Days Of Induction Chemotherapy Research Articles

Class III Obesity Is Associated with Worse Overall Survival in Previously Untreated Younger Patients with Acute Myeloid Leukemia Enrolled on SWOG 1203

Mohamed Sorror and Mary-Elizabeth Percival contributed equally to this project. Introduction: There has been inconsistent evidence supporting the association between obesity and outcomes in patients with newly diagnosed acute myeloid leukemia (AML). Prior studies have studied obesity as defined by body mass index (BMI) ≥ 30. However, this general definition of obesity can be further subdivided into class I obesity (BMI 30 to <35), class II obesity (BMI 35 to <40) and class 3 obesity (BMI ≥40). Given the high prevalence of obesity in the United States (41.9%; with class III obesity 9.2%), distinctions in degree of obesity may be associated with outcomes for patients with AML (Stierman et al, 2021). We were interested in studying outcomes in patients with AML stratified by class I, class II and class III obesity after induction chemotherapy and allogeneic hematopoietic cell transplant (HCT). Identification of at-risk patient populations could aid in design of future interventions. Methods: We retrospectively reviewed a group of 738 previously untreated subjects with AML randomized to daunorubicin and cytarabine (DA), idarubicin and cytarabine (IA), and IA with vorinostat as part of clinical trial SWOG 1203, conducted by the SWOG Cancer Research Network between 2012 and 2015. Subjects with adverse risk cytogenetics were recommended to receive HCT in their first complete remission (CR1); subjects with intermediate risk cytogenetics were selected for HCT in CR1 per local institutional standards. Nine patients who did not receive protocol therapy or had missing BMI were excluded (final cohort 729 patients). Early death was defined as death within 56 days of induction chemotherapy. Multivariable time-dependent Cox regression model and Fisher's exact test were used for analysis of overall survival (OS). HCT in first complete remission (CR1) was included as a time-dependent covariate. Results: The median age was 49 years (range, 18 to 60), 51% were male, 90% had de novo disease, and 88% had a performance status (PS) of 0-1 (Table 1). Among these patients, 1% (n=9) were underweight, 25% (n=182) were normal weight, 31% (n=225) were overweight, 20% (n=145) had class I obesity, 11% (n= 82) had class II obesity and 12% (n= 86) had class III obesity. There was no difference in the rate of achieving composite CR (CR with or without count recovery) between different weight categories (p=0.17). There was no clear trend in early death rate by weight (underweight: 11%; normal weight: 4%; overweight: 6%;class I obesity: 7%; class II obesity: 4%; class III obesity: 17%), though class III obesity had a significantly higher early death rate as compared to all the other groups combined (p=0.004). In multivariable Cox regression analyses, class III obesity was significantly associated with worse OS when compared to normal weight (hazard ratio (HR) 2.56, 95% confidence interval (CI) 1.68-3.90; p<0.001); though not statistically significant, we identified a trend towards worse OS for patients with class I (HR 1.40, 95% CI 0.95-2.06; p=0.09) and class II obesity (HR 1.48, 95% CI 0.95-2.31; p=0.09) (Figure 1). Other co-variates with a significant association with OS included age (HR 1.03, 95% CI 1.01-1.04; p<0.001), intermediate cytogenetic risk (HR 2.45, 95% CI 1.33-4.51; p=0.004), and adverse cytogenetic risk (HR 5.86, CI 3.10-11.06; p<0.001). HCT during CR1 was not found to be significantly associated with OS (HR 0.88, CI 0.67-1.15; p=0.3). No significant difference was identified in time to HCT based on BMI category. In patients who underwent HCT during CR1, class III obesity (HR 2.32, 95% CI 1.22-4.43; p=0.01) and older age (HR 1.02, 95% CI 1.00-1.04; p=0.01) were significantly associated with worse OS; in contrast no significant association was identified between OS and class I obesity (HR 1.30, 95% CI 0.77-2.20;p=0.32), while a higher HR and a trend existed for class II obesity (HR 1.76, 95% CI 0.97-3.17; p=0.06). Conclusions: Our retrospective analysis suggests that among newly diagnosed younger patients with AML, those with class III obesity are at increased risk of early death and shorter overall survival. Future directions include assessing lean body mass in addition to BMI in patients with newly diagnosed AML, as sarcopenic obesity is known to portend poor outcomes. Identifying this at-risk patient population may help guide future investigation of early weight management interventions in patients with newly diagnosed AML.

Dexamethasone Pharmacokinetics Following Standard and Short Dosing Schedules in Patients on the UKALL2011 Trial

