Clinical Outcome In Acute Leukemia Research Articles

Study the Relationship Physiology and Molecular Biology in Patients of Iraq Drug Use Parameters Acute Leukaemia (AL)

Study of paper is physiology use to analysis total in LDH is an intracellular enzyme whose activity is associated with cellular metabolism, WBCs count in blood to patients which makes it a marker of cell proliferation and cell injury and study with molecular biology of marker parameters use drug the presence of survivin in neoplastic cells contributes to tumor development and its high transcription has been reported as a predictor of poor prognosis in several hematological malignancies. However, despite being frequently present in ALs, the impact of survivin transcription in this type of hematologic malignancy remains undefined. Some studies report that survivin predicts an unfavorable clinical outcome in ALs, while others do not. In the present study, despite the small number of patients evaluated, the transcription of survivin at diagnosis did not seem to be related to a worse response to treatment or a worse prognosis. This is because, of the six patients who expressed survivin, three are in complete remission and, of the three who died, two were already considered to have an unfavorable prognosis regardless of survivin transcription, one due to advanced age and the presence of leukocytosis in the liver. Leukometry at diagnosis was another prognostic factor evaluated in this study. Patients diagnosed with AL may have elevated, normal, or decreased WBC counts at the time of diagnosis and, in general, counts greater than 30,000 WBCs/mm3 are considered to have a poor prognosis.

Serum Tumor Necrosis Factor-Alpha Levels in Acute Leukemia and Its Prognostic Significance.

IntroductionTumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that facilitates malignant cells in immune evasion, survival, and treatment resistance by generating a favorable milieu for them. It is shown to be ectopically produced by malignant/leukemic and immune cells in the tumor microenvironment, providing a tumor-supportive environment and playing an important part in the establishment and progression of malignant cells. It is linked to hyperleukocytosis, high blast count, and poor clinical outcomes in acute leukemia (AL). Considering the varied role and different expression patterns of tumor necrosis factor-alpha in acute leukemia and its clinical relevance, the present study was planned to monitor the level of tumor necrosis factor-alpha in patients with acute leukemia and its correlation with disease outcome. The aim of this study was to monitor the level of tumor necrosis factor-alpha in patients with acute leukemia at the time of diagnosis and after induction chemotherapy.Material and methodsThe study included cases classified as acute leukemia based on morphological examination, bone marrow analysis, and flow cytometry. In all patients with acute leukemia (n = 90) and controls (n = 10), the serum tumor necrosis factor-alpha level was measured using a Diaclone Human ELISA kit (Diaclone, Besancon, France) (solid phase sandwich ELISA) at diagnosis and after induction chemotherapy.ResultsTumor necrosis factor-alpha levels were substantially higher in T-acute lymphoblastic leukemia (T-ALL) cases, followed by acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL), at the time of diagnosis, compared to the control. A significant reduction in serum tumor necrosis factor-alpha level was seen in patients with acute leukemia after induction phase chemotherapy (P < 0.05). Tumor necrosis factor-alpha levels were considerably reduced (P < 0.001) in the majority of acute leukemia cases after the induction phase, while high tumor necrosis factor-alpha levels were positively correlated with incomplete remission status in the remaining cases.ConclusionTumor necrosis factor-alpha is involved in the progression of acute leukemia and its relapse. High levels of tumor necrosis factor-alpha are linked to leukocytosis, high blast counts, and worse survival in patients with acute leukemia. Monitoring of tumor necrosis factor-alpha may be helpful in patients with acute leukemia in view of available antitumor necrosis factor-alpha therapy.

The value of 18F-FDG PET/CT in the prediction of clinical outcomes of patients with acute leukemia treated with allogeneic hematopoietic stem cell transplantation.

