ALBERT

Description: Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS. Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (〉10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of

Description: Background: Because infections are a major cause of morbidity and mortality after AML induction chemotherapy, patients typically remain hospitalized for monitoring and rapid antimicrobial therapy until hematopoietic recovery. With declining early mortality and improved oral antimicrobials, interest in moving post-induction care to the outpatient setting has emerged. In the 5-year period since completing a prospective phase 2 trial evaluating an Early Hospital Discharge (EHD) strategy, EHD following AML-like induction chemotherapy has become routine at our institution. In recent retrospective analyses, we found 〉80% of EHD patients required hospital readmission, primarily for neutropenic fever. Still, the EHD strategy was safe and reduced healthcare resource utilization, and EHD patients spent 〉70% of their post-chemotherapy time as outpatients. Here, we investigated differences in the pattern of infectious complications between patients managed as outpatients following induction chemotherapy and those who remain hospitalized until hematopoietic recovery. Methods: We retrospectively identified all adults ≥18 years with untreated AML/high-grade myeloid neoplasms (≥10% blasts in blood/ bone marrow) who started intensive induction chemotherapy ("7+3" or a regimen of similar/higher intensity) at our institution from 8/1/2014-7/31/2018. Patients were considered "EHD" if they were discharged from the hospital

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: Prognostic judgment plays a critical role in the practice of oncology. These predictions help providers determine appropriate treatment options and advise patients about the future. There is, however, little known about how accurate oncology providers are in making such predictions. In this study, we aimed to determine the accuracy of oncology providers in predicting serious medical events in adults admitted to oncology services at the University of Washington. Patients and Methods: Surveys were collected from oncology providers, including physicians, advanced practice providers (APPs), and nurses for patients within 24 hours of being admitted to our inpatient oncology services. Surveys assessed provider characteristics and their predictions about 30-day outcomes (death, ICU transfer, and transition to comfort care). Estimates of these outcomes were compared with actual outcomes by evaluating area under the receiver operating characteristic curve (AUC). For patients with newly diagnosed AML, the treatment-related mortality (TRM) score was calculated as previously described [Walter et al, J Clin Oncol 2011]. Analyses accounted for clustering within patient encounter, as more than one provider may have answered a survey (e.g., a physician and a nurse). Results: Between May 2014 and April 2015, 727 surveys were collected representing 490 individual patient encounters. Among all surveys, median patient age was 54 years (range: 20-94). The primary diagnosis was leukemia in 49%, lymphoma in 22%, solid tumor in 25%, and benign hematologic problem in 4%. Respondents were 29% internal medicine house-staff, 26% oncology attendings or fellows, 21% APPs, 19% nurses, and 4% other physicians. Overall, providers overestimated the likelihood of ICU transfer (11% [9-13%] actual vs. 19% [17-20%] predicted, p

Description: Background Intensive chemotherapy for adults with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with a considerable risk of morbidity and mortality, commonly due to infections and bleeding. Little information is available on pre-treatment risk factors that predispose to these complications. Here, we investigated the relationship between baseline peripheral blood counts and (a) subsequent adverse events and (b) duration of neutropenia following administration of induction chemotherapy at our institution over the last decade for newly diagnosed AML/MDS undergoing curative-intent induction chemotherapy. Patients and Methods We retrospectively analyzed 205 consecutive adults receiving 7 + 3-like treatment regimens. Daily blood counts were recorded from initiation of chemotherapy until the day of neutrophil recovery (defined as an absolute neutrophil count [ANC] greater than or equal to 500 cells/µL). Adverse events (fever, infection, bacteremia, transfer to the intensive care unit, and death) were recorded until day 35 or administration of additional chemotherapy, whichever came first. Cytogenetic risk was classified based on revised MRC/NCRI criteria. Associations between baseline patient characteristics and adverse events were assessed using Kaplan-Meier survival curves with a log-rank test (for two groups) or log-rank test for trend (for three or more groups); patients requiring salvage therapy for persistent disease were censored on the day such therapy was initiated. Cox proportional hazards models were used to estimate the hazard ratio (HR) for the associations between age, gender, disease type, cytogenetic risk and adverse outcomes in univariate and multivariate analyses. Results The median age of our study cohort was 53 (range: 18 to 81) years. Sixty-six percent of the patients had de novo AML. Cytogenetic risk was favorable in 14%, intermediate in 60%, and adverse in 24%. Among all patients, the complete remission (CR) rate was 75%, while 2% died before response could be assessed (range: day 13 to 28) and 23% were refractory. When analyzed as a continuous variable, the baseline neutrophil count was statistically significantly associated with fever (HR=0.97 [95% confidence interval: 0.95-0.999] for each increase of 1000 cells/µL, P=0.04) and infection (HR=0.92 [0.87-0.98], P=0.01), but not bacteremia (HR=0.95 [0.89-1.01], P=0.10) or requirement for intensive care unit (ICU) care (HR=1.00 [0.93-1.07], P=0.99). For subsequent analyses, we dichotomized the study cohort based on pre-treatment ANC and compared patients with baseline ANC

