Normolle, Daniel Paul

Abstract Background: Acute myeloid leukemia (AML) carries a poor prognosis in older adults. Limited clinical trial data exist to support the use of conventional cytarabine-based regimens in this population, and practice standards have been extrapolated from studies in younger patients. Intensive chemotherapy in older adults is associated with high rates of treatment-related mortality and poor overall survival. In 2010, Kantarjian and colleagues developed a risk model for 8-week mortality using adverse prognostic risk factors, including age ≥80 years, complex karyotype (≥3 abnormalities), poor performance status (ECOG score ≥2), and serum creatinine >1.3 mg/dL. This study validates the Kantarjian model for progression-free survival (PFS) and overall survival (OS) in older patients with AML treated with intensive chemotherapy. Methods: Adults aged ≥70 years with AML (≥20% blasts in bone marrow or peripheral blood) who received intensive chemotherapy at UPMC Hillman Cancer Center between 2000 and 2011 were evaluated. Patients were stratified into low, intermediate, and high-risk groups according to the Kantarjian (2010) model and analyzed for PFS and OS using the Kaplan-Meier method. Differences in PFS and OS between risk groups were assessed with the log-rank test. ECOG performance status was estimated using historical data at the time of diagnosis. Additional variables, including AML type (primary vs. secondary), percent blasts at diagnosis, percent CD34-positive blasts, hemoglobin, leukocytes, platelets, LDH, AST, ALT, total bilirubin, albumin, and Charlson comorbidity index (CCI) were tested for added prognostic value when incorporated into the model, using Cox proportional-hazards regression for PFS and OS. Results: Clinical data were collected for 68 patients. Of these, 26 patients, all of whom were diagnosed prior to 2003, were excluded from the final analysis due to insufficient electronic health records. The remaining 42 patients were used for the validation study. Median age at diagnosis was 73 years (range: 70-87). Twenty-seven patients (64%) had primary AML, whereas 10 (24%) had AML evolving from another hematologic disorder and 5 (12%) developed AML after radiation or chemotherapy for another malignancy. Eleven (26%) patients had ≥3 karyotypic abnormalities and the remaining 31 (74%) had fewer than 3. Thirty-three (79%) patients had an ECOG performance status of 0 or 1, and the remaining 9 (21%) did not have sufficient historical data to estimate ECOG score and were given a score of 0. In total, there were 23, 16, and 3 patients categorized into the low, intermediate, and high-risk groups, respectively. These groups had non-overlapping PFS and OS curves (p <0.001 for both endpoints). The low, intermediate, and high-risk groups had median PFS of 9.6, 5.1, and 2.1 months and median OS of 14.0, 6.3, and 2.1 months, respectively. None of the additional variables were found to add significant prognostic value to the existing model. Discussion: The Kantarjian (2010) model is a valid method of risk-stratifying older adults with respect to PFS and OS, and may be useful when weighing the risks and benefits of intensive chemotherapy in these patients. In this study, we did not identify other disease characteristics or measures of organ function that significantly improved the model, although our analysis is limited by small sample size. We note that all patients in our study had an ECOG score of 0 or 1, implying selection of healthier patients for induction chemotherapy at our institution. Our results suggest that patients in the intermediate and high-risk groups may not derive significant PFS and OS benefit from intensive chemotherapy when the risks of morbidity and mortality from treatment are considered. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Determining the optimal post-remission management for elderly patients with acute myeloid leukemia (AML) remains a challenge. AML is primarily a disease of the elderly with >60% of newly diagnosed patients aged 60 years and older. For younger AML patients, post-remission therapy in the form of high-dose cytarabine (HIDAC) consolidation or allogeneic hematopoietic stem cell transplant (HSCT) is critical in maintaining durable disease control and improving survival. However, post-remission HIDAC in elderly AML patients is associated with higher rates of neurotoxicity and decreased survival benefit compared to younger patients. The optimal post-remission therapy for elderly AML patients remains undefined. The objective of this study is to determine the outcomes of using varying doses (0.25-3 g/m2) of cytarabine as post-remission consolidation therapy in an elderly AML population. Methods: We conducted a single-center retrospective analysis of AML patients aged 60 years and older treated with cytarabine as consolidation therapy at UPMC Hillman Cancer Center between January 1, 2005 and December 