The present study aimed to determine whether 18F-FDG PET/CT performed before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) can predict clinical outcomes in acute leukemia (AL). A total of 79 examinations comprising 72 patients with AL who underwent 18F-FDG PET/CT before and/or after allo-HSCT were retrospectively enrolled between January 2011 and January 2019. Outcomes were assessed using overall survival (OS) and disease-free survival (DFS). A total of 63 examinations were PET-positive, while 16 examinations were PET-negative. Increased BM and splenic 18F-FDG uptake were observed in 24 (19/79) and 14% (11/79) of examinations, respectively. 18F-FDG-avid lymph nodes were observed in 38% (30/79) of examinations. ENEMES involvement was detected in 44% (35/79) of examinations. The presence of ENEMES involvement [OS hazard ratio (HR), 6.399; 95% confidence interval (CI), 1.843–22.224; P=0.003; post-HSCT OS: HR, 7.203; 95% CI, 1.510–34.369; P=0.013; DFS HR, 3.671; 95% CI, 1.145–11.768; P=0.029], post-transplantation minimal residual disease (DFS HR, 4.381; 95% CI, 1.594–12.040; P=0.004; pre-HSCT OS HR, 11.455; 95% CI, 1.336–98.179; P=0.026) and disease status (OS HR, 0.330; 95% CI, 0.128–0.848; P=0.021; post-HSCT OS HR, 0.195; 95% CI, 0.050–0.762; P=0.019; DFS: HR, 0.278; 95% CI, 0.091–0.851; P=0.025) could serve as an adverse prognostic factor in patients with AL treated with allo-HSCT. 18F-FDG PET/CT before and/or after allo-HSCT was a predictor for OS and DFS in patients with AL. ENEMES involvement detected using 18F-FDG PET/CT may help identify patients with AL who are likely to have unfavorable clinical outcomes.

ISSUE HIGHLIGHTS - July 2020.

ISSUE HIGHLIGHTS - July 2020.

A study of disseminated intravascular coagulation in acute leukemia reveals markedly elevated D-dimer levels are a sensitive indicator of acute promyelocytic leukemia.

While the presence of disseminated intravascular coagulation (DIC) has been implicated in worse clinical outcome in acute leukemia, the relationship between different subtypes of acute leukemia and the clinicopathologic features of DIC has not been systematically well studied. In this study, we retrospectively reviewed 149 cases of newly diagnosed acute leukemia and assessed the utility of evaluating red blood cell morphologic features, and coagulation parameters in determining the presence of DIC as well as differentiating subtypes of acute leukemia. Review of our cohort demonstrates a novel finding, that elevated D-dimer concentrations ≥19 000 ng/mL fibrinogen equivalent units (FEU) are a sensitive diagnostic indicator of acute promyelocytic leukemia (APL) with moderate specificity, sensitivity 96%, specificity 92% in acute leukemia subtyping. Similar to other studies, APL showed an increased incidence of DIC (P < 0.01) compared to other subtypes of acute leukemia. Surprisingly, the presence of schistocytes on the peripheral blood smear was not a statistically significant indicator of DIC, sensitivity of 36% and specificity of 89%. Finally, the presence of DIC was not a significant indicator of poorer prognosis amongst all patients with AML. Overall we identify elevated D-dimer concentrations ≥19 000 ng/mL FEU are a sensitive indicator of acute promyelocytic leukemia (APL), with a sensitivity of 96% and specificity of 92% in the subtyping of acute leukemias, and that the presence of schistocytes in peripheral blood smears is not a diagnostically sensitive screening test for DIC with a sensitivity of 36%.

The prognostic significance of rapid peripheral blood blast clearance during the initial course of induction chemotherapy in young patients withde novoacute myeloid leukemia

The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated-measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5 days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (≥9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p = 0.0096). A rapid decline in BCP during the first 5 days of induction chemotherapy may be a good predictor of CR. Copyright © 2015 John Wiley & Sons, Ltd.