Description: Background Minimal residual disease (MRD) has been recognized as a strong, independent predictor of increased relapse risk and poor outcome for patients with acute myeloid leukemia (AML) in first complete remission (CR) undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT). As the relationship between MRD and outcome is less studied for AML patients undergoing nonmyeloablative (NMA) HCT, we herein conducted a comparative analysis to assess this association relative to that seen in MA HCT. Patients and Methods We studied 272 consecutive patients receiving NMA (n=63) or MA (n=209) HCT for AML in first CR or CR with incomplete blood count recovery (CRi) between May 2006 and May 2012. Pre-HCT bone marrow aspirates were obtained in all patients and analyzed by routine karyotyping and ten-color flow cytometry. MRD was identified as a cell population showing deviation from normal antigen expression patterns as compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Data are current as of April 1, 2013. Results Baseline characteristics of the study cohort are summarized in Table 1. Patients undergoing NMA HCT were significantly older than those undergoing MA HCT (p

Description: Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study. Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher's exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models. Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens. The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P

Description: Background: Although some adults with AML or high-risk MDS will experience long-term disease-free survival after initiation of curative-intent therapy, most patient will require therapy re-induction therapy either for primary induction failure of disease recurrence after an initial complete remission (CR) was achieved. The outcomes with standard regimens for relapsed/refractory AML are generally poor, with CR rates often not exceeding 15-20%. Data from a large single arm phase 2 study in poor-risk relapsed/refractory AML suggested tolerability and encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (G-CLAM). Given recent data suggesting benefit of escalated doses of anthracyclines in AML, the goal of our phase 1 study was to determine the maximum tolerated dose (MTD) of mitoxantrone within G-CLAM in adults with relapsed/refractory AML or high-risk MDS and estimate the efficacy of this regimen. Patients and Methods: Adults ≥18 years of age with relapsed or refractory AML (APL excluded) or high-risk MDS (〉10% blasts) were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a risk of early death with standard induction chemotherapy of ≤3%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal). Excluded were patients with concomitant illness with expected survival 7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia or infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. Results: 26 patients (14M, 12F), median age 57 (range: 37-77) years, median TRM score 1.73 (range: 0.29-3.92) with relapsed/refractory AML (n=23), or high-risk MDS (n=3) and cytogenetically favorable (n=2), intermediate (n=13), and adverse (n=11) disease characteristics were enrolled. One DLT occurred at dose level 1 (nausea) and 2 at dose level 4 (encephalitis and cardiogenic shock), establishing G-CLAM with mitoxantrone at 16 mg/m2/day as the MTD in our study. 2 patients (8% [95% exact confidence interval: 1-25%]) died within 28 days of treatment initiation from sepsis and cardiogenic shock, respectively. Overall, 13/26 patients (50% [30-70%]) achieved a CR (n=8) (31% [14-52%]), CRp (n=1) (4% [0-20%]), or CRi (n=4) (15% [4-35%]) with 1-2 cycles of re-induction therapy; one patient each achieved a leukemia-free state and partial remission (in a patient presenting with myeloid sarcomas); nine patients (35% [17-56%]) had persistent disease. We were unable to assess response in 2 patients due to early death (n=1) and refusal for marrow re-assessment (n=1). 7/13 responders (54%) had no evidence of residual disease by flow cytometry at best response. Among responders, median times to an absolute neutrophil count ≥500/µL and a platelet count of 50,000/µL were 33 (range: 17-51) and 31 (range: 18-54) days, respectively. Besides infections and neutropenic fever, nausea, hypoxia (fluid overload/infection-related), and maculopapular rash were the most common grade ≥3 adverse events. Conclusion G-CLAM with mitoxantrone up to 16 mg/m2/day is feasible, well tolerated, and effective in relapsed/ refractory AML/high-risk MDS. A phase 2 study based on these findings has been initiated. Disclosures Scott: Celgene Corporation: Consultancy, Speakers Bureau. Becker:Igenica: Research Funding. Walter:Pfizer, Inc.: Consultancy; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy.