31, 2014. Patients were excluded if they were not in complete morphologic remission prior to proceeding with cytarabine consolidation or if they proceeded directly to HSCT after consolidation therapy. Relapse-free survival (RFS) was measured from the time of post-induction bone marrow biopsy confirming remission to the date of relapse or death. Overall survival (OS) was defined as the duration from diagnostic bone marrow biopsy confirming AML diagnosis to the date of death. Kaplan-Meier analysis was used to estimate the survival distributions and log-rank test was used to compare survival functions from groups. Multivariate analysis was performed using Cox proportional hazard regression to determine the relationship of RFS and OS to patient's age, cytogenetic risk group, AML type (de novo vs secondary AML), transplant status, cytarabine dosage and number of cycles. All data was analyzed using SAS v9.4 (SAS Institute, Cary, NC, USA). Results: Out of 156 identified patients, 121 were eligible for analysis. Median age at diagnosis was 66 years (range 59-78) with 77 (64%) male patients. Thirty-six patients (30%) had secondary AML. Cytogenetic abnormalities were favorable in 7 (6%), intermediate in 86 (71%), unfavorable in 24 (20%), and unknown in 4 (3%) patients. Cytarabine was administered at a mean dose of 1.44 g/m2 (range 0.25-3.0, SD 0.84) and a median number of cycles of 4 (range 1-4). One patient (0.8%) developed reversible grade 3 neurotoxicity during cycle 2 at a dose of 2 g/m2 with ataxia, dysmetria, and tremors. For all patients, the median RFS was 12.5 months (95% CI 9.7-15.6). Median RFS was significantly different among the cytogenetic risk groups (p=0.0008 via log-rank test): favorable-risk RFS had not been reached because most subjects were in remission and alive at time of analysis, intermediate-risk RFS 13.6 months (95% CI 11.0-17.3), unfavorable-risk RFS 8.3 months (95% CI 3.5-8.9). In this study population, the median OS was 20.5 months (95% CI 16.4-27.1). Median OS was significantly different among the cytogenetic risk groups (p=0.003 via log-rank test): favorable-risk OS 131.3 months (95% CI 12.9-upper limit not reached), intermediate-risk OS 25.1 months (95% CI 18.9-39.4), and unfavorable-risk OS 10.8 months (95% CI 10.4-15.8). Average cytarabine dose did not significantly correlate with RFS or OS in the model. Multivariate analysis revealed a 27% decreased rate of relapse (HR 0.73, 95% CI 0.58-0.92, p=0.008), and 24% decreased mortality rate (HR 0.76, 95% CI 0.59-0.96, p=0.024) with each additional cytarabine cycle given. Conclusions: Our study supports the use of cytarabine as a tolerable and effective option for post-remission therapy in elderly AML patients, particularly those with favorable-risk cytogenetics. Each additional cycle administered was associated with improved RFS and OS rates in this study population. Disclosures No relevant conflicts of interest to declare.

PURPOSE Patients with centrally located early-stage non–small-cell lung cancer (NSCLC) are at a higher risk of toxicity from high-dose ablative radiotherapy. NRG Oncology/RTOG 0813 was a phase I/II study designed to determine the maximum tolerated dose (MTD), efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for centrally located NSCLC. MATERIALS AND METHODS Medically inoperable patients with biopsy-proven, positron emission tomography–staged T1 to 2 (≤ 5 cm) N0M0 centrally located NSCLC were accrued into a dose-escalating, five-fraction SBRT schedule that ranged from 10 to 12 Gy/fraction (fx) delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any treatment-related grade 3 or worse predefined toxicity that occurred within the first year. MTD was defined as the SBRT dose at which the probability of DLT was closest to 20% without exceeding it. RESULTS One hundred twenty patients were accrued between February 2009 and September 2013. Patients were elderly, there were slightly more females, and the majority had a performance status of 0 to 1. Most cancers were T1 (65%) and squamous cell (45%). Organs closest to planning target volume/most at risk were the main bronchus and large vessels. Median follow-up was 37.9 months. Five patients experienced DLTs; MTD was 12.0 Gy/fx, which had a probability of a DLT of 7.2% (95% CI, 2.8% to 14.5%). Two-year rates for the 71 evaluable patients in the 11.5 and 12.0 Gy/fx cohorts were local control, 89.4% (90% CI, 81.6% to 97.4%) and 87.9% (90% CI, 78.8% to 97.0%); overall survival, 67.9% (95% CI, 50.4% to 80.3%) and 72.7% (95% CI, 54.1% to 84.8%); and progression-free survival, 52.2% (95% CI, 35.3% to 66.6%) and 54.5% (95% CI, 36.3% to 69.6%), respectively. CONCLUSION The MTD for this study was 12.0 Gy/fx; it was associated with 7.2% DLTs and high rates of tumor control. Outcomes in this medically inoperable group of mostly elderly patients with comorbidities were comparable with that of patients with peripheral early-stage tumors.