scholarly journals Impact of Body Mass Index on Patient Outcome in Acute Myeloid Leukemia Patients Receiving Intensive Induction Therapy: A Real-World Registry Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3370-3370
Author(s):  
Julius Christoph Enssle ◽  
Sebastian Wolf ◽  
Sebastian Scheich ◽  
Sarah Weber ◽  
Michael Kramer ◽  
...  
Keyword(s):  
Body Weight ◽  
Risk Factor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Independent Risk Factor ◽  
Refractory Disease ◽  
Obese Patients ◽  
Dosing Strategy ◽  
Related Mortality ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a hematologic malignancy that is treated in medically fit patients with intensive induction chemotherapy (IT) and postremission therapy to achieve a complete and long-term remission. The incidence of obesity in the general population is steadily increasing and has been identified as a major risk factor for all-cause mortality. Despite previous studies assessing the role of obesity in AML patients undergoing IT, there is an ongoing debate on the impact of obesity on patient outcome as well as the optimal dosing strategy in obese AML patients. We conducted a retrospective registry study assessing 1677 AML patients who were treated with IT for newly diagnosed AML. The primary endpoint was overall survival (OS) while event-free survival (EFS), the rate of first complete remission (CR1), relapse/refractory disease and non-relapse/refractory-related mortality (NRRrM), treatment-related toxicities, patient comorbidities and chemotherapy dosing strategies were analyzed as secondary endpoints. Obese patients (body mass index, BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, p = 0.015) without a significant difference in median EFS (7.8 vs. 9.89 months, p = 0.3) compared to non-obese patients (BMI < 30). The cumulative incidence (CI) of NRRrM was significantly increased in obese patients compared to non-obese patients while no differences could be observed regarding the CI of relapsed or refractory disease. Obesity was identified as an independent risk factor for death (HR 1.27, [95% CI 1.07-1.51], p = 0.005) in a multivariable Cox regression analysis. When the cohort was stratified by age (≥/< 60 years), the difference in OS as well as the significantly increased CI of NRRrM was only observed in patients ≥ 60 years. Notably, obese patients demonstrated higher rates of cardiovascular and metabolic comorbidities regardless of their age. No disparities for OS, EFS, CR1 rate or treatment-related toxicities were observed when the entire study population was stratified for the used dosing strategy (dose calculation using total body weight, idealized body weight, adjusted idealized body weight or capped at body surface area of 2 m 2). In conclusion, the present study identifies obesity as a major independent risk factor for worse overall survival and increased CI of non-relapse/refractory-related mortality in older (≥60 years) AML patients undergoing curative IT. These findings may be most likely attributed to obesity related comorbidities and not to dose adaption of chemotherapy in obese AML patients. Disclosures Schliemann: Boehringer-Ingelheim: Research Funding; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fransecky: Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Medac: Honoraria; Takeda: Honoraria. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Müller-Tidow: Janssen: Consultancy, Research Funding; Bioline: Research Funding; Pfizer: Research Funding. Platzbecker: Celgene/BMS: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Baldus: Jazz: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria.

