Poor Prognosis In Acute Leukemia Research Articles

Establishment and validation of prognostic nomogram in acute leukemia with trisomy 8

ABSTRACTObjectiveThis study aims to construct a nomogram model for predicting poor prognosis in acute leukemia with trisomy 8.MethodsA retrospective analysis was conducted on 244 patients with primary acute leukemia with trisomy 8 who received treatment in our hospital, and they were randomly divided into the modeling group (122 cases, including 78 cases with good prognosis and 44 cases with poor prognosis) and the verification group (122 cases). R software was used to construct a nomogram model for predicting poor prognosis in acute leukemia with trisomy 8.ResultsThe results of multivariate analysis showed that age >51 years old, and white blood cell count ≤20 × 109/L were risk factors for poor prognosis in acute leukemia patients with trisomy 8 (P < 0.05), and chemotherapy + transplantation was a protective factor for poor prognosis in acute leukemia patients with trisomy 8 (P < 0.05). The nomogram for poor prognosis of acute leukemia patients with trisomy 8 was constructed using the above four risk predictors. The Hosmer-Lemeshow goodness of fit test was = 6.371, P = 0.497, and the area under the ROC curve was 0.817 (95%CI: 0.742-0.892). The slope of the calibration curve of external validation was close to 1, Hosmer-Lemeshow goodness of fit test was χ2 = 6.507, P = 0.448, and the area under the ROC curve was 0.834 (95%CI: 0.748-0.921).ConclusionThe nomogram model constructed in this study for predicting poor prognosis among acute leukemia patients with trisomy 8 demonstrates excellent discrimination and consistency.

High Expression of PKM2 Was Associated with the Poor Prognosis of Acute Leukemia

PurposeTo explore the clinical significance of plasma pyruvate kinase M2 (PKM2) in assessing the incidence and prognosis of acute leukemia.MethodsPlasma samples from 56 acute myeloid leukemia (AML) patients, 40 acute lymphoblastic leukemia (ALL) patients, and 66 plasma samples from healthy individuals were collected. The level of plasma PKM2 was detected by enzyme-linked immunosorbent assay. The clinical significance of PKM2 in acute leukemia was assessed by analyzing receiver operating characteristic and survival curves.ResultsThe plasma levels of PKM2 in AML or ALL patients were significantly higher than those in healthy individuals, respectively. PKM2 can be used as a potential diagnostic index with the AUC of 0.827 for AML and 0.837 for ALL. The level of plasma PKM2 in ALL patients with a BCR/ABL-positive genotype was significantly higher than that in patients with a BCR/ABL-negative genotype (p<0.05). The event-free survival and the overall survival of acute leukemia patients with higher PKM2 expression was worse than those with lower PKM2 expression.ConclusionThis study showed that higher levels of PKM2 was negatively correlated with the prognosis of acute leukemia. Therefore, PKM2 can be used as a potential index to assess the incidence and prognosis of acute leukemia.

Deregulation of folate pathway gene expression correlates with poor prognosis in acute leukemia.

The present study analyzed the mRNA expression levels of genes involved in the transport and metabolism of methotrexate (MTX) (RFC1, ABCC1, ABCB1, GGH, FPGS, ATIC, TS, MTHFR, MTRR, MS and MTHFD1) in patients with acute leukemia (AL). The expression levels of the examined genes were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in patients with AL (ALL:50/AML:19) and 66 healthy individuals. The mRNA expression levels of RFC1, MS, MTRR, MTHFR and ABCB1 were decreased (P<0.05), while those of GGH, FPGS, TS and MTHFD1 (P<0.05) were overexpressed in patients with AL. Patients with high mRNA levels of GGH (OR=4.28, 95% CI=1.29–14.14), TS (OR=7.14, 95% CI 1.84–27.81), MTHFR (OR=4.81, 95% CI=1.31–17.64), ABCB1 (OR=4.61, 95% CI=1.33–15.97) and ABCC1 (OR=5.50, 95% CI=1.12–27.06) had a higher chance of relapse. Interestingly, high mRNA levels of RFC1 are a protective factor in the risk of AL relapse (OR=0.22, 95% 0.06–0.80). The results of the present study indicated that deregulation of folate pathway gene expression is associated with poor prognosis in AL and that the expression levels of these markers could serve as novel molecular targets for the treatment of patients with AL.

