scholarly journals Role of Allogeneic Transplantation for FLT3/ITD Acute Myeloid Leukemia: Outcomes from 133 Consecutive Newly Diagnosed Patients from a Single Institution

2011 ◽  
Vol 17 (9) ◽  
pp. 1404-1409 ◽  
Author(s):  
Amy E. DeZern ◽  
Anthony Sung ◽  
Sharon Kim ◽  
B. Douglas Smith ◽  
Judith E. Karp ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Newly Diagnosed ◽  
Single Institution ◽  
Acute Myeloid

Mechanisms of Suppression Used by Regulatory T Cells in Patients Newly Diagnosed with Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2938-2938 ◽  
Author(s):  
Miroslaw J Szczepanski ◽  
Marta Szajnik ◽  
Malgorzata Czystowska ◽  
Magis Mandapathil ◽  
Ann Welsh ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Regulatory T Cells ◽  
Myeloid Leukemia ◽  
Neutralizing Antibodies ◽  
Hematologic Malignancies ◽  
Cell Contact ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract An elevated frequency of CD4+CD25high regulatory T cells (Treg) has been reported in the peripheral blood in patients with various solid tumors and hematologic malignancies. Although the increase in Treg seems to be a characteristic feature of most tumors, the functional role of Treg and the mechanisms of suppression, especially in patients with hematologic malignancies, have been less well defined. We investigated Treg-mediated suppression and the responsible mechanisms in thirty newly diagnosed acute myeloid leukemia (AML) patients prior to any treatment and twenty five healthy donors (NC). The percentage of circulating CD4+ CD25high Treg was higher (p <0.0001) in the AML patients (4.5 ±0.2%, range 1.7–8.2%) compared to NC (1.5 ± 0.08%, range 0.9–3.1 %). To evaluate the suppressive function, CD4+CD25high T cells (S) were co-cultured with sorted, CFSE-labeled autologous CD4+CD25high T cells (R) at different S/R ratios. Suppression mediated by Treg co-incubated with proliferating autologous responders was significantly higher (p<0.001) in AML than that mediated by control Treg. To evaluate the role of cytokines produced by Treg in suppression and a need for cell-to- cell contact, transwell analysis of S/R co-cultures was performed. Co-incubation in the presence of transwell inserts (TRI) resulted in significant reduction of suppression (p<0.05), and the addition of neutralizing antibodies to IL-10 and TGF-β1 in the presence of TRI further decreased suppression mediated by Treg. These data suggest that both immunoinhibitory cytokine production and cell-to-cell contact are necessary for suppression. To explore other potential mechanisms of Treg suppression, we evaluated the expression by Treg of ectonucleotidases CD39 and CD73 and the capability of Treg to produce adenosine. CD4+CD25high T cells of AML patients had higher expression (p<0.01) of CD39 and more efficiently hydrolyzed ATP to adenosine relative to Treg in NC. These data indicate that various mechanisms of suppression may be utilized by Treg in patients with AML. The increase frequency of Treg mediating potent suppression by various mechanisms is likely to play a role in host anti-tumor immune responses. Therefore, modulation of the frequency and functions of Treg might provide new immunotherapeutic approaches in AML.

scholarly journals FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013?

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 220-226 ◽  
Author(s):  
Mark Levis
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Current Treatment ◽  
Flt3 Mutation ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
First Remission ◽  
Acute Myeloid

Abstract Patients with acute myeloid leukemia who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. The results of an FLT3 mutation test, which can be influenced by several variables, need to be interpreted according to the clinical setting and there is a need for internationally standardized FLT3 mutation assays. Because of the lack of prospective studies, the role of allogeneic transplantation as consolidation therapy is still somewhat controversial, but the preponderance of evidence suggests that transplantation in first remission, if possible, is probably the best option. Clinically useful FLT3 inhibitors are hopefully on the near horizon and are being studied in the context of current treatment paradigms.

scholarly journals Outcome of patients aged 60‐75 years with newly diagnosed secondary acute myeloid leukemia: A single‐institution experience

2019 ◽  
Vol 8 (8) ◽  
pp. 3846-3854 ◽  
Author(s):  
Sarah Bertoli ◽  
Suzanne Tavitian ◽  
Pierre Bories ◽  
Isabelle Luquet ◽  
Eric Delabesse ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Single Institution ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Assessing Early Mortality in Intensively-Treated Acute Myeloid Leukemia in a Developing Country: Genetic, Laboratory Findings, and Comorbidities Add Prognostic Information

