngeneic BMT, could be a curative treatment in MMB3.19-challenged recipient mice. This vaccination protocol significantly improved survival of mice by eliciting long-lasting host immune responses that survived lethal irradiation, and were even protective against post-BMT tumor rechallenge. Furthermore, we demonstrated that mature donor lymphocytes can also play a limited role in mounting the antitumor response, but our pre-BMT vaccination strategy obviated the need for either established de novo immune reconstitution or the use of multiple post-BMT immunizations.

Epigenetic changes in the myelodysplastic syndrome.

Epigenetic mechanisms, such as DNA methylation and histone modifications, drive stable, clonally propagated changes in gene expression and can therefore serve as molecular mediators of pathway dysfunction in neoplasia. Myelodysplastic syndrome (MDS) is characterized by frequent epigenetic abnormalities, including the hypermethylation of genes that control proliferation, adhesion, and other characteristic features of this leukemia. Aberrant DNA hypermethylation is associated with a poor prognosis in MDS that can be accounted for by more rapid progression to acute myeloid leukemia. In turn, treatment with drugs that modify epigenetic pathways (DNA methylation and histone deacetylation inhibitors) induces durable remissions and prolongs life in MDS, offering some hope and direction in the future management of this deadly disease.

Antitumor effects and cytotoxicity of recombinant plant nucleases.

Recombinant plant nucleases R-TBN1 and R-HBN1 were isolated to homogeneity and examined for their antitumor effects and cytotoxicity. Although antiproliferative effects of both recombinant nucleases were not significant on the ML-2 cell culture in vitro, the nucleases were strongly cytostatic in vivo after their administration intravenously as stabilized conjugates with polyethylene glycol (PEG). Recombinant nucleases were as effective against melanoma tumors as previously studied pine pollen (PN) and mung bean nucleases and their effects were reached at about 10 times lower concentrations compared to the use of bovine seminal RNase (BS-RNase). Because the recombinant nucleases R-HBN1 and R-TBN1 share only 67.4% amino acid identity and showed only partial immunochemical cross-reactivity, their similar anticancerogenic effects can be mainly explained by their catalytical similarity. Both recombinant nucleases showed lower degree of aspermatogenesis compared to BS-RNAse and PN nuclease. Unlike BS-RNase, aspermatogenesis induced by both recombinant nucleases could not be prevented by the homologous antibody complexes. Owing to relatively low cytotoxicity on the one hand, and high efficiency at low protein levels on the other, recombinant plant nucleases R-HBN1 and R-TBN1 appear to be stable biochemical agents that can be targeted as potential antitumor cytostatics.

PR1 vaccination in myeloid malignancies.

The graft-versus-leukemia (GVL) effect following allogeneic stem cell transplantation is testament to the effectiveness of the immune system in recognizing and eliminating leukemia cells. The successful identification of a range of leukemia-associated antigens (LAAs) that drive the GVL response in recent years has stimulated research in the development of vaccines to treat hematological malignancies. Here, we review the current experience with the PR1 vaccine. PR1 is a nine amino acid, HLA-A(*)0201-restricted peptide, shared by two myeloid LAAs, proteinase (PR)3 and neutrophil elastase (NE). PR3 and NE are found in the primary (azurophil) granule proteins of normal granulocytes and are overexpressed in myeloid leukemia cells. PR1 induces powerful HLA-A(*)0201-restricted CD8+ T-cell responses that selectively kill myeloid leukemia cells in vitro. The detection of low frequencies of PR1-specific CD8+ T cells in patients with chronic myeloid leukemia and at higher frequencies in patients entering molecular remission after allogeneic stem cell transplantation supports the concept that there is natural immunity to PR1, which can be boosted further by vaccination to enhance immunity to leukemia. Preliminary reports indicate that PR1 peptide vaccination induces significant increases in PR1-specific CD8+ T cells, with rapid and durable remissions in some patients with myeloid leukemia. These promising early results point the way to optimizing the administration of peptide vaccines to improve the treatment of otherwise refractory myeloid leukemias.

Leukemia suppressor function of Egr-1 is dependent on transforming oncogene.

