Acute Myeloid Leukemia Status Research Articles

FLAG-Ida Regimen as Bridge Therapy to Allotransplantation in Refractory/Relapsed Acute Myeloid Leukemia Patients.

Patients with primary refractory or first relapse acute myeloid leukemia (AML) are considered to have worse clinical outcomes after treatment. For these patients, the achievement of complete remission appears crucial for them to be able to undergo allotransplantation, which might be the only possible treatment. We used the FLAG-Ida (fludarabine, cytarabine [cytosine arabinoside], granulocyte colony-stimulating factor, idarubicin) regimen in patients with primary refractory/first relapse AML as a bridge to transplantation. We studied its efficacy in terms of overall response and overall survival to assess which variables (age, lactate dehydrogenase, bone marrow blast count, peripheral blood blast count, platelet count, white blood cell count, de novo or secondary AML, molecular-cytogenetic risk, duration of response, and relapsed or refractory disease) might have an effect on outcome. We analyzed the data from 108 consecutive adult patients (52 males, 66 females; median age, 49 years; range, 17-72 years) with newly diagnosed AML refractory to standard induction regimens or relapse after first complete remission, who had received the FLAG-Ida protocol as salvage therapy from January 2005 to December 2015. An overall response was achieved in 48 patients (44%). On multivariate analysis, the variables with a positive effect on the response rate were molecular-cytogenetic risk (P= .009), duration of first response in relapsed AML (P= .003), AML status (relapsed or refractory; P= .047), and peripheral blood blast count (P= .016). On multivariate analysis, overall survival was significantly associated with FLAG-Ida response (hazard ratio, 0.343; P= .001) and receipt of allotransplantation (hazard ratio, 0.277; P< .001). Our data seem to confirm the value of FLAG-Ida in this setting and might suggest its best usage as bridge therapy for patients awaiting allotransplantation.

Importance of Achieving Complete Remission (CR) after Intensive Therapy for Acute Myeloid Leukemia (AML) in Older Adults Age ≥60 Years: Analysis of Risk Factors for Early Mortality and Re-Induction, and Impact of Quality of Response on Overall Survival (OS) in the ECOG-ACRIN E2906 Randomized Trial

Background: The results of the primary endpoint of the E2906 North American Intergroup phase 3 trial - demonstrating significantly inferior OS after single agent clofarabine versus standard intensive daunorubicin & cytarabine induction and consolidation - strongly support the use of intensive therapy for patients age ≥60 years with newly-diagnosed AML who are fit for treatment. This result was achieved despite similar CR rates (including CRi - CR with incomplete blood count recovery) and similar early (30- & 60-day) induction mortality between study arms, raising the question as to the importance of achieving CR as an endpoint. Therefore, we performed a follow-up analysis to address the factors that contribute to early mortality, the necessity for 2nd induction cycle to achieve CR, and to assess the survival impact of the quality of remission.Methods: E2906 design, study population and results for the primary objective were reported previously (ASH 2015, abstr. #217a). We performed this updated analysis to evaluate clinical risk factors for early mortality and re-induction, and to assess the impact of response quality on OS. Univariate comparisons were made with Fisher's exact test (category) and t-test (continuous variable), and logistic regression models were used to examine risk factors associated with early mortality, and with requiring a 2nd cycle of induction therapy. We performed a landmark analysis (beginning Day 60 after initiation of therapy) to determine the impact of response quality (CR/CRi, morphologic leukemia-free-state (MLFS), and treatment failure - i.e. residual/refractory AML) on OS. Survival comparisons were performed with log-rank test.Results: A total of n=727 patients were registered to E2906, the median age is 68 years (range 60-86) and the median follow-up of surviving patients is now 18.3 months. Adjusting for treatment, cytogenetic risk group, FAB subtype, WBC count, and secondary AML, increasing age (p=0.06) and performance status (PS) >1 (p=0.05) were associated with 30-day mortality and only PS >1 (p=0.06) with 60-day mortality. Treatment arm (p=0.003), adverse cytogenetic risk group (p=0.02), increasing age (p=0.03) and baseline WBC <10K (p=0.03) were each independently associated with higher risk of receiving 2nd cycle induction, but there was no difference in CR/CRi (44.2% vs. 42.2%, p=0.58) or in median OS (13.8 versus 12.0 months, p=0.11) for those receiving 1 vs. 2 induction cycles, respectively.We next performed a landmark analysis (day 60, n=608 evaluable patients) to evaluate OS in relation to the quality of response (Table). We observed an advantage in achieving CR and CR/CRi, although the benefit of CRi diminished greatly after 12 months, and OS after MLFS appeared more similar to treatment failure (Figure, p<0.001). The relative adverse impact of CRi and MLFS (vs. CR) was most pronounced for patients treated with clofarabine, where median OS was shorter for those achieving CRi (12.2m vs. 22.6m standard therapy, p=0.007) and MLFS (6.6m vs. 13.4m standard therapy, p=0.15).Conclusion: This follow-up analysis confirms the importance of CR regardless of the number of cycles of induction therapy required to achieve remission, and identifies risk factors associated with early mortality and with requiring re-induction. At longer follow-up the OS after CRi appears to be inferior to true CR, particularly after clofarabine. We hypothesize that this may be due to higher rates of minimal residual disease in CRi, and studies to determine this are being performed. MLFS is not associated with a better overall survival than frank treatment failure (i.e. residual disease) and therefore its value as a response category is uncertain. These results highlight the role of standard intensive remission induction therapy with the intent of achieving CR, which remains the standard of care for fit older adults. [Display omitted] [Display omitted] DisclosuresForan:karyopharm: Honoraria; novartis: Honoraria; medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Melnick:Janssen: Research Funding. Altman:Novartis: Honoraria; BMS: Honoraria; Janssen: Honoraria; Syros: Honoraria. Al-Kali:Novartis: Research Funding; Celgene: Research Funding.