scholarly journals Genome-Wide CRISPR Screening in Acute Myeloid Leukemia Cells Identifies Genes in the PI3K/AKT/mTOR and MEK/ERK Pathways That Define Sensitivity to Trametinib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1395-1395
Author(s):  
Tamilla Nechiporuk ◽  
Alisa Damnernsawad ◽  
Daniel Bottomly ◽  
Quinlan Morrow ◽  
Suyoun Choi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Molecular Pathways ◽  
Refractory Disease ◽  
Loss Of Function ◽  
Ras Pathway ◽  
Genetics Research ◽  
Genome Wide ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a challenging disease to treat due to its heterogeneity and high level of relapsed/refractory disease. Exploration of molecular pathways that drive AML have implicated broad activation of the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pro-survival pathways in the pathogenesis of the disease. Among the most frequent genetic perturbations, direct mutation of N- or K-RAS as well as mutation of nearby pathway regulators (PTPN11, NF1) are identified in ~20% of patients with AML. An additional ~35% of AML patients exhibit mutations in FLT3 or KIT, upstream receptor tyrosine kinases known to activate the RAS pathway. Moreover, relapsed/refractory disease in response to novel molecularly targeted FLT3 inhibitors often results in RAS pathway mutations underpinning the connection between these molecular pathways in AML. These findings resulted in several preclinical studies and ongoing clinical trials testing the efficacies of MEK1/2 inhibitors in AML either as a single agent or in combination with FLT3 inhibitors. To elucidate pathways leading to changes in trametinib sensitivity and resistance in a FLT3-ITD genomic landscape, we performed a genome-wide CRISPR screen for trametinib sensitivity in MOLM13 AML cells, which carry a FLT3-ITD mutation. Results from both the genome-wide screen and independently generated cell lines with decreased sensitivity to trametinib indicated involvement of a diversity of genes and pathways, including the tumor-suppressor, PTEN (a negative regulator of PI3K/AKT/mTOR), AMBRA1 (an autophagy regulator via the mTOR pathway), and DUSP7 (a phosphatase negatively regulating downstream ERK activity). Cells engineered to have loss-of-function for these genes as well as cells cultured for resistance to trametinib showed perturbed signaling in downstream PI3K/AKT/mTOR and MEK/ERK signaling cascades. Our work identified genes whose loss of function in the disease-implicated pathways confer trametinib resistance in AML and provide a rationale for selecting combinatorial trametinib/FLT3 inhibitors treatment based on unique patient mutational and gene expression landscapes. Disclosures Tyner: Incyte: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Takeda: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Constellation: Research Funding; Aptose: Research Funding; Genentech: Research Funding; Syros: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Array: Research Funding; Agios: Research Funding; Agios: Research Funding; Aptose: Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Constellation: Research Funding; Petra: Research Funding; Syros: Research Funding; Petra: Research Funding.

Gemtuzumab in Children with Relapsed and Refractory Acute Myeloid Leukemia Treated on Compassionate-Use Basis: A Report of the AML-BFM Study Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1637-1637 ◽  
Author(s):  
Mareike Rasche ◽  
Beate Lerius ◽  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
C. Michel Zwaan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Treatment Options ◽  
Refractory Disease ◽  
Compassionate Use ◽  
Advisory Committees ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use. PATIENTS AND METHOD: In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients. RESULTS: Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock. CONCLUSION: To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future. Disclosures Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.

A High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Is Obesity a Risk Factor for APL? Implication of Targeted Therapy to Control Obesity and APL Prevention.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3099-3099
Author(s):  
Julianne Qualtieri ◽  
Jason Tedesco ◽  
Bipin N. Savani ◽  
Gregory Ayers ◽  
Meera Kumar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Body Weight ◽  
Risk Factor ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Ideal Body Weight ◽  
Promyelocytic Leukemia ◽  
Ideal Body ◽  
Acute Myeloid

