Effect of MYH10 Variant on Acute Leukemia with Low Platelet Count Prognosis

Abstract Background: Acute myeloid leukemia (AML) is a blood disorder characterized by abnormal white blood cell count, anemia, or abnormal platelet count. It is associated with molecular genetic changes. While platelet counts vary at first diagnosis，platelets recover after chemotherapy. Objectives:This study aimed to; (1) Investigate whether the platelet count and genotype at first diagnosis are related to chemotherapy and their significance on chemotherapy prognosis; (2) Determine whether newly diagnosed patients with low platelet count have a poor prognosis and if it can be used as a separate prognostic predictor; (3) Determine whether the mutation genotype affects platelet count and its prognosis at first diagnosis. Methods: A retrospective chart review of 301 AML patients was conducted. Univariate, multivariate unconditional Logistic regression and Cox regression analyses were also conducted. Bioinformatics technology was used to extract the GSE12662 data set from the GEO database to analyze differentially expressed genes in AML patients. Besides, biological functions, pathways, proteins, and prognosis were assessed. Conclusion: Increased platelet count in AML patients after chemotherapy was an independent risk factor affecting complete remission. The platelet count also had some guiding significance for evaluating the sensitivity of patients to chemotherapy. MYH10 causes thrombocytopenia in acute myeloid leukemia via RUNX1 gene alteration and influence of prognostic factors. MYH10 variant detection improves the identification of AML molecular characteristics and its prognostic impact on AML, helping in the response analysis to chemotherapeutic agents and further treatment decisions.

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Prognostic Impact of 3q21 and 3q26 Cytogenetic Abnormalities in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v120.21.2594.2594 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2594-2594

Author(s):

Mario Annunziata ◽

Piera Angelillo ◽

Laura Vicari ◽

Clelia Criscuolo ◽

Felicetto Ferrara

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Platelet Count ◽

Myeloid Leukemia ◽

Median Overall Survival ◽

Chromosome 3 ◽

Prognostic Impact ◽

Acute Myeloid

Abstract Abstract 2594 Background: Abnormalities affecting long arm of chromosome 3 are rare but recurrent in Acute Myeloid Leukemia (AML) and are detected in a variable percentage of AML patients according to different series. The 2008 World Health Organization classification recognizes AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) as a distinct subtype characterized by a poor prognosis. Allogeneic stem cell transplantation seems to improve outcome in eligible patients with these aberrations. Inappropriate expression of the ecotropic viral integration site 1 (EVI1) was demonstrated in virtually all patients with t(3;3)(q21;q26.2) and inv(3)(q21q26.2); as well as in a majority of patients with other 3q26 rearrangements. Other chromosome 3 abnormalities are rarely recognized in AML patients; clinical and prognostic relevance of these alterations is not yet defined. The aim of this study is to assess the prognostic impact of chromosome 3 abnormalities on disease characteristics and treatment outcome in AML. Patients and methods: A total of 580 consecutive adult patients were diagnosed with AML at our institution between February 2002 and July 2012. Conventional cytogenetic analysis performed on diagnostic bone marrow samples detected the presence of 3q abnormalities in 16 patients (2.7%). Two patients were lost to follow-up and were not evaluated for survival analysis. Molecular status of FLT3 and NPM1 was also performed and results are available for 10 patients. Median follow-up time for patients in this series was 47 months ( range 6–125). Results: There were 10 male and 6 female patients, the median age being 64.5 years (range 33–81), 10 patients had de novo AML while 6 evolved from a previously diagnosed myelodysplastic syndrome (MDS). Karyotype from MDS phase was available in 2 patients; both acquired 3q rearrangement at time of progression to AML. At time of diagnosis median haemoglobin value was 9.0 g/dL (range 4–11); median leucocyte count was 10.5 × 103̂/L (range 2.3 – 431). Median platelet count was 116 × 109̂/L (range 28 – 529), consistently with previous studies, which have shown that these patients present with higher platelet count at diagnosis when compared with no 3q rearranged ones. Regarding cytogenetic features 3 patients had t(3;3)(q21;q26), 3 patients had inv(3) (q21; q26), 3 patients showed a balanced rearrangement involving 3q26, while 6 patients harbored a del3q. One patient showed monosomy 3. Additional chromosomal changes were demonstrated in 5 patients, two of them had a complex karyotype (see Table 1), 3 had a monosomy 7. Thirteen patients out of 14 received intensive induction chemotherapy; complete remission (CR) was achieved in 5 patients (CR rate: 35.7%), the remaining 7 patients were resistant to induction as well as to salvage chemotherapy. Four patients underwent autologous stem cell transplantation. Median overall survival in this series is 5.5 months (range 0 – 20). At present only one patient is still alive and in CR, 20 months after diagnosis. Median disease free survival (DFS) for patients achieving a CR was 9 months (range 6–20). Median overall survival for patients resistant to first-line therapy was 3 months (range 0–6). Clinical features and treatment outcome of the patients are summarized in Table 1. Conclusions: The incidence of 3q abnormalities in our single institution series is 2.4%, in keeping with previous studies. Our findings confirm the association between these alterations and thrombocytosis at diagnosis, preceding MDS or multilineage dysplasia, presence in all FAB subtypes (except M3), association with additional chromosomal abnormalities as well as the poor response to conventional chemotherapy (CR rate 35.7%), and very short DFS in spite of obtaining CR. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Impact of Anti-Apoptotic and Multidrug Resistance Phenotypes in Elderly Acute Myeloid Leukemia Patients.