Expression analysis of BECN1 in acute myeloid leukemia: association with distinct cytogenetic and molecular abnormalities.

In acute myeloid leukemia (AML), it has been shown that AML-derived cells often remain sensitive to autophagy-inducing stimuli, leading to the idea that harnessing the autophagy can be pertinent to AML cytotoxic therapy. Despite this promising notion, to date, there is no comprehensive study addressing autophagy-related genes expression status in AML. As a critical mediator, BECN1 influences the onset and advance of autophagy and several studies have pointed to the BECN1 recurrent allelic deletion and expression variation in a broad range of tumors. To explore this caveat, we chose this alteration-prone gene to investigate in our study. We have analyzed the expression status of BECN1 in a series of 128 de novo AML patients using real-time quantitative polymerase chain reaction (qRT-PCR). In our favorable subgroup, BECN1 expression did not alter (P = 0.301), but in intermediate and unfavorable patients, we have had BECN1 low expression compared to the normal controls (P = 0.008 and P < 0.001, respectively). We found evidence for the association of reduced expression of BECN1 with FLT3-ITD mutation (19 of 27 patients), monosomal karyotype (all of 11 patients), higher age, and WBC count. Overall, remarkable association of reduced expression of BECN1 with FLT3-ITD mutation and monosomal karyotype and their functional relationship is interesting which should be addressed and verified in future studies.

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.

Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) Not in First Remission

Background: Approximately 60 - 80% of AML patients achieve a complete remission [CR] with one or two cycles of induction chemotherapy, leaving many patients with refractory AML [PIF]. Unfortunately, the majority of patients in CR1 ultimately relapse. With salvage therapy, only 30-50% achieve CR2. Those with PIF or relapsed AML have shortened survival and few therapeutic options.Risk stratification is primarily based on karyotype, however other factors including age, initial white blood cell count, secondary AML and mutational status are also utilized to determine prognosis. HCT is an effective option for treatment of AML with intermediate/high risk features in CR1. It has also been utilized in refractory or relapsed disease. Advances in HCT over the last decade have improved overall survival (OS) and extended this option to older patients.Our aim is to characterize outcomes after HCT for AML patients who are not in CR1.Methods: We analyzed 136 AML patients who were not in CR1 at the time of HCT from 2004 - 2013. The conditioning regimen was fludarabine and myeloablative doses of PK targeted busulfan. IWG AML response criteria were used to define disease status at the time of transplant. Cytogenetic risk was based on the NCCN AML guidelines. OS is defined as the time from HCT until the time of death from any cause. Disease free survival (DFS) is defined as the time from HCT to the time of relapse or death from any cause.Results: Disease status consisted of 74 (54.4%) in CR2, 6 (4.4%) in CR3 or beyond, 27 (18.9%) were PIF, 21 (15.4%) with relapsed AML (REL) that was treated but still present at time of transplant, and 8 (5.7%) who received either no treatment or a hypomethylating agent (HMA). Median age was 52.0 (21.8 - 72.5) years, and 80 (59%) were male. Time from most recent treatment to HCT was < 1 month in 8 (5.8%), 1-3 months in 75 (55.8%), >3 months in 50 (36.8%) and not applicable in 3. Ninety-six (70.6%) had de novo AML, while 40 (29.4%) had secondary AML. Cytogenetic risk was favorable in 32 (23.5%), intermediate in 57 (42%), poor in 40 (29.4%) and unknown in 7 (5.1%). Graft-versus-host disease prophylaxis was tacrolimus with methotrexate or sirolimus, or mycophenolate mofetil. Donors included 41 (30.2%) matched related, 2 (1.4%) mismatched related, 65 (47.8%) matched unrelated and 28 (20.6%) mismatched unrelated donors. Peripheral blood stem cells were used in 97.2% of cases.Two year OS, DFS, cumulative incidence (CI) of relapse and CI-NRM for all patients was 45.3%, 35.2%, 47.1% and 18.2%, respectively. Two-year DFS stratified by disease status at time of HCT was 41.9%, 33.3%, 25.9%, 33.3% and 12.5% in CR2, CR3 or beyond, PIF, REL and HMA, respectively(p=0.011 for CR2 vs HMA) (Figure 1). Two-year DFS stratified by cytogenetic risk was 43.8%, 31.6%, 37.1% and 14.3% in favorable, intermediate, poor and unknown, respectively (p>0.05) (Figure2). CI-Rel stratified by disease status was 43.2%, 16.7%, 66.7%, 42.9% and 50% in CR2, CR3 or greater, PIF, REL and HMA, respectively (Figure 3).Conclusions: We analyzed 136 AML patients after undergoing HST outside of CR1 and the cumulative incidence of relapse at two years was 47%. Relapse was highest in those with primary induction failure or residual disease after either no or low intensity therapy. These data suggest that patients with active disease at the time of transplant fare worse than those who are transplanted in remission, highlighting the importance of effective upfront therapies in order to obtain the maximum potential benefit from HCT. Cytogenetic risk stratification did not significantly impact outcomes, although those with favorable risk cytogenetics trend towards higher 2-year DFS vs those with intermediate or poor-risk disease. Trials looking at the impact of maintenance therapy post-transplant may be valuable in this patient population.Table 1Disease Status @ HSCTCR2CR3 or beyondPIFRESHMA/untreated2 years41.9% (30.6 - 52.8)33.3% (4.6 - 67.6)25.9% (11.5 - 43.1)33.3% (14.9 - 53.1)12.5% (0.7 - 42.3)Table 2Cytogenetic Risk GroupFavorableIntermediateUnfavorableUnknown2 years43.8% (26.5 - 59.8)31.6% (20.1 - 43.7)37.1% (22.5 - 51.8)14.3% (0.7 - 46.5)Table 3Cumulative Incidence of RelapseCR2 (1)CR3 or beyond (2)PIF (3)REL (4)HMA/untreated (5)2 years43.2% (32.2 - 54.6)16.7% (0.0 - 53.5)66.7% (48.1 - 82.9)42.9% (23.0 - 64.0)50.0% (18.1 - 81.9) [Display omitted] [Display omitted] [Display omitted] DisclosuresSweet:Novartis Pharmaceuticals: Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Karyopharm Therapeutics Inc: Research Funding; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy; Pfizer: Research Funding; Kalo-Bios: Consultancy; Amgen: Consultancy. Perkins:PDL Biopharma: Research Funding. Field:PDL Biopharma: Research Funding.