Dexamethasone (Dex) is a key component of ALL therapy, with glucocorticoid sensitivity strongly linked to prognosis. However, it also contributes to both short and long term toxicities. The UKALL 2011 trial (ISRCTN64515327) investigated a shorter schedule of Dex as part of randomisation 1 (R1) (10mg/m2 x 14 days vs 6mg/m2 x 28 days), in an attempt to bring about a more rapid cytoreduction whilst limiting toxicities associated with long term steroid exposure. There are limited data regarding Dex pharmacokinetics, however large variability has been reported in children being treated for ALL (Yang et al. 2008).To investigate Dex pharmacokinetics in the context of the UKALL2011 randomised dex dosing and scheduling, blood samples were collected up to 8h post oral administration of Dex on one of the first three days, and one of the last three days of induction chemotherapy. Plasma Dex levels were analysed using a fully validated tandem reverse phase LC-MS method, and non-compartmental pharmacokinetic analysis was performed using Pheonix WinNonlin.Pharmacokinetic parameters from day one sampling are shown in the table below. Exposure, as defined by AUC0-12h, and Cmax were significantly higher on the short arm (n=72) compared to the standard arm (n=53) (p=<0.0001 for both). However, there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy, despite having a longer duration of treatment, and vice versa. This variation is displayed in the greater than 20-fold variation in AUC0-12h values observed on the two arms (short: 69.1-1,606; standard: 38.3-1,009 hr*ng/mL). When AUC values were extrapolated to the duration of Dex therapy on short and standard arms, patients on the standard arm had a significantly larger overall exposure compared to those on the short arm (short: 16,318 (14,177-19,568) vs. standard: 22,570 (18,012-25,550) hr*ng/mL, median (95% CI) p=0.01).Early response data would indicate a trend towards a higher Dex exposure (AUC) in patients with a day 8 bone marrow blast count <5% versus those patients with a day 8 blast count >5 % (595.3 (458.5-843.7) vs 441.7 (387.5-552.1) hr*ng/mL, median (95% CI) p=0.0006). However, there was no statistical difference between the two randomisation arms in terms of day 8 blast count (p=0.2). Pharmacokinetic profiles also differed between the two days of treatment, with AUC0-12h being significantly higher at the end of induction chemotherapy (n=52, study day 1: 562.5 (435.7-756.5); study day 2:794.5 (648.7-1041) hr*ng/mL, (median (95% CI) p=0.0003).The UKALL 2011 R1 found no statistical difference in terms of steroid related toxicity or MRD response between short and standard Dex dosing. The data generated from patients recruited to the pharmacology sub-study shows considerable variation in Dex pharmacokinetics and suggest that pharmacokinetic variability may be a more important factor than variation in dosing regimen on the two arms of the randomisation. Furthermore, a significantly higher cumulative exposure of patients on the standard arm suggests that in a drug treatment with markedly variable pharmacokinetics, duration of therapy may be more important in terms of the likely impact on clinical response and toxicity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic significance and risk factors of minimal residual disease ≥1% on 19th day of induction chemotherapy in children with acute lymphoblastic leukemia

To assess the prognostic value of minimal residual disease on 19th day of induction chemotherapy (D19 MRD) and the risk factors of D19 MRD ≥ 1% in children with acute lymphoblastic leukemia (ALL) treated following the Chinese Children's Cancer Group ALL protocol. We retrospectively analyzed the data of 243 children with ALL diagnosed between January 1, 2015 and December 31, 2018 in the Department of Pediatrics of Nanfang Hospital (Guangzhou China). Kaplan Meier-survival analysis was performed to compare the survival time between the patients with D19 MRD < 1% and those with D19 MRD ≥ 1%; logistic regression analyisis and Chi-square test were used to identify the risk factors of D19 MRD ≥ 1%. Compared with those with D19 MRD ≥ 1%, the children with D19 MRD < 1% had significantly better 3-year overall survival (100% vs 90.2%, P=0.004) and event-free survival (97.6% vs 71.6%, P < 0.001). Univariate analysis showed that the odds ratio (OR) for mediastinal invasion, T-cell immunophenotype, TEL/AML1 fusion gene and the presence of blasts in peripheral blood on the 5th day were 4.47 (95%CI: 0.275-72.968, P=0.034), 5.250 (95%CI: 1.950-14.133, P=0.02), 0.330 (95%CI: 0.112-0.970, P=0.036) and 4.407 (95%CI: 1.782-10.895, P=0.01), respectively. The initial risk stratification (P < 0.001), white blood cell grades (P=0.018) and its counts (P=0.027), and the number of blasts on the 5th day (P < 0.001) were significantly different between the two groups. Multivariate analysis showed that initial risk stratification as intermediate and high risks (OR=2.889, 95% CI: 1.193-6.996) and the presence of blasts in peripheral blood on the 5th day (OR=4.477, 95% CI: 1.692-11.843) were independent risk factors for poor early treatment response. D19 MRD ≥ 1% is a predictor of poor prognosis in children with ALL. Mediastinal invasion, T-cell immunophenotype and the presence of blasts in peripheral blood on the 5th day are all risk factors for poor early treatment response, while TEL/AML1 fusion gene is a protective factor; the initial risk stratification as intermediate to high risk and the presence of blasts in peripheral blood on the 5th day are independent risk factors for poor early treatment response of the patients.

Progression of the Radiologic Severity Index is associated with increased mortality and healthcare resource utilisation in acute leukaemia patients with pneumonia

BackgroundPneumonia is a major cause of mortality and morbidity, but the development of new antimicrobials is lacking. Radiological assessment of pneumonia severity may serve as an effective intermediate endpoint to...

Patterns of Care and Clinical Outcomes with 7+3 Induction Chemotherapy for Patients (pts) with Acute Myeloid Leukemia (AML) in the United States (US): A Large Population-Based Study

Patterns of Care and Clinical Outcomes with 7+3 Induction Chemotherapy for Patients (pts) with Acute Myeloid Leukemia (AML) in the United States (US): A Large Population-Based Study

Improved Survival of Patients with AML By Addition of Cladribine to Standard DA3+7 Induction Chemotherapy (DAC) - Single Center Experience at University Medical Centre Ljubljana, Slovenia

