Treatment-naive Acute Myeloid Leukemia Research Articles

Incidence of drug-induced myelosuppression and associated adverse events (AEs), quality of life (QOL), and medical resource use (MRU) in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

e19072 Background: This study aimed to provide a comprehensive overview of the evidence available on drug-induced myelosuppression in patients with MDS or AML. Methods: A systematic literature review (SLR) was conducted using MEDLINE, Embase, and Cochrane to identify studies published 2002-2022 explicitly targeting drug-induced myelosuppression with current and emerging treatments used for MDS and/or AML (venetoclax [VEN], azacitidine [AZA], magrolimab, sabatolimab, decitabine [DEC], cedazuridine, lenalidomide [LEN], low-dose cytarabine [LDAC], intensive chemotherapy [IC]) in terms of drug-induced AEs, treatment discontinuation, QOL, and MRU. Article selection was based on predefined eligibility criteria (PICO+ framework), with a focus on specific geographic regions (USA, UK, Spain, Italy, France, Germany). Results: A total of 48 studies reporting on VEN, AZA, DEC, LEN, LDAC, and IC based regimens met the inclusion criteria. In MDS populations, myelotoxicity was reported in all blood cell lineages in association with AZA, DEC, and LEN monotherapies. In AML populations, myelosuppression was reported in all blood cell lineages in association with all regimens except LEN. In general, the reported incidence of myelosuppressive AEs was higher in studies published prior to 2010 and in studies of patients with AML or MDS who had received prior treatments vs more recent studies (2018-2022) and studies of treatment-naive patients, respectively. Differences observed between the two time periods might be explained by improved supportive care (AEs prophylaxis and management). In treatment-naive AML populations, the incidence of any-grade febrile neutropenia, leukopenia, and anemia was up to 3-fold higher with AZA combination therapy vs monotherapy, and the incidence of any-grade neutropenia and febrile neutropenia was 2-fold higher with LDAC combination regimens vs monotherapy, suggestive of an additive effect. The most common reasons for treatment discontinuation were AEs and disease progression. QOL significantly improved with AZA monotherapy; however, hematologic improvement was not explicitly mentioned as the main driver. There were no data on combination therapies to indicate whether the improvement in QOL compensated for the added drug-induced AEs. The few studies that reported on the impact of myelosuppression on MRU did not provide conclusive results. Conclusions: This SLR suggests that combining ≥2 myelosuppressive drugs may result in increased toxicity; however, the lack of evidence on the impact of myelotoxicity on QOL and MRU with ≥2 myelosuppressive drugs limits informed decision-making in routine clinical practice. Further research is needed to explore the impact of drug-induced myelosuppression in patients with MDS or AML.

Application of a Validated Composite Comorbidity Score Measuring Both Fitness and Cytogenetic Risk to Assess Outcomes in 1L AML Patients Who Received Venetoclax Plus Azacitidine in Viale-A