Genome-Wide Association Study of Overall and Progression-Free Survival after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (DISCOVeRY-BMT study)

While survival outcomes after HLA-matched unrelated donor (URD) blood and marrow transplant (BMT) have significantly improved over the last 2 decades, about 40% of patients die of various causes before one-year post-URD BMT. We performed a genome-wide association study (GWAS) named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) of overall (OS) and progression-free (PFS) survival in 3,532 patients treated for AML, ALL or MDS and reported to CIBMTR from 2000-2011 and their 8/8 HLA-matched URDs. Cohort 1 consisted of 2,609 patients with 10/10 HLA-matched URD BMT from 2000-08; Cohort 2 consisted of 923 patients with 10/10 HLA-matched URD BMT from 2009-11 and 8/8 (but <10/10) HLA-matched URD BMT from 2000-11. Genotyping on recipients and donors was performed using the HumanOmniExpress-24 BeadChip (Illumina, San Diego, CA), containing approximately 730,000 single nucleotide polymorphisms (SNPs); the CEU reference panel from the 1000 Genomes project (March 2012 release) was used to impute additional genotypes not available on the GWAS chip or that failed typing. Samples were pre-phased with SHAPEIT and genotypes inferred using IMPUTE2. After quality control, Cohort 1 included 2,108 recipients and 2,052 donors and Cohort 2 included 773 recipients and 760 donors of European-American ancestry typed at 637,655 markers and ~9 million imputed SNPs. Each SNP was measured for association with OS and PFS using Cox proportional hazard models in R. All models included age at BMT, diagnosis (AML, ALL, MDS), disease status at BMT (early, intermediate, advanced), cell source (blood, marrow) and year of BMT. P-values were combined using METAL software with weights proportional to the square root of the number of cases. We report results for a combined P -value (Pmeta) <5x10-8.The T allele of rs9990017 in recipients is significantly associated with better OS (Table) yielding about a 30% decreased hazard of all causes of death including disease relapse, graft-versus-host disease, infection and organ failure. Analysis of the effect of donor genotype at this SNP shows no evidence of association with OS or PFS. The strongest imputed association in this region (info score >.98) was rs9857765 with the T allele at this locus conferring a significantly improved OS in both cohorts (Table).Two SNPs (rs9845520 and rs9839074) in strong linkage disequilibrium (r2 =.94) with both rs9857765 and rs9990017, are predicted to affect transcription factor binding (Regulomedb score=2b) of the highly-conserved gene MBNL1 and the common allele in rs9839074 is predicted to be in an important position in the GATA1 (erythroid development) motif and a binding site for CEBPB, STAT3 and FOS across multiple cell lines. MBNL1 protein is expressed in most blood and marrow hematopoietic cells, while MBNL1 mRNA is expressed in many organs. CEBPB regulates immune response genes, is required for normal macrophage function/differentiation and can interact with (among others) glucocorticoid receptor, IL-6, TNF-alpha and transporter proteins conferring multi-drug resistance (ABCC2, ABCB1). Normal activation of STAT3 is required for self-renewal of embryonic stem cells and differentiation of TH17 cells, while constitutive activation of STAT3 is associated with poor prognosis in acute leukemia. FOS is involved with CD16+ signaling in NK cells, vitamin D receptor gene regulation in osteoporosis, and proliferation of hematopoietic cells, among other roles.A region on 13q34 showed evidence of association with PFS; recipients whose donor had a T allele at rs11617176 showed improved PFS compared to those whose donors had the C allele (see Table). This region contains variants identified in other GWAS of mean platelet volume, coronary artery disease, interstitial lung disease, response to tocilizumab in rheumatoid arthritis patients and renal transplant outcomes, among others.Our study, DISCOVeRY-BMT, is the first GWAS for URD BMT survival outcomes. Confirmation of these findings in a third cohort, genotyping of imputed SNPs, and further studies of the functional consequences of these SNPs may provide more individualized risk prediction and prognosis, while confirmation of rs11617176 may aid in donor selection. [Display omitted] DisclosuresHahn:Novartis: Equity Ownership; NIH/NHLBI: Research Funding. McCarthy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NHLBI: Research Funding.