Background: Polish Adult Leukemia group demonstrated that addition of cladribine to standard daunorubicin + cytarabine (DAC) induction chemotherapy for acute myeloid leukaemia (AML) increases remission rate and prolongs overall survival. The approach was subsequently included in NCCN guidelines. At University Medical Centre Ljubljana, Slovenia we started using DAC induction regimen in May 2014 for all patients up to 60 years of age, eligible for intensive chemotherapy. We compared the outcome of patients treated with DA3+7 (in use from January 2012 until April 2014) with the outcome of patients treated with DAC in the period from May 2014 to December 2017.Methods: We retrospectively analyzed all consecutive patients diagnosed with AML between January 2012 and December 2017, aged 60 or less, who were eligible for intensive chemotherapy according to ECOG performance status, echocardiography and spirometry results. Exclusion criteria were severe organ impairment and acute promyelocytic leukaemia. The induction regimen in the period January 2012 -April 2014 consisted of daunorubicin 60 mg/m2 on days 1,3 and 5 and continuous infusion of cytarabine 200 mg/m2 from day 1 to 7 (DA3+7) while in the period May 2014 - December 2017 cladribine 5 mg/m2 in a 3-hour infusion on days 1 through 5 was added to DA3+7. Consolidation treatment was the same for both groups and consisted of 2 or 3 courses of cytarabine. Eligible patients with unfavorable characteristics (monosomal /complex kariotype, FLT3 ITD or KMT2A rearrangements, therapy-related AML) proceeded to alogenic bone marrow transplantation (BMT). Patients who did not achieve remission after induction chemotherapy received rescue chemotherapy and also proceeded to alogenic BMT. The efficacy of induction treatment was assessed by bone marrow aspiration in the aplasia between days 7 and 10 after the last day of induction chemotherapy, and before the first consolidation therapy.Results: 50 patients with AML (27 women, 23 men) were treated with DA3+7. 58 patients (31 women, 27 men) were treated with DAC. There were no significant differences in the median age of the patients in both groups (54,4 years in the DA group vs 54,5 years in the DAC group; p=0,853). There were also no significant differences in the proportion of patients with unfavorable cytogenetics or therapy-related AML (50% in the DA group vs 51,7% in the DAC group; p= 0,858). Remission after induction chemotherapy was achieved in a significantly higher proportion of patients in the DAC group (47/58= 81,0%) compared to the DA group (30/50 =60%; p=0,016). Survival was significantly higher in the DAC group compared to the DA group (p=0,034) with a median survival of 18 months in the DA group, while in the DAC group the median survival was not reached. No diferences in toxicity between the DA and DAC regimen were observed.Conclusions: We confirmed results from other research groups by demonstrating improved remisssion induction rate and improved overall survival of AML patients aged 60 years or less treated with DAC induction compared to the standard DA3+7 induction chemotherapy. For evaluating the long-term overall survival further follow up is needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Intensification of induction chemotherapy before consolidation chemoradiotherapy improves progression-free survival and time without treatment in patients with locally advanced pancreatic cancers.

AimsTo assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer.MethodsCharts of patients treated between February 2010 and November 2016 with consolidation capecitabin based-CRT were retrospectively reviewed in this bicentric study. Patients who underwent Gemcitabine as ICT (Group G) were compared to patients treated with intensive ICT (group I). Primary objectives were progression-free survival (PFS), defined as the time from the first day of ICT to progression or last follow-up, and Time without treatment (TWT), as the time from the last day of CRT to progression.ResultsPatients’ characteristics were balanced between group I (Folforinox: n = 24; GemOx: n = 6) and group G (n = 16) including mean age (63.7 vs 68.1 years), and performance status (PS 0-1 :90% vs 93.7%). Median PFS (17.8 months vs 12 months; p = 0.02) and TWT (7.4 months vs 2.5 months p = 0.01) were statistically better in group I vs group G. These results remained statistically and clinically significant by comparing Folfirinox subgroup to Gemcitabine. A trend to a better median overall survival was observed in group I (20.4 months) vs group G (18.3 months; p = 0.07). After adjusting for ICT duration, PS, and CA19.9 level, ICT intensification remains independently prognostic. Toxicity profile was in accordance with Literature.ConclusionThis study shows ICT intensification before CRT is an interesting approach in patients with locally advanced pancreatic cancer. Further studies are needed to confirm these results, and to assess the specific role of CRT in this setting.

Abstract 707: Personalization of dexamethasone in acute lymphoblastic leukemia

Abstract Synthetic glucocorticoids, such as dexamethasone (Dex), are pivotal in the treatment of childhood acute lymphoblastic leukemia (ALL) but are associated with significant variability, both in terms of toxicity and efficacy. We aimed to investigate three key variables to better understand how Dex personalization may be achieved: pharmacokinetics (PK), intracellular Dex accumulation, and cellular response, following Dex binding to the glucocorticoid receptor (GR) in ALL cells. For Dex PK studies, blood samples were collected post oral administration on one of the first three days of induction chemotherapy in 99 patients on the UKALL 2011 trial receiving either 6mg/m2 for28 days (standard arm) or 10mg/m2 for 14 days (short arm). Plasma Dex levels were analysed using a validated LC/MS method, and a non-compartmental pharmacokinetic analysis. To assess intracellular Dex levels, cell lines, primagraft (n=9) and primary patient samples (n=6) were studied. The plasma Dex LC/MS method was optimized to quantify Dex in ALL cell lysates. Dex accumulation was also assessed using flow cytometric analysis of Dex conjugated to FITC. Cellular Dex sensitivity was assessed using Alamar Blue assays. There was a wide Dex PK variability, with AUC0-12h, and Cmax significantly higher on the short compared to the standard arm; 564 (202-1606) versus 408 (142-1009), median (range), p=0.0003 and 0.0006, respectively. However there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy. Dex GI50 values ranged from 37 - &amp;gt; 1000 nM and 2 - &amp;gt; 1000 nM in cell lines and patient samples respectively. Western blotting indicated wildtype GR in all samples, with R3D11 and REH cell lines serving as hemizygous deleted and GR negative controls. Dex accumulation in cell lines was 2.1 and 1.8 (range 1.2 - 2.1) pmol/106 cells in PreB697 and Dex resistant sub-lines, respectively. While patient samples exhibited greater variability, Dex accumulation was not significantly different between sensitive and resistant cells; mean of 1.0 versus 1.4 (range 0.1-2.3, 0.4-4.4 pmol/ 106 cells, p=0.17). Flow cytometry Dex FITC accumulation confirmed these data, with a mean fluorescence intensity of 4.2 versus 4.1 (range 1.5-5.9, 2.0 - 9.1, respectively; p=0.97). These data suggest that while PK and cellular response are hugely variable, variations in drug accumulation do not appear to play a key role in Dex response in ALL cells. Importantly, 62% of patient cell samples had Dex GI50 values greater than plasma concentrations observed in any patient, on both arms on the UKALL 2011 trial. A combined approach incorporating PK assessments and cellular response in ALL cells should be further investigated, to allow a comprehensive understanding of Dex pharmacology with a view to optimizing its clinical utility. Citation Format: Rosanna K. Jackson, Ali Alhammer, Zach Dixon, Gareth J. Veal, Julie AE Irving. Personalization of dexamethasone in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 707. doi:10.1158/1538-7445.AM2017-707

