Im, Annie

Background: Hypomethylating agent (HMA) and venetoclax (Ven) frontline therapy for acute myeloid leukemia (AML) is astandard of care for patients (pts) deemed to be poor candidates for intensive induction due to age or fitness. However, given its attractive risk-benefit ratio, there is an increasing interest to extend the preference for HMA + Ven to other pts, including those who are fit for intensive therapy but with adverse risk disease. Unfortunately, most pts treated in this fashion will require future therapies for relapsed/refractory (R/R) disease and intensive therapy is given consideration mostly for pts with a path to allogeneic hematopoietic stem cell transplantation (alloHCT). Little is known about the outcomes of pts who receive intensive induction therapy after use of a frontline less-intensive regimen in the modern era. In this multi-center study, we seek to describe the experience with such a patient population and identify predictors of differential clinical outcomes. Methods: We conducted a multi-center, retrospective study of pts with AML treated with frontline less-intensive chemotherapy, followed by intensive induction chemotherapy for R/R disease. We first described the baseline characteristics of this cohort. Nominal variables were summarized with frequency and percentage while continuous variables were summarized with median and interquartile range (IQR). Overall response rate (ORR) was defined as complete remission (CR), complete remission with incomplete count recovery, or morphologic leukemia free state. Differences in ORR were analyzed with Fisher's exact test for nominal variables and Wilcoxon rank-sum test was used for continuous variables. Kaplan-Meier analysis was used to determine median overall survival (OS) after induction chemotherapy. Log-rank testing and Cox proportional hazard models were used to determine survival differences for nominal and continuous variables, respectively. Statistical significance was determined as p-value <0.05. Results: A total of 23 pts were included in this study. Median age at diagnosis was 64 years (IQR: 62-71). The majority of pts were male (n=12, 52%), white (n=20, 87%), and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 (n=18, 82%). The majority of pts (61%) at time of frontline therapy had AML arising out of MDS. As expected, the majority of pts had adverse risk ELN cytogenetics (n=16, 70%) with an enrichment for disease harboring TP53 mutation (n=6, 27%) and complex karyotype (n=9, 39%). Fifteen pts (65%) had frontline therapy with azacitidine backbone, 6 pts (26%) with decitabine; some pts received both before intensive therapy. The median number of cycles of frontline therapy was 2 (IQR: 2-5). Median WBC at time of R/R therapy was 1.9 x 10 9/L (IQR: 0.8-6.45), while hemoglobin was 8.4 g/dL (IQR: 7.5-9.45), platelets were 41 x 10 9/L (IQR: 19.5-116.5), and marrow blasts were 25% (IQR: 16.5-30%). The plurality of pts received CPX-351 as intensive R/R therapy (n=9, 39%). Other regimens included 7+3 (n=2, 9%), FLAG-Ida + Ven (n=2, 9%), HiDAC + Mitoxantrone +/- Ven (n=4, 17%) ( Table 1). ORR after intensive R/R therapy was 27% (n=6), with 23% achieving CR. CPX-351 after HMA + Ven was specifically associated with an ORR of 33% (CR rate 22%). Median OS after initiation was 5.8 months. Thirty- and 60-day mortality was 17% and 26%, respectively. Five patients (23%) proceeded to alloHCT ( Table 1). Univariate differences in response rate and median survival were analyzed for each of the aforementioned variables as illustrated in Table 1. While none of the covariates reached statistical significance for impacting ORR or OS, ECOG PS trended towards significantly impacting OS ( p=0.074) and the median OS among patients proceeding to alloHCT was numerically doubled (8.0 vs. 4.0 months, p=0.11) ( Figure 1). Conclusions: Intensive therapy for R/R AML after prior frontline less-intensive therapy was associated with an ORR rate of 27% and median OS of 5.8 months in our cohort. This approach may be an appropriate strategy for a subset of pts, particularly those eligible for alloHCT. The relatively small and heterogeneous nature of this cohort limits strong conclusions regarding efficacy. As the use of frontline HMA + Ven continues to expand, further studies with larger sample size are needed to determine which pts would and would not benefit from intensive induction therapy in the R/R setting.

SummaryIn young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front‐line setting. Recently, time‐to‐event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post‐autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six‐month [hazard ratio (HR) = 7·68], 12‐month (HR = 6·68), and 18‐month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non‐relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high‐risk group with inferior post‐relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up‐front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.

Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015]. A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.

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.