Effect of initial absolute monocyte count on survival outcome of patients with de novo non-m3 acute myeloid leukemia

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1 LEUKEMIA & LYMPHOMA, 2016 VOL. 57, NO. 11, ORIGINAL ARTICLE: CLINICAL Effect of initial absolute monocyte count on survival outcome of patients with de novo non-m3 acute myeloid leukemia Jianhua Feng a, Wei Zhang b, Junqing Wu b, Shenmeng Gao c, Haige Ye b, Lan Sun b, Yi Chen b, Kang Yu b and Chong-Yun Xing b a Division of Pediatric Hematology-Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China; b Division of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China; c Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China ABSTRACT Increased absolute monocyte count (AMC) at presentation has recently been associated with clinical outcome in different types of hematological malignancies. This study aimed to assess the prognostic value of AMC on survival in 193 adult patients with de novo non-m3 acute myeloid leukemia (AML). The median AMC for all patients at diagnosis was /L, with 41.4, 31.1 and 27.5% of patients showed low (< /L), normal ( /L), and high AMC (> /L), respectively. Univariate analysis revealed that high AMC appeared as a poor prognostic factor for overall survival (OS) (p ¼ ), but not for disease free survival (DFS) (p ¼ ). On multivariate analysis, initial high AMC remained an independent predictor of OS (hazard ratio 2.01, p ¼ 0.017). Our results suggest that AMC at diagnosis, which provides additional prognostic information independently from conventional factors related to patient clinical characteristics or tumor biological features, could be a novel prognostic marker for AML. ARTICLE HISTORY Received 27 December 2015 Revised 26 February 2016 Accepted 10 March 2016 KEYWORDS Acute myeloid leukemia; absolute monocyte count; prognosis; survival Introduction Acute myeloid leukemia (AML) is a heterogeneous group of malignant hematological neoplasm, characterized by the uncontrolled rapid proliferation of immature hematopoietic cells.[1,2] Despite advances in understanding disease biology, improvement in chemotherapy and supportive care for adult AML, the long-term survival remains poor due to the majority relapse or are refractory to therapy.[3,4] As of today, most of the available prognostic indicators for classification of AML patients comprise patient clinical characteristics (such as age) and tumor biological features (such as cytogenetics and molecular features),[5,6] whereas scant data are available on the contribution of the tumor microenvironment to the patients biological and clinical diversity. Recently, peripheral monocytes, which reflect the tumor microenvironment, has been reported to correlate with survival in various types of hematological malignancies, including diffuse large B-cell lymphoma (DLBCL),[7,8] Follicular lymphoma (FL),[9] adult T-cell leukemia/lymphoma,[10] chronic lymphocytic leukemia (CLL),[11] and Hodgkin Lymphoma (HL).[12,13] However, to our knowledge, no studies regarding the impact of peripheral absolute monocyte count (AMC) at diagnosis in AML are available. Thus, the primary aim of this retrospective study was to evaluate the prognostic value of AMC at the time of diagnosis in a cohort of 193 newly diagnosed AML patients. Patients and methods Patients In this retrospective study, we evaluated a total of 193 previously untreated adult patients with de novo AML (excluding acute promyelocytic leukemia [M3]) treated at the First Affiliated Hospital of Wenzhou Medical University from April 2010 to August Patients with preceding hematological disorders or therapyrelated AML were excluded. The diagnosis and classification of the AML subtypes were based on the morphological, immunophenotypic, and cytogenetic features of leukemic blast cells according to FAB [14] and WHO 2008 criteria.[15] All patients were 18 years of age or older, with complete clinical and laboratory data. Written informed consent was obtained from each patient before entering the study according to CONTACT Chong-Yun Xing kevin @163.com Division of Hematology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou , Zhejiang, PR China ß 2016 Informa UK Limited, trading as Taylor & Francis Group