Abstract Abstract 3099 Poster Board III-36 Background Epidemiological and occupational risk factors reveal that acute promyelocytic leukemia (APL) predominantly in adults and has an increased incidence in certain regions such as Latin America and northeastern Italy. Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. RARs are implicated in the development of APL and metabolic diseases such as obesity and diabetes mellitus; however, there is no consistent link reported between APL and obesity. Risk factors associated with the development of APL are unclear at this time. In our experience, we observed that several patients diagnosed with APL are morbidly obese and pose a challenge in chemotherapy dosing. Methods In an institutional review board approved study, we conducted a case-controlled study on patients diagnosed with acute myeloid leukemia (AML) at our institute between January 1999 and December 2008. Results In this single institution study, 469 patients diagnosed with AML during this time period, 61 (13%) patients had APL. Of those, 44 patients had complete data sets available for final analysis. Forty nine patients who served as control subjects with non-APL acute myeloid leukemia matched for age and sex were obtained from the same patient set. The median age at diagnoses of APL was 41 years vs. 50 years for the non-APL group. Among the APL group, 23 (52%) patients were female. Thirty patients (69%) were Caucasians, 9 (19%) African Americans and 5 (11%) Hispanics. All patients with APL had cytogenetic confirmation of t(15; 17). Additional cytogenetic abnormalities were present in 11 (25%) APL patients. Other cytogenetics abnormalities were trisomy 8 (14%), 21 (3%), del 20q (3%) del 12q (3%) and complex karyotype (2%). All patients received induction therapy with all-trans-retinoic acid (ATRA) and an anthracycline (daunorubicin or idarubicin) at the time of induction. Thirty six (81%) patients with APL underwent dose adjustment based on the patient's ideal body weight, while 30 (63%) patients with non-APL acute myeloid leukemia received dose reduction based on ideal body weight. Median overall survival was 38.3 month (22.8 to 55.6) and 20.2 months (18.6 to 31.6) among APL and non-APL patients (logrank p=0.002) Using the Wilcoxon rank sum test, the median weight of patients with APL was 96.2 kg (range, 59.8-203.5), and the median weight of patients with non-APL was 81.4 kg (range, 49.6-151.5) (p=0.003). The median body mass index (BMI) for APL patients was 32.4 compared to 27.3 among non-APL patients (p=0.008). 57% of APL patients were obese (BMI>30) compared to only 31% non-APL patients (chi-square p=0.01). Controlling for disease subtype, neither BMI (p=0.111) nor obesity status (p=0.203) had statistically significant impact on APL survival. Hypertension and dyslipidemia were the frequent co-morbid illnesses at the time of diagnosis of APL. Conclusions These results support that a higher proportion of patients diagnosed with APL have a BMI of >30 in comparison to patients with non-APL AML. Larger population-based studies will help define if obesity is a risk factor for developing APL. If this link is confirmed, RXR ligands need to be explored for specific therapeutic applications among obese individuals. Disclosures No relevant conflicts of interest to declare.

Excess Treatment-Related Mortality in Obese Children and Adolescents with Acute Myeloid Leukemia on AAML0531: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2790-2790 ◽  
Author(s):  
Lillian Sung ◽  
Robert Gerbing ◽  
Todd A. Alonzo ◽  
Yi-Cheng Wang ◽  
Etan Orgel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Obese Patients ◽  
Obese Children ◽  
Free Survival ◽  
Competing Events ◽  
The Impact ◽  
Treatment Related Mortality ◽  
Related Mortality ◽  
Acute Myeloid

Abstract Background: Therapy for children with acute myeloid leukemia (AML) is intensive and treatment-related mortality (TRM) occurs in about 5 to 10% of patients. Previous data illustrated that obese children and adolescents with AML treated according to CCG 2961 were more likely to experience TRM, with HR 2.66 (95% CI 1.38-5.11; P = 0.003), when compared to middleweight patients. Since this trial, the backbone of AML chemotherapy and supportive care have changed and thus, it is unknown whether the impact of obesity persists in contemporary trials. The objective was to determine whether obesity was associated with increased TRM, reduced survival and prolonged compared to middleweight patients with AML. Methods: AAML0531 enrolled patients between August 14, 2006 and June 15, 2010. For this analysis, we included patients 0 to 18 years of age with de novo AML. Chemotherapy consisted of 5 cycles of chemotherapy and patients were randomized to receive or not receive gemtuzumab once during Induction I and Intensification II. Best allogeneic donor hematopoietic stem cell transplantation (HSCT) was recommended for those with > 15% bone marrow blasts after Induction I in those without favorable risk cytogenetics and poor risk cytogenetics irrespective of response following Induction I. Matched family donor HSCT was recommended for those with good response after Induction I with standard risk cytogenetics and an available donor. Obesity was defined using definitions from the Centers for Disease Control and Prevention (CDC). Underweight was defined as a body mass index percentile less than 5th percentile, and obese 95th percentile and greater. Categories were determined using z-scores for the weight-for-height data for those 0 to 2 years of age. All outcomes were censored at the time of HSCT. The primary outcome was TRM, defined as death as first event occurring on therapy or within 30 days of going off therapy. Cumulative incidence of TRM was estimated treating relapse and failure as competing events. Kaplan Meier analysis was conducted for overall survival (OS), event free survival (EFS), and disease free survival (DFS). Cumulative incidence of relapse rate (RR) was estimating treating deaths as competing events. Results: There were 1004 patients included. When comparing middleweight and obese patients, there was no significant difference in gender (P=0.814), white vs non-white race (P=0.116), cytogenetic risk group (all P>0.05) or MRD positivity after Induction 1 (P=0.750). The median age was higher for obese patients (12.0 vs 9.4 years; P=0.007 years) compared with middle weight patients. The proportion of patients who were Hispanic or Latino patients was higher among obese compared with middle weight patients (28% vs 17%; P=.001). Survival outcomes are shown in Table 1. When evaluating median time to neutrophil recovery, obese patients, when compared to middleweight patients, had shorter duration of neutropenia for cycles 1-3 (P<0.05). Conclusions: TRM rates continue to be higher for obese patients treated with contemporary AML protocols. Toxicity is not mediated through prolonged neutropenia. Future work should compare the rate of toxicity among obese versus non-obese patients and evaluate the impact of underweight status. Disclosures No relevant conflicts of interest to declare.

