Solid Tumor Patients Research Articles

Accelerating Clinical Development of Idasanutlin through a Physiologically Based Pharmacokinetic Modeling Risk Assessment for CYP450 Isoenzyme-Related Drug-Drug Interactions.

Idasanutlin is a potent inhibitor of the p53-MDM2 interaction that enables reactivation of the p53 pathway, which induces cell cycle arrest and/or apoptosis in tumor cells expressing functional p53. It was investigated for the treatment of solid tumors and several hematologic indications such as relapsed/refractory acute myeloid leukemia, polycythemia vera, or non-Hodgkin lymphoma. For safety reasons, it cannot be given in healthy volunteers for drug-drug interaction (DDI) explorations. This triggered the need for in silico explorations on top of the one available CYP3A clinical DDI study with posaconazole in solid tumor patients. Idasanutlin's clearance is dependent on CYP3A4/2C8 forming its major circulating metabolite M4, with contributions from UGT1A3 and biliary excretion. Idasanutlin and M4 have low permeability, very low clearance, and extremely low unbound fraction in plasma (<0.001), which makes in vitro data showing inhibition on CYP3A4/2C8 enzymes challenging to translate to clinical relevance. Physiologically-based pharmacokinetic models of idasanutlin and M4 have been established to simulate perpetrator and victim DDI scenarios and to evaluate whether further DDI studies in oncology patients are necessary. Modeling indicated that idasanutlin and M4 would show no or weak clinical inhibition of selective CYP3A4/2C8 substrates. Co-administered strong CYP3A and CYP2C8 inhibitors might lead to weak or moderate idasanutlin exposure increases, and the strong inducer rifampicin might cause moderate exposure reduction. As the simulated idasanutlin systemic exposure changes would be within the range of observed intrinsic variability, the target population can take co-medications that are either CYP2C8/3A4 inhibitors or weak/moderate CYP2C8/3A4 inducers without dose adjustment. SIGNIFICANCE STATEMENT: Clinical trials for idasanutlin are restricted to cancer patients, which imposes practical, scientific, and ethical challenges on drug-drug interaction investigations. Furthermore, idasanutlin and its major circulating metabolite have very challenging profiles of absorption, distribution, metabolism and excretion including high protein binding, low permeability and a combination of different elimination pathways each with extremely low clearance. Nonetheless, physiologically-based pharmacokinetic models could be established and applied for drug-drug interaction risk assessment and were especially useful to provide guidance on concomitant medications in patients.

Clinico-demographic and Outcome Predictors in Solid Tumor Patients with Unplanned Intensive Care Unit Admissions: An Observational Study.

ObjectivesCritically ill solid organ malignancy patients admitted to intensive care unit (ICU) as unplanned medical admissions behave differently from other subsets of cancer patients (hematolymphoid malignancies and cancer patients admitted for postoperative care). These patients if appropriately selected may benefit from the ICU care. There is paucity of data on critically ill unplanned admissions of solid organ malignancies from South Asia. We analyzed data of patients with solid tumors with unplanned admissions to the ICU to determine the clinical, epidemiological characteristics, and predictors of hospital mortality in an Indian ICU.Materials and methodsThis prospective, observational study was done in our 14-bedded mixed medical–surgical ICU from July 2014 to November 2015. We included all consecutive adult unplanned admissions with solid organ malignancies having ICU stay of >24 hours. Surgical admissions, hematolymphoid malignancies, advanced malignancy with no treatment options, and those cured of cancer >5 years were excluded.ResultsTwo hundred and thirty-five consecutive patients were included in this cohort. ICU and hospital mortalities were 36.6 and 40%, respectively. On multivariate analysis, cancer status [odds ratio (OR): 3.204; 95% confidence interval (CI): 1.271–8.078], invasive mechanical ventilation (OR: 5.940; 95% CI: 2.632–13.408), and sequential organ failure assessment (SOFA) score on the day of ICU admission (OR: 1.199; 95% CI: 1.042–1.379) were independent predictors of hospital mortality.ConclusionAcute respiratory failure and septic shock are the common reasons of unplanned ICU admission for patients with solid organ malignancies. With good patient selection, more than half of such patients are likely to be discharged alive from the hospital.How to cite this articleSiddiqui SS, Narkhede AM, Chaudhari HK, Ravisankar NP, Dhundi U, Sarode S, et al. Clinico-demographic and Outcome Predictors in Solid Tumor Patients with Unplanned Intensive Care Unit Admissions: An Observational Study. Indian J Crit Care Med 2021;25(12):1421–1426.

