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Acute myeloid leukemia (AML) patients refractory to induction therapy or relapsed within 1 year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in preclinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single-cell RNA sequencing using prospectively acquired patient specimens identified IFN response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well tolerated, with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.Significance:This study demonstrates a favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML, thus supporting further investigation of this combination in a randomized trial. It also shows the utility of a novel application using multiplexed single-cell analyses to detect on-target activity and identify biomarkers of response.This article is highlighted in the In This Issue feature, p. 403

Supplementary Data from Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis

As allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, geriatric assessment (GA) has been identified as a useful tool for predicting outcomes, particularly functional status. However, very few studies have examined the longitudinal change in GA measures in the post-alloHCT period. The objectives of this study were to describe the longitudinal change in GA and quality of life (QoL) measures after alloHCT and to identify predictors of greater functional decline post-transplantation. In this single-center prospective cohort study, patients age ≥50 years scheduled for alloHCT completed a cancer-specific GA and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) survey at baseline prior to alloHCT and then at 3, 6, and 12 months post-transplantation. Changes in GA and QoL measures at each post-transplantation time point (3, 6, and 12 months) compared to baseline were analyzed using paired t-tests. Exploration of potential predictors of greater post-transplantation functional decline, as measured by instrumental activities of daily living (IADL) and the Medical Outcomes Study Physical Health scale (MOS-PH), were examined using linear regression and the chi-square 2-sample test of proportions. Mean functional status generally exhibited a pattern of decline at 3 to 6 months post-alloHCT, with recovery to near baseline by 12 months. Mean mental health and emotional QoL were lowest at baseline and improved at all post-transplantation time points. Differences in baseline clinical characteristics were not associated with any differences in functional trajectories. Differences in baseline GA measures-patient-rated Karnofsky Performance Status, IADL, MOS-PH, Timed-Up-and-Go, Blessed Orientation-Memory-Concentration test, and Mental Health Inventory 5-also did not predict greater functional decline at 3 months. Patients whose IADL was improved or maintained at 3 months generally maintained their functional status at 6 and 12 months. Similarly, most patients who had an IADL decline at 3 months still had a functional decline at 6 months, although a proportion did have functional recovery by 12 months. Compared with patients who had improved/maintained IADL at 3 months, those with a decline in IADL at 3 months were significantly more likely to have persistent functional decline at 6 months (P < .0001) and 12 months (P=.02). In older alloHCT recipients, mean functional status declines short term after alloHCT with the possibility of recovery by 6 to 12 months, whereas mean mental and emotional health improve post-alloHCT. Functional decline at 3 months post-alloHCT is associated with persistent functional decline at 12 months.

7043 Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients aged ≥1 year in the US and in adults in Europe. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 significantly improved overall survival and remission rates versus conventional 7+3, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the FLT3 inhibitor midostaurin (MID). Herein, we report preliminary results for the cohort of adults treated with CPX-351 + MID in the V-FAST (Vyxeos – First Phase Assessment with Targeted Agents) trial. Methods: V-FAST is an open-label, multicenter, multiarm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (midostaurin, venetoclax, enasidenib). Eligible adults in the CPX-351 + MID cohort were aged 18 to 75 years, had newly diagnosed AML with a FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation, were fit for intensive chemotherapy, and had an ECOG performance status of 0 to 2. The dose-exploration phase (3+3 design) determined a recommended phase 2 dose of CPX-351 100 units/m2 (daunorubicin 44 mg/m2 + cytarabine 100 mg/m2) on Days 1, 3, and 5 + MID 50 mg BID on Days 8 to 21. There were no dose-limiting toxicities, and additional patients were enrolled in the expansion phase at this dose. Results: A total of 23 patients received CPX-351 + MID and had sufficient data to be included in the analysis (cutoff date: 1/20/2022). Patient baseline characteristics are shown in the Table. Treatment-emergent adverse events (TEAEs) in ≥40% of patients included febrile neutropenia (78%), nausea (65%), increased alanine aminotransferase (57%), leukopenia (57%), thrombocytopenia (57%), headache (43%), and hyponatremia (43%). All patients experienced a grade 3/4 TEAE, primarily hematologic events. Nonhematologic grade 3/4 TEAEs in ≥2 patients included pneumonia (17%), lung infection (13%), and hyperglycemia (9%). There were no grade 5 TEAEs and no deaths on or before Day 60. Complete remission was achieved by 18/22 (82%) evaluable patients after the first induction cycle. Conclusions: Preliminary results from the V-FAST trial suggest CPX-351 + MID is feasible, with a manageable safety profile and promising remission rates in adults with newly diagnosed AML who have a FLT3 mutation. Clinical trial information: NCT04075747. [Table: see text]

