Kinetics and apoptotic profile of circulating endothelial cells as prognostic factors for induction treatment failure in newly diagnosed acute myeloid leukemia patients

Abstract Introduction. The circulating endothelial cells (CEC) are proposed to be a noninvasive marker of angiogenesis. The number of CEC in peripheral blood of patients (pts) with acute myeloid leukemia (AML) has not been investigated so far. Patients and Methods. We evaluated the count of resting (rCEC) and activated (aCEC) CEC and circulating endothelial progenitor cells (CEPC) as well as apoptotic CEC (CECAnnV+) in 62 AML pts at the time of diagnosis and 30 healthy controls. Additionally in 26 pts measurements were performed at the time of response evaluation and in 15 pts also 24 h after the first and last dose of chemotherapy. The levels of CEC were correlated with known prognostic factors and response to treatment. CEC were evaluated by the four colour flow cytometry using a panel of previously described monoclonal antibodies and an appropriate analysis gate. CEPC were defined as negative for hematopoietic marker CD45 and positive for endothelial cells markers CD34, CD31 and the endothelial progenitor marker CD133. Resting CEC were defined as CD45−, CD133−, CD31+, CD34+, CD146+ and negative for activation markers (CD105, CD106). CD105 or CD106 positive mature endothelial cells were classified as activated CEC. Apoptotic CEC were CD146 and Annexin V positive. Results. In untreated AML pts we observed 10-fold higher CEC level (median 29,3/μL) than in the control group (2,95/μL) p<0,0001. The numbers of aCEC (12,7/μL), rCEC (12,3/μL) and CEPC (1,7/μL) were significantly higher in AML pts at diagnosis when compared to healthy controls (aCEC 0,9/μL, rCEC 1,6/μL and 0,1/μL; p<0,0001). CECAnnV+ count was also 10-fold higher in AML (1,5/μL) than in controls (0,15/μL; p<0,0001). Both CEC and CECAnnV+ counts did not correlate with WBC, hemoglobin and platelets count as well as percentage of blasts in bone marrow and absolute blast count. The positive correlations between CEC number and CEPC count (r=0,435; p<0,001), CECAnnV+ count (r=0,502; p<0,01) as well as LDH activity (r=0,328; p<0,02) were found. The significant decrease of aCEC and rCEC numbers 24 hours after the first dose of chemotherapy was noted in patients who achieved complete remission (CR)(p<0,04) but not in pts refractory to treatment. Moreover aCEC, rCEC, CEPC and CECAnnV+ counts determined at the time of response’s evaluation were significantly lower then at the time of diagnosis in pts who achieved CR (p<0,01) and did not differ in refractory AML. There was no difference between levels of both viable and apoptotic CEC in AML pts in CR and in the control group (p>0,05). Conclusions. The CEC and CECAnnV+ levels are significantly higher in AML patients than in healthy subjects and correlate with response to treatment. Further investigation should be undertaken to better determine their prognostic and therapeutic value.

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Bone Marrow Lymphocyte Subsets in Newly Diagnosed Acute Myeloid Leukemia Patients and Their Relation to Standard Prognostic Factors and Response to Induction Therapy

Journal of Advances in Medicine and Medical Research ◽

10.9734/jammr/2018/46278 ◽

2019 ◽

Vol 28 (8) ◽

pp. 1-8

Author(s):

Hoda Mohamed El Gendi ◽

Noha Bassiouny Hassan Mostafa ◽

Marina Mounir William Labib

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Prognostic Factors ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Lymphocyte Subsets ◽

Newly Diagnosed ◽

Acute Myeloid

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Circulating endothelial cells and their progenitors in acute myeloid leukemia

Oncology Letters ◽

10.3892/ol.2016.4859 ◽

2016 ◽

Vol 12 (3) ◽

pp. 1965-1970 ◽

Cited By ~ 7

Author(s):

Asmaa Mohammed Zahran ◽

Sanaa Shaker Aly ◽

Hanan Ahmed Altayeb ◽

Arwa Mohammed Ali

Keyword(s):

Endothelial Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Circulating Endothelial Cells ◽

Acute Myeloid

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Efficacy and safety of cladribine addition to induction treatment of newly diagnosed acute myeloid leukemia: a systematic review and meta-analysis

Hematology ◽

10.1080/16078454.2021.1962047 ◽

2021 ◽

Vol 26 (1) ◽

pp. 577-587

Author(s):

Qianying Pan ◽

Juan Li

Keyword(s):

Systematic Review ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Meta Analysis ◽

Induction Treatment ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Acute Myeloid

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Number of Mutations and Type of Prior Myeloproliferative Neoplasm Are Prognostic Factors in Acute Myeloid Leukemia Post Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2018-99-114428 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2806-2806 ◽

Cited By ~ 1

Author(s):

Edmond Chiche ◽

Sarah Bonnet ◽

Sarah Bertoli ◽

Andrew T Kuykendall ◽

Lauris Gastaud ◽

...

Keyword(s):

Clinical Trials ◽

Acute Myeloid Leukemia ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Induction Treatment ◽

Calr Mutations ◽

Acute Myeloid

Abstract BACKGROUND Post myeloproliferative neoplasms (MPN) acute myeloid leukemia (AML) occurs respectively in 1.5%, 7.0% and 11% of patients with essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). This subgroup of AML has very poor prognosis and are often excluded from clinical trials. Therefore, only few cohorts including molecular data are available. MATERIAL AND METHODS We retrospectively collected data from 111 patients treated in four centers in France for post MPN-AML. Clinical, molecular and treatment information was available for all patients at AML and MPN stages. DNA was extracted from samples at diagnosis of MPN chronic phase, at diagnosis of AML phase and after induction treatment. JAK2-V617F mutations were identified by qPCR (Ipsogen® MutaQuant kit, Qiagen, Germany), MPL-W515L/K mutations were identified by PCR (Ipsogen® MutaScreen kit, Qiagen, Germany) and CALR mutations were identified by conventional sequencing (Applied Biosystems, 3500Genetic Analyzer). NGS on 36 genes using Ampliseq librairy and Ion Proton sequencing (Thermofisher, Waltham, MA, USA) were performed in 96/111 patients. Overall response rate (ORR) was defined by complete remission (CR), CR with incomplete hematologic recovery (CRi), partial remission (PR) and stable disease (SD). Overall survival (OS) was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analyses were performed using SPSS v.22 software (IBM SPSS Statistics). RESULTS 111 patients treated for post MPN-AML were retrospectively included in this study. Sex ratio M/F was 54%/46%. Median age at AML diagnosis was 66 years (28-89, range). Cytogenetic categories were favorable, intermediate and adverse in 2 (2%), 51 (46%) and 47 (42%) patients, respectively. 25/111 (23%) patients had a monosomal karyotype (MK). Median number of additional mutations excluding from JAK2/MPL/CALR mutations was 2 (0-6, range). The most frequent additional mutations were TP53 (23%), ASXL1 (17%), TET2 (13%), SRSF2 (10%), DNMT3A (8%), SF3B1 (8%) and RUNX1 (8%). Only 2 patients were mutated for NPM1 and 2 and 4 patients were FLT3-ITD and FLT3-TKD, respectively. Prior MPN were PV, ET and PMF in 20%, 34% and 46% of patients, respectively. First line treatment was intensive chemotherapy (IC) for 61 (55%) patients, hypomethylating agents (HMA) for 10 (9%) or other treatments including best supportive care, cytoreduction for the other ones. 24/111 (22%) underwent to ASCT. ORR was 54% (with 30/71 (42%) in CR/CRi) in patients treated by IC or HMA. We did not identify factors predicting a higher rate of CR/CRi. OS was 12 months [6-18] and was not influenced by transplant, cytogenetic categories or by the type and allele frequencies of JAK2/CALR/MPL mutations. OS was significantly longer in the group treated with HMA as compared to IC (10 versus 46 months, respectively, p=0.006); in patients with prior PV as compared to ET or MF (26 months [0-57] versus 10 months [7-13] versus 10 months [4-16] respectively, p=0.07) and in patients with presence of additional mutations other than JAK2/CALR/MPL (5 months [0-12] versus 46 months [32-60] in 38 patients without mutation versus 58 patients with presence of at least one mutation, respectively, p=0.04). By multivariate analysis, only presence of additional mutations was predictive for OS with a hazard ratio (HR) = 0.42 [0.18-0.97] (p=0.04). Finally, we followed the VAFs of JAK2 in seven patients before and after IC. We observed in 2 patients an increase of JAK2 clone correlated with CR whereas no variation of VAFs was associated with absence of CR. CONCLUSIONS In conclusion, we confirmed the poor prognosis of post MPN AML. Classical AML prognostic factors were not validated in our cohort. We identified the presence of mutations other than JAK2/MPL/CALR as the main prognostic factor whereas post-PV AML appeared to do better than post-ET and post-PMF AML. The very poor result of IC with or without ASCT highlights the need to develop specific clinical trials in this subgroup of AML. Disclosures Kuykendall: Celgene: Honoraria; Janssen: Consultancy. Sallman:Celgene: Research Funding, Speakers Bureau. Cluzeau:CELGENE: Consultancy; MENARINI: Consultancy; JAZZ PHARMA: Consultancy.

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Fludarabine Based Regimen (FLAI) Is an Effective Treatment for Induction of Multidrug Resistant Pgp-Positive Acute Myeloid Leukemia Patients.

Blood ◽

10.1182/blood.v106.11.1857.1857 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1857-1857 ◽

Cited By ~ 1

Author(s):

Domenico Russo ◽

Daniela Damiani ◽

Michele Malagola ◽

Antonio De Vivo ◽

Mauro Fiacchini ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Multidrug Resistance ◽

Myeloid Leukemia ◽

Multidrug Resistant ◽

Response To Treatment ◽

Induction Treatment ◽

Newly Diagnosed ◽

Match Pair ◽

Acute Myeloid

Abstract Induction treatment of acute myeloid leukemia (AML) is conventionally based on regimens containing cytarabine (Ara-C), one anthracycline and, sometimes, a third drug, such as etoposide. Primary P-glycoprotein (Pgp) overexpression is the most important mechanism of multidrug resistance (MDR) in AML cells and it is almost always associated with less response to treatment. To deal with this problem, in 1997, we started a treatment program with a regimen including Fludarabine (FLUDA) for the induction of newly diagnosed AML patients. FLUDA showed to be toxic against the MDR cells, in vitro, and able to enhance Ara-C cytotoxicity by increasing cell concentration of Ara-C 5′ triphosphate and inhibiting DNA repair. Between 1997 and 2004, 110 newly diagnosed AML patients aged less than 60 years were induced with FLAI (Fludarabine 25 mg/sqm/day days 1–5, Ara-C 2 gr/sqm/day days 1–5, Idarubicine 10 mg/sqm/day days 1, 3, 5) in the context of three consecutive prospective multicentric trials. At diagnosis, all the patients were assessed for the Pgp expression by an indirect immunofluorescence method with the anti-p170 monoclonal antibody MRK-16. The results were expressed as the mean fluorescence index (MFI) and patients with a MFI > 6 were setted as MDR+ve. We correlated the Pgp-expression, with the response to the induction. Interestingly, the Pgp+ve (MFI > 6) patients treated with FLAI entered CR as well as the Pgp-ve (MFI < 6). Twenty-four out of 39 Pgp+ve patients (61%) and 54 out of 71 Pgp-ve patients (76%) achieved a CR after a single induction course of FLAI (p= 0.1). This observation strongly supported the original hypothesis that fludarabine could play a favourable role against MDR+ve cells. In order to validate this finding we compared the results obtained in an hystorical group of 136 newly diagnosed AML patients younger than 60 years treated with a non-fludarabine containing regimen AI (Ara-C 200 mg/sqm/day c.i. days 1 - 7, Idarubicine 10 mg/sqm/day days 1, 3, 5). In the non-fludarabine group, 22 out of 69 Pgp+ve patients (32%) and 42 out of 67 Pgp-ve patients (63%) achieved a CR after one course of the induction therapy. This difference was stastically significant (p= 0.0006). Based on these observations, we decided to conduct a match pair study to confirm the superiority of FLAI for overcoming the primary multidrug resistance Pgp-mediated in AML.

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Neutropenic fever prophylaxis during induction therapy for acute myeloid leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18531 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18531-e18531

Author(s):

Nassim H. Nabbout

Keyword(s):

Acute Myeloid Leukemia ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Standard Of Care ◽

Neutropenic Fever ◽

White Blood Count ◽

Induction Treatment ◽

Newly Diagnosed ◽

Oral Antibiotics ◽

Acute Myeloid

e18531 Neutropenic Fever Prophylaxis During Induction Therapy for Acute Myeloid Leukemia Nassim Nabbout, MD, Salam Kadhem, MD, Rawaa Ebrahem, MD, Rossa Khalaf, MD, Baharat Malhotra, MD, K. James Kallail, PhD Background: Neutropenic fever is an oncological emergency [1] that occurs at a high rate in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy. Oral antibiotics have been considered standard of care for prophylaxis for these patients once they develop neutropenia [2]. To determine the efficacy of this approach, we conducted a retrospective review of newly diagnosed AML patients. Methods: All adult patients who underwent induction treatment for newly diagnosed AML at one Wichita, Kansas medical center between January 1, 2011 and December 31, 2013 were identified. The medical records were reviewed and pre-specified variables were collected. Results: Thirty-eight patients were included and their charts were reviewed. Nineteen (50%) were males. Thirty-six patients (95%) were white. The average white blood count on day 1 of treatment was 34000 cell/mm3 and the range was 1300 - 305,000 cell/mm3. The average ANC was 3700 cell/mm3 with the range of 10 - 28288 cell/mm3. All patients received prophylactic oral antibiotics once they became neutropenic. In all, but one patient, this regimen consisted of combination of levofloxacin, acyclovir, and fluconazole. Thirty-four patients (89%) developed neutropenic fever while they were on oral prophylactic antibiotics. Two patients (5%) developed septic shock. Four patients (11%) died during the first 21 days of induction, all due to infections, and three (8%) went to hospice. Causative organisms were identified in 11 patients (29%). All patients were switched to intravenous vancomycin and cefepime once they became febrile. Conclusions: Eighty-nine percent of patients developed neutropenic fever despite prophylaxis with oral antibiotics. These dismal results suggest that the current standard of care for neutropenic fever prophylaxis is ineffective and highlight the need for a different approach. Future studies should consider changing the regimens of antibiotics and/or the route of administration toward more aggressive prophylactic strategies.

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Decitabine Versus Intensive Chemotherapy for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-116102 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2713-2713 ◽

Cited By ~ 1

Author(s):

Eun-Ji Choi ◽

Je-Hwan Lee ◽

Han-Seung Park ◽

Jung-Hee Lee ◽

Miee Seol ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Treatment Options ◽

Induction Treatment ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Monosomy 7 ◽

Elderly Aml ◽

Acute Myeloid

Abstract Background Elderly patients with acute myeloid leukemia (AML) has generally poor prognosis prognosis in accordance with their unfavorable clinical and biologic features. Hypomethylating agents have shown potential in the treatment of AML as well as myelodysplastic syndrome (MDS). In this retrospective study, we compared the outcomes of elderly AML patients according to induction treatment options: decitabine versus intensive chemotherapy. We also tried to identify specific subsets of patients who are most likely to benefit from decitabine or intensive chemotherapy. Methods This study included elderly patients aged 65 years or older who received induction treatment with decitabine or intensive chemotherapy for newly diagnosed AML at a single institute. The endpoints for this study were overall survival (OS), response, and event-free survival (EFS). Response included complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with partial hematologic recovery (CRh). Results A total of 107 patients, decitabine for 75 and intensive chemotherapy for 32, were analyzed. Decitabine was given as 20 mg/m2/day for 5 days every 4 weeks. Median 5 courses (range, 1-43) were delivered to the patients and 16 patients were still on decitabine treatment at the time of analysis. Intensive chemotherapy regimens included cytarabine plus daunoruribin (n=21) or idarubicin (n=10), and hyper-CVAD (n=1): 25 patients received one course and 7 received two courses for induction treatment. The rate for CR + CRi + CRh (CRR) was 38.6% (39 of 101 assessable patients). With a median follow-up duration of 14.8 months (95% confidence interval [CI], 12.0-22.8) among surviving patients, 79 patients died and 22 relapsed. The median OS and EFS were 12.3 months (95% CI, 10.0-14.7) and 4.1 months (95% CI, 2.5-5.7), respectively. Decitabine showed lower CRR (26.1% vs. 65.6, P<0.001) with similar EFS (median 3.4 vs. 6.1 months, P=.338) and OS (median 11.0 vs. 14.8 months, P=.124) compared to intensive chemotherapy (Figure 1). Multivariate analysis demonstrated that induction treatment option, peripheral blood (PB) blast percentage, and leukemia type (secondary vs. de novo) were independent risk factors for CRR. A presence of FLT3-ITD mutation, complex karyotype, and higher PB blast percentage were independently associated with shorter OS. Subgroup analysis for OS showed that intensive chemotherapy was superior to decitabine in patients with FLT3-ITD mutation (median 9.5 vs. 2.6 months, P=.025) and poor cytogenetic risk (10.8 vs. 6.1 months, P=.027), but decitabine showed tendency towards a longer OS compared to intensive chemotherapy in those with monosomy 7 or del(7q) (11.7 vs. 3.3 months, P=.093; Figure 2). Conclusion Decitabine showed similar OS to intensive chemotherapy despite of lower response rate in elderly AML patients. Clinical outcomes of specific subgroups seemed to be different according to induction treatment options. Further studies are warranted for selection of optimal treatment options for elderly AML patients. Disclosures No relevant conflicts of interest to declare.

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A Prospective Clinical Study of the Efficacy and Adverse Reactions of Azacitidine Combined with IA Regimen As the Induction Treatment of Newly Diagnosed AML

Blood ◽

10.1182/blood-2021-145026 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4408-4408

Author(s):

Lifen Kuang ◽

Juan Li

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Risk Group ◽

Induction Treatment ◽

Newly Diagnosed ◽

Significant Difference ◽

Acute Myeloid

Abstract Objective: This single-arm prospective research (ChiCTR2100044731) aimed to evaluate the efficacy and safety of azacitidine combined with IA regimen in the induction treatment of newly diagnosed acute myeloid leukemia (AML), with a view to further improving the efficacy of acute myeloid leukemia with poor prognosis. Methods: Newly diagnosed AML (non-M3) patients who received azacitidine combined with IA regimen induction chemotherapy in the Department of Hematology of the First Affiliated Hospital of Sun Yat-sen University from November 2019 to February 2021 were enrolled, and the efficacy and side effect were analyzed. Results: A total of 33 patients were enrolled. The median age of the enrolled patients was 43.36 years (17-63), including 16 males (48.5%) and 17 females (51.5%). According to NCCN risk stratification, there were 3 patients (9.1%) in the favor group (9.1%) ,13 cases (39.4%) in the intermediate group and 17 cases (51.5%) in the poor group.The CR rate of one cycle of azacitidine combined with IA regimen was 66.7%, with a PR rate of 12.1% and a NR rate of 21.2%. After propensity score matching with the newly diagnosed AML patients who received IA regimen as induction chemotherapy in our center, a paired study was carried out. The results showed that there was no significant difference between the 2 groups in the treatment CR rate (66.7% for azacitidine combined with IA vs 54.5% for IA, P=0.592, Fig1). Subgroup analysis (table 1) showed combination of azacitidine with IA significantly improved the CR rate of patients with a ratio of blasts in the bone marrow greater than 67% (83.3% vs 30.8%, P=0.014) and patients in the intermediate NCCN risk group (100.0% vs 37.5%, P=0.001).The duration of agranulocytosis in the azacitidine combined with IA chemotherapy group was longer than that in the IA group (21 days vs 19 days, P=0.045). There was no significant difference in the number of platelet transfusions and the number of red blood cell transfusions between the two groups, and there was no significant difference in the incidence of infection between the two groups (table 2). Conclusions: The remission rate of induction chemotherapy for azacitidine combined with IA regimen and IA regimen in newly diagnosed non-M3 AML patients is comparable. Patients with a ratio of immature cells in bone marrow greater than 67% and patients in the intermediate NCCN risk group may benefit from azacitidine combined with the IA regimen. The combination of azacitidine with IA regimen aggravated granular bone marrow suppression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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