We have shown that deregulated expression of either c-Myb or E2F-1 blocks terminal differentiation of M1 myeloid leukemia cells at the blast stage, whereas deregulated c-Myc blocks differentiation at the intermediate stage. Each of these oncogenes potentiates M1 leukemia in vivo. The zinc-finger transcription factor Egr-1 abrogates the block in M1 terminal differentiation imparted by oncogenic c-Myc or E2F-1, suppressing their leukemia-promoting function in nude mice. In this study, we asked whether Egr-1 also abrogates the block in terminal differentiation and suppresses leukemia imparted by deregulated c-Myb. Interestingly, the ectopic expression of Egr-1 in M1 cells expressing deregulated c-Myb only partially abrogated the block in terminal differentiation and did not suppress the leukemic phenotype. Two important implications from these data are that the leukemia suppressor function of Egr-1 is not directly related to how early the transforming oncogene blocks the differentiation program and that the tumor suppressor function of Egr-1 is dependent on the specific oncogene. Egr-1 is dominant to c-Myc- and E2F-1-, but not to c-Myb-, driven leukemia. These findings extend the notion that the molecular nature of genetic lesions responsible for leukemia determines the effectiveness of any given tumor suppressor.

Possible protective effect of green tea intake on risk of adult leukaemia.

In a case-control study of 107 adults with leukaemia and 110 orthopaedic controls in China, a reduced risk was found with longer duration, higher quantity, and frequency of green tea intake.

Intakes of selected food groups and beverages and adult acute myeloid leukemia.

Few studies have explored the association between diet and adult acute myeloid leukemia (AML). In a hospital-based case-control study among 111 cases and 439 controls, AML risk was negatively associated with milk intake among women (OR 0.25, 95% CI 0.08-0.73) and tea (OR 0.50, 95% CI 0.23-1.09), and positively associated among women with beer (OR 2.48, 95% CI 1.05-5.85), wine (OR 2.32, 95% CI 1.05-5.09), and beef (OR 4.78, 95% CI 1.35-16.94). Our findings support a role of diet in adult AML; however, further research is needed to explore gender differences in risk.

Caloric restriction prevents radiation-induced myeloid leukemia in C3H/HeMs mice and inversely increases incidence of tumor-free death: implications in changes in number of hemopoietic progenitor cells.

OBJECTIVES: Previously, we found a clear decrease in the incidence of radiation-induced myeloid leukemia in C3H/HeMs mouse caused by caloric restriction (CalR). In this report, CalR before and after irradiation was examined to determine whether they exert different effects on the prevention of radiation-induced myeloid leukemogenesis and the consequent extension of life span by CalR. METHODS: The C3H/HeMS strain, which is prone to radiation-induced myeloid leukemia, was used. Groups subjected to different CalR timings, pre- and postirradiation, were compared with groups not subjected to CalR during their lifetime for the incidences of neoplasms, specifically that of myeloid leukemia, and the incidence of tumor-free death. A single dose of 3Gy X-ray was administered to mice at 10 weeks old. Results of colonization assay before and after CalR were compared with the incidence of leukemogenesis among the groups. RESULTS: Irrespective of the CalR timing in terms of irradiation, there was a significant difference in the prevention of myeloid leukemogenesis, and a consequent difference in longevity (731 approximately 805 days for CalR groups vs. 697 days for the group without CalR; Log rank, P<0.03). During CalR, the number of hemopoietic progenitor cells (HPCs), potential leukemogenic targets, significantly decreased (0.4 x 10(4) vs. 4.2 x 10(4) of granulomacrophage colony forming units per spleen; 1.3 x 10(4) vs. 7.6 x 10(4) of the splenic colony forming units per spleen), but this decreased number of HPCs returned to that of the non-CalR control group, when the CalR group was returned to nonrestricted diet (returned to 1.5 x 10(4) granulomacrophage colony-forming units per spleen; returned to 2.8 x 10(4) splenic colony-forming units per spleen). Although preirradiation CalR followed by a conventional non-CalR diet negates the potential preventive effect, prevention conferred by pre-and postirradiation CalR suggests different underlying mechanisms; preirradiation CalR prevents the initiation of direct genotoxic leukemogenesis, while postirradiation CalR the indirect, epigenetic, leukemogenesis. CONCLUSION: The incidences of tumor-free death significantly increased in all the groups undergoing CalR except for the group subjected to preirradiation CalR, which contributed to the longevity of the groups undergoing CalR.

Childhood and maternal infections and risk of acute leukaemia in children with Down syndrome: a report from the Children's Oncology Group.

Children with Down syndrome (DS) are highly susceptible to acute leukaemia. Given the potential role of infections in the aetiology of leukaemia in children without DS, we investigated whether there was an association between early-life infections and acute leukaemia in children with DS. Maternal infections during pregnancy were also examined. We enrolled 158 incident cases of acute leukaemia in children with DS (97 acute lymphoblastic leukaemia (ALL) and 61 acute myeloid leukaemia (AML)) diagnosed at Children's Oncology Group institutions between 1997 and 2002. DS controls (N=173) were selected from the cases' primary care clinics and frequency matched on age at leukaemia diagnosis. Data were collected on demographics, child's medical history, mother's medical history, and other factors by maternal interview. Analyses were conducted using unconditional logistic regression adjusted for potential confounders. A significant negative association was observed between acute leukaemia and any infection in the first 2 years of life (adjusted odds ratio (OR)=0.55, 95% confidence interval (CI) (0.33-0.92); OR=0.53, 95% CI (0.29-0.97); and OR=0.59, 95% CI (0.28-1.25) for acute leukaemia combined, ALL, and AML respectively). The association between acute leukaemia and maternal infections during pregnancy was in the same direction but not significant. This study offers support for the hypothesis that early-life infections may play a protective role in the aetiology of acute leukaemia in children with DS.