Zinc finger protein 382 is downregulated by promoter hypermethylation in pediatric acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are characteristic of AML. Zinc finger protein 382 (ZNF382) has been suggested to be a tumor suppressor gene possibly regulated by promoter hypermethylation in various types of human cancer. However, ZNF382 expression and methylation status in pediatric AML is unknown. In the present study, ZNF382 transcription levels were evaluated by quantitative reverse-transcription PCR. Methylation status was investigated by methylation-specific (MSP) PCR and bisulfate genomic sequencing (BGS). The prognostic significance of ZNF382 expression and promoter methylation was assessed in 105 cases of pediatric AML. The array data suggested that the ZNF382 promoter was hypermethylated in the AML cases examined. MSP PCR and BGS analysis revealed that ZNF382 was hypermethylated in leukemia cell lines. Furthermore, treatment with 5-aza-2′-deoxycytidine (5-Aza) upregulated ZNF382 expression in the selected leukemia cell lines. The aberrant methylation of ZNF382 was observed in 10% (2/20) of the control samples compared with 26.7% (28/105) of the AML samples. ZNF382 expression was significantly decreased in the 105 AML patients compared with the controls. Patients with ZNF382 methylation showed lower ZNF382 transcript levels compared with patients exhibiting no methylation. There were no significant differences in clinical characteristics or cytogenetic analysis between the patients with or without ZNF382 methylation. ZNF382 methylation correlated with minimal residual disease (MRD). Kaplan-Meier survival analysis revealed similar survival times in the samples with ZNF382 methylation, and multivariate analysis revealed that ZNF382 methylation was not an independent prognostic factor in pediatric AML. The epigenetic inactivation of ZNF382 by promoter hypermethylation can be observed in AML cell lines and pediatric AML samples. Therefore, our study suggests that ZNF382 may be considered a putative tumor suppressor gene in pediatric AML. However, further studies focusing on the mechanisms responsible for ZNF382 downregulation in pediatric leukemia are required.