2 EFFECT OF AMC IN ACUTE MYELOID LEUKEMIA 2549 the Declaration of Helsinki, and the study was approved by the Institutional ethics committee. Medical records were reviewed to determine age, gender, white blood cell (WBC) count as well as AMC, hemoglobin level, platelet count, and the proportion of peripheral blood and bone marrow (BM) blast cells. The values for WBC count as well as the AMC were obtained from the clinical laboratory records, and were determined either by manual differential (in cases flagged for abnormal values) or the hematology automatic analyzer Sysmex XE-2100 (Sysmex, Kobe, Japan). All patients received conventional induction chemotherapy (idarubicin 8 10 mg/m 2 or daunorubicin mg/m 2 per day on days 1 3 and cytarabine 100 mg/m 2 per day on days 1 7). Ninety one patients who did not achieve complete remission (CR) in the first course of induction chemotherapy, as evaluated by the persistence of blasts in the BM aspirate between day 28 and day 45 of induction chemotherapy, received a second course of induction therapy.[16 18] A total of 41 patients did not achieve CR after at least two cycles of induction therapy and salvage therapy was administered.[19] Of the remaining 152 patients who achieved CR after induction therapy, 124 patients received high-dose cytarabine-based consolidation (2000 mg/m 2 every 12 h on days 1 3, total six doses); the other 28 patients received allogeneic hematopoietic stem cell transplantation (HSCT) as postremission therapy. Cytogenetic analysis BM samples obtained at diagnosis were systematically examined for cytogenetic abnormalities by R- and/or G-banding techniques and classification according to the International System for Human Cytogenetic Nomenclature.[20] Whenever possible, at least 20 metaphases were analyzed. Cytogenetic failures were observed in four patients. Risk status based on cytogenetics was according to NCCN guideline.[21] Basically, favorable risk refers to aberrations t(8;21), inv(16), and t(16;16). Unfavorable risk was defined as monosomy of chromosome 7 or 5, loss of chromosomal arm 5q or 7q, inv(3), 11q23-non t(9;11), t(3;3), t(6;9), t(9;22), and three or more aberrations. Intermediate risk includes normal karyotype, trisomy of chromosome 8, t(9;11) and all other aberrations. Statistical analysis The aim of the study was to determine the influence of the initial AMC on the clinical outcome of AML patients. The lower ( /L) and the upper limits ( /L) of normal monocyte absolute value were used as cutoff points. Categorical covariates were compared using the chi-square test or Fisher s exact test and numerical covariates were compared using the Wilcoxon rank-sum test. Overall survival (OS) was measured from the date of initial diagnosis to the date of death or last follow-up. Disease free survival (DFS) was measured from the date of CR to the time of relapse or death. Patients undergoing allogeneic HSCT were censored at the time of transplantation. OS and DFS were calculated by the Kaplan Meier method. Survival curves were compared using the log-rank test. The Cox proportional hazards model was used for univariate analysis. Variables that were statistical significant in the univariate analysis were included in the multivariate Cox proportional hazards model. All tests were two-sided and a p value < 0.05 was considered statistical significant. All statistical analyses were performed using Stata version 12 software (StataCorp LP, College Station, TX). Results Patient characteristics Patient characteristics are summarized in Table 1. Overall 112 (58.0%) of the 193 patients were males. Median age was 47 years (range: years). Median WBC count was /L (range: / L). The median percentages of peripheral blood and BM blasts were 54% (range: 0 98%) and 65.5% (range: %), respectively. According to the FAB classification, there were one patient with M0 (0.5%), one patient with M1 (0.5%), 37 patients with M2 (19.2%), 93 patients with M4 (48.2%), 46 patients with M5 (23.8%), three patients with M6 (1.6%), and one patient with M7 (0.5%). A total of 11 patients (5.7%) were not morphologically classified. Chromosomal analysis could be performed in 189 patients. A total of 56, 121, and 12 patients showed favorable, intermediate, and unfavorable karyotype, respectively. The median follow up for the entire cohort of 193 patients was 10 months. The estimated 5-year OS was 31% (95% confidence interval [CI]: 20 42%). A total of 84 deaths were recorded. The estimated 5-year DFS was 41% (95% CI: 27 53%). The median AMC for all patients at diagnosis was /L, with 41.4, 31.1, and 27.5% of patients showed low (< /L), normal ( / L), and high AMC (> /L, the upper boundary was /L), respectively. Patients with high AMC tended to more often have high WBC count