Ekspresja CD10 na minimalnych komórkach resztkowych u dzieci z ostrą białaczką limfoblastyczną B-komórkową

BackgroundThe most common childhood malignancy is B-cell precursor acute leukemia (BCP-ALL). Leukemic cells remaining in the patient's bone marrow during treatment are the major cause of relapse; therefore, minimal residual disease monitoring (MRD) during the induction therapy is predicting factor of treatment outcome. Multicolor flow cytometry (MFC) is the commonly used technique during follow-up of leukemia in bone marrow. Materials and methodsMRD was assessed by MFC in 44 patients with BCP-ALL from the Oncology and Hematology Department, Children's University Hospitalin Krakow diagnosed between 2011 and 2013. The level of residual leukemic cells and the quality of antigen expression was assessed on leukemic cell on diagnosis day and 15th day of induction chemotherapy. Six-color panel of monoclonal antibodies was used. To achieve expected sensitivity of the method (10-4), at least 300.000 nucleated cells were collected. ResultsCD10 expression was changed in residual leukemic cells of most patients on day 15 of treatment, in comparison to day 0. The most significant decrease of CD10 expression occurs in standard risk group. CD10 level is correlated with the level of blasts in day 15, which is the most significant in high-risk group. The patients, in whom the level of CD10 expression increases during treatment, were statistically significantly associated with worse response to therapy. ConclusionsThe immunophenotypic shifts at day 15 were observed in most patients. Not only are the quantitative MRD results important, but also qualitative changes of immunophenotype of residual leukemic cells might bring additional clinical information.

Abstract TP401: Chemotherapy-associated Cerebral Vasospasm in Children With Leukemia: A Prospective Study Using Transcranial Doppler Ultrasound

Introduction: Intrathecal (IT) cytarabine, an antineoplastic agent with poorly understood neurotoxicity, is commonly administered to children with newly diagnosed leukemia on the first day of induction chemotherapy for central nervous system prophylaxis. Five recent case reports demonstrated severe diffuse cerebral vasospasm leading to neurologic sequelae 4-11 days after administration of IT cytarabine. While these patients developed overt consequences, subclinical vasospasm may lead to more subtle forms of neurotoxicity in a larger group of patients. Recognition of subclinical vasospasm could prevent both overt and subtle consequences. Objective and Hypothesis: We evaluated cerebral blood flow velocities (CBFVs), a marker of vasospasm, as measured by transcranial Doppler (TCD) ultrasound, before and after the administration of IT cytarabine. We hypothesized that IT cytarabine increases CBFVs in pediatric leukemia patients in the first two weeks after treatment. Methods: In this prospective before and after study, TCDs were performed on each subject prior to induction chemotherapy and subsequently around days +1, +4, and +8 of induction, before other IT medication administration and within the window of expected vasospasm based on prior cases. Results: In this interim analysis, we found elevated CBFVs compared to age-matched normal values in all arterial distributions measured (though more prominently in anterior circulation), even prior to the administration of IT chemotherapy. Substantial increases in CBFVs were observed after the administration of IT cytarabine in some subjects, though this trend was not observed in all cases. Conclusions: The observed elevations in CBFVs are likely in part due to decreased blood viscosities that resulted from hematologic changes secondary to leukemia. The observed changes in CBFVs after IT cytarabine administration are probably partially due to treatment effects, but the variability between patients suggests that patient and/or disease-specific characteristics may predispose certain children to cerebral vasospasm and its neurologic sequelae. This ongoing study aims to identify clinical features that allow risk stratification in order to develop clinical pathways for preventing neurotoxicity.

Abstract CT115: Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial

Abstract Dexamethasone (Dex) is a key component of ALL therapy, with glucocorticoid sensitivity strongly linked to prognosis. However, it also contributes to life threatening toxicities. The ongoing UKALL 2011 trial is investigating a new schedule of Dex (10mg/m2 × 14 days vs 6mg/m2 × 28 days), in an attempt to bring about a more rapid cytoreduction whilst limiting toxicities associated with long term steroid exposure. There are limited data regarding Dex pharmacokinetics, however large variability has been reported in children with ALL (Yang et al. 2008). For Dex pharmacokinetic studies, blood samples were collected up to 8h post oral administration on one of the first and last three days of induction chemotherapy. Plasma Dex levels were analysed using a validated LC-MS method, with a range of 5-250ng/ml, and non-compartmental pharmacokinetic analysis was performed. Pharmacokinetic parameters from day one sampling are shown below. Exposure, as defined by AUC0-12h, and Cmax were significantly higher on the short arm (p = 0.0002 and 0.0007, respectively). However there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy, despite having a longer duration of treatment. This is reflected in the AUC0-12h ranges observed on the two arms (short: 202-1606; standard: 38-1009 hr*ng/mL). Pharmacokinetic profiles also differed between the two days of treatment, with AUC0-12h being significantly higher at the end of induction chemotherapy (n = 37, study day 1: 655 ± 322; study day 2: 894 ± 496 hr*ng/mL, p = 0.003). Based on these preliminary data it will be important to consider pharmacokinetic variability when analysing the results generated from the UKALL 2011 trial. Further evaluation of relationships between pharmacokinetic variation, dose scheduling and clinical outcome may enable better stratification of Dex therapy for future patients. Dexamethasone pharmacokinetics in short and standard therapy arms following day one samplingPharmacokinetic parameters (mean ± SD)Half life (hr)Tmax (hr)Cmax(ng/mL)Clearance(L/hr/m2)AUC0-12h(hr*ng/mL)Short (n=43)3.96 ± 3.21.9 ± 1.0128 ± 558.1 ± 5.3692 ± 325Standard (n=33)3.68 ± 2.11.7 ± 1.187 ± 419.2 ± 12.7443 ± 202 Citation Format: Rosanna K. Jackson, Julie AE Irving, Gareth J. Veal. Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT115.

Micafungin as primary antifungal prophylaxis in patients presenting with acute myeloid leukemia

ObjectiveTo study the efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing induction chemotherapy for acute myeloid leukemia. Patients and methodsA prospective observational single-center study of 41 patients from the hematology department between May 2012 and April 2015. Micafungin was administered once daily from the first day of induction chemotherapy to the end of the neutropenic phase. ResultsNeither Candida nor Aspergillus infection was documented in our 41 patients from the first day of micafungin infusion to the end of the neutropenic phase. Patients were followed for three months after discontinuation of micafungin and none of them contracted an invasive fungal infection. Only one patient presented with grade III–IV hepatic and ionic toxicities. ConclusionMicafungin is associated with a good safety profile and is an interesting option for preventing invasive fungal infections in the high-risk population of patients presenting with hematological disorders.

The prognostic significance of rapid peripheral blood blast clearance during the initial course of induction chemotherapy in young patients withde novoacute myeloid leukemia

The early clearance of blast cells in peripheral blood (PB) during induction chemotherapy can predict the clinical outcome in acute leukemia. We retrospectively analyzed the kinetics of white blood cell (WBC) count, blast cell percentage (BCP), and blast cell count (BCC) in PB in 78 patients with de novo acute myeloid leukemia who underwent a uniform induction chemotherapy between December 2001 and December 2015 at Jichi Medical University. By a repeated-measures analysis of variance, the interaction of the decline in BCP with the achievement of complete remission (CR) was stronger than those of the decline in WBC or BCC. A receiver operating characteristic curve analysis for the achievement of CR showed that the areas under the curve for the decline in WBC, BCP, and BCC were 0.592, 0.703, and 0.634, respectively, and a decline in BCP of 9.25%/day within 4 or 5 days from induction chemotherapy was the optimal cutoff value. A multivariate analysis showed that a rapid decline in BCP (≥9.25%/day) was a significant predictive factor for CR, independent of the cytogenetic risk (p = 0.0096). A rapid decline in BCP during the first 5 days of induction chemotherapy may be a good predictor of CR. Copyright © 2015 John Wiley & Sons, Ltd.

A New Model to Predict Remission Status in Acute Myeloid Leukemia (AML) Patients Based on Day 14 Bone Marrow (D14 BM) Biopsy

Introduction: Although day D14 BM after initiation of induction chemotherapy is accepted standard of care in AML patients (pts), it has poor predictive value and low accuracy for refractory disease. Currently there are no established clinical and laboratory factors which accurately predict which AML pts with positive D14 BM require immediate reduction chemotherapy for persistent disease and which pts achieve complete remission (CR)Methods: We retrospectively analyzed pretreatment factors and post-induction response in AML pts to determine if clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation.Results: Among 297 pts with D14 BM biopsies, 183 pts (61%) had positive D14 BM (either ≥ 5% myeloblasts or cellularity ≥ 20%). Of those with a positive D14 BM biopsy, no reinduction chemotherapy was given to 89 pts of which 57 (64%) pts had persistent disease at count recovery and 32 (36%) pts achieved CR. Persistent disease at count recovery after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, history of relapsed disease, and poor-risk disease category than pts with positive D14 BM who achieved CR. Age, D14 BM cellularity, and WBC at first day of induction chemotherapy had no significant influence on remission status in pts with a positive D14 BM (Table 1). We developed, and tested in a validation cohort, new prediction model using both D14 BM status and clinical/laboratory factors such as the percentage of blasts, history of relapsed disease, and poorer disease risk category. Then we compared results of this prediction model to that of D14 BM alone without the usage of clinical/laboratory prognostic factors. Our prediction model significantly improved the positive predictive value (84% vs.64% P=0.001) and the accuracy of prediction of recovery marrow status (0.88% vs. 80%, P=0.002) in AML pts with positive D14 BM (Table 2).Conclusion: In this study we developed and validated a new prediction model for interpreting D14 BM biopsies in AML pts after induction chemotherapy. With the addition of readily available clinical and laboratory information, our multivariable model provides a more accurate prediction of recovery bone marrow status and identification of patients with positive D14 BM who may not benefit from early reduction chemotherapy.Table 1Clinical and Laboratory Characteristics of AML Patients with Positive D14 BM Who Did Not Receive Immediate Reinduction Chemotherapy.Persistent AML at count recoveryCR+CRiP valueNumber5732Age, years Median (min, max)59 (19, 75)55.5 (20, 78)0.064*WBC Count at Induction, x 109/L Median (min, max)5.7 (0, 285)3 (0, 95)0.25*D14 Cellularity, % Median (min, max)10 (5, 40)10 (3, 60)0.079*D14 Blasts, % 0-10 10%-30 >3013 20 2415 13 40.0023*Disease Status Before Induction Therapy De novo Relapsed19 3826 6<0.0001**Antecedent Hematologic Disorder Yes No25 326 260.021**Risk Favorable/Normal High13 4419 130.0013***AML, acute myeloid leukemia; CR, complete remission; CRi, complete remission with incomplete count recovery; D, day; WBC, white blood cell.*Wilcoxon rank sum test. **Fisher's exact test. ***Chi-square testTable 2Performance of Models in Prediction of Recovery Bone Marrow using the D14 BM with and without Clinical/laboratory Diagnostic Factors (N = 203)SensitivitySpecificityPPVNPVAccuracyP value*Without prognostic factors0.880.770.640.930.800.002With prognostic factors**0.780.930.840.900.88*Comparison of accuracies by two-sample binomial test. **The percentage of myeloblasts in the D14 BM, disease status, and risk category were used as prognostic factors.NPV, negative predictive value; PPV, positive predictive variable. DisclosuresNo relevant conflicts of interest to declare.