Blood ◽

10.1182/blood.v106.11.2363.2363 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2363-2363

Author(s):

María-Belén Vidriales ◽

Lilia E. Suarez ◽

Jose García-Laraña ◽

Raimundo García-Boyero ◽

María-José Moreno ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Multidrug Resistance ◽

Significant Influence ◽

Myeloid Leukemia ◽

De Novo ◽

Response Analysis ◽

Poor Performance Status ◽

Prognostic Impact ◽

Cd34 Expression ◽

Acute Myeloid

Abstract Elderly patients with acute myeloid leukemia (AML) have an unfavorable outcome, which has been related to both the poor performance status of many of these patients and the biological characteristics of the malignant clone, including the expression of multidrug resistance (MDR) phenotypes. We have quantitatively analyzed by flow cytometry the expression of apoptosis- (bcl-2, bax, APO2.7) and MDR- (P-gp, MRP, LRP) associated proteins in a group of 117 elderly (>65 years) uniformly treated de novo AML patients according to the Pethema LMA-98 protocol. Upon analyzing factors influencing the response to induction therapy, as expected, patients with good and intermediate cytogenetics (n=76) more frequently achieved morphological complete remission (mCR) (63%) than patients having poor cytogenetics (n=23) (mCR: 30%). In addition, CD34 expression also influenced response; thus, 81% (21/26) of CD34-negative patients achieved mCR vs only 46% (42/91) of CD34-positive cases (p=0,008). Neither age nor WBC counts showed a significant influence in response rate. As far as apoptosis and MRD proteins is concerned, interestingly, responding cases showed a lower expression of the bcl-2, MRP and LRP proteins (bcl-2 RFI (relative fluorescence intensity) 10±5.5 vs 13±6, p=0.02; MRP RFI 1.9±0.8 vs 2.7±1.8, p=0.008; LRP RFI 6.2±4.9 vs 8.7±7.5, p=0.01 in responding vs non-responding patients). By contrast, expression of APO 2.7, Bax, and MDR-1 did not influenced response. Analysis of relapse free survival showed that only the number of cycles of chemotherapy required to achieve mCR had prognostic influence (p=0.008), with no significant influence for age, WBC counts, CD34 expression, or cytogenetics. In turn, a high percentage of early apoptotic cells in bone marrow at diagnosis (p=0.01), as well as a low bcl-2/bax ratio (p=0.05), and low MRP expression (p=0.04) were associated with a prolonged RFS. Moreover, upon grouping AML patients according to the expression of MRP and the bcl-2/bax ratio (> and < of the mean of both parameters), only patients with both low MRP expression and low bcl-2/bax ratio (n=16) achieved a plateau phase in the RFS curve after 20 months of follow-up, while the remaining patients showed a continuous relapse trend. In summary, our results show that, in addition to high bcl-2 and bcl-2/bax ratio, a high expression of the LRP and MRP multidrug resistant proteins have an adverse prognostic influence in elderly AML patients. The combination of these parameters contribute to identify distinct groups of patients at a different risk of relapse.

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Impact of Transporter Genes Polymorphisms in Standard Induction of Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.4842.4842 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4842-4842 ◽

Cited By ~ 1

Author(s):

Juan Eduardo Megías ◽

Pau Montesinos ◽

María José Herrero ◽

Federico Moscardó ◽

Virginia Bosó ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Platelet Count ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Multivariable Analysis ◽