Background: Approximately half of adults with acute myeloid leukemia (AML) are unable to receive standard intensive chemotherapy (IC) due to older age or comorbidities (Griffiths et al. Leuk Res. 2020;91:106339). Although age is prognostic, several factors define patient fitness, such as comorbidities and cytogenetic risk. A better determination is needed to assess patient fitness for AML treatment regimens as there is no currently defined standard. The AML composite model (AML-CM) is a validated system used to determine fitness for transplant and potentially other intensive regimens. The randomized double-blind phase 3 VIALE-A trial demonstrated that in older adults who were unfit for IC based on modified Ferrara criteria, venetoclax (VEN), an oral BCL-2 inhibitor, combined with azacitidine (AZA) increased median overall survival (mOS) to 14.7 mo compared with 9.6 mo with placebo (PBO)+AZA. However, the Ferrara criteria contain limited patient characteristics to ascertain fitness for IC. Therefore, we aimed to assess the benefit of VEN+AZA vs PBO+AZA in patients with differential fitness and disease biology across the spectrum of AML-CM score. Methods: VIALE-A (NCT02993523) evaluated the efficacy of VEN+AZA compared to PBO+AZA in patients with treatment-naive AML who were ineligible for IC due to age or comorbidities. Patients (N = 431) were randomized 2:1 to receive VEN+AZA or PBO+AZA, respectively. AML-CM score was determined retrospectively based on age, comorbidities, and cytogenetic risks (Sorror et al. JAMA Onc. 2017;3:1675). Patients in each treatment arm were stratified into 3 risk groups by AML-CM scores: group A, score 1 - 4 (patients who could potentially benefit from IC); group B, score 5 - 9 (patients with decreased benefit from IC); and group C, score ≥10 (patients who could potentially benefit from a clinical trial or palliative care). Results: Of 431 patients enrolled to VIALE-A, 380 were categorized by AML-CM score and 51 could not be categorized due to missing data. Missing data included ELN risk, obesity, hepatic comorbidities, and hypoalbuminemia. Some patients with missing data were included in the analysis group if that data would not have impacted AML-CM group assignment. The proportion of patients in AML-CM groups A, B, and C, respectively, was 22 (9%), 172 (68%), and 59 (23%) in the VEN-AZA arm and 10 (8%), 92 (72%), and 25 (20%) in the PBO-AZA arm. Patients with higher AML-CM scores generally had poor prognostic disease characteristics, adverse ELN risk, decreased pulmonary function, and other comorbidities (Table). Composite complete remission (CRc [CR + CRi]) rates (groups A/B/C) were 17 (77%)/116 (67%)/34 (58%) with VEN-AZA, and 5 (50%)/24 (26%)/7 (28%) with PBO-AZA (Table). The median time to first CRc response in the VEN-AZA arm was 1.2 mo for group A, 1.3 mo for group B, and 1.1 mo for group C. In the PBO-AZA arm, the median time to first CRc was 4.2 mo, 3.0 mo, and 2.6 mo for groups A, B, and C, respectively (Table). The median duration of CRc across groups A, B, and C was 25.1 mo, 17.1 mo, 17.8 mo, respectively, in the VEN-AZA arm and 9.4 mo, 13.5 mo, and 8.5 mo in the PBO+AZA arm (Table). The mOS was 38.8 mo, 14.2 mo, and 10.2 mo in groups A, B, and C, respectively, in the VEN+AZA arm, and 17.7 mo, 8.6 mo, and 6.6 mo, respectively, in the PBO+AZA arm (Table). Early deaths within 30 days in groups A, B, and C, respectively, were 0 (0%), 9 (5%), and 8 (14%) in the VEN-AZA arm, and 0 (0%), 2 (2%), and 3 (12%) in the PBO+AZA arm. Of 22 deaths across both treatment arms in all AML-CM groups, there was 1 death within 30 days (VEN+AZA, group B) that was due to disease progression, and 21 deaths within 30 days that were due to adverse events. Conclusion: Based on the AML-CM score, most patients enrolled in VIALE-A were considered to have decreased benefit from IC, and nearly a quarter of patients evaluated were determined to be the frailest. Under this scoring system, patients in VIALE-A treated with VEN+AZA had higher CRc rates and prolonged duration of CRc and OS compared with those treated with PBO+AZA across all 3 AML-CM groupings. Notably, patients who scored >10 on the AML-CM scale, for whom the recommended treatment is enrollment in clinical trials and/or palliative care, had improved outcomes with VEN+AZA compared with PBO+AZA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Circulating Microbial Metabolite Drives the Clonal Expansion of Pre-Leukemic Cells