293. Lung Cancer and Hematologic Malignancy ( HM) Patients Are Associated with the Highest Risk of Progressing to Severe Disease and Mortality in Cancer Patients with COVID-19

BackgroundSeveral studies have shown that underlying cancer is a risk factor for progression of COVID-19 to severe illness and fatal outcome but there is very little data that specifies which underlying cancer puts this patient population at the highest risk. MethodsWe retrospectively collected de-identified data on 1115 cancer patients diagnosed with COVID-19 between January and November 2020, at 12 centers in Asia, Australia, Europe, North America, and South America. Patient characteristics including age, type of malignancy (hematologic malignancy [HM], lung cancer, and non-lung cancer were determined in association with severe illness as well as all-cause mortality within 30 days after COVID-19 diagnosis.ResultsBy multivariable logistic regression analysis, independent risk factors for 30-day mortality in cancer patients included age > 65 (OR 6.64; 95% CI 3.351to 12.55; p< 0.0001), ALC < 0.5 K/microliter (OR 2.10; 95% CI 1.16 to 3.79; p=0.014), and anemia at < 10g/dl (OR 2.41; 95% CI 1.30 to 4.44; p=0.005). Among cancer patients, the 30-day mortality rate was significantly higher in patients with lung cancer than in patients with non-lung cancer solid tumors, including those with lung metastases (22% vs 9%; p=0.001). Patients with HM tended to have higher 30-day mortality than patients with non-lung cancer solid tumors (13% vs 9% p=0.07) and tended to have a lower mortality rate than patients with lung cancer (p=0.07). Furthermore, HM patients were more likely to be lymphopenic and anemic at diagnosis as well as progress to LRTI and be placed on ventilatory support compared to non-lung cancer solid tumor patients ( p= or < 0.01). In addition, lung cancer and HM patients were more likely to develop hypoxia and require hospital admission than non-lung cancer solid tumor patients ( p=0.01). ConclusionLung cancer and HM patients are associated with the highest risk of progressing to severe disease and mortality in cancer patients with COVID-19. Hence, cancer patient population should be given the highest priority as far as prevention [vaccination with boosters if needed] as well as preemptive early therapy with monoclonal antibodies right after the onset of COVID-19.Disclosures Monica Slavin, MBBS,MD, F2G (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Pfizer (Advisor or Review Panel member)

Abstract P224: Update from the Phase 2 registrational trial of repotrectinib in TKI-pretreated patients with ROS1+ advanced non-small cell lung cancer and with NTRK+ advanced solid tumors (TRIDENT-1)