Description: Background: Despite improvements in supportive care, treatment of AML remains associated with complications. We have developed a multivariate model – the Treatment-Related Mortality (TRM) score – which includes age, performance status, and 6 other covariates to predict 28-day mortality with c-statistic = 0.82 (1.0 = perfect prediction, 0.5 = no prediction) (Walter et al. J Clin Oncol 2011). We investigated associations between TRM score and complications developing during AML treatment. Patients and Methods: 179 adults (median age 53 [range: 18-77] years) with newly diagnosed AML treated at our institution from 2002-2012 with 7 + 3 or similar therapy were included. Documented infections, ICU transfer, and death until the earlier of day 28 or administration of additional chemotherapy were recorded. Patients were categorized by quartiles of TRM score. All outcomes were treated as time-to-event endpoints. The survival probabilities in the absence of infection or ICU transfer were estimated using the Kaplan-Meier method; the 10 patients in the ICU at the start of chemotherapy were excluded from analysis of ICU transfer as an adverse event. Outcomes between TRM scores by quartile were assessed using log-rank test for trend; scores above and below the median were compared using Cox regression. Multivariate models were adjusted for gender, cytogenetic risk, baseline absolute neutrophil count, and year of treatment. Results: The median TRM score was 4.6 (quartiles 2.3 and 10.5). Documented infections occurred in 72 patients (40%), ICU transfer in 14 (8%), and death in 4 (2%) within 28 days of induction. Patients with higher ranges of TRM scores were more likely to develop infections (Ptrend=0.006; Fig 1a) and require ICU transfer (Ptrend=0.003; Fig 1b). In particular, TRM scores above the median were associated with increased risk of infection (P=0.02; Fig 1c) and ICU transfer P=0.0004; Fig 1d). After multivariable adjustment, the risk of documented infection was 1.72 (95% CI: 1.06-2.81)-fold higher for patients with TRM 〉4.5. Consistent with our recent analysis, baseline grade 4 neutropenia was also independently associated with infection (HR 2.2 [95% CI: 1.38-3.52]) (Buckley et al. Am J Hematol 2014). There was only one ICU transfer, and there were no deaths among the 92 patients with TRM score less than the median. Although supportive care measures have improved in recent years, a high TRM score was still associated with ICU transfer in the subset of patients treated from 2007-2012 (P=0.001). Conclusions: The TRM score is associated not only with death, but also with other early adverse events. A cut-point of 4.5, which will need to be confirmed in an independent study cohort, may separate low- from high-risk patients in terms of susceptibility to infection and likelihood of requiring an ICU transfer. The TRM score may thus improve assessment of the risks of intensive induction chemotherapy and help allocate health care resources. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Severe thrombocytopenia (platelet count 1000 patient) retrospective analyses, MF patients with severe thrombocytopenia had a median survival of 15 months, compared to 34-44 months for those with a platelet count 50,000-100,000/μL and 47-89 months with a platelet count 〉100,000/μL (Masarova L, et al. EJH 2018;100:257-263; Alhuraiji A, et al. JCO 2016;34:7068). Options for patients with severe thrombocytopenia are limited, and clinical trials often exclude them due to risk of treatment-related cytopenias. Pacritinib (PAC) is an oral JAK2/IRAK1 inhibitor that was evaluated for spleen volume reduction (SVR) and total symptom score (TSS) in two phase 3 studies (PERSIST-1 [P1] and PERSIST-2 [P2]) in MF patients, including those with severe thrombocytopenia. P1 studied JAK inhibitor naive patients with no lower platelet limitation, and P2 was limited to patients with a platelet count