Inflammatory mediators, including cytokines and microbial ligands, are implicated in the development of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A consequence of aging and various autoimmune and inflammatory conditions is loss of intestinal barrier integrity and translocation of microbial species and metabolites into circulation. More recent findings revealed that patients with inflammatory bowel disease (IBD) harbor mutant hematopoietic clones and often present with clinical manifestations of MDS/AML. Moreover, intestinal barrier dysfunction is commonly reported at diagnosis in patients with MDS and AML. These observations led us to speculate that microbial-derived signals may contribute to the expansion of pre-leukemic hematopoietic stem and progenitor cells (HSPCs) and development of myeloid malignancies. To determine if loss of intestinal barrier integrity contributes to the expansion of pre-leukemic DNMT3a-mutant HSPCs, we generated a model of IBD by inducing gut epithelial injury using dextran sulfate sodium (DSS). Upon gut epithelial injury, we observed a significant expansion of DNMT3a-mutant HSPCs, but not of wild-type (WT) HSPCs, in vivo. Unexpectedly, DNMT3a-mutant HSPCs do not exhibit a competitive advantage over WT cells in the absence of intestinal barrier dysfunction, such as following DSS or high-dose radiation. Fecal material from DSS-treated WT mice was sufficient to induce expansion of DNMT3a-mutant HSPCs and this expansion was prevented with broad-spectrum antibiotics. These findings indicate that the competitive advantage of DNMT3a-mutant HSPCs following gut epithelial injury was due to alterations in the microbiome. In parallel sequencing studies, we identified a significant enrichment of gram-negative bacterial phyla in stool samples from the IBD mouse model, IBD patients, and treatment-naive AML patients. All gram-negative bacteria uniquely generate a microbial intermediate, ADP-heptose, as part of the lipopolysaccharide biosynthesis pathway. ADP-heptose can enter the blood circulation and freely translocate into cells and activate the ALPK1-TIFA complex ("TIFAsome"). Alpha-protein kinase 1 (ALPK1) and tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with an FHA domain (TIFA) are overexpressed in primary human MDS and AML HSPCs as compared to healthy donors and their expression is correlated with poor prognosis. Gram negative bacteria and corresponding ADP-heptose levels were also significantly increased in the plasma of individuals with intestinal barrier injury, such with IBD, MDS, or upon aging, as compared to young healthy individuals. The circulating levels of ADP-heptose from aged individuals and IBD or MDS patients were sufficient to induce the TIFAsome in leukemic cells. Moreover, administration of disease relevant levels of ADP-heptose resulted in expansion and enhanced function of mouse DNMT3a-mutant HSPCs and of human AML cell lines and primary MDS cells in vivo. Expansion of DNMT3a-mutant HSPCs and human MDS/AML cells was directly related to overexpression of ALPK1, as WT HSPCs or ALPK1-deficient AML cells did not respond to ADP-heptose. To gain deeper mechanistic insight, we examined global transcriptional and epigenetic changes in purified WT and DNTM3a-mutant HSCs treated with ADP-heptose. DNMT3a-mutant HSCs treated with ADP-heptose resulted in epigenetic changes and increased expression of gene programs related to non-canonical NF-kB, ERK/MAPK, cell cycle activation, cell survival, and stem cell function. Indeed, ADP-heptose caused increased cycling and self-renewal of DNMT3a-mutant HSPCs, but not WT HSPCs, via the TIFAsome in vitro and in vivo. Based on the enriched pathways in DNMT3a-mutant HSCs treated with ADP-heptose, we screened small molecule inhibitors of TIFAsome activation. We found that targeting UBE2N abrogated ADP-heptose-mediated signaling via the TIFAsome and expansion of patient-derived AML xenografts. In summary, we report that conditions leading to intestinal barrier dysfunction and circulating ADP-heptose from gram-negative bacteria induce expansion of pre-leukemic and MDS/AML cells via ALPK1-TIFA. Lastly, we provide a potential therapeutic strategy to prevent the competitive advantage of pre-leukemic cells prior to overt malignant transformation.

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highlyselective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survivaland rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recoveryafter intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversionand improvement in quality-of-life. Trial Registration Number: NCT04102020 (ClinicalTrials.gov).

AML-176: Characteristics, Treatment Patterns and Predictors of Outcomes in Treatment-Naive Acute Myeloid Leukemia Patients Judged Ineligible for Intensive Chemotherapy in Sweden

Context: There is limited recent population-based data on outcomes for novel agents and different treatment combinations in acute myeloid leukemia (AML) patients judged ineligible for intensive chemotherapy. Objective: To characterize patients, treatment patterns, and predictors of overall survival (OS) in treatment-naive AML patients judged ineligible for intensive chemotherapy. Design: A retrospective population-based study using data from the National Board of Health and Welfare, the Swedish AML Register, and medical records. Patients: Incident AML patients from 2012 to 2019 that were judged ineligible for intensive chemotherapy (n=1,335). Among a subgroup of patients with detailed information on treatment patterns and responses, patients with a hypomethylating agent (HMA; n=120) or low-dose cytarabine (LDAC; n=18) were selected for subgroup analyses. Patients were followed until death or censoring in 2020. Main Outcome Measures: Time-varying hazard ratios (HRs) for OS with 95% confidence interval (CI) for the calendar period for AML diagnosis, first-line treatment type, sex, age, AML etiology, and cytogenetic risk group. Responses were defined as complete remission (CR), including CR with incomplete hematological recovery, or primary induction failure. Results: In total, 122 (19.3%) and 278 (39.6%) patients received HMA during the earlier and later calendar periods (2012–15 and 2016–19), respectively. Among all patients, the median OS from AML diagnosis was 2.52 (95% CI 2.28–2.88) months. First-line treatment exposure to novel agents (HMA or venetoclax) compared to palliative or other low-intensive treatment was associated with lower risk of death at 1 years after AML diagnosis (HR 0.26 [95% CI 0.21–0.31], 0.39 [95% CI 0.29–0.53], and 0.62 [95% CI 0.40–0.95], respectively). Age at AML diagnosis, sex, AML etiology, and calendar period of diagnosis were not significantly associated with OS in the multivariable model, while cytogenetic risk group was borderline statistically significant. In the subgroup study, CR rates were 0% and 20% for patients exposed to LDAC- and HMA-based regimens, respectively. Conclusions: A greater proportion of patients received first-line treatment with HMA over time, which was associated with lower risk of death. However, most patients treated with HMA became refractory to HMA treatment, highlighting the need for optimized treatment strategies.