scholarly journals Leukemic Cluster Growth in Culture Is an Independent Risk Factor for Acute Myeloid Leukemia and Short Survival in Patients with Myelodysplastic Syndrome

2008 ◽  
Vol 119 (4) ◽  
pp. 226-235 ◽  
Author(s):  
Michael Bernimoulin ◽  
Martin Stern ◽  
André Tichelli ◽  
Martine Jotterand ◽  
Alois Gratwohl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Independent Risk Factor ◽  
Cluster Growth ◽  
Short Survival ◽  
Acute Myeloid

Neutropenia in adult acute myeloid leukemia patients represents a powerful risk factor for COVID-19 related mortality

2021 ◽  
pp. 1-9
Author(s):  
Maximilian Stahl ◽  
Varun Narendra ◽  
Justin Jee ◽  
Andriy Derkach ◽  
Molly Maloy ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myeloid Leukemia ◽  
Related Mortality ◽  
Acute Myeloid

scholarly journals Excess body weight is an independent risk factor for severe forms of COVID-19

Metabolism ◽  
2021 ◽  
pp. 154703
Author(s):  
Léa Pietri ◽  
Roch Giorgi ◽  
Audrey Bégu ◽  
Manon Lojou ◽  
Marie Koubi ◽  
...  
Keyword(s):  
Body Weight ◽  
Risk Factor ◽  
Independent Risk Factor ◽  
Excess Body Weight

scholarly journals Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3433-3433
Author(s):  
Caitlin Siebenaller ◽  
Madeline Waldron ◽  
Kelly Gaffney ◽  
Brian P. Hobbs ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Smoking Status ◽  
Consolidation Therapy ◽  
Peripheral Vascular ◽  
Consolidation Chemotherapy ◽  
Advisory Committees ◽  
History Of ◽  
Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Discovery of a Novel Dihydroorotate Dehydrogenase Inhibitor That Induces Differentiation and Overcomes Ara-C Resistance of Acute Myeloid Leukemia Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2663-2663
Author(s):  
Satoshi Kitazawa ◽  
Yukiko Ishii ◽  
Keiko Makita-Suzuki ◽  
Koichi Saito ◽  
Kensuke Takayanagi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oral Administration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Dihydroorotate Dehydrogenase ◽  
Once Daily ◽  
Hl60 Cells ◽  
Pyrimidine Nucleotide ◽  
Acute Myeloid