Hepatic Function ◽

Hematologic Toxicity ◽

Prognostic Impact ◽

Ocular Toxicity ◽

Acute Myeloid

Abstract Background: The intake of anthracyclines in blast cells could be affected by several transporters, including influx transporters (SLC22A16 and SLCO1B1) and efflux pumps of ABC family. Previous studies suggested that single nucleotide polymorphisms (SNPs) of genes coding for anthracyclines transporters may influence their effectiveness or toxicity, although their impact in acute myeloid leukemia (AML) induction therapy remains undetermined Methods: SNPs of anthracycline transporter genes (ABCB1: rs1128503, rs1045642, rs2032582 and haplotype; ABCC1: rs4148350; ABCC2: rs8187710; ABCG2: rs2231142, rs2231137; SLCO1B1: rs4149056; SLC22A16: rs12210538, rs714368) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry-based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission or resistance. Patients dying during induction were considered as no evaluable for efficacy. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Renal and hepatic toxicities were also evaluated with analytic markers (renal function with urea and creatinine; hepatic function with bilirubin, AST, ALT, FA and GGT). Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, ECOG, leukocyte and platelet count at diagnosis (R® version 3.1.2). Results: The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR or hematologic toxicities. Nevertheless, several associations were obtained between transporter genes polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2). Variant allele of ABCB1 SNPs was previously related with lower activity of ABCB1 pump in kidney cells and lower anthracycline clearance. Accordingly, we obtained nephrotoxicity associated with these SNPs. Association between cardiac toxicity and ABCG2 polymorphisms was found in agreement with previously published works. The ocular toxicity associated with SLCO1B1 was also correlated with low platelet count at diagnosis in multivariable analysis. Table 1. Significant association between SNPs in gene transporters and different toxicities Toxicity Gene/SNP Genotypes Grade 0-1 n (%) Grade 2-4 n (%) OR (95%IC) P Cardiotoxicity ABCG2 rs2231142 CC CA 171 (83.0) 9 (47.4) 35 (17.0) 10 (52.6) 5.64 (1.86-17.80) 0.002 Lung toxicity ABCG2 rs2231142 CC CA 174 (84.5) 12 (63.2) 32 (15.5) 7 (36.8) 3.37 (1.09-10.40) 0.031 Skin toxicity SLCO1B1 rs4149056 TT TC 112 (71.8) 21 (48.8) 44 (28.2) 22 (51.2) 2.43 (1.17-5.06) 0.015 Nephrotoxicity ABCB1 haplotype Other genotypes TT/TT/TT 175 (89.3) 21 (72.4) 21 (10.7) 8 (27.6) 3.74 (1.24-10.85) 0.002 Ocular toxicity ABCC1 rs4148350 GG GT/TT 205 (99.0) 16 (88.9) 2 (1.0) 2 (11.1) 13.7 (2.08-90.47) <0.001 Ocular toxicity SLCO1B1 rs4149056 TT CC 155 (99.4) 23 (92.0) 1 (0.6) 2 (8.0) 9.97 (1.39-71.39) 0.019 Table 2. Significant association between SNPs in gene transporters and analytic markers of renal and hepatic function Hematologic toxicity Gene/SNP Genotypes Mean values (mg or U/dL) Logarithm of the difference (95%IC) P Urea ABCB1 rs1045642 CC TT 57.98 70.89 0.20 (0.01 to 0.40) 0.044 Urea ABCB1 rs2032582 GG TT 56.34 72.07 0.23 (0.03 to 0.42) 0.021 Urea ABCB1 haplotype Other genotypes TT/TT/TT 59.29 78.14 0.24 (0.04 to 0.43) 0.019 Bilirubin ABCB1 rs1045642 CC CT TT 1.77 2.59 2.91 0.021 (0.01 to 0.40) 0.39 (0.12 to 0.65) 0.036 0.004 ALT SLCO1B1 rs4149056 TT TC 90.92 161.02 0.30 (0.01 to 0.60) 0.049 Conclusions: This study shows a prognostic impact of transporter genes polymorphisms in adult AML patients regarding induction chemotherapy efficacy and toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Disclosures No relevant conflicts of interest to declare.

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Review for "Optimizing Venetoclax Dose in Combination with Low Intensive Therapies in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: An Exposure-Response Analysis"

10.1002/hon.2646/v1/review2 ◽

2019 ◽

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Response Analysis ◽

Newly Diagnosed ◽

Exposure Response ◽

Acute Myeloid

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Prognostic Impact of microRNAs (miR-155, miR-10a, let-7a) on the Outcome of Adult Patients with Acute Myeloid Leukemia.

Zagazig University Medical Journal ◽

10.21608/zumj.2019.14277.1302 ◽

2019 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

Al Shaimaa Hatem ◽

Ahmed Gab~Allah ◽

Rania Ghonaim ◽

rasha Haggag

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Adult Patients ◽

Prognostic Impact ◽

Acute Myeloid

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FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Blood Cancer Journal ◽

10.1038/s41408-021-00495-3 ◽

2021 ◽

Vol 11 (5) ◽

Author(s):

Naval Daver ◽

Sangeetha Venugopal ◽

Farhad Ravandi

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Agent ◽

Prognostic Significance ◽

Treatment Algorithm ◽

Molecular Testing ◽

Prognostic Impact ◽

Cell Transplant ◽

Newly Diagnosed ◽

Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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