AML-196: The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine Is Well Tolerated and Effective in AML Patients: Phase 1b Results

Context: Magrolimab, an anti-CD47 antibody, induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing prophagocytic “eat me” signals. Magrolimab + AZA is clinically effective in acute myeloid leukemia (AML) and myelodysplastic syndrome. Objective: To report Phase 1b data of magrolimab + AZA in untreated AML. Design: This is an open-label, nonrandomized, Phase 1b, interventional study. Interventions: Patients received a magrolimab priming/intrapatient dose-escalation regimen (1–30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks in cycle 3 and beyond) and AZA (75 mg/m2 on days 1–7 on a 28-day cycle). Patients or Other Participants: Treatment-naive AML patients unfit for intensive chemotherapy. Main Outcomes Measures: Outcome measures included the percentage of patients with adverse events (AEs), objective response (OR), time to response, and duration of response. Results: Fifty-two patients were treated with magrolimab + AZA. Overall, 64% had poor-risk cytogenetics, and 65% had TP53 mutations. Magrolimab + AZA was well tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (≥15% of patients) were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). On-target anemia was generally transient and reversible, and no immune-related AEs associated with magrolimab were observed. Of 34 patients evaluable for efficacy, 22 (65%) achieved an OR, 15 (44%) achieved complete response (CR), 4 (12%) with CR with incomplete count recovery (CRi), 1 (3%) with partial response, 2 (6%) with morphological leukemia-free state (MLFS), 11 (32%) with stable disease (SD), and 1 (3%) with progressive disease (PD). Time to response was 2.04 months. In TP53-mutant patients, 15/21 (71%) achieved an OR, 10 (48%) achieved a CR, 4 (19%) with CRi, 1 (5%) with MLFS, 5 (24%) with SD, and 1 (5%) with PD. The median overall survival for TP53-mutant patients (n=34) and TP53–wild-type patients (n=16) was 12.9 and 18.9 months, respectively, with a median follow-up of 4 and 12 months, respectively. Conclusions: Magrolimab + AZA was well tolerated, with efficacy in both TP53-mutant and TP53–wild-type AML patients. A Phase 3 trial evaluating magrolimab + AZA in untreated TP53-mutant AML patients is planned (NCT04778397). Magrolimab, an anti-CD47 antibody, induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing prophagocytic “eat me” signals. Magrolimab + AZA is clinically effective in acute myeloid leukemia (AML) and myelodysplastic syndrome. To report Phase 1b data of magrolimab + AZA in untreated AML. This is an open-label, nonrandomized, Phase 1b, interventional study. Patients received a magrolimab priming/intrapatient dose-escalation regimen (1–30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks in cycle 3 and beyond) and AZA (75 mg/m2 on days 1–7 on a 28-day cycle). Treatment-naive AML patients unfit for intensive chemotherapy. Outcome measures included the percentage of patients with adverse events (AEs), objective response (OR), time to response, and duration of response. Fifty-two patients were treated with magrolimab + AZA. Overall, 64% had poor-risk cytogenetics, and 65% had TP53 mutations. Magrolimab + AZA was well tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (≥15% of patients) were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). On-target anemia was generally transient and reversible, and no immune-related AEs associated with magrolimab were observed. Of 34 patients evaluable for efficacy, 22 (65%) achieved an OR, 15 (44%) achieved complete response (CR), 4 (12%) with CR with incomplete count recovery (CRi), 1 (3%) with partial response, 2 (6%) with morphological leukemia-free state (MLFS), 11 (32%) with stable disease (SD), and 1 (3%) with progressive disease (PD). Time to response was 2.04 months. In TP53-mutant patients, 15/21 (71%) achieved an OR, 10 (48%) achieved a CR, 4 (19%) with CRi, 1 (5%) with MLFS, 5 (24%) with SD, and 1 (5%) with PD. The median overall survival for TP53-mutant patients (n=34) and TP53–wild-type patients (n=16) was 12.9 and 18.9 months, respectively, with a median follow-up of 4 and 12 months, respectively. Magrolimab + AZA was well tolerated, with efficacy in both TP53-mutant and TP53–wild-type AML patients. A Phase 3 trial evaluating magrolimab + AZA in untreated TP53-mutant AML patients is planned (NCT04778397).

