ALBERT

Description: [1]  Mauna Loa and Kilauea volcanoes, Hawaii, are thought to be coupled by pore pressure diffusion through an asthenospheric melt layer. However, abundant observations of independent activity of these volcanoes suggest a complicated relationship. Here, we analyze surface deformation data, deep seismicity and gas measurements, to reveal strong coupling of these volcanoes between 2003 and 2008. In early 2005, we find a shift from anti-correlation to correlation of magma-chamber inflation. The shift is preceded by a seismic swarm in the mantle beneath Mauna Loa and accompanied by a large silent slip event beneath the south flank of Kilauea. This suggests that these volcanoes are coupled during mantle-driven surges and that the 2005 silent slip event was triggered by accelerated magma supply at Kilauea.

Description: Key Points CMV reactivation after HCT is associated with a reduced risk of early relapse in patients with AML but not other disease groups. The benefit, however, is offset by an increased risk of nonrelapse mortality.

Description: Abstract 2191 Background: Treatment protocols for newly diagnosed AML typically use age (often 60 years) alone to restrict eligibility to either younger or older patients. Implied in this practice is the assumption that age is the principal predictor of therapeutic failure in AML due to either early treatment-related mortality (TRM) or resistance to therapy in patients who do not incur TRM. Yet, clinical observation and previous studies indicate that other prognostic factors modulate the effect of age on TRM and resistance, suggesting that age as sole or primary criterion for treatment allocation may be suboptimal. Methods: To test this hypothesis in newly-diagnosed non-APL AML, we quantified the relative effects of age and other covariates using 1,127 patients (median age: 57 years) treated on Southwest Oncology Group (SWOG) trials from 1986–2009 and 1,604 patients (median age: 61 years) treated on various protocols at M.D. Anderson Cancer Center (MDA) from 2000–2008. We calculated weekly hazard rates (the probability of death in week × given that the patient was alive at the beginning of the week) for both cohorts overall and in various age subgroups. We used the area under the receiver operator characteristic curve (AUC) to quantify the effects of covariates for prediction of TRM and resistance (no TRM but patient does not enter CR or relapses within 1 year of CR), where an AUC of 1 indicates that a covariate is perfect at prediction while an AUC of 0.5 indicates no prediction (i.e. it is no better than flipping a coin). Results: Despite the use of different treatment protocols, survival in the SWOG and MDA cohorts was virtually superimposable. In both cohorts, the maximum weekly hazard occurred at weeks 3 and 4 from start of treatment, after which it decreased. The maximum hazard was relatively independent of age and remained between weeks 3 and 5 in patients age 70 years, respectively. The existence of such a discrete cut-point suggested that patients who die early are qualitatively distinct and prompted us to examine the relative effect of age and other covariates in patients who (a) died within the first 30 days of treatment (our empirically-based definition of TRM, 9% of MDA and 12 % of SWOG patients, respectively) and (b) survived at least 30 days but did not enter complete remission or relapsed within 1 year (“resistant”, 43% of MDA and 59% of SWOG patients, respectively). A model including age alone to predict early mortality had an AUC of 0.67, while a model including performance status (PS) alone had an AUC of 0.72. By comparison, a more refined model hat included PS, age, platelet count, cytogenetics, secondary AML, albumin, white blood cell count, peripheral blood blast count, and LDH yielded an AUC of 0.86. Elimination of age resulted in a model with an AUC that was only minimally lower (0.85). Prediction of resistance was more difficult with a model including age, secondary AML, cytogenetics, peripheral blood blasts, race, hemoglobin, and marrow neutrophils giving an AUC of only 0.70. Elimination of age had little effect (AUC 0.67) while age alone gave an AUC of 0.64. Conclusion: Age alone appears inadequate in predicting resistance and particularly TRM. The use of models based on several covariates improves predictive ability, but the ability to predict resistance is still limited, suggesting the value of randomized trials to assess treatment designed to reduce resistance. The observation that elimination of age has little effect on the predictive ability of such models, suggests that age is primarily a surrogate for other covariates. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3551 Background: With intensive chemotherapy, many acute myeloid leukemia (AML) patients will enter complete remission (CR). Empirically, the bone marrow is typically examined 14 days after initiating induction therapy, and re-treatment is commonly considered if significant residual blasts remain. However, many patients receiving single induction will enter CR without additional therapy despite substantial amounts or residual marrow blasts on day 14, leaving considerable uncertainty about the value of early marrow assessments. An emerging alternative approach to predict the efficacy of induction therapy includes the assessment of peripheral blood blast (PBB) dynamics. Rapid clearance of PBB, determined either by review of manual differential counts or flow cytometry is predictive of CR (likelihood of 76–90%) and overall survival. We investigated whether mathematical modeling of early PBB dynamics using automated complete blood cell (CBC) counts and the manual differential could further refine our ability to predict CR. Patients and Methods: We identified 111 adult patients with circulating PBB who underwent curative-intent, single-cycle induction chemotherapy for newly diagnosed AML between April 1999 and December 2011. Therapy regimens included “7+3”-like (56.8%), and regimens of similar/higher (29.7%) or lower (13.5%) intensity. PBBs were quantified as WBC count from the automated CBC times percentage of blasts by manual differential (100 cells). Cytogenetic abnormalities, NPM1/Flt3 status, day 14 and recovery bone marrow data were extracted from patient records. In the 62 patients with 〉3 measurable PBB counts, the rate of PBB clearance was calculated by fitting an exponential decay curve to the data points of absolute PBB counts, starting on day 1 of chemotherapy. This subgroup of patients had similar baseline parameters as the whole group, including age, WBC count at diagnosis, cytogenetic risk, percent of secondary AML, therapy regimens were similar, and CR rates were identical (69 vs. 68%). Results: An exponential decay curve [N(t) = N0×e-xt, with x=decay constant] resulted in an excellent goodness of fit of early PBB dynamics (mean r2=0.93). Rapid PBB clearance was highly predictive of CR achievement, with an optimal cut-off of x=1.4 (corresponding to a 4.2-log reduction in tumor burden if maintained over the course of a weeklong chemotherapy) based on the receiver operating characteristic (ROC) curve. All but 1 of the 27 patients with x〉1.4 achieved CR (positive predictive value [PPV]=96%) the only non-responder with x〉1.4 had a combination of negative prognostic factors including secondary AML, unfavorable cytogenetics, older age, and lower intensity treatment. PPV of PBB clearance rate of 96% for predicting CR compared favorably to alternative previously published approaches such as day of PBB clearance or percentage of day 14 bone marrow blasts (84 and 85% respectively in our study). Day 14 marrow assessments did not add prognostic information in 26/27 patients who had fast PBB clearance rate (x〉1.4). In univariate analyses, CR achievement was significantly correlated with a higher PBB clearance rate, younger age, primary AML, more favorable cytogenetics, and treatment intensity. In multivariate analyses including age, primary vs. secondary AML, cytogenetics, type of therapy, and PBB clearance rate (57 patients), only the PBB clearance rate remained statistically significantly associated with CR achievement. Importantly, information from CBC differentials is routinely available in most institutions and associated costs are low. Unlike determination of the exact day of PBB clearance that coincides with profound cytopenia, the PBB clearance rate is measured while PBB are still abundant, rendering the latter method less prone to sampling and observer errors. Conclusion: our findings suggest that early marrow assessment may not be necessary in AML patients who experience rapid PBB clearance upon induction treatment initiation as they have an almost 100% chance of achieving CR. Disclosures: Vainstein: Neumedicines Inc: Employment.