Central Nervous System Leukemia in Acute Myeloid Leukemia

Central nervous system leukemia (CNSL) is less common in patients with acute myeloid leukemia (AML) compared to patients with acute lymphoblastic leukemia. CNSL in AML patients is rare with an incidence less than 5%. Before high dose cytarabine was incorporated into induction and consolidation regimens the incidence was higher, approximately 20%. Because of the low incidence of CNSL in AML routine evaluation (lumbar puncture with cerebrospinal fluid analysis) in patients with no CNS symptoms is not indicated at diagnosis or relapse. Patients with acute myelomonocytic leukemia, high risk or relapsed acute promyelocytic leukemia or AML with inversion 16 or chromosome 11 abnormalities may have a higher risk of CNSL. High white blood cell count at diagnosis, elevated LDH and age less than 2 years of age may also increase risk of CNSL. This study was undertaken to evaluate the incidence of CNSL in patients with newly diagnosed and relapsed AML. 298 adult patients with AML were identified through the Mayo Clinic Arizona Cancer Registry between January 2002 and February 2012. 270 had records available for retrospective review. Data on AML status (newly diagnosed/relapsed disease), cytogenetics, molecular markers, white blood count at diagnosis and lumbar puncture results was collected. 9 (4%) patients underwent lumbar puncture. 8 patients had CNS symptoms. CNS evaluation in the asymptomatic patient was performed because of high white blood cell count and myelomonocytic AML at diagnosis. 6 (67%) of the patients who underwent lumbar puncture were found to have CNSL. Of the patients with CNSL all were symptomatic, 4 had relapsed or refractory AML (1 post allogeneic hematopoietic stem cell transplant (HCT)) and 2 had initial diagnosis of AML. All patients with CNS leukemia had myelomonocytic AML. No trend in cytogenetic subtype was noted. Most patients did not have white blood count at diagnosis or molecular markers available for evaluation. AML can be a difficult disease to cure. Patients with CNSL have worse outcome and need altered treatment regimens. CNSL occurring after HCT has an even more dismal prognosis. Currently there is no indication to evaluate for CNSL in asymptomatic patients either at diagnosis, relapse or pre HCT. This small review is notable because all patients with CNSL had myelomonocytic AML. It has been suggested previously that these patients are at higher risk for CNSL. Perhaps the risk for CNSL in those with myelomonocytic AML has a higher incidence than previously reported and this patient population should have routine evaluation of the CNS. Should asymptomatic patients with myelomonocytic AML undergo lumbar puncture at initial diagnosis, relapse or pre HCT? Would prophylactic administration of intrathecal chemotherapy benefit this population? Further prospective study of the incidence of CNSL in patients with AML would be beneficial.

Serum 25-hydroxyvitamin D levels in relation to disease status and prognosis in acute myeloid leukemia

Background Low vitamin D levels are linked to higher incidence of cancer. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for acute leukemia. Aim of the work To evaluate the relationship between serum 25-hydroxyvitamin D (25[OH]D) levels and disease status in acute myeloid leukemia (AML) and correlate these levels with prognostic markers of the disease. Materials and Methods Sixty AML patients, 32 newly diagnosed, 15 in relapse, and 13 in complete remission, as well as 30 healthy control individuals were studied using enzyme-linked immunosorbent assay for the measurement of serum 25[OH]D. Results There was a significantly lower white blood cell count, hemoglobin level, platelet count, and serum vitamin D level among AML patients compared with the control group. Vitamin D-insufficient patients showed lower hemoglobin levels and platelet counts, together with a higher lactate dehydrogenase level, higher percentage of peripheral blood blasts infiltration, and higher percentage of bone marrow blasts' infiltration compared with vitamin D-sufficient patients. Vitamin D levels showed a significantly higher median value among patients who had favorable cytogenetics and a higher median value among those who showed complete remission than those newly diagnosed or in relapse. Survival curve analysis showed shorter overall survival of vitamin D-insufficient patients compared with vitamin D-sufficient patients. Conclusion and Recommendations Vitamin D level is related to the active stage of the disease and therefore aggressiveness of the disease. It can be used as a prognostic tool for survival in AML patients. It is recommended that further evaluation be carried out on a large number of patients with a longer follow-up period and that it is incorporated into the routine evaluation of all AML patients. Additional studies are needed to determine the exact role of vitamin D in acute leukemia and whether it could be used as a therapeutic or a preventive approach.

Outcomes and Prognostic Factors for Patients with Acute Myeloid Leukemia Admitted to the Intensive Care Unit