Poster: AML-176: Characteristics, Treatment Patterns and Predictors of Outcomes in Treatment-Naive Acute Myeloid Leukemia Patients Judged Ineligible for Intensive Chemotherapy in Sweden

Poster: AML-176: Characteristics, Treatment Patterns and Predictors of Outcomes in Treatment-Naive Acute Myeloid Leukemia Patients Judged Ineligible for Intensive Chemotherapy in Sweden

AML-243: Gemtuzumab Ozogamicin plus Standard Chemotherapy Carries a Comparable Burden of Hospitalization Compared with Standard Chemotherapy Alone in Acute Myeloid Leukemia

Context For patients with de novo acute myeloid leukemia (AML), adding fractionated dosing of gemtuzumab ozogamicin (GO) to standard chemotherapy (SC) has resulted in improved outcomes. Such combination therapies may be perceived to increase the hospitalization burden (i.e., increasing either hospital admissions or length-of-hospital-stay [LOS]). Objective To evaluate whether adding GO to SC is associated with an increased hospitalization burden. Design In this phase 3 open-label trial, patients were enrolled between January 2008 and November 2010, and randomized 1:1 to GO+SC or SC alone. Data shown are for the safety reporting period (up to 28 days after last dose of study treatment). Setting Multicenter study conducted in France. Patients Patients were aged 50-70 years, had treatment-naive AML, and received fractionated-dose GO+SC (n=131) or SC alone (n=137) in the ALFA-0701 trial ( NCT00927498 ). Interventions Induction: 3+7 daunorubicin+cytarabine with/without GO 3 mg/m2 on days 1,4, 7. Consolidation: 2 courses with/without GO 3 mg/m2 on day 1. Main outcome measures Primary outcomes were previously published. In this post hoc analysis, we compared number of hospital admissions (planned or unplanned) and LOS with GO+SC vs SC, in the as-treated population and by treatment phase (induction vs consolidation). Results The mean number of hospital admissions was identical for GO+SC vs SC (2.9), with no significant difference in mean LOS (10.9 vs 10.0 weeks, p=0.16). Similarly, the mean number of intensive care unit admissions was 1.1 vs 1.0 for GO+SC vs SC, with mean LOS 1.25 vs 1.54 weeks, p=0.71. For patients receiving induction chemotherapy (including second induction/salvage), no significant difference was seen in LOS between GO+SC vs SC (mean 6.1 vs 5.6 weeks, p=0.64). For patients receiving consolidation chemotherapy (n=97 in each treatment arm), no significant difference was seen in mean LOS (6.5 vs 6.1 weeks for GO+SC vs SC, p=0.42). Conclusions This analysis shows that, in the ALFA-0701 trial, adding GO to SC for frontline AML did not significantly alter the associated hospitalization burden. Adding GO to SC is therefore not expected to increase healthcare resource utilization or related costs. Sponsor Pfizer.

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia.

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n=164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR=1·81; 95% CI: 1·24-2·64, P<0·005). PBB-RC was also associated with improved CR rates (OR per 5%=1·97; 95% CI: 1·27-3·01, P<0·005) and overall survival (OS) [hazard ratio (HR) per 5%=0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR=2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.