Abstract Background: Repotrectinib is a next-generation ROS1/TRK tyrosine kinase inhibitor (TKI) that is currently in a registrational Phase 2 trial (TRIDENT-1). A previous update from the TRIDENT-1 trial showed a generally well tolerated safety profile in 185 treated patients. Interim efficacy data were previously presented. In ROS1+ NSCLC patients with 1 prior TKI and prior platinum-based chemotherapy (EXP-2), confirmed overall response rate (cORR) was 40% (2 of 5 patients); in ROS1+ NSCLC patients with 1 prior TKI without prior platinum-based chemotherapy (EXP-4), cORR was 67% (4 of 6 patients); in ROS1+ NSCLC patients with 2 prior TKIs without prior platinum-based chemotherapy (EXP-3), cORR was 40% (2 of 5 patients). In NTRK+ TKI-pretreated advanced solid tumor patients (EXP-6), cORR was 50% (3 of 6 patients). In addition, efficacy was demonstrated in patients who developed solvent front mutations (SFM) following prior ROS1/TRK TKI treatment. cORR was 67% (4 of 6 patients) and 50% (2 of 4 patients) in ROS1+ NSCLC and NTRK+ solid tumors patients with SFMs, respectively. One patient who developed a SFM after entrectinib treatment (EXP-2) had a cCR with 5.6+ months duration of response. Methods: TRIDENT-1 (NCT03093116) is an ongoing registrational Phase 2 trial enrolling patients whose cancers harbor a ROS1 or NTRK gene fusion. Patients are enrolled into 6 defined expansion cohorts (EXP 1-6), based on cancer type and prior therapy. The primary endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Results: An updated safety analysis across Phase 1 and Phase 2 patients (n=243) based on a data cut-off date of 4 May 2021 was conducted. Treatment-emergent adverse events (TEAEs) observed in ≥20% of patients were dizziness (62%), dysgeusia (43%), constipation (33%), dyspnea (30%), paresthesia (28%), anemia (26%), and fatigue (26%). Grade ≥3 treatment-related AEs (TRAEs) were observed in 17% of patients; no Grade 5 TRAEs were observed. The majority (77%) of dizziness TEAEs were Grade 1 and 4% were Grade 3; none of the dizziness events led to treatment discontinuation. Dose modifications remained infrequent including 24% of patients with a TEAE that led to a dose reduction and 10% of patients with a TEAE that led to drug discontinuation. Updated efficacy information for TKI-pretreated ROS1+ NSCLC and NTRK+ advanced solid tumor patients is being collected and will be available for presentation. Conclusions: Repotrectinib is a next-generation ROS1/TRK inhibitor. In an ongoing registrational Phase 2 trial, repotrectinib was generally well tolerated with low frequency of dose modifications. Updated Phase 2 efficacy data will be available for presentation. Citation Format: Jessica J. Lin, Byoung Chul Cho, Christoph Springfeld, D. Ross Camidge, Benjamin Solomon, Christina Baik, Vamsidhar Velcheti, Young-Chul Kim, Victor Moreno, Anthonie J. van der Wekken, Enriqueta Felip, Dipesh Uprety, Denise Trone, Shanna Stopatschinskaja, Alexander Drilon. Update from the Phase 2 registrational trial of repotrectinib in TKI-pretreated patients with ROS1+ advanced non-small cell lung cancer and with NTRK+ advanced solid tumors (TRIDENT-1) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P224.

Abstract LBA006: Identification of novel, tumor specific pHLA targets recognized by TILs from CPI responders in a high-throughput, high-diversity pHLA library screening platform (3T-TRACE)

Abstract Background The ideal cancer target antigen is selectively expressed on neoplastic cells, absent on normal tissues, and contributes to the survival of cancer cells. Recent clinical trial reports identified T cell receptors (TCRs) recognizing intracellular targets presented as peptides in the context of HLA (pHLA) molecules as the critical molecular mediators of deep and long-lasting anti-tumor responses in a few solid tumor patients with complete responses to checkpoint inhibitor (CPI) treatment. The pHLA targets recognized by these TCRs may thus represent the long sought-after, ideal targets for solid tumor targeting with high-potency therapeutic modalities. Here we describe an immune-response guided target identification platform (3T-TRACE) and its utility to identify novel, intracellular targets, and their corresponding T cell receptors (TCRs) for the treatment of solid tumors. We provide an overview of the frequency and expression levels of the most promising, novel cancer testis antigens (CTAs) and tumor associated antigens (TAAs) identified. Methods By employing single cell sequencing methods, we identified TCRs that are uniquely associated with CPI responses and generated recombinant TCRs for screening against yeast display libraries expressing synthetic peptides in the context of the matching HLA complex, reviewed in (Figure 1). We analyzed over 140,000 CD8/CD4+ TILs from over 90 patient tumor biopsies and/or peripheral blood samples, including colorectal, lung, breast, ovarian, melanoma, and renal cancer (Figure 2). High value TCRs were selected based on the following criteria: high TCR clonality, immunophenotype indicative of T cell activation, shared alpha and/or beta TCR chains across patient samples (Public TCRs) and TCRs with anti-tumor activities. Statistical- and machine learning algorithms were developed to predict human peptides from the library selection data. Predicted target peptides were tested in in vitro T cell co-cultures for TCR activation. Antigen processing assays or mass spec analysis was employed to validate immunological processing of the epitope to identify bona fide targets. Results Among the first 100 targets identified by 3T-TRACE, we found 15 novel cancer testis antigens (CTAs) and 42 tumor associated antigens (TAAs) that were not previously described as targets in CPI treated solid tumor patients (Figure 3). Conclusions By combining TCR repertoire profiling with a library-based, antigen identification approach we found a strong enrichment of CTA- and TAA targets recognized by TCRs on TILs from CPI responders (Figure 4). Our findings are consistent with previous reports, demonstrating long-lasting responses induced by epitope spreading and CD8 T cell responses towards self-antigens, including CTAs and TAAs. Citation Format: Hans-Peter Gerber, Marvin Gee, Leah Sibener. Identification of novel, tumor specific pHLA targets recognized by TILs from CPI responders in a high-throughput, high-diversity pHLA library screening platform (3T-TRACE) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA006.