3 2550 J. FENG ET AL. Table 1. Baseline patient characteristics [median (range) or n (%)]. Characteristics All patients (n ¼ 193) Low initial AMC (< /L) (n ¼ 80) Normal initial AMC ( /L) (n ¼ 60) High initial AMC (> /L) (n ¼ 53) p Value Age (years) 47 (18 83) 46.5 (18 75) 44 (18 81) 53 (18 83) Male/female 112/81 47/33 38/22 27/ WBC count (10 9 /L) 14.2 ( ) ( ) ( ) ( ) Hemoglobin (g/l) 78 (20 161) 78.5 (39 127) 80 (52 131) 75 (20 161) Platelets (10 9 /L) 40 (3 560) 40 (4 207) 43.5 (3 256) 35 (9 560) Blasts in peripheral blood 54 (0 98) 61.5 (0 98) 37 (0 91) 59 (0 92) (%) Blasts in bone marrow (%) 65.5 ( ) 74.2 ( ) ( ) 71 ( ) FAB subtypes M0 1 (0.5) 1 (1.3) M1 1 (0.5) 1 (1.3) M2 37 (19.2) 18 (22.5) 13 (21.7) 6 (11.3) M4 93 (48.2) 32 (40.0) 30 (50.0) 31 (58.5) M5 46 (23.8) 21 (26.3) 12 (20.0) 13 (24.5) M6 3 (1.6) 3 (3.8) M7 1 (0.5) 1 (1.3) Unclassified 11 (5.7) 3 (3.8) 5 (8.3) 3 (5.7) Cytogenetic risk group a Favorable 56 (29.0) 19 (23.8) 21 (35.0) 16 (30.2) Intermediate 121 (62.7) 53 (66.3) 34 (56.7) 34 (64.2) Unfavorable 12 (6.2) 5 (6.3) 5 (8.3) 2 (3.8) Missing 4 (2.1) 3 (3.8) 0 1 (1.9) Anthracycline during induction Idarubicin (8 10 mg/m 2 ) 172 (89.1) 72 (90.0) 52 (86.7) 48 (90.6) Daunorubicin (45 mg/m 2 ) 15 (7.8) 5 (6.2) 6 (10.0) 4 (7.5) Daunorubicin (60 mg/m 2 ) 6 (3.1) 3 (3.8) 2 (3.3) 1 (1.9) CR b 102 (52.8) 42 (52.5) 32 (53.3) 28 (52.8) 1 No. of patients who underwent HSCT 28 (14.5) 15 (18.8) 8 (13.3) 5 (9.4) AMC: absolute monocyte count; WBC: white blood cell; FAB: French-American-British; HSCT: hematopoietic stem cell transplant. a Comparison of the two cytogenetic subgroups (favorable versus other). b Achieved complete remission (CR) after one course of induction therapy. than patients with low and normal AMC (p ¼ ). While patients with normal AMC tended to more often have low percentages of peripheral blood and BM blasts than patients with low and high AMC (p ¼ and p ¼ , respectively). Patient characteristics according to AMC at diagnosis are summarized in Table 1. Prognostic impact of AMC at time of diagnosis Kaplan Meier analysis showed no difference in OS (p ¼ ) [Figure 1A] or DFS (p ¼ ) [Figure 1B] between low AMC group and normal AMC group. However, high AMC group had a significantly worse OS compared with normal AMC group (p ¼ ) [Figure 1C] while no statistical difference was observed for DFS (p ¼ ) [Figure 1D]. Results of the univariate and multivariate analyses for factors influencing OS in patients with the initial AMC /L are reported in Table 2. The univariate analysis showed the following clinical parameters were significantly associated with OS: AMC (as a categorical variable), age, and cytogenetic characteristics. Whereas when the AMC was regarded as a numerical variable, the relationship between the AMC and OS approached, but did not reach, statistical significance (p ¼ 0.059). Multivariate analysis that included all the parameters which were significant in univariate analysis revealed that the initial high AMC (vs. normal) was independently associated with shorter OS (HR ¼2.01, 95%CI , p ¼ 0.017). Cytogenetic risk group was also shown to be an independent prognostic factor for the OS. In addition, the initial AMC remained an independent predictor of OS (HR ¼2.17, 95%CI , p ¼ 0.006) if analyses were not censored at allogeneic HSCT in first CR [Table 3]. Due to the relatively high frequency of patients who presented with M4/M5 leukemia (myelomonocytic/monocytic) involving the monocyte population in our cohort, we further analyzed the prognostic significance of AMC according to FAB subtype in patients with the initial AMC /L. Kaplan Meier analysis showed that the initial high AMC was associated with a short OS, when compared with a normal AMC, in the M4/M5 AML patients (p ¼ ) [Figure 2A]. However, there were too few non-m4/m5 AML patients (n ¼ 27) to make a similar analysis in this subgroup meaningful (p ¼ ) [Figure 2B]. Univariate and multivariate analyses identified the AMC to be an