Pro- and Antiapoptotic Proteins Expression on Bone Marrow and Peripheral Blood CD34+Cells in Acute Leukemia (AL) Patients

Abstract 4996It was shown that drug resistance, poor-risk cytogenetics and poor prognosis in AL is associated with high level of Bcl-2 expression and low Bax/Bcl-2 ratio (<0,3). Fas-antigen (CD95) as a protein triggering the extrinsic apoptotic pathway is differently expressed on hematopoietic precursors. More immature CD34+/CD38- AML blast cells have lower expression of Fas/Fas-L and lower Fas-induced apoptosis than CD34+/CD38+cells. CD34+/CD38− leukemia precursors also have a reduced sensitivity to daunorubicin in vitro and increased expression of multidrug resistance genes (mrp/lrp). CD34+ leukemia cells have not yet been properly characterized regarding the expression of angiotensin converting enzyme (ACE) which regulatory influence on hematopoiesis is now beeing extensively investigated. ACE expression on blast cells is high, but it’s still unknown how CD34+ACE+ leukemia cells behave after chemotherapy. Recent publications indicate that CD34+ACE+ hematopoietic precursors transplanted into NOD/SCID mice contribute 10-fold higher numbers of multilineage blood cells than their CD34+ACE- counterparts.We have studied the dynamics of Bcl-2, Bax, CD95 and ACE expression on CD34+ cells in peripheral blood (PB) and bone marrow (BM) in AL pts during treatment. PB and BM samples were collected before and on +36 day after chemotherapy. The antigens were detected by flow cytometry using monoclonal antibodies. We calculated 10 000 cells in each sample.19 pts were included in the study: 10 - AML and 9 - ALL. The control group comprised 8 healthy donors. At time of diagnosis there were 40±5,7% of CD34+ cells in BM and 26±4,9% - in PB. There was no significant difference between AML and ALL. CD34+ cells in BM and PB of healthy donors constituted 1,6% and 0,27%, respectively. After induction therapy (+36 day) CD34+ cells decreased in BM to 6,1%±3,3 (p=0,0001), in PB to 3,7%± 2,7 (p=0,0008) in all pts. The data on antigens expression on CD34+ cells of BM and PB are presented in table 1CD34+/Bcl-2+CD34+/Bax+CD34+/CD95+CD34+/ACE+BMPBBMPBBMPBBMPBAML pts n=100 day38±11,6*41±1424,4±7,929,2±7,6*16,4±8,523,2±7,821,7±9,520,8±8,7*36 day13,5±3,4**23,7±5**46,2±11,550,3±1119,9±5,536,4±1034±6,635±9,2**ALL pts n=90 day36±1133,7±1246,2±9,437,4±3,7*3,4±1,1*7,1±2,5*41±10,933,2±9,7*36 day18,4±5,826±8,938±11,840,5±1026,2±9,1**40,9±9,2**34±1062,8±10**Donors n=811,7±1,626,1±5,922,8±467,8±6,713,4±3,247,7±11,628±5,368,2±10,2*− p<0.05 compare with donors**− p<0.05 compare with day 0CD34/Bcl-2 expression in BM in AML pts is significantly higher (p=0,04) at the diagnosis comparing with donors. CD34/Bcl-2 expression in PB in AML pts and in BM and PB in ALL pts is higher too, but not significantly. This expression level decreased substantially in BM and PB in AML pts on +36 day comparing with day 0 (p<0,05). We did not found significant changes in ALL pts. CD34/Bax expression in PB is significantly lower (p=0,003) both in AML and ALL pts in comparison with donors. In AML, not in ALL, chemotherapy caused augmentation of Bax expression in CD34+ BM and PB cells on +36 day.BM and PB CD34+ cells in donors had different expression characteristics of Bcl-2 and Bax, demonstrating much higher level of pro- and antiapoptotic markers in PB cells. On the contrast CD34+ leukemia cells in BM and PB had similar characteristics regarding CD34/Bcl-2 and CD34/Bax expression. This fact demonstrates the heterogeneity of donor CD34+cells in BM and PB and points that leukemia CD34+cells in BM and PB are rather similar.CD95 expression on CD34+ BM and PB before treatment is significantly lower (p=0,01, p=0,008) in ALL pts in comparison with donors, and this expression level increased after chemotherapy (p<0,05). CD34/CD95 expression in AML pts is similar with donors, and we didn’t find changes after treatment.CD34/ACE coexpression in BM cells of leukemia pts and donors did not differ much at any time of evaluation. But CD34/ACE expression in PB cells of AML and ALL pts was much lower (p<0,05) than in donors and substantially increased on the day 36.So, our data demonstrate that Bcl-2, Bax, CD95 and ACE expression on CD34+ cells in AL pts and donors significantly differs. The chemotherapy provokes critical changes in CD34/CD95 expression in BM and PB in ALL pts, CD34/Bcl-2 expression in AML pts and ÑÂ34/ACE expression in PB in all AL pts. Disclosures:No relevant conflicts of interest to declare.

Prognostic significance of retinopathy at presentation in adult acute leukemia.

Retinal changes are common in adult acute leukemia patients at presentation, but their prognostic significance is controversial. A 5-year study has been carried out with newly diagnosed acute leukemia patients aged 12-77 years. Seventy-seven cases (49 AML, 28 ALL) were studied prospectively for the presence of intraretinal hemorrhages (IRH), white-centered hemorrhages, cotton-wool spots, and macular hemorrhages. They were treated according to standard chemotherapy protocols, and then achievement of complete remission (CR) and the duration of overall survival (OS) were compared between the groups with and without these different retinal features. No association was found between the presence of any retinal abnormality and CR induction rate, although there was a trend to a lower CR rate among patients with IRH. The median OS of those with IRH was 72 days, compared with 345 days among those without IRH (p=0.002). A WBC at presentation greater than 50x10(9)/l and age greater than 40 years were also associated with shorter OS (p<0.0001 and p=0.0045, respectively). However, after regression analysis, IRH remained statistically significant as a poor prognostic indicator (p=0.01). We conclude that the presence of IRH is an indicator of poor prognosis in acute leukemia.

The Wilms tumor suppressor gene WT1 induces G1 arrest and apoptosis in myeloblastic leukemia M1 cells

WT1 was isolated as a tumor suppressor gene of Wilms tumor. However, high expression of WT1 correlates with poor prognosis in acute leukemia. In addition suppression of WT1 expression by WT1 anti-sense oligonucleotide inhibits proliferation of leukemia cells, suggesting that WT1 is important for their proliferation. To further elucidate the biological significance of WT1 in leukemic cell growth, we overexpressed exogenous WT1 in murine M1 myeloblastic leukemia cells using the isopropyl-β- d-thiogalactoside (IPTG)-controlled expression system. We found that induction of one splicing variant of WT1 [ WT1-17AA(+)-KTS(−)] in M1 cells induces cell cycle arrest and apoptotic cell death. These results suggest that the role of WT1 is different depending on the type of leukemia cell in which it is expressed.

Idarubicin is active on MDR cells: evaluation of DNA synthesis inhibition on P388 cell lines

Multidrug resistance is frequently found in patients affected by hematological malignancies and has been related to a poor prognosis of acute leukemia. In the present paper we report results concerning the activity of idarubicin, an anthracycline derivative, on the leukemic P388 and P388 doxorubicin-resistant cell lines. The results clearly show that idarubicin inhibits DNA synthesis in the resistant cell line more actively than doxorubicin.

Multidrug Resistance (mdr1) in Adult Acute Leukemia at Diagnosis: Correlation with Response to Induction Chemotherapy

<i>Background:</i> Multidrug resistance is caused by overexpression of P-glycoprotein (P-gp, encoded by the mdrl gene), a transmembrane energy-dependent efflux pump which acts by expelling a wide variety of cytostatic drugs from the cytosol, thus decreasing intracellular drug accumulation. The multidrug-resistant phenotype has been identified as a major cause of treatment failure in many malignancies. In acute leukemia, overexpression of P-gp has been observed at diagnosis as well as in patients with resistant disease. The aim of the present study was to correlate response to induction therapy with mdrl gene expression in newly diagnosed acute leukemia. <i>Material and Methods:</i> The mdrl gene product P-gp expression was studied in 51 adult patients with newly diagnosed leukemia (9 acute lymphoblastic leukemias, 42 acute nonlymphoblastic leukemias) by means of immunocytochemistry and the alkaline phosphatase/anti-alkaline phosphatase method, using the two monoclonal antibodies C219 and MRK16. In all patients induction therapy was performed according to currently ongoing German multicenter trials. <i>Results:</i> At diagnosis, the mdr phenotype was observed in 47% of the patients. Following induction therapy, 56% of the P-gp-positive patients were induced into remission, compared to 78% of the P-gp-negative patients. The surface marker CD34, known to be associated with a poor prognosis in acute leukemia, was expressed in 58% of the samples. In cases where both markers were positive, the complete remission rate was only 50% as compared to 82% when both markers were negative. 8 of 11 P-gp-positive patients refractory to initial chemotherapy expressed both markers, thus indicating the existence of a possible subgroup with a very poor prognosis. <i>Conclusions:</i> Our data are concurrent with other reports and support increasing evidence that mdrl gene expression contributes to chemoresistance in newly diagnosed acute leukemia as an independent factor.