7020 Background: Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells such as acute myeloid leukemia (AML). This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. We report data from a Phase 1b trial of magrolimab+AZA in frontline TP53-mutant ( TP53m) AML. Methods: Patients (pts) with frontline AML not suitable for intensive chemotherapy received IV magrolimab starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as maintenance dose. AZA 75 mg/m2 was given IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by ELN 2017 criteria. Results: 72 TP53m AML pts were treated (Table). Common all-grade TEAEs were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common Grade 3+ TEAEs were febrile neutropenia (37.5%), anemia (29.2%; Grade 3, 26.4%; Grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Objective response rate (ORR) by intent-to-treat was 48.6% (33.3% CR, 8.3% CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh], 1.4% morphologic leukemia-free state [MLFS], 5.6% partial response). Stable disease was reported in 16.7%, progressive disease (PD) in 5.6%. 30- and 60-day mortalities were 8.3% and 18.1%, respectively. Response assessment was unavailable in 4.2% who discontinued due to AEs and 6.9% due to other, prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (mos; range 1.7–7.2) and to CR was 3.0 mos (range 1.8–9.6). 45.2% (14/31) of evaluable CR/CRi/CRh/MLFS pts achieved negative MRD by flow cytometry (investigator reported). Of 24 CR patients, 8 had a longitudinal TP53 VAF assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to SCT in 9 pts (12.5%), PD 26 (36.1%), death 8 (11.1%), AE 13 (18.1%), and other 14 (19.4%). Median durations of CR and CR/CRi were 7.7 mos (95% CI: 4.7, 10.9) and 8.7 mos (95% CI: 5.3, 10.9), respectively. Median overall survival (OS) for the 72 pts was 10.8 mos (95% CI: 6.8, 12.8) with median follow up 8.3 mos. Conclusions: In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing. Clinical trial information: NCT03248479. [Table: see text]

12117 Background: Patients with hematologic malignancies are less likely to receive outpatient palliative care (OPC) compared to patients with other cancer types. Little is known about the characteristics or health care utilization of patients with hematologic malignancies who are co-managed by OPC. In this study, we evaluated referral patterns and health care utilization of patients with hematologic malignancies who were seen in an embedded OPC clinic. Methods: We conducted a retrospective cohort study of patients who established care with an embedded OPC nurse practitioner from 3/2016 – 5/2020 at a quaternary academic medical center. We obtained information about patients’ demographics, clinical characteristics, and reasons for referral to OPC from the electronic health record. Information about costs and health care utilization were provided by our finance team. For patients who were followed by OPC for at least 6 months, we used two-tailed t-tests to compare the number of hospitalizations and emergency department (ED) visits, as well as total costs, for the 6 months before and the 6 months after initiating OPC. This was approved by the UCSF IRB. Results: A total of 120 patients received OPC. Median age was 59 years (range 24-89), 48% were female, and 64% were Non-Hispanic White. Myeloma was the most common cancer (n = 50/120, 41.7%), followed by aggressive lymphoma (n = 21/120, 17.5%), and acute myeloid leukemia (n = 18/120, 15%). The primary reason for referral was for symptom management, such as pain (60%, n = 72/120), mood symptoms (12.5%, n = 15/120), and fatigue (7.5%, n = 9/120). Ten percent (n = 12/120) were referred for goals of care conversations prior to stem cell transplant (SCT). An advance directive was on file for 29% (n = 35/120) of patients, of which 34% (n = 12/35) were completed after OPC enrollment. Of the 38 patients who died, the median time from PC enrollment to death was 15.3 months, and 39% died on hospice. For the 65 patients who were followed by OPC for at least 6 months, the total number of inpatient hospitalizations, excluding SCT, went from 0.82 to 0.54 (p = 0.11) per person in the 6 months before compared to the 6 months after initiating OPC. ED visits went from 0.28 to 0.18 (p = 0.33). The total direct cost of inpatient hospitalizations, excluding SCT, decreased from $43,428 to $13,226 (p = 0.01), and the cost of ED visits went from $640 to $297 (p = 0.32) per person. Conclusions: There is an important role for embedded OPC for patients with hematologic malignancies, long before the end-of-life period, to manage symptoms and support decision-making. OPC is associated with a trend towards lower health care utilization and decreased hospitalization costs. Prospective studies are warranted to further explore the impact of OPC on symptoms and patient/caregiver experience, as well as to clarify how OPC impacts health care utilization.