Quantitative Assessment of WT1 Gene Transcript After Hematopoietic Stem Cell Transplantation Is a Powerful MRD Marker to Predict the Clinical Outcome in Acute Leukemia

Abstract 4461 BackgroundWT1 is a panleukemic marker that is expressed in 90% of acute leukemias and has been used as MRD marker after chemotherapy or transplantation. However, the threshold of WT1 to predict relapse and outcome in acute leukemia (AL) patients post transplantation has not been well studied. ObjectiveWe evaluated the predictive value of quantitative Wilms' tumor gene (WTl) assessment for relapse following hematopoietic stem cell transplantation (HSCT) in patients of AL. MethodsThe quantitative assessment of WT1 expression by real-time quantitative PCR (RQ-PCR) was measured in 63 AL patients (pts) with 326 bone marrow samples at the different time points post transplant. ROC (Receiver Operating Characteristic) curve was used to determine the WT1 threshold in order to predict clinical relapses. Furthermore, AL patients were divided into WT1 positive and negative groups according to the threshold of WT1, and the clinical outcomes of these patients post transplant were analysed retrospectively. ResultsBM samples from 19 pts who relapsed post transplanted showed significantly higher WT1 expression levels compared to the samples from 44 pts in remission (P<0.01), with a median expression level of 1270 (range 55–47596) and 132 (range 0–2959) copies WT1/104ABL, respectively. Ten of 18 relapsed patients died from recurrence, and had higher levels of WT1 expression than that of other 8 patients. Based on the ROC curve, the cut-off value of WT1 was 585 copies WT1/104ABL, dividing 63 patients into WT1-positive group (>585,n=21) and the negative group (≤585,n=42). The WT1-negative group had longer relapse- free survival (RFS) (P<0.01) and overall survival (OS) (P<0.01) than that of positive group. ConclusionOur data suggest that, in the HSCT setting, the sequential and quantitative analysis of WT1 may be useful as a leukemia marker for monitoring MRD, and predicting AL relapse post transplant. Disclosures:No relevant conflicts of interest to declare.

Combination of Mitoxantrone,Ara-C and Homoharringtonine In Treatment of Refractory and Relapsed Acute Myeloid Leukemia

Abstract 4294Advances in effective chemotherapy have improved clinical outcomes in acute leukemia in recent years. 5-year survival rate approaches 50–60% for acute myeloid leukemia (AML). However, the prognosis remains poor for patients who are relapsed or refractory to first-line therapy. Drug resistance and early disease recurrence are major contributing factors in the limited survival of patients with AML. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation. New combinations of different agents were employed in refractory patients to overcome drug resistance. The current study is to evaluate the efficacy of a MAH regimen comprising Mitoxantrone,Ara-C and Homoharringtonine in refractory or relapsed AML. 37 patients aged 14–65 years with refractory or relapsed AML (15 refractory AML patients, 22 relapsed AML patients) were treated with the MAH regimen(Mitoxantrone 10mg qd, iv.gtt, for 2□‘3 days;Ara-C 100mg bid, iv.gtt, for 5□‘7 days; Homoharringtonine 4mg qd iv.gtt, for 5□‘7 days). Chemotherapy duration lasted for 5 or 7days depended on bone marrow cellurarity. 15 (40.5%)and 1 (2.7%) patients achieved complete remission (CR) and partial remission (PR) respectively. The overall response rate was 43.2%. There was no relation between remission duration and previous chemotherapy. All patients who achieved CR received a consolidation and intensification therapy. The median overall survival (OS) for all patients was 97 days (range 18–487 d). For the patients who were in CR or PR,the median relapse-free survival(RFS) was 147 days(range 4 to 341 d). All patients experienced profound myelosuppression. The most common observed side effect of the regimen was infection because of grade ‡W neutropenia, which could be observed in 33 patients(89.1%). 4 patients died in aplasia due to severe infection and brain hemorrhage. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×109/l was (16.0±6.4)d. Platelet levels of more than 20×109/l were achieved in a median time of (12.7±6.2)d. Nonhematological side effects, consisting mainly of gastrointestinal toxicity(21/37,56.8%) and transient liver ALT and AST increase (4/37), were generally mild to moderate and tolerated. To a conclusion, MAH regimen can be employed in treatment of the refractory or relapsed AML patients who were not responded to other regimen. It is effective and is good tolerant.It could provide some refractory patients the chance to receive hematopoietic stem cell transplantation. Disclosures:No relevant conflicts of interest to declare.