Breastfeeding and the risk of childhood leukemia: a meta-analysis.

OBJECTIVE: The authors used a meta-analytic technique to (1) quantify the evidence of an association between duration of breastfeeding and risk of childhood acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML), (2) assess the influence of socioeconomic status (SES) on any such associations, and (3) discuss the implications of these findings for the evaluation of whether breastfeeding reduces the risk of childhood leukemia. METHODS: A fixed effects model was employed to systematically combine the results of 14 case-control studies addressing the effect of short-term (< or = 6 months) and long-term (>6 months) breastfeeding on the risk of childhood ALL and/or AML. Subgroup analyses of studies that did and did not adjust for SES were also performed. RESULTS: A significant, negative association was observed between long-term breastfeeding and both ALL risk (odds ratio [OR]=0.76; 95% confidence interval [CI] 0.68, 0.84) and AML risk (OR=0.85; 95% CI 0.73, 0.98). Short-term breastfeeding was similarly protective for ALL and AML. Results for studies that adjusted and did not adjust for SES were not significantly different from the results for the 14 studies combined. CONCLUSIONS: This meta-analysis showed that both short-term and long-term breastfeeding reduced the risk of childhood ALL and AML, suggesting that the protective effect of breastfeeding might not be limited to ALL as earlier hypothesized. Potential bias introduced by different participation rates for case and control samples that differed in SES can be minimized by implementing larger case-control studies with SES-matched, population-based controls.

Phase II trial of cladribine and cytarabine in relapsed or refractory myeloid malignancies.

To evaluate the efficacy of cladribine and cytarabine in children with relapsed or refractory myeloid malignancies, we administered cytarabine (200 mg/m2 per day) by continuous subcutaneous infusion and cladribine (8.9 mg/m2 per day) by continuous intravenous infusion concomitantly for 5 days to nine patients younger than 21 years. After one course, five patients had no response, two patients had partial responses, one had stable disease, and one had progressive disease. Two patients received a second course: one patient had stable disease after one course and progressive disease after the second; another patient had a partial response after one course and no response after the second. Despite the efficacy of the cladribine and cytarabine regimen in treating newly diagnosed acute myeloid leukemia (AML) in a previously reported study, the combination was not effective for relapsed or refractory childhood AML.

Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.

BACKGROUND AND OBJECTIVES: The Italian Society of Hematology (SIE) and the two affiliated Societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of essential thrombocythemia (ET) using evidence-based knowledge and consensus formation techniques. DESIGN AND METHODS: Key questions on the optimal management of ET patients were formulated by an Advisory Council (AC) and approved by an Expert Panel (EP) composed of 7 senior hematologists. The AC systematically reviewed the published literature from 1980 to August 2002, and articles were graded according to their internal validity and quality. Using the Delphi technique, the EP was asked to answer the key questions according to the available evidence. From September 2002 to March 2003, four Consensus Conferences were held in accordance with the Nominal Group Technique with the goal of solving residual disagreement on recommendations. RESULTS: The EP provided recommendations on when to start platelet-lowering therapy, the most appropriate platelet-lowering agent, the use of anti-platelet therapy, and the management of women in childbearing age and of pregnant women. INTERPRETATION AND CONCLUSIONS: By using evidence and consensus, recommendations for the treatment of key problems in ET have been issued. Statements are graded according to the strength of the supporting evidence and uncertainty is explicitly declared.

Inhibition of acute lymphoblastic and myeloid leukemias by a novel kinase inhibitor.

In recent years, synthetic tyrosine kinase inhibitors have made a rapid transition from basic research to therapeutic application. These compounds represent a major clinical advance in the approach to cancer in their relative specificity of action and decreased toxicity. We report here the effects of a novel tyrosine kinase inhibitor CR4 that interferes with growth-promoting pathways to markedly inhibit the growth and survival of both Philadelphia-positive and -negative acute lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). While efficiently ablating leukemic cell growth, normal cell growth and differentiation remain unaffected by CR4. CR4 demonstrates an ability to inhibit the function of multiple growth-critical kinases and yet exhibits a low level of cytotoxicity. These findings suggest that CR4 may prove to be highly effective as a therapeutic agent.