Survey of Serum Aspergillus Antigen in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia or Allogeneic Hematopoietic Stem Cell Transplantation: Role in Predicting Invasive Aspergillosis and in Modifying the Therapeutic Strategy

IntroductionInvasive aspergillosis (IA) remains an important cause of mortality in immunocompromised acute myeloid leukemia (AML) patients receiving induction chemotherapy and in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies. Early diagnostic is critical and challenging given the efficacy and availability of several new anti-fungal therapies. In this study, we evaluated the performance of different factors in predicting the occurrence of IA, including the Aspergillus antigen galactomannan (GM) detection in sera.MethodsWe included all AML patients receiving induction chemotherapy and patients undergoing allo-HSCT for any hematological malignancy at our center between April 2006 and April 2014 with available data on Aspergillus antigen GM. Serologic detection of circulating GM fungal biomarker was considered during the 100 days following the first day of induction chemotherapy in AML patients or from the day of allo-HSCT. Usual follow-up included two GM tests per week, only patients with at least three serum GM results were considered. The GM tests have been performed routinely using the ELISA kit (Platelia Aspergillus antigen ELISA, Biorad), giving the results in index values. Demographic, GM index results and diagnostic data were collected. IA cases were classified as proven or probable according to the EORTC criteria. The value of the first antigen test, the delay to positivity, and the slope of the progression of the index value between the first two antigens concentrations were considered as predictors of IA. ROC curves for each predictor and their combination were performed and prognostic scores were established.ResultsA total of 775 patients were included : i) 292 AML patients, 153 (52%) males with a median age of 62 years (range: 17-79), 15% were classified as favorable, 8% as intermediate I, 18% as intermediate II and 59% as unfavorable according to cytogenetics and molecular markers; ii) 483 allo-HSCT patients, 293 (61%) were males, median age was 48 years (range: 18-70), among them 234 (48%) AML, 66 (14%) multiple myeloma, 46 (10%) Myelodysplastic syndromes, 38 (8%) Non-Hodgkin Lymphoma and the rest of patients had other hematological disorders; 233 (48 %) patients received reduced intensity conditioning and 250 (52%) myeloablative conditioning. The disease status at allo-HSCT was complete remission (CR) in 366 (76%) patients and the rest of patients were in less than CR. HSC source was peripheral blood in 42.2% (90 identical siblings, 150 10/10 matched unrelated, 54 9/10 mismatched unrelated), bone marrow in 42.6% (105 identical siblings, 162 10/10 matched unrelated, 45 9/10 mismatched unrelated) and cord blood in 15.2%.A total of 877 episodes with 16121 GM serum antigen results was considered (median: 18 GM tests per patient). During the follow-up, we identified 121 episodes with at least one positive GM test with a cumulative incidence at day 100 of 13.8%. We also diagnosed 48 IA (2 proven, 46 probable), with a cumulative incidence at day 100 of 5.5% in total, 7.2% in AML and 4.3% in allo-HSCT, respectively. We then classified the GM positive episodes in 82 false-positive (68%) and 39 true-positive episodes (32%) for IA, respectively. A majority of IA events occurred during the first 30 days of follow up, GM positivity showing a positive predictive value of 41% versus a negative predictive value of 99%.The three IA predicting factors had similar independent effects and their combinations were performed, allowing the establishment of an area under ROC of 0.79 (95% CI: 0.70-0.89). Cut off values of the first positive GM serum and slope were equal or higher than 1.04 and 0.04, respectively, and delay to positivity equal or less than 15 days. To simplify the practical use in clinical practice, the prognostic score defining the IA risk probability was defined as the number of predictors present (values from 0 to 3). This score was tested on positive follow-up giving values of 0, 1, 2 or higher for 45 (37%), 39 (32%) and 37 episodes (31%), respectively. A score superior or equal to 2 was indicative of IA in 62% of the cases (figure 1).ConclusionAs IA has a significant impact on hematology patient's survival, this GM predictive score combining three predictors (value of the first antigen index, delay of positivity and slope of the index values) may help clinicians to conclude about starting an early preemptive IA treatment. [Display omitted] DisclosuresNicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

The comparison of treatment outcome on two protocols for childhood acute lymphoblastic leukemia

Objective To compare the effects of childhood CCLG-2008 regimen and childhood acute lymphoblastic leukemia (ALL)-2006 regimen. Methods The clinical characteristics and the treatment outcomes of children with ALL were retrospectively analyzed. 35 patients (group Ⅰ) who were initially diagnosed between Aug 2008 to Aug 2010 were systematically treated according to ALL-2006 without monitoring minimal residual disease (MRD). 30 patients (group Ⅱ) who were initially diagnosed between Sep 2010 and Aug 2011 were systematically treated according to CCLG-2008, and the therapeutic regimens were adjusted by reassignment of risk group according to MRD at specific time (the 33rd day of induction chemotherapy and the 12nd week after the beginning of chemotherapy). MP-FCM Coulter FC-500 was used in the detection of MRD. Results Both groups were followed up for 3 years after diagnosis. The rates of serious infection in two groups were no significant difference (P = 0.615). The mortality rates of two groups were 28.6 % (n = 10) and 6.6 % (n = 2), respectively, and there was no significant difference (P= 0.233). The relapse rates in two groups were 28.6 (10/35) % (n = 10) and 6.6 % (2/30) (n = 2), respectively, and that in group Ⅰ was higher than that in group Ⅱ (P= 0.041). The 3-year overall survival (OS) rates in two groups were 80.0 % and 93.3 %, respectively (P = 0.126). The event-free survival (EFS) rates in two groups were 65.7 % and 90.0 %, respectively (P = 0.024). After elimination of the confounding influence by sex, age, FAB subtype, WBC count, chromosome karyotype and CNSL at diagnosed, CCLG-2008 regimen was used to calculate the EFS of ALL patients. CCLG-2008 regimen was more significant in the assessment of prognosis (P = 0.037, 95 % CI 0.075-0.924). Conclusion CCLG-2008 regimen do not increase the rates of serious infection and death, but can reduce the relapse rate, which is beneficial to increase the patients EFS. Key words: Child; Leukemia, lymphoid; Prognosis; Antineoplastic combined chemotherapy protocols