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Fernanda Rodrigues Mendes ◽  
Wellington F Silva ◽  
Raphael Bandeira Melo ◽  
Douglas R. A. Silveira ◽  
Elvira Velloso ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Newly Diagnosed ◽  
Laboratory Findings ◽  
Tumor Lysis ◽  
Acute Myeloid

Background: Early death (ED) during first-line therapy for acute myeloid leukemia (AML) is acknowledged as a pending issue worldwide. Few pivotal studies from developed countries have identified baseline characteristics related to poor outcome. Retrospective reports from Brazil and Mexico indicate alarming ED rates from real-world data, raising the question of which factors contribute towards this finding in low-income centers. In this study, we aimed to identify risk factors for ED in AML to increase the prediction power of previously known tools such as Charlson's Comorbidity Index (CCI) as well as to examine the role of anti-infective prophylaxis in our cohort. Methods: This is a retrospective cohort study involving adult patients (pts) newly diagnosed with AML treated at Instituto do Cancer do Estado de Sao Paulo, Brazil between June 2011 and June 2020. Only pts receiving the classic "7+3" regimen were included. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). The primary endpoint was ED rate, calculated by the Kaplan-Meier method. A Cox regression model selected by a stepwise method was used to find risk factors. Post-chemotherapy events (secondary endpoints) constituted any documented infection, bleeding, thrombosis, and acute kidney injury (AKI) during the first 30 days. Results: Overall, 206 out of 337 pts (61%) entered in the analysis. The median age was 54 years (range,17-74) and 50.5% were male. The median time between symptoms' onset and hospital admission was 7 weeks (0-48). Thirteen pts (6.3%) presented with leukostasis, of which 9 proceeded leukapheresis. At the presentation, clinical tumor lysis syndrome was seen in 12% of patients (associated with extramedullary disease [p<0.001], among other factors). Other baselines clinical and laboratory findings are summarized in table 1. Pre-chemotherapy infection was found in 67% of patients (positive blood culture: 26.3%). 45-day mortality was 23.8% (95% CI 17.8-29.4) (Figure 1), being 39.8% in pts above 60y. Dose reductions for liver or kidney dysfunction were not, per si, associated with higher ED. Multivariable Cox regression models examined the utility of baseline markers in predicting ED in our cohort and the best-fitted model by Akaike information criteria (AIC) is outlined in a forestplot (Figure 2). Briefly, in a model controlled for age, adding phenotype, genetic risk, platelets and C-reactive protein (CRP) to CCI resulted in improved prediction in our cohort (AIC 479 vs 542). CRP, AGR, and CCI were independently associated with short-term survival in AML (figure 3, 4, and 5). Noticeably, 13/20 diabetic patients died during the first 45 days (unadjusted HR 4.29 [95% CI 2.33-7.92]). Only antibacterial prophylaxis with quinolone was associated with decreased ED (unadjusted HR 0.38 [95% CI 0.15-0.95]), while the use of fluconazole or anidulafungin did not affect survival. Colonization during hospitalization occurred in 71% (mainly vancomycin-resistant Enterococcus [77%] and carbapenemase-producing Enterobacteriaceae [44%]). Any sort of colonization was associated with ED (OR 4.41 [95% CI 1.89-12.08]). Thromboembolic events were registered in 11.9% (95% CI 7.9-17.4, mostly catheter-related) and were marginally associated with central nervous system disease (OR 4.31 [95% CI 0.84-18.25) and diabetes mellitus (DM) (OR 3.24 [95% CI 0.94-9.82) 20.8 vs 7.9%, p=0.097). Bleeding was observed in 17.6% and was associated with monocytic AML subtypes, tumor lysis, and DM. Complete response was attained in 50.5% (95% CI 43.4- 57.5). Presumed or confirmed invasive fungal infection was diagnosed during induction in 26.6%, but empirical amphotericin was prescribed in 60.2%. 66.5% of subjects developed any grade of AKI, with the need for hemodialysis in 10.3%. Conclusion: This is the first Brazilian study to evaluate risk factors for ED in newly diagnosed AML in the public setting, as well as to address which events explain such higher mortality in comparison to American and European reports. In line with the literature, age itself was not associated with mortality when adjusted for other variables such as CCI and genetic stratification. Interestingly, we found that the baseline CRP levels are significantly correlated with ED, highlighting the role of infection and inflammation at the AML diagnosis. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of the Slit-Robo Family in Adult Patients with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3816-3816
Author(s):  
Aleksandra Golos ◽  
Dorota Jesionek-Kupnicka ◽  
Tadeusz Robak ◽  
Ewa Wawrzyniak ◽  
Lidia Anna Gil ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Involvement ◽  
Control Group ◽  
Newly Diagnosed ◽  
Low Expression ◽  
Acute Myeloid