AbstractAbstract 3613 AimPatients with acute myeloid leukemia (AML) receiving intensive chemotherapy commonly experience life-threatening complications requiring intensive care unit (ICU) support. Limited information is available regarding which patients are likely to benefit from an ICU admission and their subsequent outcomes. The present study has considered a more homogenous patient population than the majority of previous reports of ICU outcomes in AML, as patients were only included if they were within an induction or consolidation chemotherapy cycle for recently-diagnosed AML. MethodsThis is a retrospective study of 505 consecutive adult patients with newly-diagnosed AML who were treated at the Royal Brisbane or Princess Alexandra Hospitals with intensive chemotherapy between 1st January 1999 and 31st December 2010. Hematology and ICU databases were cross-referenced to identify patients admitted to ICU in the setting of intensive induction or consolidation chemotherapy attempting to achieve or maintain complete remission 1 (CR1). Statistical analyses were undertaken to identify risk factors for ICU admission, short- and long-term outcomes, and prognostic factors predicting survival following ICU admission. ResultsEighty-three patients (16.4%) were identified who had required a total of 92 ICU admissions, complicating 9.4% of induction and 6.7% of consolidation chemotherapy cycles. The median age of patients admitted to ICU was 53 years. Neutropenia was present in 70.7% of patients on admission to ICU, with a median duration of 13 days. The primary indication for ICU admission was hemodynamic instability in 46.7% of patients and respiratory impairment in 40.2% of patients; the underlying pathology was most commonly infection (75.0%). Vasopressors were required in 67.4% of admissions, mechanical ventilation in 58.7%, and hemodialysis in 15.2%. Median APACHE III score was 89 and SOFA score was 11.There were no baseline characteristics found to be associated with an increased likelihood of ICU admission during chemotherapy. Survival to ICU discharge, hospital discharge, 6 months, and 12 months were 67.4%, 60.9%, 48.9%, and 38.6%, respectively. Patients admitted to ICU had worse overall survival than patients not requiring ICU admission (median OS = 0.7 years vs 3.5 years, 5 year OS = 24.3% vs 46.0%, respectively; P < 0.0001) (Figure 1). The increased mortality was predominantly the result of early deaths, as ICU patients surviving to hospital discharge had a similar long-term survival to other patients who survived chemotherapy (median OS = 6.7 years vs 4.1 years, 5 year OS 38.0% vs 47.8%; P = 0.83) (Figure 2). Leukemia-free survival from the time of CR1 was not significantly different between groups (P = 0.054). Multivariate analysis identified independent prognostic factors predicting mortality prior to hospital discharge to be mechanical ventilation use and higher fibrinogen, and mortality at 12 months to be associated with mechanical ventilation use and AML cytogenetic risk group. Notably, survival in patients admitted to ICU was not significantly influenced by the AML status (active disease vs CR1), whether the patient was receiving an induction or consolidation cycle, or the dose of cytarabine used. ConclusionsAdmission to ICU is associated with an increased mortality rate compared to those patients not requiring ICU admission. However, a substantial proportion of patients recover from the acute event, and subsequently experience long-term survival. Prognostic factors predicting short-term survival tend to be related to the acute illness, while longer-term survival is more significantly affected by characteristics of the underlying AML. No factors predicted an outcome sufficiently poor to indicate futility of ICU care. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

CAG (cytarabine, aclarubicin, G-CSF) Regimen Is Effective and Well Tolerated in 367 Elderly Patients with AML in China and Japan: A Meta-Analysis

Abstract 4290 Background:Current therapy is still unsatisfactory in elderly patients (pts) with acute myeloid leukemia (AML). CAG regimen (cytarabine, aclarubicin, G-CSF) has been commonly used in China and Japan for the treatment of elderly AML pts. The aim of this study is to summarize the data and to analyze the efficacy as well as the toxic effects of CAG regimen in elderly AML pts. Methods:The databases of PubMed, Wanfang Data, as well as American Society of Hematology (ASH) annual meeting abstracts were searched for articles published in English, Chinese and Japanese languages from January 1995 to December 2010. Eligible studies were relevant clinical trials of elderly AML pts treated with CAG regimen. Complete remission (CR) rate, odds ratio (OR) and 95% confidence intervals (CIs) of chemotherapy were compared through a meta-analysis using a random-effects or fixed-effects model. Results:19 trials with a total of 367 elderly AML pts were identified and included for analysis. Among the 367 AML pts treated with CAG, 266 pts were newly diagnosed AML, 54 pts were relapsed/refractory (R/R) AML. The AML status was not specified in the rest 47 pts. The CR rate for the 367 elderly AML pts was 52.0% (95% CI 46.8%-57.2%). Interestingly, no significant difference in CR rates was noted between the newly diagnosed (54.7%, 95% CI 48.6%-60.7%) and R/R AML pts (45.7%, 95% CI 32.4%-59.6%) (Q=1.332, p=0.248). Three studies compared the CR rates of elderly AML pts according to the karyotype. The CR rate was significantly higher in pts with intermediate (72.4%, 95% CI 58.0%-83.3%) cytogenetics than those with unfavorable one (35.7%, 95% CI 18.7%-57.2%) (Q=7.803, p=0.005). These elderly AML pts tolerated CAG well with low cardiotoxicity (0.73%, 2/273) and ED (8.48%, 29/342). Conclusions:CAG regimen induced high CR rates in elderly pts with new and relapsed/ refractory AML. This regimen was well tolerated with low cardiotoxicity and early death rate. Disclosures:No relevant conflicts of interest to declare.

Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan

BackgroundRisk factors and outcomes in hematological patients who acquire invasive fungal sinusitis (IFS) are infrequently reported in the modern medical era.MethodA retrospective study of hospitalized patients with hematological disease was conducted at National Taiwan University Hospital between January 1995 and December 2009.ResultsClinical characteristics and outcomes with their associated radiographic and microbiological findings were analyzed. Forty-six patients with IFS and 64 patients with chronic non-invasive sinusitis were enrolled as comparsion. IFS developed more commonly in patients with acute myeloid leukemia (AML) and with prolonged neutropenia (absolute neutrophil count less than 500/mm3 for more than 10 days) (p < 0.001). Aspergillus flavus was the most common pathogen isolated (44%). Serum Aspergillus galactomannan antigen was elevated in seven of eleven patients (64%) with IFS caused by aspergillosis but negative for all three patients with mucormycosis. Bony erosion and extra-sinus infiltration was found in 15 of 46 (33%) patients on imaging. Overall, 19 of 46 patients (41.3%) died within 6 weeks. Patients with disease subtype of AML (p = 0.044; Odds Ratio [OR], 5.84; 95% confidence interval [95% CI], 1.02-30.56) and refractory leukemia status (p = 0.05; OR, 4.27; 95% CI, 1.003-18.15) had worse prognosis. Multivariate analysis identified surgical debridement as an independent good prognostic factor (p = 0.047) in patients with IFS.ConclusionsPatients of AML with prolonged neutropenia (> 10 days) had significantly higher risk of IFS. Early introduction of anti-fungal agent and aggressive surgical debridement potentially decrease morbidity and mortality in high risk patients with IFS.