Immune Reconstitution and Immune Correlates of Clinical Outcome IN Acute LEUKEMIA PATIENTS Treated with Haploidentical STEM CELL TRANSPLANTATION.

Abstract 46The broader application of haploidentical stem cell transplantation (haplo-HCT), is limited by the delayed immune reconstitution (IR) secondary to the procedures for GvHD prophylaxis. This ultimately results in a high-rate of infectious complications and non-relapse mortality. We dynamically analyzed immunoreconstitution (IR) in patients undergoing haplo-HCT for acute leukemias enrolled in two different phase I-II clinical trials aimed at improving IR. In the first trial (TK007), 28 patients (out of 50 enrolled) received suicide-gene transduced donor T cells at day +42 after a T-cell depleted graft, in the absence of post-transplant immunosuppression. In the second trial (TrRaMM), 40 patients received an unmanipulated graft and a rapamycin-based GvHD prophylaxis. T-cell immune reconstitution was more rapid in TrRaMM than in TK007 patients, with a threshold of CD3 cells>100/μl reached at days +30 and +90, respectively. In both trials IR was mainly composed of Th1/Tc1 lymphocytes with an inverted CD4/CD8 ratio. While in TrRaMM patients we observed an early expansion of naïve and central memory T cells, producing high amounts of IL-2, in TK patients IR was mainly composed of activated effectors. Furthermore, in TrRaMM patients we detected high levels of CD4+CD25+CD127- T regulatory cells (up to 15% of circulating T lymphocytes) that persisted after rapamycin withdrawal, and was significantly superior to that observed in TK patients and in healthy controls. Interestingly, in contrast to the different kinetics of T-cell reconstitution, no differences were observed in time required to gain protective levels of CMV-specific T cells, as shown by ψIFN ELISPOT analysis. Protective frequencies of CMV-specific lymphocytes were observed 3 months after HCT in both groups, a time-point that in TrRaMM patients corresponds to the average time of rapamycin withdrawal. In both trials the number of circulating CMV-specific T cells was inversely correlated to the number and severity of subsequent CMV reactivations and days of antiviral therapy. GvHD was diagnosed in 16 TrRaMM patients (40%) and in 10 TK patients (35% of patients who received TK cells). Severity of GvHD was different in the two cohort of patients with 5 TrRaMM patients (12,5%) and only 2 TK patients (7%) with grade III-IV GvHD. Of interest, in the TrRaMM group CMV-specific immunity was significantly hampered by the immunosuppressive treatment required to treat GvHD. On the contrary, in the TK group, the administration of ganciclovir was able to activate the suicide machinery and control GvHD without impairing viral-specific T-cell immunocompetence. These results matched with the kinetics of CMV reactivations. We observed that while in TrRaMM patients 80% of viral reactivations occurred after the immunosuppressive therapy, in TK patients no significant differences could be assessed before and after therapy. IFN-ψ ELISPOT might thus be a relevant and predictive test to guide patient-specific clinical monitoring and antiviral treatment. Overall, these results show that early immune reconstitution can be promoted in haplo-HCT by different strategies associated with a wide range of alloreactive potential. The risks and benefits associated with alloreactivity should guide the therapeutic choice tuned on patient disease status and co-morbidities. Disclosures:Bordignon:Molmed Spa: Employment.

Expression of MRP1 gene in acute leukemia.

Overexpression of the multidrug resistance-associated protein 1 (MRP1) gene has been linked with resistance to chemotherapy in vitro, but little is known about its clinical impact on acute leukemia patients. Our aim was to investigate the possible association between MRP1 gene expression level and clinical outcomes among Iranian leukemia patients. This was an analytical cross-sectional study on patients referred to the Hematology, Oncology and Stem Cell Research Center, Sharyatee Public Hospital, whose diagnosis was acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL). All molecular work was performed at NIGEB (public institution). To correlate with prognostic markers and the clinical outcome of acute leukemia, MRP1 gene expression was assessed in 35 AML cases and 17 ALL cases, using the quantitative real-time polymerase chain reaction and comparing this to the chemotherapy response type. Mean expression in AML patients in complete remission (0.032 +/- 0.031) was significantly lower than in relapsed cases (0.422 +/- 0.297). In contrast, no significant difference in MRP1 mRNA level was observed between complete remission and relapsed ALL patients. There was a difference in MRP1 expression between patients with unfavorable and favorable cytogenetic prognosis (0.670 +/- 0.074 and 0.028 +/- 0.013, respectively). MRP1 expression in M5 was significantly higher (p-value = 0.001) than in other subtypes. The findings suggest that high MRP1 expression was associated with poor clinical outcome and was correlated with the M5 subtype and poor cytogenetic subgroups among AML patients but not among ALL patients.

Topoisomerase IIα mRNA and protein expression vs. in vitro drug resistance and clinical outcome in acute leukaemia

The objective of this study was to correlate the expression of topoisomerase (topo) IIalpha to in vitro drug sensitivity and to the clinical outcome in patients with acute leukaemia. Leukaemic cells were isolated from bone marrow or blood from 94 patients. Topo IIalpha mRNA (n=58) and protein (n=60) expression was determined by real-time RT-PCR and flow cytometry, respectively. In both groups, chemosensitivity testing by a bioluminescence ATP assay was performed to a variable extent for both topo IIalpha poisons and non-topo IIalpha targeting drugs. Topo IIalpha mRNA expression varied with relative values ranging from 0.03 to 14.20 (median 1.10). The median value for topo IIalpha protein-positive cells was 23% (range 0-99%). Cell samples from patients with a high (>median value) percentage of topo IIalpha-positive cells were significantly more sensitive to the topo IIalpha active drugs etoposide and daunorubicin, and showed a borderline value for idarubicin (p=0.08), while there was no difference for non-topo IIalpha targeting drugs. However, we did not find any significant differences in mRNA expression or the percentage of topo IIalpha-positive cells in patients who achieved complete remission after at most two induction courses compared with those who did not, nor did we find any difference in survival when patients with high mRNA expression/percentage of topo IIalpha-positive cells were compared with patients with low values. We conclude that expression of topo IIalpha, determined as percentage of topo IIalpha-positive cells, in leukaemic cells correlates to chemosensitivity in vitro against topoisomerase poisons but that it does not predict clinical outcome in acute leukaemia.

Significance of lung resistance-related protein in clinical outcome of acute leukemic patients with reference to p-glycoprotein

Abstract Lung resistance-related protein (LRP) over-expression in leukemic blast cells from acute leukemia patients, and the effect of LRP or P-glycoprotein (P-gp) on the clinical outcome of acute leukemia were investigated individually by dividing patients into four groups. The complete remission (CR) rate of group I (LRP and P-gp both negative) was 81.7%, group II (only LRP-positive) 87.5%, group III (only P-gp-positive) 87.1%, and group IV (LRP and P-gp both positive) 40.0%. There were no statistical differences between group I and group II or group III, but a significant difference was observed between group I, II, or III and group IV. Median overall survival in group IV was significantly shorter (4.6 months) than in group I, II, or III, although no significant differences were observed between group I and groups II or III (18.9, 20.5, 31.8 months). There was a tendency for disease-free survival in group III to be longer than that in group I, II or IV. The reasons for these findings are discussed. Our present results indicate that the coexistence of LRP and P-gp strongly influenced effectiveness of induction chemotherapy, and long term prognosis, whereas isolated presence of LRP or P-gp did not.