Description: Background Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) typically receive intensive chemotherapy to achieve disease remission. Generally, these patients remain hospitalized until blood count recovery due to the risk for infections and bleeding during pancytopenia. However, a recent small pilot study at our institution suggested that early discharge (ED) following induction/salvage therapy for MDS/AML may be safe and may reduce cost. We therefore conducted a phase 2 study to test this care strategy in a larger cohort of patients (NCT01235572). Methods Patients aged 18-75 years with high-risk MDS or AML (other than acute promyelocytic leukemia) were enrolled before or during induction or salvage chemotherapy and provided with outpatient care teaching. Patients were considered eligible for ED if they fulfilled the following medical and logistic criteria: ECOG performance status of 0-1, adequate organ function; no active bleeding; agreeable to close outpatient follow-up; reliable caregiver; and residency within 60 minutes of the outpatient clinic. Patients who met medical but not logistic criteria served as inpatient controls. If readmitted, ED was again possible if all medical/logistic criteria were met. Patients remained on protocol until blood count recovery, additional chemotherapy was administered, or a maximum of 45 days. Our goal was to compare the number of early deaths, healthcare costs and resource utilization among ED patients versus inpatient controls. Safety was monitored with early stopping if the early death rate was 〉7% in the ED group, with a predefined interim analysis after 30 patients. All data are provided as median (range). Results One hundred and seven eligible patients were enrolled over a 2-year period. Two patients died during chemotherapy. Twenty-seven patients failed to meet medical ED criteria after completion of chemotherapy and were taken off study, mostly due to poor performance status. Eighteen patients, age 51.4 (22-70) years, met medical but not logistic ED criteria and served as controls; they were followed for 14 (9-41) days, with 7 patients taken off study at the time of hospital discharge before blood count recovery. Sixty patients, age 51.6 (22-71) years, met all ED criteria and were discharged upon completion of induction (n=19) or salvage (n=41) chemotherapy for AML (n=50) or MDS (n=10). A median number of 1 (1-3) readmission occurred in 53 of these patients, primarily for neutropenic fever; 8 patients were readmitted twice and 3 patients were readmitted 3 times prior to coming off study. Overall, ED patients spent 12.8 (0-38) and 7.5 (0-33) days as out- and inpatients, respectively, for a total of 62.7% (0-100%) of the study time spent as outpatients. ED patients required 0.41 (0-1.9) clinic visits and 0.13 (0-0.66) physician visits per outpatient day. Duration of IV antibiotics was similar in ED and control patients (10 [0-40] vs 12 [0-40] days; p=0.38) as was number of red blood cell transfusions (0.27 [0.0-0.94] vs 0.29 [0.08-0.548] units/study day; p=0.21). In contrast, ED patients required fewer platelet transfusions (0.21 [0.09-1.25] vs 0.33 [0.21-0.80] units/ study day; p=0.02). Six patients in the ED group required between 1-6 days of intensive care unit (ICU) care (p= 0.17 for the difference in ICU days between discharges and controls). Three deaths occurred in the ED group during the study period: two of sepsis (2 and 7 days after readmission), and one of fungal sinusitis (11 days after readmission). The median daily total professional and facility charges, dated from the day of re-evaluation until removal from protocol, were significantly lower for patients discharged early compared to inpatient controls: $3,871 [$360.86-$13,361] vs $6,283 [$4,868-$11,898], p

Description: Introduction Mangement of AML typically calls for a bone marrow aspirate 7-10 days after completion of induction therapy with standard or high-dose cytarabine (HiDAC)-containing regimens (day 14 marrow). If this marrow contains 〉5-10% blasts, National Comprehensive Cancer Network guidelines recommend a second course of induction therapy. However, nearly 70% of patients who have persistent blasts in a day 14 marrow do not begin reinduction within 1 week. Additionally, at least in patients given higher doses of cytarabine as part of induction therapy, blast counts often continue to decrease between days 14 and 21, and many such patients will achieve complete remission (CR) without a second induction. These findings call into question the value of a day 14 marrow. Methods Our database contained 154 patients with newly diagnosed AML or MDS with 10-19% blasts seen in our hospital from 2008-2013. Patients lived at least 21 days after receiving induction therapy with regimens containing standard-dose cytarabine (114 patients, typically given “3+7” ) or high-dose cytarabine (40 patients). The treatments were not given on protocol, thus granting physicians discretion to determine when to examine the marrow. Marrow exams performed between days 10 and 17 after starting induction were considered a “day 14 marrow.” Response was assessed at least 21 days from the start of the initial induction course. Our goals were (1) to identify pretreatment factors (described below) associated with the decision to obtain a day 14 marrow and (2) to determine the influence obtaining a day 14 marrow had on the likelihood of CR on course 1, after accounting, by multivariable logistic regression, for age, cytogenetic risk (SWOG criteria), pretreatment blast % (morphologic count in marrow; peripheral blood if no marrow available), and type of AML (de novo vs. secondary). Results 116 of 154 patients (75%) had a day 14 marrow. Patients who had and did not have a day 14 marrow were similarly-aged (average 53 in both groups), had similar pretreatment blast percentages (52% vs 47%, respectively), and