Cancer initiating cells (CIC) are suggested to be responsible for drug resistance and cancer relapse that are associated with poor prognosis. Therefore, drugs effective for CIC could fulfill an unmet clinical need. We performed a drug screen with chemical libraries to find out new compounds which specifically eradicated CIC established in the previous report (Yamashita et al., Cancer Research, 2015). We obtained compounds with a carboxylic acid skeleton as hit compounds. Interestingly, FF1215T, one of the hit compounds, was shown to inhibit growths of CIC by decreasing intracellular pyrimidine nucleotide levels. Finally, we identified dihydroorotate dehydrogenase (DHODH), which was essential for de novo pyrimidine synthesis as the target of the hit compounds in a ligand fishing assay. FF1215T inhibited DHODH enzymatic activity with the 50% inhibitory concentration value of 9 nM, which showed greater potency than well-known DHODH inhibitors brequinar (12 nM), teriflunomide (262 nM), and vidofludimus (141 nM). Growing evidence suggests that DHODH is considered to be a promising target to overcome a differentiation blockade of acute myeloid leukemia (AML) cells (Sykes et al., Cell, 2016).Therefore, we explored the effect of FF1215T on AML growth and differentiation. FF1215T demonstrated growth inhibitory effect in multiple human AML cell lines such as U937, MOLM13, HL60, and MV4-11 with the 50% growth inhibition values of 90-170 nM. FF1215T decreased intracellular pyrimidine nucleotide levels, induced DNA damage marker γ-H2AX possibly due to the replication stress, and finally led to apoptosis in HL60 cells. Cell cycle analysis revealed that FF1215T treatment arrested HL60 and THP1 cells at S phase and increased sub-G1 population in these cells. In addition, our DHODH inhibitors induced upregulation of cell-surface CD11b and CD86, which are monocyte and macrophage differentiation markers, morphological changes, and phagocytic activities in several AML cells, indicating differentiation of AML cells toward monocyte and macrophage by DHODH inhibition. FF1215T also depleted UDP-GlcNAc, a substrate for Protein O-GlcNAcylation, and diminished global O-GlcNAcylation and O-GlcNAcylated protein expressions such as c-Myc, SOX2, and OCT4, which play important roles in maintenance and self renewal of stem cells. We also found that our DHODH inhibitors induced CD11b and CD86, and increased the ratio of macrophage-like cells in primary patient-derived AML cells and these effects were rescued by uridine supplementation (Fig). Inhibitions of colony formations of primary AML cells were also shown after 14 days of FF1215T treatment. In exploring the value of DHODH inhibitors in the clinic, we identified that our DHODH inhibitors worked to overcome the resistance of standard therapy Ara-C. Our DHODH inhibitors were effective against Ara-C-resistant models of HL60 cells as well as HL60 parental cells. Notably, our DHODH inhibitors synergistically inhibited growths of Ara-C-resistant THP1 cells and enhanced CD11b upregulation of THP1 cells when combined with Ara-C by activating conversion of Ara-C to its active form Ara-CTP. Next, we optimized the hit compounds and identified an orally available DHODH inhibitor FF14984T that achieved high and prolonged plasma concentrations in vivo. Oral administration of 10 and 30 mg/kg FF14984T once daily for 10 days exhibited significant anti-tumor effects in mice xenografted with HL60 cells. These treatments showed strong reduction of CTP in tumor and induction of DHO in tumor and plasma. When 30 mg/kg FF14984T was orally administrated to orthotropic MOLM13-xenografted mice once daily for 12 days, hCD45+ cells proportions in bone marrow were decreased whereas hCD11bhigh/hCD45+ ratio increased, indicating that FF14984T induced AML differentiation in vivo. Finally, oral administration of 30 mg/kg FF14984T once daily significantly prolonged survival of mice in U937 orthotropic models. Taken together, we developed a novel potent DHODH inhibitor FF14984T that induced cellular differentiation and anti-leukemic effects on cell lines and primary AML cells. FF14984T is possibly a promising therapeutic option for Ara-C-resistant AML patients that can also benefit from the combination therapy of FF14984T and Ara-C. Identifying the precise mechanism of AML differentiation by DHODH inhibitor and its effects on CIC are currently ongoing. Disclosures Kitazawa: FUJIFILM Corporation: Employment. Ishii:FUJIFILM Corporation: Employment. Makita-Suzuki:FUJIFILM Corporation: Employment. Saito:FUJIFILM Corporation: Employment. Takayanagi:FUJIFILM Corporation: Employment. Sugihara:FUJIFILM Corporation: Employment. Matsuda:FUJIFILM Corporation: Employment. Yamakawa:FUJIFILM Corporation: Employment. Tsutsui:FUJIFILM Corporation: Employment. Tanaka:FUJIFILM Corporation: Employment. Hatta:FUJIFILM Corporation: Research Funding. Natsume:FUJIFILM Corporation: Research Funding. Kondo:FUJIFILM Corporation: Research Funding. Hagiwara:FUJIFILM Coporation: Employment. Kiyoi:FUJIFILM Corporation: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding.

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