Abstract Introduction: SLIT-ROBO is newly discovered ligand-receptor family of neuronal guidance molecules. Recently, it has been proved that these proteins are involved in both, physiologic and pathologic angiogenesis. In animal models, it was shown both, pro-and antiangiogenic of SLIT-ROBO signaling. Moreover, the interaction of SLIT ligands with their roundabout receptors (ROBO) results in promotion of apoptosis, adhesion and blocking of cell cycle. There is evidence that SLIT-ROBO proteins are involved in pathogenesis of solid tumors, both in angiogenesis dependent and independent way. The role of SLIT-ROBO proteins in biology of acute myeloid leukemia (AML) remains unknown.The only two hitherto published studies considering ROBO4 expression in AML have revealed its increased expression in the blasts cells. The aim of the study was to evaluate the role of SLIT-ROBO proteins in AML. The expression of SLIT ligands, and their receptors ROBO was assessed in bone marrow of newly diagnosed AML patients and in the control group. The expression level of the proteins was correlated with known prognostic factors, response to treatment and overall survival (OS), as well as angiogenesis activity. To our knowledge, it has been the first study investigating the whole family of SLIT-ROBO proteins in AML. Methods: Expression SLIT-ROBO proteins was assessed in bone marrow biopsy specimens of 79 newly diagnosed AML patients with median age 59 years [18-87]. The paraffin-embedded tissue blocks were retrieved and subjected to immunohistochemistry for SLIT ligands (SLIT1, SLIT2, SLIT3), and their receptors ROBO1, ROBO2, ROBO3, and ROBO4. The positive blasts cells were semi-quantitatively analyzed according to previously published methods (Perrone et al, 2006). For the purpose of analysis the patients were divided into "low-expressers" and "high-expressers". Concurrently, all samples were immunostained for CD34 to calculate microvessel density (MVD) as an equivalent of angiogenesis. The control group was composed of 23 BM biopsies form patients with newly diagnosed lymphoma without bone marrow involvement. Results: Expression of ROBO receptors and SLIT ligands in AML patients and in the control group. In our study higher expression of ROBO1, ROBO2, and ROBO3 was observed more often in AML patients compared to the control group (p<0.0001, p<0.001, and p=0.09, respectively, Fig 1.). In contrast, low expression of SLIT1, SLIT2, and SLIT3 ligands has been shown more often in AML than in control BM samples (p<0.0001, p=0.003, and p=0.001, respectively,Fig.2.). Higher expression of ROBO1, ROBO2, and ROBO3 was more often in AML patients ≥60 years (p=0.04, p=0.008, and p=0.02, respectively).Conversely, low expression of ROBO4 was more often observed in elderly AML (p=0.06). The majority of patients with de novo AML had low expression of SLIT1 and SLIT2 (p=0.053 and p=0.055, respectively). As to ROBO, higher expression of ROBO2 in the group with secondary AML was more frequent (p=0.09). No significant correlations between the SLIT-ROBO proteins' expression,neither cytogenetic risk group nor clinical stage parameters such as WBC, hemoglobin level, proportion of leukemic blasts in BM, or LDH activity were found. Similarly, neither of the SLIT-ROBO proteins influenced the complete remission rate (CR) and overall survival (OS). Relationship between SLIT-ROBO expression and angiogenesis activity in AML patients and control group. Significantly higher MVD in BM of AML patients than in control group (Me 51 [9-140] vs 16 [4-78], p<0.0001) has been observed. ROBO4was the only protein that expression correlated significantly with MVD. Higher expression of ROBO4 was associated with higher MVD in both, AML and the control group (p=0.05 and p=0.01, respectively). Conclusions: SLIT-ROBO family members play a role in biology of AML. ROBO4 is involved in both, physiologic and pathologic angiogenesis A better understanding of SLIT-ROBO signaling pathway in leukemic blasts may create new optionsfor AML therapy. Acknowledgments: AG and DJ-K both equally contributed to the study. This work was supported by grants from Medical University of Lodz, Lodz, Poland (502-03/1-093-01/502-14-077 and 503/1-093-01/503-11-001). Disclosures Robak: Eisai Inc: Research Funding. Wierzbowska:Janssen, Celgene: Consultancy.

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