Population Pharmacokinetics of Daunorubicin in AML: Influence on Clinical Outcome

Daunorubicin (Dnr) has been the choice of anthracycline in the induction chemotherapy of Acute Myeloid Leukemia (AML) along with Cytarabine for the past 4 decades. Drug resistance and relapse of the disease has been the major concern in the success of AML therapy. Several factors, including pharmacokinetics (PK) of Dnr could have impact on treatment outcome as pharmacokinetic effects might limit the amount of drug that reaches the tumor. In this study, we analyzed the factors influencing plasma PK of Daunorubicin and its major metabolite Daunorubicinol (DOL) in AML patients receiving induction chemotherapy and compared PK parameters with clinical outcome (relapse).Sixty four adult denovo AML patients were enrolled in the study after obtaining informed consent. Dnr was given as 1 hour bolus infusion at a dose of 60mg/m2/day for the first 3 days of induction chemotherapy. Peripheral blood were collected at 0, 15min, 1hr, 2hr, 4hr, 6hr and 24hr on the first day of induction chemotherapy. Plasma levels of Dnr and DOL were measured using high performance liquid chromatography coupled with fluorescence detector. Population PK was analyzed by nonlinear mixed effects modeling using Monolix version 4.3.2. Common single nucleotide polymorphisms in ABCB1, ABCG2, CBR1 and CBR3 genes were screened by PCR followed by either sequencing or restriction digestion. In vitro cytotoxicity of the primary AML cells to Dnr was assessed by MTT cell viability assay and IC50 was calculated using ADAPT5 software. The role of plasma Dnr PK on relapse of disease was estimated using nonparametric Mann-Whitney U test.Demographics of the patients enrolled in the study are listed in table 1. PK parameters of Dnr and DOL showed wide inter-individual variation (table2). Older patients had a trend towards lower Dnr clearance (CL) (p=0.09). Patients harboring FLT3-ITD mutations had higher CL than the patients without mutation though not reaching statistical significance. Patients with variants of SNPs rs20572 (exon3) and rs9024 (3’UTR) in CBR1 (which were in complete linkage disequilibrium) had a trend towards significantly higher Dnr AUC [median-0.2711; (0.04903-2.165) vs. median 0.2117; (0.0546-0.9036); p=0.06] than patients with wild-type.Among the 64 patients, complete remission (CR) was documented in 42 (65%) of which, 31% relapsed eventually [median time to relapse 328 (104-864) days]. AML patients who relapsed had significantly lower Dnr AUC [median 0.17 (0.049-2.165) vs. median 0.31 (0.1-1.74); p=0.009] and higher DOL AUC [median 8.67 (1.6-20.1) vs.4.99 (1.3-16.5); p=0.015].Also, relapsed patients had higher Dnr clearance (CL)[median -546.54 (41.5-1632)vs. 329.3 (42.9-944.5); p=0.011] and lower DOL CL[median-9.8 (4.9-56)vs. median- 19.7 (6.1-57); p=0.015]than patients who did not relapse. IC50 of Dnr was higher in patients who relapsed (median-0.7 (0.02-1.46) vs. median- 0.23 (0.007-1.11); p=0.056) than in patients who did not relapse.To the best of our knowledge, this is the first population PK report in AML which is designed to evaluate various factors which might influence Dnr and DOL PK in AML. Though the number is small, our results suggest that plasma PK of Dnr influences clinical outcome in AML. Lower systemic exposure of Dnr in relapsed patients suggests that amount of drug required to completely eradicate the leukemic cells is not achieved and escalating dose might be an option to decrease relapse rates. Cellular pharmacokinetics of Dnr in these patients is ongoing in the lab, which will be more informative and help in prognosticating and dose adjustment for better treatment outcome.This data provides a probable biological basis for the previously reported clinical benefit of decreased relapses following the increase of the dose of DNR in induction to 90mg/m2/day (Tallman et al. NEJM 2009).Wide inter-individual variation in Dnr PK also suggests that this increased dose may not be necessary for all patients. Further studies are required to confirm this finding in a larger cohort of patients and to work towards strategies for TDM of Dnr in AML [Display omitted] [Display omitted] DisclosuresSrivastava:Octapharma: Consultancy, Other.

Treatment outcome of childhood standard-risk and median-risk acute lymphoblastic leukemia with CCLG-2008 protocol

To estimate the significance of the adjustment of acute lymphoblastic leukemia (ALL) risk group by monitoring minimal residual disease(MRD). Totally 285 children ALL patients who were diagnosed and systematically treated according to CCLG-2008 in Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC, from April 2008 to August 2011 were prospectively selected. Among these cases, 62.8% (n = 179) were boys and 37.2% (n = 106) were girls and the median age was 5.3(0.5-14.0). The patients who were at high-risk group initially were excluded. The grouping of cases: the patients were divided into two groups according to the dates of initial diagnosis. Group I had 126 patients who were initially diagnosed between April 2008 and December 2009 in whom therapeutic regimen was not adjusted by reassignment of risk group by MRD. Group II had 159 patients who were initially diagnosed between January 2010 and August 2011 whose therapeutic regimen was adjusted by reassignment of risk group by MRD at specific time (33rd day of induction chemotherapy and 12 weeks after the beginning of chemotherapy). MP-FCM Coulter FC-500 was used in the detection of MRD. Among these 285 patients, 94.0% (n = 268) were diagnosed as B-lineage acute lymphoblastic leukemia and 6.0% (n = 17) were T-lineage acute lymphoblastic leukemia. In group I, 61.9% (n = 78) patients belonged to low-risk group, 38.1% (n = 48) median-risk; in group II, before the adjustment, the rates of the low-risk group and median-risk group were 68.6% (n = 109) and 31.4% (n = 50) , respectively, while after the adjustment they were altered to 53.5% (n = 85) and 39.6% (n = 63) , furthermore 6.9% (n = 11) patients went into the high-risk group. Both groups were followed up for 2.5 years after their diagnoses, the disease of 7.4% (n = 21) patients relapsed, and the rates of two groups were 12.7% (n = 16) and 3.1% (n = 5) respectively, P = 0.009. The rate of serious infection (such as sepsis, pulmonary infection) of all these patients was 32.3% (92/285) , there was no significant difference between the two groups [28.6% (36/126) vs.35.2% (56/159) , P = 0.392]. The mortality of all these patients was 6.7% (19/285) , and that of group I was higher than that of group II [10.3% (13/126) vs. 3.8% (6/159) , P = 0.044]. The 2.5 years overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) of group I were all lower than those of group II in Kaplan-Meier survivorship analysis (all P < 0.05). The two groups were followed up for 2.5 years after their diagnoses, after elimination of the confounding influence of sex, age, FAB subtype, WBC count, ratio of blast cells in bone marrow at diagnosed, chromosome karyotype and fusion gene, reassignment of risk group by MRD was used to calculate the OS, EFS and DFS of ALL patients (all P < 0.05). After the adjustment the risk group was more significant in the assessment of prognosis. The reassignment of risk group in low and median risk groups children with acute lymphoblastic leukemia by MRD did not increase the rate of serious infection but could reduce the relapse rate and mortality, and was beneficial to increase the patients' OS, EFS and DFS.

Imatinib in combination with allogeneic hematopoietic stem cell transplantation improved the outcome of adult Philadelphia chromosome-positive acute lymphoblastic leukemia

To investigate the role of imatinib in induction therapy for newly diagnosed adult patients with Philadephia chromosome-positive acute lymphoblastic leukemia (Ph⁺ALL), as well as the status of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of adult Ph⁺ ALL in imatinib era. Retrospectively analyzed 97 newly diagnosed adult Ph⁺ ALL patients from 2005 to 2013. According to whether administrated imatinib in the induction therapy and the administrating duration (≥3 d) , they were divided into imatinib (n=37) and non-imatinib group (n=60), and the former group was further divided into early-use (n=26) and late-use imatinib groups (n=11) (bounded by the fourteenth day of induction chemotherapy). We compared the overall response rate (ORR) and the negative rate of BCR-ABL fusion gene in patients who achieved complete remission (CR) or CR with incomplete recovery of blood cells (CRi) among the three groups at the end of the first induction therapy. There were 44 cases underwent allo-HSCT (transplant group) and 33 cases only adopted imatinib-based chemotherapy (non-transplant group) in 77 patients who administrated imatinib as a maintenance therapy, we further compared the incidences of overall survival (OS) , disease-free survival (DFS), relapse and nonrelapse mortality (NRM) between the two groups; and dynamically monitor polymerase chain reaction (PCR) negativity of patients who were in CR1 state before transplant (n=34) at the following timepoints of achieving CR or CRi, the first consolidation therapy, beginning the pretreatment of transplant and attaining hematopoietic reconstruction after transplant. After the first induction therapy, the ORR of imatinib group was significantly higher than of non-imatinib group (97.3%, 72.9% respectively, P=0.002), but early-use and late-use imatinib groups had no statistical significance in ORR (100% , 90.9% respectively, P=0.297); the rate of negativity of imatinib and non- imatinib groups were 20.0% and 0 respectively (P=0.041) in patients who achieved CR or CRi. The negative rate of patients in CR1 state before transplant attained 20.8%, 42.3%, 51.8%, 76.8%, respectively at the previously described 4 timepoints. And the differences between the fourth and the third, the third and the first timepiont all reached statistical significance (P=0.044, 0.022, respectively). The 5-year OS of transplant and non- transplant groups showed statistical difference (47.0%, 28.0% respectively, P=0.016), also for 5-year DFS (P=0.001) and the cumulative rate of relapse (P=0.000) of the former surpassing the latter; the cumulative rate of NRM between these two groups had no statistical significance (P=0.370). Conventional induction chemotherapy in combination with imatinib in the first induction therapy of adult Ph⁺ ALL, not only improved the rate of hematologic remission, also the rate of molecular response. Imatinib used as a consolidation and maintenance therapy after remission, and allo-HSCT scheduled as soon as possible improved the prognosis.

Applicability of gene expression profile of childhood acute lymphoblastic leukemia at diagnosis and at the end of the induction phase of chemotherapy at a cancer hospital in the state of Goiás (Brazil)

The present study compared the gene expression pattern of some previously described genes at the time of diagnosis and after induction chemotherapy for childhood acute lymphoblastic leukemia (ALL) in patients submitted to Brazilian Childhood Leukemia Treatment Group (GBTLI) ALL-99 Protocol. Samples were obtained at the time of diagnosis from 16 patients with ALL and on the 28th day of induction chemotherapy the bone marrow samples were obtained from 12 children. The genes expression profiles in diagnostic and induction samples were analyzed by array-based qPCR and then related to the clinical and biological prognostic factors. The results showed significant associations (p ≤ 0.05) between gender and immunophenotype, immunophenotype and age, immunophenotype and risk group, presence of CD10 and RUNX1 expression, risk group, and immunophenotype. A significant positive correlation was observed between the expression levels of BAX and BCL2. There was a significant difference (p = 0.008) between the gene expression pattern at the time of diagnosis and after induction chemotherapy. The expression pattern of these genes after the induction phase of treatment approached the expression profile of the control group, indicating a good induction response in children treated according to the GBTLI ALL-99 protocol. The findings of the current research could be routinely useful for clinical practice and could assist in the discovery phase of medical applications.