COVID-19 Outcomes Among Participants in the NHLBI Myelodysplastic Syndromes (MDS) Natural History Study

Introduction: The NHLBI MDS Natural History Study (NCT02775383) is an ongoing prospective cohort study conducted across 144 sites in the U.S. and Israel intended to establish a data and biospecimen repository to advance the understanding of MDS. In response to the COVID-19 pandemic, the study also collected data on COVID-19 infection and management. Here, we report a summary of COVID-19 outcomes from participants in this study and the impact of the pandemic on study operations. Methods: This prospective cohort study initiated in June, 2016 is enrolling patients (pts) undergoing diagnostic work up for suspected or newly diagnosed MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenia. Study enrollment was paused from Mar. 27, 2020 to May 18, 2020 due to COVID-19. Previously untreated pts underwent a bone marrow assessment with a centralized histopathology review at enrollment for assignment to a longitudinal cohort (MDS, MDS/MPN overlap, idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or “At-Risk” (pts with sub-threshold dysplasia, select karyotype, or select genetic mutations) for follow-up every six months;or a cross-sectional cohort (other cytopenia or cancers) with no further follow-up. COVID-19 outcomes, including tests, status, hospitalizations and treatments for COVID-19, were collected for all eligible pts. Protocol deviations related to COVID-19 were also collected. Fisher's exact test was used for comparing the proportions of pts tested or positive between groups. Results: Of 758 eligible pts with available COVID-19 data, 507 (67%) were assigned to the longitudinal cohort and 251 (33%) to the cross-sectional cohort or are pending assignment. Among longitudinal pts, 74 (15%) had ICUS, 240 (47%) MDS, 47 (9%) MDS/MPN overlap, 11 (2%) AML with <30% blasts, and 135 (27%) At-Risk for MDS. The median age over all pts was 72 years (range=21-95) and 66% were male, 92% White, 4% Black, 2% Asian, and 2% other. Among 244 pts (32%) tested for COVID-19 (Table 1), 23 (9%) were positive. Twelve (>50% of the positive pts) were in Wisconsin, California (CA), and Missouri (Figure 1), with 8 identified from Sep. to Dec. 2020, which overlaps with third waves of COVID-19 reported in CA and in the Midwest. Tests from 17 (74%) of the 23 pts were based on a polymerase chain reaction (PCR) assay. The proportion of pts positive were similar between pooled disease (ICUS, MDS, MDS/MPN, AML <30%), At-Risk, and cross-sectional groups (8%, 8%, 16%, respectively;Table 2) but the proportions tested differed significantly (39%, 28%, and 25%, respectively, p=0.004). Among all positive pts, 21 (91%) are recovering or have recovered (16 with sequelae), 1 (4%) died, and 1 outcome is unknown (Table 1). The one participant who died had MDS with excess blasts-1 (MDS-EB1, 5-9% blasts). Eight pts (35% of positive pts) required hospitalization (median duration of 7 days (range=2-17)) or treatment (tx) in response to COVID-19, 7 of whom required both. In the 8 pts who required tx for COVID-19, 4 reported Remdesivir-use, 3 of whom were diagnosed with MDS or MDS/MPN overlap. The study monthly accrual rates were similar when compared pre- vs. post-study pause (23 vs. 22 pts, respectively) but the rate of missed follow-up visits increased from 5% to 11% post-pause. About half (49%) of the 144 COVID-19-related study deviations occurred during the months the study was paused. Conclusions: In this analysis of 758 pts with MDS and related conditions, the largest reported for these diagnoses, the COVID-19 mortality rate (13%) in MDS was lower than has been reported in a smaller (n=61) case study (39%, Feld et al Blood 2020) but is similar to the rates for MDS observed annually each year prior to study pause (range=11-19%) and to the rate reported in a larger (n=2186) observational study of cancer patients (16%, Rivera et al Cancer Discov 2020). Infection rates were similar across disease groups. The pandemic also resulted in substantial study-specific challenges, including incre sed rate of deviations, the study being paused, and difficulty sourcing material for biospecimen processing. Data on vaccine efficacy and rates of pts with long-haul symptoms post-COVID may be of interest in future work. [Formula presented] Disclosures: Padron: BMS: Research Funding;Kura: Research Funding;Taiho: Honoraria;Stemline: Honoraria;Blueprint: Honoraria;Incyte: Research Funding. Komrokji: Novartis: Honoraria;Geron: Honoraria;Acceleron: Honoraria;Agios: Honoraria, Speakers Bureau;Abbvie: Honoraria, Speakers Bureau;JAZZ: Honoraria, Speakers Bureau;BMS: Honoraria, Speakers Bureau. Saber: Govt. COI: Other. Al Baghdadi: Bristol-Myers Squibb: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Current holder of individual stocks in a privately-held company;Epizyme: Current holder of individual stocks in a privately-held company;Heron Therapeutics: Current holder of individual stocks in a privately-held company;Morphosys: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Membership on an entity's Board of Directors or advisory committees;Cardinal Health: Membership on an entity's Board of Directors or advisory committees. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees;Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees.

Phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non-small cell lung cancer previously treated with a checkpoint inhibitor: Toxicity update (Lung-MAP non-matched sub-study S1800A)

Background: The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of immunotherapy agents in both treatment-naïve and previously treated cancer patients (pts) and irrespective of histology. Pts with tumors that develop resistance is a significant area of unmet need. Vascular endothelial growth factor (VEGF) has been shown to modulate the tumor immune microenvironment and combination immune checkpoint and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types. Lung-MAP is a master protocol for pts with stage IV, previously treated NSCLC. Pts who were not eligible for a biomarker-matched substudy enrolled in S1800A. The adverse event profile will be presented. Methods: S1800A is a phase II randomized trial for pts who previously received PD-1 or PD-L1 inhibitor therapy for at least 84 days and platinum-based doublet therapy with ECOG 0-1 stratified by PD-L1 expression, histology and intent to receive ramucirumab in the standard of care (SOC) arm. Pts were randomized 1:1 to pembrolizumab and ramucirumab P+R or SOC (docetaxel +R [SOC w R];docetaxel, pemetrexed or gemcitabine [SOC wo R]). The primary endpoint was overall survival. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and evaluation of toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts enrolled and 140 determined eligible [69 (49%) P+R;46 (33%) SOC w R;25 (18%) SOC wo R]. Treatments for those who received SOC wo R included 3 on docetaxel (19%);12 on gemcitabine (75%);and on 1 on pemetrexed (6%). 131 were eligible for adverse event (AE) assessment. The most common AE were fatigue (38%), proteinuria (28%), hypertension (23%), diarrhea (22%) and hypothyroidism (22%) on P+R;fatigue (61%), anemia (48%), diarrhea (41%) and neutropenia (39%) on SOC w R and anemia (56%), leukopenia (56%), fatigue (44%) and neutropenia (44%) on SOC wo R. Grade ≥ 3 treatment-related AEs occurred in 32% of pts on P+R, 54% of pts on SOC w R and 56% of pts on SOC wo R. Cardiac and thromboembolic events occurred in 12% of pts on P+R, 11% of pts on SOC w R and 0% of pts on SOC wo R. Grade 5 AE occurred in 2 pts on P+R (respiratory failure and cardiac arrest), 3 pts on SOC w R (2 respiratory failure and sepsis) and 1 pt on SOC wo R (sepsis). Four patients were diagnosed with COVID-19 (1 on P+R and 3 on SOC) and 3 died (1 on P+R and 2 on SOC). Conclusions: Grade 3 toxicities were lower in P+R compared to SOC arms with or without R. Cardiac and thromboembolic events were similar in arms that included R. P+R was generally well-tolerated. Efficacy outcomes will be presented when data matures.