4 EFFECT OF AMC IN ACUTE MYELOID LEUKEMIA 2551 Figure 1. Survival outcomes according to absolute monocyte count (AMC) at diagnosis of acute myeloid leukemia. (A) Overall survival after diagnosis. Low AMC (n ¼ 80) vs. normal AMC (n ¼ 60). p ¼ (B) Disease-free survival after complete remission. Low AMC (n ¼ 65) vs. normal AMC (n ¼ 50). p ¼ (C) Overall survival after diagnosis. Normal AMC (n ¼ 60) vs. high AMC (n ¼ 53). p ¼ (D) Disease-free survival after complete remission. Normal AMC (n ¼ 50) vs. high AMC (n ¼ 37). p ¼ Table 2. Univariate and multivariable analyses for overall survival. Univariate analysis Multivariable analysis Covariate Hazard ratio (95%CI) p Value Hazard ratio (95%CI) p Value AMC (10 9 /L; continuous variable) 1.04 ( ) AMC (10 9 /L; high vs. normal) 2.17 ( ) ( ) Age (years; continuous variable) 1.02 ( ) ( ) Cytogenetics (favorable vs. other) 0.48 ( ) ( ) WBC count (10 9 /L; 30 vs. <30) 1.34 ( ) Blasts in peripheral blood (%; 40 vs. <40) 1.34 ( ) Blasts in bone marrow (%; 90 vs. <90) 1.13 ( ) AMC: absolute monocyte count; WBC: white blood cell; 95%CI: 95% confidence interval. Table 3. Univariate and multivariable analyses for overall survival without censoring patients receiving allogeneic hematopoietic stem cell transplant in first complete remission. Univariate analysis Multivariable analysis Covariate Hazard ratio (95%CI) p Value Hazard ratio (95%CI) p Value AMC (10 9 /L; high vs. normal) 2.30 ( ) ( ) Age (years; continuous variable) 1.02 ( ) ( ) Cytogenetics (favorable vs. other) 0.54 ( ) ( ) AMC: absolute monocyte count; 95%CI: 95% confidence interval.

5 2552 J. FENG ET AL. Figure 2. Survival outcomes according to absolute monocyte count (AMC) at diagnosis of acute myeloid leukemia and FAB subtype. (A) Overall survival after diagnosis in M4/M5 AML patients. Normal AMC (n ¼ 42) vs. high AMC (n ¼ 44). p ¼ (B) Overall survival after diagnosis in non-m4/m5 AML patients. Normal AMC (n ¼ 18) vs. high AMC (n ¼ 9). p ¼ Table 4. Univariate and multivariable analyses for overall survival in patients with M4/M5 subtypes. Univariate analysis Multivariable analysis Covariate Hazard ratio (95%CI) p Value Hazard ratio (95% CI) p Value AMC (10 9 /L; high vs. normal) 2.22 ( ) ( ) Age (years; continuous variable) 1.03 ( ) ( ) Cytogenetics (favorable vs. other) 0.35 ( ) ( ) AMC: absolute monocyte count; 95%CI: 95% confidence interval. independent predictor for survival in patients with M4/ M5 subtypes [Table 4]. Discussion To our knowledge, no other studies assessing the role of AMC in AML have been published to date. Here we studied the prognostic value of AMC at diagnosis in a retrospective cohort of 193 newly diagnosed AML. In keeping with date from other types of hematological malignancies,[7 13] high AMC at diagnosis represented an independent predictor of poor survival in AML. Additionally, by the receiver operating characteristic (ROC) curve analysis, /L was confirmed as the cutoff point of AMC for survival outcome of AML patients with the initial AMC /L (data not shown). Despite the growing body of evidence supporting the role of the tumor microenvironment during carcinogenesis,[22 24] the incorporation of prognostic variables based on the tumor microenvironment into routine clinical practice remains a challenge. The evidence linking monocytes with survival in AML raises the possibility that the AMC at diagnosis, the widely available clinical parameter derived from a complete blood count, may be easily incorporated into prognostic classification practice for AML. Currently, the biological reasons for the correlation between the number of circulating monocytes and prognosis in cancer mostly remain speculative. Fortunately, previously published experimental studies involving in the initiation, promotion, and progression of cancer provide valuable insights into the mechanisms underlying the prognostic effect of AMC in cancer. It is well known that monocytes, as the key component of inflammatory response, might directly promote cancer cell growth by producing various proinflammatory cytokines including interleukin-1 (IL- 1), interleukin-6 (IL-6), and tumor necrosis factor (TNF).[25,26] Moreover, a subpopulation of immunosuppressive cells, the myeloid-derived suppressor cells (MDSCs) has recently been reported to play a role in cancer immune tolerance. Given that monocytes exposed to tumor cells may acquire MDSC-like properties and exhibit enhanced immune-suppressive activity, as shown in malignant glioma [27] and melanoma,[28] it is possible that one of the explanations for the association between monocytosis and adverse prognosis in AML could relate to their immunosuppressive function. Furthermore, tumor cell-derived cytokines and chemokines, such as monocyte chemoattractant protein-1 and vascular endothelial growth factor, could trigger differentiation of monocytes into tumor-associated macrophages (TAMs).[29,30] Considering that TAMs could contribute to systemic immunosuppression and have an important role in tumor angiogenesis, invasion and migration,[25,31 33] not surprisingly then, peripheral blood monocytosis reflects a high tumor burden in patients with cancer, which in turn correlates with