Abstract 1340: High NK cell number predicts poor overall survival in de novo treatment naive acute myeloid leukemia

Abstract Introduction Acute myeloid leukemia (AML) is a deadly disease associated with high mortality and morbidity. Previous studies report defects in NK cell maturation and function in AML patients leading to innate immune evasion. Considering that the number of NK cells may be an important indicator of innate immune regulation of AML, our group sought to understand the prognostic significance of NK cell number in de novo AML patients. Methods Patient samples were obtained from the Oregon Health and Science University (OHSU) Pathology Department between September 2010 and March 2016. This cohort study includes 82 newly diagnosed adult AML patients who had a bone marrow biopsy that was subjected to flow cytometry and a targeted-NGS panel within 30 days prior to induction treatment. Patients were excluded if they had antecedent hematological diseases or therapy-related AML. Bone marrow immunophenotyping was performed using the Ion Torrent PGM platform. Absolute numbers of NK cells were estimated from flow cytometric analysis of the bone marrow samples whereby lymphocytes were identified based on CD45 staining and light side scatter and NK cells were defined as CD3-/CD56+. Results This retrospective cohort of 82 newly diagnosed AML patients were 53.7% male with a median age of 61 years (range 18 - 83). Using 2017 ELN risk stratification guidelines, 36.6% of patients were classified as favorable, 26.8% as intermediate, and 36.6% as adverse. Absolute NK cell numbers in the bone marrow ranged from 1 to 896 cells/μl with a median of 98. When stratifying NK cells by staining intensity to identify subpopulations, the number of CD56 bright NK cells ranged from 0 to 69 cells/μl (median 3) and the number of CD56 dim NK cells ranged from 1 to 585 cells/μl (median 77). Overall survival (OS) was measured from diagnosis to date of death or last contact and varied from 1 day to 5.7 years (median 20.5 months). There were 3 deaths in the first week after diagnosis. Separate Cox proportional hazards regression models were applied to each NK cell group in both the univariable and multivariable settings, with the latter models accounting for patient age and ELN risk. Higher absolute numbers of NK cells (CD3-/CD56+) were significantly correlated with worse OS in both model settings, with a multivariable p-value of 0.001. The number of bright NK cells was a significant predictor of OS in the univariable model but lost significance when controlling for other variables. However, similar to the number of all NK cells and contrary to previous reports, higher counts of dim NK cells were significantly associated with shorter survival times, with a multivariable p-value of 0.001. Conclusions In this study, we show that higher NK cell numbers at diagnosis are associated with worse OS and thus play an important role in prognostication for AML patients. This association with survival is most evident in patients at least 60 years old or those with intermediate or adverse ELN risk. Citation Format: Weiwei Wang, Guang Fan, Andy Kaempf, evan Lind, Tomi Mori, Byung Park, Jennifer Saultz. High NK cell number predicts poor overall survival in de novo treatment naive acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1340.

Heterogeneity in refractory acute myeloid leukemia

Successful clinical remission to therapy for acute myeloid leukemia (AML) is required for long-term survival to be achieved. Despite trends in improved survival due to better supportive care, up to 40% of patients will have refractory disease, which has a poorly understood biology and carries a dismal prognosis. The development of effective treatment strategies has been hindered by a general lack of knowledge about mechanisms of chemotherapy resistance. Here, through transcriptomic analysis of 154 cases of treatment-naive AML, three chemorefractory patient groups with distinct expression profiles are identified. A classifier, four key refractory gene signatures (RG4), trained based on the expression profile of the highest risk refractory patients, validated in an independent cohort (n = 131), was prognostic for overall survival (OS) and refined an established 17-gene stemness score. Refractory subpopulations have differential expression in pathways involved in cell cycle, transcription, translation, metabolism, and/or stem cell properties. Ex vivo drug sensitivity to 122 small-molecule inhibitors revealed effective group-specific targeting of pathways among these three refractory groups. Gene expression profiling by RNA sequencing had a suboptimal ability to correctly predict those individuals resistant to conventional cytotoxic induction therapy, but could risk-stratify for OS and identify subjects most likely to have superior responses to a specific alternative therapy. Such personalized therapy may be studied prospectively in clinical trials.

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

AbstractOlder patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML

AbstractPevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2. PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity9s Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity9s Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged ≥65 Years with Acute Myeloid Leukemia

Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged ≥65 Years with Acute Myeloid Leukemia

Correlative Biomarkers of Response to Venetoclax in Combination with Chemotherapy or Hypomethylating Agents in Elderly Untreated Patients with Acute Myeloid Leukemia