Rapid Assessment of the Heterogeneous Methylation Status of CEBPA in Patients with Acute Myeloid Leukemia by Using High-Resolution Melting Profile

Epigenetic inactivation of tumor-suppressor genes, often in association with aberrant DNA methylation of CpG islands in the promoter region of these genes, is a key factor in tumorigenesis. CCAAT/enhancer binding protein alpha (CEBPA) methylation is a favorable prognostic biomarker for acute myeloid leukemia; however, rather than the complete methylation observed in inherited disorders, CEBPA methylation is heterogeneous. In this study, we established an algorithm called the "methylation index," deduced from high-resolution melting profiles, which includes Tm shifting (ΔTm) and Tm width ratio (fold of width), to evaluate the heterogeneous methylation status. The methylation index was highly correlated with the exact methylation levels detected by using the MassARRAY method (R(2) = 0.80; P < 0.001). Within-run reproducibility for the methylation index was 0.9% as the coefficient of variation, and between-run reproducibility was 2.6%. It was determined that with a cutoff methylation index of 1.412, the best measures of sensitivity and specificity could be obtained (97.14% and 95.89%, respectively) to discern low or high CEBPA methylation status. This novel algorithm for calculation of the methylation index from high-resolution melting profiles for CEBPA methylation is compatible with measurement of the methylation level as assayed using MassARRAY and could be a simple and efficient screening method for determination of CEBPA methylation status in acute myeloid leukemia.

Acute Myeloid Leukemia and Survival on the Intensive Care Unit (ICU) - Biology- and Treatment-Related Determinants of Outcome - An Analysis of the AML-CG

AbstractAbstract 2166 Background:An established factor for predicting the mortality of patients admitted to an ICU is the Severe Acute Physiology Score (SAPS) II. However, for patients with acute myeloid leukemia (AML) it is uncertain whether factors beyond SAPS II do influence the ICU outcome. Therefore we examined additional factors including age and factors related to AML biology and its treatment in the so far largest cohort of patients with AML worldwide regarding their ICU outcome. Methods:Retrospective analysis of 256 patients with 366 admissions to medical ICU between 2004 and 2009 in 3 large German hematologic centers. Patient age and gender, reason for ICU admission, duration of intensive care, SAPSII, need for invasive mechanical ventilation (IMV), renal replacement therapy and/or vasopressors, laboratory values at ICU admission for creatinine, bilirubin and C-reactive protein, AML karyotype, presence of FLT3-ITD and/or NPM1-mutation, FAB classification, last AML treatment, AML status and allogeneic transplant status were evaluated as potential risk factors. Correlations were analyzed using the Mann-Whitney U test. Univariate analysis was performed using the log rank test for the time until death on ICU occurred. Significant risk factors were studied in multivariate analysis (Cox regression). Results:At the time of analysis (08/2010) the median age of patients was 55.3 (range 19.7–84.9) years, and 47.5% were female. 46% of ICU admissions were due to infectious complications. A respiratory problem was present in 60% of the ICU transfers. IMV, vasopressors and renal replacement therapy were necessary in 51.3%, 42.6% and 22.7%, respectively, of the ICU courses. ICU survival was 64.8%. AML status was primary diagnosis/induction phase in 53.3%, postremission phase in 15.8% and relapse/refractory in 27.6% of ICU courses. 66.4% of admissions to ICU had conservative treatment (no transplant), 15.8% underwent allogeneic hematopoietic stem cell transplantation (allo SCT) in the same hospital stay (peritransplant status) and 14.5% had had allo SCT in a former hospital stay (posttransplant status). AML karyotype was favourable in 7.1%, intermediate in 47.8% and unfavourable in 20.2%. SAPS II was available in 208 ICU transfers. Duration of intensive care was 8.1 (mean)/3.0 (median) days with a range from 0.5–76 days. In univariate analysis risk factors predicting diminished ICU survival were high SAPS II (p=0.008), sepsis as reason for ICU admission (p=0.007), need for IMV (p<0.001), use of vasopressors (p<0.001), renal replacement therapy (p=0.002), intermediate or unfavourable AML karyotype (p=0.027), FAB classification other than AML M3 (p=0.012), postremission or relapse/refractory status of AML (p=0.029) and posttransplant status of AML (p=0.002). ICU mortality was lower in primary diagnosis/induction phase and higher in posttransplant phase of AML than predicted by the median SAPS II of these cohorts. In multivariate analysis the only significant predictor of inferior ICU survival was the extent of vasopressor treatment (hazard ratio (hr) 1.83, 95% CI 1.09–3.08; p=0.022), whereas high SAPS II was of borderline significance (hr 1.02, 95% CI 1.00– 1.03; p=0.064). Conclusions:In contrast to the broad majority of ICU patients, SAPS II is not an optimal predictor of ICU survival in patients with AML. Disease status was of high relevance with an AML status of primary diagnosis/induction phase indicating a better and posttransplant (but not peritransplant) status a worse ICU survival than predicted by SAPS II. The strongest predictor for ICU mortality was the extent of vasopressor use. In contrast age up to the 8th decade had no impact on ICU survival. These results may help to better define ICU admission and treatment policies for patients with AML. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A clinico-genomic model of performance status in acute myeloid leukemia.

6558 Background: ECOG Performance Status (PS) is a well known clinical predictor of survival in patients with Acute Myeloid Leukemia (AML). Altered levels of certain cytokines e.g. IL-6, IL-1, IL-2, TNF-α, and CRP can lead to decreased functional status and increased mortality in cancer patients, suggestion a state of frailty. Methods: Clinically annotated microarray data from 377 patients with newly diagnosed AML from two publicly available datasets: GSE1159; and GSE12417 with ECOG PS, and Overall Survival (OS) data were analyzed. A “frailty profile” was developed by utilizing a set of previously characterized genesets/pathways that define the aforementioned cytokines. OS was used as the primary endpoint. Standard Kaplan-Meier survival curves were generated using the two-sided log-rank test. Results: The frailty profile was queried in the 377 patients, and by unsupervised clustering methods, two cohorts (n = 58) of patient samples that represented extremes of survival (cohort 1, median survival (MS) 4.9 months, cohort 2 MS 46.3 months; p < 0.0001) were identified. Standard Kaplan-Meier survival curves were also generated for these 58 patients based on ECOG PS, and there was no statistically significant difference in OS (MS for ECOG 0-1 was 14 months, ECOG ≥ 2 was 8.8 months; p = 0.29). We then developed a clinic-genomic classification of these patients into three risk groups: low, intermediate and high risk depending on a) cohort based on frailty profile and b) ECOG PS, to evaluate if the frailty profile adds any additional information to the clinically estimated ECOG PS. This combined analysis revealed that low-risk patients (cohort 2 plus ECOG 0-1) had a statistically significant higher MS of 56.1 months when compared to intermediate risk (MS 9.85 months) and high-risk (MS 8.35 months) patients; p = 0.02. Conclusions: A clinico-genomic model that combines the widely utilized ECOG PS, with a genomic frailty profile (representing genesets/pathways for cytokines associated with poor functional status) might represent a unique and more refined way of selecting AML patients for induction therapy. This may be especially valuable in elderly AML patients for whom the ECOG PS is not always an accurate measure of functional status. No significant financial relationships to disclose.

A Comparison of Two Methods for Screening CEBPA Mutations in Patients with Acute Myeloid Leukemia

The goal of the study was to compare the performance of a fluorescence-based multiplex PCR fragment analysis to a direct sequencing method for detecting CEBPA mutations in patients with acute myeloid leukemia. Thirty-three samples were selected from a larger study of 107 cases of acute myeloid leukemia by screening for CEBPA mutations by sequence analysis. Of ten identified mutations, six (insertions and deletions) were detected by both sequencing and fragment methods. The fragment analysis method did not detect the remaining four base substitutions because the method cannot detect changes that result in identically sized products. The multiplex PCR fragment length analysis method therefore failed to detect substitution mutations accounting for 40% of total CEBPA mutations in our patient set. Our results indicate that fragment length analysis should not be used in isolation, and that direct sequencing is required to evaluate CEBPA gene mutational status in acute myeloid leukemia. A combination of the two assays may offer some advantages, chiefly in permitting more sensitive detection by fragment length analysis of insertions and deletions.

Incidence and Prognostic Value of FLT-3 and NPM1 Genes Abnormalities in Acute Myeloid Leukemia in the Côte D'or Population, France

Context: In acute myeloid leukemia (AML), the recently described FLT-3 and NPM1 genes abnormalities were found to have a prognostic value in AML with normal karyotype and a specific therapeutic strategy was proposed according to these abnormalities. We look for the incidence and prognostic value of these abnormalities in cases diagnosed on a well defined population.Material and Methods: AML diagnosed according to WHO classification between 01/01/2001 and 31/12/2006 in the population of the Côte d'Or department, were included. Karyotype analyses were performed in 81% of the cases. The FLT3 D835 mutation, the FLT3 internal duplication (ITD) and the NPM1 mutation were systematically studied on the biological material of the diagnosis cryopreserved in the Ferdinand Cabanne Biobank of Burgundy, by PCR and DNA sequencing techniques. The vital status of the patients was update on 31/10/2007. The relative survival was calculated with the STATA (V9) software.Results: 100 de novo AML and 47 secondary AML (sAML) were registered (72 females and 75 males). The world standardized incidence rate was 2.4 in men and 1.5 in women for de novo AML instead of what it was respectively of 1.1 and 0.6 in sAML. The urban predominance was present in both type of AML. The karyotype was normal in 38% (45/119) of cases (35% of de novo AML and 21% of sAML). It was abnormal in 62% of cases (74/119)(51% of de novo AML and 49% of sAML). Molecular analyses were performed in 78 de novo AML and in 24 sAML. FLT3 ITD was present in 19% (15/78) de novo AMl and in any sAML. The FLT3 D835 mutation was present in 6.5% of de novo AML and in 8% of sAML. NPM1 was mutated respectively in 26% and 4% of the cases. There was a significantly higher WBC count and proportion of blast cells in peripheral blood in FLT3 ITD cases. Overall and relative survivals of FLT3 ITD cases were decreased compared to FLT3 wild type cases. No difference according to NPM1 status was found.Conclusions: These data confirm the bad prognostic value of FLT3 ITD status in AML observed in clinical series. Furthermore their particular interest lies in the fact that they are the first molecular data in AML produced on a population-based series indicating the feasibility of such epidemiological studies.

A confused 55-year-old man. Disseminated toxoplasmosis.

We present a case of a 55-year-old man with acute myeloid leukemia status after bone marrow transplantation who developed multiorgan failure and died within a week of the onset of symptoms. A postmortem examination revealed disseminated toxoplasmosis. We discuss the clinical presentation, epidemiology, and life cycle of toxoplasmosis.

A Confused 55-Year-Old Man

We present a case of a 55-year-old man with acute myeloid leukemia status after bone marrow transplantation who developed multiorgan failure and died within a week of the onset of symptoms. A postmortem examination revealed disseminated toxoplasmosis. We discuss the clinical presentation, epidemiology, and life cycle of toxoplasmosis.

Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes

AbstractFms-like tyrosine kinase 3 (FLT3) mutations are associated with unfavorable outcomes in children with acute myeloid leukemia (AML). We used DNA microarrays to identify gene expression profiles related to FLT3 status and outcome in childhood AML. Among 81 diagnostic specimens, 36 had FLT3 mutations (FLT3-MUs), 24 with internal tandem duplications (ITDs) and 12 with activating loop mutations (ALMs). In addition, 8 of 19 specimens from patients with relapses had FLT3-MUs. Predictive analysis of microarrays (PAM) identified genes that differentiated FLT3-ITD from FLT3-ALM and FLT3 wild-type (FLT3-WT) cases. Among the 42 specimens with FLT3-MUs, PAM identified 128 genes that correlated with clinical outcome. Event-free survival (EFS) in FLT3-MU patients with a favorable signature was 45% versus 5% for those with an unfavorable signature (P = .018). Among FLT3-MU specimens, high expression of the RUNX3 gene and low expression of the ATRX gene were associated with inferior outcome. The ratio of RUNX3 to ATRX expression was used to classify FLT3-MU cases into 3 EFS groups: 70%, 37%, and 0% for low, intermediate, and high ratios, respectively (P < .0001). Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients. (Blood. 2004;104:2646-2654)

Acute Bleeding After Bone Marrow Transplantation (BMT)– Incidence and Effect on Survival. A Quantitative Analysis in 1,402 Patients

AbstractAcute bleeding after bone marrow transplantation (BMT) was investigated in 1,402 patients receiving transplants at Johns Hopkins Hospital between January 1, 1986 and June 30, 1995. Bleeding categorization was based on daily scores of intensity used by the blood transfusion service. Moderate and severe episodes were analyzed for bleeding sites. Analysis of the cause of death and the interval of the bleeding episode to outcome endpoints was recorded. Survival estimates were computed for 1,353 BMT patients. The overall incidence was 34%. Minor bleeding was seen in 10.6%, moderate bleeding was seen in 11.3%, and severe bleeding was seen in 12% of all patients. Fourteen percent of patients had moderate or severe gastrointestinal hemorrhage, 6.4% had moderate or severe hemorrhagic cystitis, 2.8% had pulmonary hemorrhage, and 2% had intracranial hemorrhage. Sixty-one percent had 1 bleeding site and 34.4% had more than 1 site. Moderate and severe bleeding was more prevalent in allogeneic (31%) and unrelated patients (62.5%) compared with autologous patients (18.5%). Significant distribution of incidence was found among the different diagnoses, but not by disease status in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma. Bleeding was associated with significantly reduced survival in allogeneic, autologous, and unrelated BMT and in each disease category except multiple myeloma. Survival was correlated with the bleeding intensity, bleeding site, and the number of sites. Although close temporal association was evident to mortality, bleeding was recorded as the cause of death in only the minority of cases compared with other toxicities after BMT (graft-versus-host disease, infections, and preparative regimen toxicity). Acute bleeding is a common complication after BMT that is profoundly associated with morbidity and mortality. Although bleeding was not a direct cause of death in the majority of cases, it has a potential prognostic implication as a predictor of poor outcome in clinical assessment of patients after BMT.