had a similar proportion with de novo AML (66% vs 68%). Patients who had a day 14 marrow more often received 3+7 (79% of standard-dose cytarabine patients had a day 14 marrow vs 65% of HiDAC, p=0.06). Only 60% of patients with favorable risk cytogenetics had a day 14 marrow vs 79% of patients with intermediate or unfavorable risk (p=0.03). Considering the 3+7 group separately, only a higher pretreatment blast count predicted the likelihood of a day 14 marrow (53% with a day 14 marrow vs 38% without, p=0.02). No factors were predictive in the HiDAC group. As expected, favorable cytogenetics were associated with a higher CR rate while age, pretreatment blast %, and de novo vs secondary AML did not influence CR. After accounting for these covariates, there was no difference in the rate of CR between patients who did and did not have a day 14 marrow (66% vs 74%, p=0.61). The same was true when standard and high-dose cytarabine were analyzed separately (p=0.80 and 0.26, respectively). 18 patients with a day 14 marrow had resistant disease and received a second induction course; of these, two achieved CR. Likewise, two patients without a day 14 marrow were reinduced for resistant disease, and one entered CR. While the response to the second induction was not included in the analysis, results would not be expected to vary significantly given the CR rates with the second course. Conclusions These results suggest that while patients are more likely to have a day 14 marrow if they have intermediate- or poor-risk cytogenetics and receive 3+7, the decision to obtain a day 14 marrow does not lead to a higher CR rate. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points Patients with abnl(17p) AML have a poor outcome after allogeneic hematopoietic stem cell transplantation.

Description: Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal ( 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status 40% was also

Description: Abstract 3806 Background: Hospital admission for neutropenic fever in patients with AML is standard practice. However, discharge practices vary once patients become afebrile, with many patients hospitalized until rise in the absolute neutrophil count (ANC) to 〉 500/μL (ANC recovery). Data to support this practice are sparse. We hypothesized that patients admitted for neutropenic fever, particularly if in complete remission (CR) or about to enter CR following the chemotherapy course associated with neutropenic fever, might be safely discharged earlier (ED). Benefits of ED are less exposure to hospital pathogens, reduced cost, increased availability of beds for patients more in need of urgent care, and potentially, enhanced psychological well-being. Methods: We identified patients age 18–70 with newly diagnosed AML who were admitted to the University of Washington Medical Center with neutropenic fever between January 2008 and May 2010. We compared subsequent (within 30 days of discharge) deaths, intensive care unit (ICU) admissions, and readmissions for neutropenic fever according to discharge ANC, regarded as a numerical variable using the Mann-Whitney U test and as 〈 500/μL vs. 〉 500/μL using the Fisher Exact test. We used the Mann-Whitney U or Spearman correlation to analyze the relation between ANC at discharge and other covariates that might have affected outcome: age, ECOG performance status at admission for neutropenic fever, days inpatient, remission status, and type of infection (pneumonia, gram negative bacteremia, other). Results: We evaluated 49 patients discharged after admission for neutropenic fever, 26 of whom were discharged with an ANC 〈 500/μL. 35 of the patients were in CR or entered CR following the chemotherapy course associated with their neutropenic fever admission. Patients who were discharged with lower ANC were more likely to be readmitted with neutropenic fever (Mann-Whitney U p = 0.03), although this was not true using ANC categorized as 〈 vs. 〉 500/μL (Fisher Exact p = 0.24, 95% confidence interval -0.47, 0.11). There was no relation between ANC at discharge and subsequent admission to an ICU (Mann-Whitney U p = 0.50, Fisher Exact p = 0.64, 95% confidence interval 0.2, 0.34 using the 500/μL ANC cut off). One patient died: a 55 year old discharged with ANC 0/μL after successful treatment of neutropenic fever died 19 days after hospital readmission with fever of unknown origin. Stenotrophomonas maltophilia pneumonia and sepsis were discovered 14 days after readmission. Assuming a beta distribution and rates of death of 1/26 for discharge with ANC 〈 500/μL and 0/23 for discharge with ANC 〉 500/μL, the probability that a discharge ANC with 〈 500/μL is associated with a higher death rate is 0.019. The number of events was too small for a multivariate analysis. However, patients with better performance status (〈 ECOG 2) or who spent a shorter time in hospital after admission for neutropenic fever were more likely to be discharged with lower ANC (Fisher exact p = 0.09 and Spearman p = 0.02 respectively), while the likelihood of discharge with ANC 〈 500/μL was unrelated to age, remission status, or type of infection. Thus we examined the relation between ANC and readmission for neutropenic fever separately in patients with better or worse performance status and in patients who spent more or less than the median time (8 days) in hospital after admission for neutropenic fever. This analysis indicated that patients discharged with lower ANC were more likely to be readmitted only if they had spent more than 8 days in hospital or if they were performance status 〈 2. Conclusions: Our results suggest that an ANC of 500/μL is an excessively high cut off for discharge following hospitalization for neutropenic fever. The rate of rise of the ANC, as well as its absolute value, may also play a role. Disclosures: No relevant conflicts of interest to declare.

Description: Background Treatment outcomes for older patients with newly diagnosed AML remain poor. TST is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies, including AML. Phase I/II monotherapy studies in patients with relapsed AML and MDS have shown TST to have adequate safety and promising efficacy. Pre-clinical AML blast proliferation assays have demonstrated synergy between TST and both cytarabine and hypomethylating agents. For this reason, we performed a randomized, open-label Phase II trial using TST in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS (i.e. RAEB-2). Methods Patients ≥60 years old with untreated AML or high risk MDS were randomized to receive TST 120 mg daily by mouth days 1-21 with 5 days of either cytarabine 1 g/m2/day IV or decitabine 20 mg/m2/day IV delivered every 35 days. Patients received up to three 35-day cycles if they had at least stable disease with an acceptable toxicity profile following the initial course. Patients who did not achieve a complete remission (CR) or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were taken off study; patients who obtained CR/CRi were eligible to receive up to 2 additional cycles (maximum of 5). The primary objective was to determine the rates of CR and 4 month survival using TST in combination with either cytarabine or decitabine for older patients with untreated AML or high-risk MDS. Results A total of 26 patients have been treated, with 14 receiving TST/cytarabine and 12 receiving TST/decitabine. The median age was 69 (range, 60-83), and 22 patients (85%) presented with an ECOG performance status of 1. Nineteen patients (73%) had AML and 7 (27%) had MDS RAEB-2. Nineteen patients (73%) had intermediate-risk and 7 (27%) had adverse-risk disease by European Leukemia Net criteria. Fourteen patients (54%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 54%, with 10 patients (39%) achieving a CR and 4 patients (15%) achieving a CRi. Five patients required 3 cycles, four patients required 2 cycles and five patients required 1 cycle of therapy to achieve maximal disease response. CR/CRi was attained in 3 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Of the 14 patients who achieved a CR/CRi (54%), 7 were treated on each of two study arms. Nine of the 14 patients who achieved a CR/CRi were referred for allogeneic hematopoietic cell transplantation (HCT), 3 patients deferred HCT, and 1 patient died of sepsis in CRi 133 days after starting induction. Ten patients were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 5.7 months (range, 0.5-13.4), 21 patients (81%) lived longer than 4 months. Five (19%) of the 26 patients died within 4 months of starting therapy. Of these five patients, three died of sepsis on subsequent salvage protocols, one with a history of myeloproliferative disorder died of splenic infarct within 15 days of starting therapy and a fifth patient died at age 83 during cycle 2 of unknown cause. Eight patients (31%) were treated completely as outpatients without requiring hospitalization, and 15 patients (58%) were hospitalized at some point during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study. Conclusions These results demonstrate that TST at 120 mg daily in combination with cytarabine or decitabine resulted in a 54% CR/CRi rate in 26 older patients with untreated AML or high-risk MDS. This approach was well tolerated as predominantly outpatient therapy and may warrant further study in a controlled trial. Disclosures: Wang: Cell Therapeutics, Inc.: Employment. Myint:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment, Equity Ownership.