Abstract Background: We recently reported encouraging antileukemic activity of venetoclax, an orally available selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA; NCT02203773) or low dose cytarabine (LDAC; NCT02287233) in patients aged ≥65 years with treatment-naive acute myeloid leukemia (AML) who are not fit for standard induction therapy [Pollyea et al, ASCO 2016 (abstract 7009); Lin et al, ASCO 2016 (abstract 7007)]. Here we present the genetic and molecular markers observed in this patient population, and their correlation with responses. Methods: The data cut-off dates were: 10FEB2016 (venetoclax+HMA study), and 15FEB2016 (venetoclax+LDAC study). Patient responses were assessed according to the IWG criteria for AML. Given the selectivity of venetoclax to inhibit BCL-2, but not BCL-xL, the baseline expression of BCL-2 and BCL-xL proteins in blasts isolated from peripheral blood was determined by flow cytometry. The expression levels of BCL-2 were compared between those who achieved a response [complete remission (CR), CR with incomplete marrow recovery (CRi), partial remission (PR), morphologically leukemia free state (MLFS)] and those who did not achieve a response by the data cut-off dates [resistant disease (RD), progressive disease (PD)]. Next-generation sequencing (NGS) was performed on the blasts from bone marrow aspirates to identify recurrent mutations in genes associated with AML. Patients were classified into the following molecular subgroups based on the mutations data and site reported cytogenetics: (i) chromatin-RNA splicing group consisting of mutations in chromatin remodeling factors (ASXL1, EZH2), in splicing factors (SRSF2, SF3B1, ZRSR2), and/or in the transcription factor, RUNX1 (ii) NPM1 mutation (iii) MLL translocation (iv) TP53 mutations or &gt;3 chromosomal aberrations (Papaemmanuil et al. NEJM 2016). Results: Data from 45 patients enrolled in the venetoclax+HMA study and 26 patients enrolled in the venetoclax+LDAC study are reported here. The demographic and baseline characteristics are summarized in Table 1. BCL-2 and BCL-xL protein expression were determined in 16/45 (36%) patients from the venetoclax+HMA study and 11/26 (42%) patients from the venetoclax+LDAC study. Remaining 44/71 (62%) patients were not included in this analysis for the following reasons: not evaluable for clinical response (n=7), non-availability of the specimen (n=8), and insufficient blasts in peripheral blood (n=29). The percentage of blasts expressing BCL-xL was low (range 0-22%, median 0.6%), whereas the percentage of blasts expressing BCL-2 (BCL-2+) varied (6-99%, median 75%). 16/27 (59%) evaluable patients who achieved a response of CR/CRi/PR/MLFS had an average of 78% blasts BCL-2+. The remaining 11/27 (41%) patients who have not yet achieved a response had an average of 64% blasts BCL-2+ and were separated into two groups: a low percent of BCL-2+ blasts (median 11%, n=5) and a high percent of BCL-2+ blasts (median 82%, n=6) (Figure 1). Pre-treatment bone marrow aspirates were available for NGS analysis from 40/45 patients (venetoclax+HMA study) and 21/26 patients (venetoclax+LDAC study). The data are summarized in Table 2. The chromatin-RNA splicing group comprised the largest subset of patients (n=28), of which 19 (68%) patients achieved a CR/CRi. Majority [10/11 (91%)] of the patients with NPM1 mutation had a CR/CRi. Conversely, 3/12 (25%) patients with TP53 aneuploidy or &gt;3 chromosomal aberrations and 2/6 (33%) with MLL translocation achieved a CR/CRi to date. IDH1/2 mutations were identified in 11/45 (24%) patients in the venetoclax+HMA trial and 7/21 (33%) patients in venetoclax+LDAC trial. 10/11 (91%) patients from the venetoclax+HMA trial and 5/7 (71%) patients from the venetoclax+LDAC trial were responders. Conclusions: The results from this small data set showed that patients who achieved a response to venetoclax plus HMA or LDAC had a higher percent of blasts with BCL-2+. Among patients classified as non-responders, it remains to be determined if those with high percent of BCL-2+ blasts (n=6) will achieve a response with longer time on venetoclax therapy. Patients with specific genetic alterations such as chromatin-RNA splicing and NPM1 mutation may correlate with better odds of response to a venetoclax containing regimen. Samples are being analyzed to confirm these early findings as the two studies continue to enroll more patients. Disclosures Chyla: AbbVie Inc.: Employment, Other: may own stock. Popovic:AbbVie Inc.: Employment, Other: may own stock. Potluri:AbbVie Inc.: Employment, Other: may own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock. Huang:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Mabry:AbbVie Inc.: Employment, Other: May own stock. Bhathena:AbbVie Inc.: Employment, Other: may own stock.

Results from Ongoing Phase 2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD)

Results from Ongoing Phase 2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD)