ABSTRACT
Background: Etavopivat, an investigational, once-daily, selective, activator of erythrocyte pyruvate kinase (PKR) increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers and patients (pts) with sickle cell disease (SCD).1,2 Aims: We report results of an open-label (OL) extension cohort from a Phase 1 study (NCT03815695) designed to characterize the safety and clinical activity of etavopivat at a maximal pharmacodynamic dose in pts with SCD. Methods: 15 pts were enrolled to receive etavopivat 400 mg once daily for 12 wks, followed by a 4-wk follow-up. Assessments included safety, pharmacokinetics, pharmacodynamics, RBC health parameters and systemic markers of SCD pathophysiology. Results: Of 15 pts (age 32.3 ±10.1 yr;HbSS/SC n=13/2), 14 completed 12-wks of treatment (tx);1 pt discontinued tx after ∼2 wks. Etavopivat 400 mg once daily was generally well tolerated. Adverse events (AEs) reported during tx and follow-up were commonly low grade (Gr) and consistent with pts' SCD. Gr1-2 AEs in >2 pts (n [%]) were sickle cell pain events (9 [60%]);headache (5 [33%]);and upper respiratory tract infection (3 [20%]). The Gr3-4 AE in >1 pt was sickle cell vaso-occlusion (VOC;4 [27%]). On-tx serious adverse events (SAEs;1 pt each) were Gr3 VOC post Gr3 COVID (not tx-related) and Gr3 left femoral deep vein thrombosis (possibly related, resulting in tx discontinuation as stated above). SAEs (1 pt each) during the 4-wk follow-up were Gr3 acute chest syndrome + Gr3 VOC, Gr3 non-cardiac chest pain and Gr3 syncope (all unrelated). Observed increases in ATP and decreases in 2,3-DPG were durable over 12 wks of etavopivat tx. Etavopivat tx normalized hemoglobin (Hb)S-oxygen affinity to that of HbA. Etavopivat tx over 12 wks improved overall sickle RBC health, demonstrated by a reduction in point of sickling as well as improved measures of deformability and hydration of sickle RBCs (all P<0.01;Figure). Etavopivat tx over 12 wks was associated with a sustained significant increase in Hb compared with baseline (BL;P<0.0001), with mean maximal increase of 1.5 (range 0.7-2.3) g/dL. Ontx increase in Hb >1g/dL was achieved in 11 (73%) pts, for whom the mean maximal Hb increase was 1.8 (1.2-2.3) g/dL. Absolute reticulocytes, indirect bilirubin and lactate dehydrogenase significantly decreased from BL and were sustained over the 12wk period (all P<0.05), indicative of increased RBC lifespan and decreased hemolysis. Several markers of disease activity significantly decreased from BL during daily etavopivat tx, including the inflammatory marker tumor necrosis factor-α , which decreased by 35% (P<0.001). Based on preliminary exploratory analysis with an aggregate duration of etavopivat exposure of 3.32 pt-yrs in the OL cohort, a decrease in the trend for VOC Hospitalizations was observed: annualized historical and on-tx VOC Hospitalization rates were 0.93 and 0.30, respectively;the 1 on-tx VOC Hospitalization was COVID-related. Summary/Conclusion: Etavopivat 400 mg once daily for up to 12 wks demonstrated a tolerable safety profile and showed improvements in various markers of RBC health in pts with SCD. Rapid and sustained increases in Hb were associated with decreases in reticulocyte counts and markers of hemolysis, supporting increased sickle RBC lifespan and improved anemia. Together, these results support further evaluation of etavopivat in the Phase 2/3 Hibiscus Study (NCT04624659) currently enrolling pts. (Figure Presented).
ABSTRACT
Background: Patients (pts) with malignancies are at increased risk of morbidity and mortality from COVID-19. Among these pts, some of the higher case fatality ratios (CFR) reported are among pts with myeloid malignancies, ranging from 37 to 50% (Mehta V, Cancer Discov 2020;Ferrara F, Leukemia 2020). Levine Cancer Institute (LCI) has a robust hematologic malignancy and cellular therapy program that serves many pts with myeloid malignancies, seeing nearly 100 new diagnoses of acute myeloid leukemia per year. A strategy to mitigate risks associated with COVID-19 was established at LCI in partnership with Atrium Health's (AH) Hospital at Home (HAH). HAH was a system wide platform using telemedicine and home health services to assess and monitor COVID-19 + pts at high risk of complications. To augment HAH for our medically complex cancer pts, a virtual health navigation process involving expertise from across LCI, including a specialized nurse navigation team, was developed to rapidly identify LCI pts + for SARS-CoV-2, monitor them under physician supervision, and escalate care as needed with AH HAH. Along with the navigation platform, data-driven guidelines for detecting, monitoring, and managing LCI pts + for SARS-CoV-2 were swiftly employed across the extensive LCI network. Herein we report on the outcomes for LCI pts with myeloid malignancies + for SARS-CoV-2 and outline the employed risk mitigation strategies and their potential impact on these outcomes. Methods: An automated daily list of LCI pts + for SARS-CoV-2 was provided by AH Information Services. Each pt's chart was reviewed by a nurse navigator for hematologic or oncologic diagnosis, outpatient or inpatient status, and COVID-19 symptoms. Pts without a cancer diagnosis were not assigned a navigator. If hospitalized, a pt was not assigned a navigator;following discharge, if enrolled in HAH, a navigator was assigned. In collaboration with HAH, an algorithm for directing care was utilized (Figure 1). A diagnosis-specific navigator contacted and screened the pt with an assessment tool, which scored pts for surveillance and treatment needs (Table 1). Documentation was forwarded to the primary hematologist/oncologist. Comprehensive guidelines for testing, scheduling, management of + pts, research, and process changes were created, disseminated, and actively updated through LCI's EAPathways. For outcome analysis for pts with myeloid malignancies, pt vital status was updated through data cutoff (7/3/21). Results: From inception on 3/20/20 to 12/2/20, 974 LCI patients were identified as SARS-CoV-2 + and reviewed for nurse navigation. Of the 974 pts, including pts with benign and malignant diagnoses, 488 were navigated. Among all SARS-CoV-2 + LCI pts, 145 (15%) had a hematologic malignancy, including 37 (4%) pts with myeloid malignancies. Characteristics are shown in Table 2. Of the 37 pts, 18 (49%) were navigated. 70% with myeloid malignancies were on active treatment at the time of + test. Nearly 50% of those on active treatment were navigated. 46% were hospitalized with COVID-19, with this being the main reason for no assigned navigator. 24% of hospitalized pts were eventually assigned a navigator. Only 3 pts had undergone allogeneic stem cell transplantation (allo-SCT) with a median time from transplant to detection of SARS-CoV-2 of 9 months (range, 7-23). 2 out of 3 cases post allo-SCT were asymptomatic. No pt died from COVID-19 following allo-SCT. Among the navigated pts with myeloid malignancies, there was no death related to COVID-19. 4 pts, all of whom were hospitalized, died from COVID-19 (N=2, myelodysplastic syndrome with 1 on azacitidine;N=2, myeloproliferative neoplasm, both on hydrea). A CFR of 11% was demonstrated for LCI pts with myeloid malignancies. Conclusions: A multidisciplinary response strategy liaising between AH HAH and LCI followed, assessed, and assisted cancer pts + for SARS-CoV-2. With our embedded nurse navigation team's specialized attention along with enhanced physician oversight and close collaboration with AH HAH, opportunities f r care escalation or adjustments in cancer-focused care were promptly identified. In this setting, among the high-risk population of pts with myeloid malignancies, a lower CFR than has been reported was observed. A virtual navigation platform with HAH capabilities is a feasible, safe, and effective way to monitor and care for this high-risk population. [Formula presented] Disclosures: Moyo: Seattle Genetics: Consultancy. Chai: Cardinal Health: Membership on an entity's Board of Directors or advisory committees. Avalos: JUNO: Membership on an entity's Board of Directors or advisory committees. Grunwald: Amgen: Consultancy;Agios: Consultancy;Astellas: Consultancy;Daiichi Sankyo: Consultancy;Stemline: Consultancy;Bristol Myers Squibb: Consultancy;PRIME: Other;Trovagene: Consultancy;Blueprint Medicines: Consultancy;AbbVie: Consultancy;Med Learning Group: Other;Pfizer: Consultancy;Sierra Oncology: Consultancy;Janssen: Research Funding;Incyte: Consultancy, Research Funding;Gilead: Consultancy;MDEdge: Other;PER: Other;Cardinal Health: Consultancy;Karius: Consultancy. Copelan: Amgen: Consultancy.
ABSTRACT
Background: Reports suggested cancer patients were at greater risk for increased morbidity and mortality from COVID-19. A process to mitigate these risks was established at Levine Cancer Institute (LCI) in partnership with Atrium Health's (AH) Hospital at Home (HAH) initiative. This virtual health navigation process employed expertise from the departments of Hematologic Oncology and Blood Disorders, Oncology, and Supportive Oncology, including a specialized nurse navigation team, to rapidly identify COVID-19 positive LCI patients, monitor them under physician supervision, and escalate care as needed with AH HAH program. Methods: AH Information Services created an automated list of LCI COVID-19 positive patients with a daily database. Each patient was reviewed by a nurse navigator. Review included hematologic or oncologic diagnosis, outpatient or inpatient status, and any COVID-19 symptoms. Once a malignant diagnosis was confirmed, a diagnosis-specific navigator contacted and screened the patient with a COVID assessment tool. Documentation was forwarded to the primary oncologist/hematologist. The tool scored patients for surveillance and treatment needs. A score of 0-2 prompted phone assessment every 48-72 hours, and score of 3-5 required every 24-48 hour calls with physician involvement when appropriate. If score of ≥6, care was escalated to LCI nurse/physician for admission to AH acute care HAH or conventional inpatient admission. Results: From inception on 3/20/2020 to data review date of 12/2/2020, 974 LCI patients were identified as COVID-19 positive and reviewed for nurse navigation (Table). Of the 974, 488 were navigated. Given limited resources, patients with benign conditions were not assigned a navigator, though a similar process was created for sickle cell disease. Of the 974, 75 are now deceased. Only 25 are deceased among the 488 navigated. Conclusions: The COVID-19 pandemic presented unprecedented circumstances to our patients and their clinicians. LCI expeditiously put policies and procedures in place to mitigate the intersection of COVID-19 and cancer. The multidisciplinary response strategy liaising between AH HAH and LCI followed, assessed, and assisted LCI COVID19 positive patients. With our embedded nurse navigation team's specialized attention along with enhanced physician oversight and close collaboration with AH HAH, opportunities for care escalation or adjustments in cancerfocused care were promptly identified. Analysis is ongoing to elucidate the lower mortality rate observed among navigated patients.