6 EFFECT OF AMC IN ACUTE MYELOID LEUKEMIA 2553 poor clinical outcome. However, in order to address the above possible mechanisms underlying the prognostic effect of AMC in AML, the correlation of the AMC with the density of MDSCs and TAMs needs to be analyzed in future studies using both quantitative and functional assays. One of the limitations in our study was the retrospective nature, thus selection bias was difficult to be well balanced. For example, although both the morphological diagnosis and immunophenotyping were utilized for accurate diagnosis, with the ratios of 48.2 and 23.8% in our cohort, cases of M4 and M5 are substantially more frequent as compared with western cases, where the prevalence are 20 30% and about 10%.[34,35] Additionally, only 12/189 (6.35%) patients presented with unfavorable cytogenetics in our cohort, this proportion seems very low even for a group of patients whose median age was between 45 and 50 years.[36] Besides the population genetic diversity, the patient selective bias may be responsible for a particular FAB subtype or cytogenetic feature of AML in our cohort. Therefore, caution should be taken in interpreting the results of this study, or it is possible that our results might not be generalizable to other populations. Moreover, although the independent prognostic significance of the initial AMC was confirmed in multivariate analysis, there was still other heterogeneity that we still cannot rule out, such as distribution of highrisk genomic aberrations (e.g. FLT-3 ITD), which were not examined in our analysis due to the limited date. Thus, the prognostic role of the AMC should be revalidated in the multivariate context including genetic information in the further prospective studies. In summary, this study is the first to show the relationship between AMC at diagnosis and survival for AML patients. The findings in our study may represent proof of principle of the biological effect of the tumor microenvironment in AML course. Thus AMC at diagnosis, which provides additional prognostic information independently from conventional factors related to patient clinical characteristics or tumor biological features, could be a novel prognostic marker for AML. In addition to the presence or absence of high AMC at diagnosis of AML, several factors relevant to AMC should be further investigated as having prognostic value, including the following: (1) the AMC was obtained only at diagnosis of AML in our study, which did not allow an analysis for the role of AMC evaluated after allogeneic HSCT in predicting the transplant outcome regarding to risk of opportunistic infections, death, and recurrence of the original disease; (2) Kaplan Meier analysis showed that the most significant difference in OS appeared within the first few months [Figure 1C]. Due to the direct correlation between the AMC and total WBC demonstrated in our study, it seems reasonable to suppose that complications related to hyperleukocytosis in patients with an elevated AMC drive the difference in OS. These factors should be further analyzed in order to provide further information regarding our observation. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at Funding information This work was supported by the Zhejiang Provincial Natural Science Foundation of China [Grant Nos. LQ14H080002, Y ]. References [1] Estey E, Dohner H. Acute myeloid leukaemia. Lancet. 2006;368: [2] Lane SW, Scadden DT, Gilliland DG. The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood. 2009;114: [3] Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106: [4] Pulte D, Gondos A, Brenner H. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood. 2009;113: [5] Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18: [6] Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. 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