Abstract P02-02: First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy &amp;gt;85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in &amp;gt;20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.

Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis

BackgroundMost immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with immune-checkpoint inhibitors (ICI) in Thailand.MethodsAll solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher’s exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant.ResultsirAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3–4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51–0.96; p = 0.028).ConclusionirAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations.

Targeting tumor microenvironment and metastasis in children with solid tumors.

Purpose of reviewThe prognosis of pediatric patients with metastatic solid tumors remains poor, necessitating development of novel therapeutic strategies. The biology of the pediatric tumor microenvironment (TME) presents obstacles for the efficacy of current therapeutic approaches including immunotherapies. Targeting various aspects of the TME in pediatric patients with solid tumors represents a therapeutic opportunity that may improve outcomes. Here we will discuss recent advances in characterization of the TME, and clinical advances in targeting the immune, vascular, and stromal aspects of the TME.Recent findingsAlthough immunotherapies have shown limited success in the treatment of pediatric solid tumor patients thus far, optimization of these approaches to overcome the TME shows promise. In addition, there is increasing focus on the myeloid compartment as a therapeutic target. Vascular endothelial growth factor (VEGF) targeting has resulted in responses in some refractory pediatric solid tumors. There has been relatively little focus on stromal targeting; however, emerging preclinical data are improving our understanding of underlying biology, paving the way for future therapies.SummaryAlthough translation of TME-targeting therapies for pediatric solid tumors is in the early stages, we are optimistic that continued exploration of approaches aimed at rebalancing the TME will lead to improved outcomes for this population.

A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

WT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer.

Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses.

Four-Fold Increased Mortality from Sars-Cov-2 Infection in Patients with Hematologic Versus Non-Hematologic Malignancies Treated at the Largest Tertiary COVID-19 Center in Chicago/Rush University Medical Center (March 1, 2020-December 31,2020)

▪N.K.Y., P.C., & P.R.Y. contributed equally to this studyIntroduction: Many studies have concluded that active cancer patients infected with SARS-CoV-2 have a more complicated infection course and worse outcomes compared to the general patient population hospitalized with COVID-19. However, little evidence exists whether having a history of cancer plays a significant role in these observations. Patients with hematologic malignancy (HM) might have worse prognosis among all cancer patients but the reason remains unclear. Our objective is to evaluate outcomes and severity of COVID-19 in patients with Hematological Malignancy (HM) versus Solid-tumors (ST) in different clinical settings and also compare these outcomes within the group of patients with hematological malignancies.Methods: This retrospective study examines risk factors and outcomes of COVID-19 in patients with a history of cancer and laboratory-confirmed COVID-19 diagnosis between March 1 st, 2020, and December 31 st, 2020, at Rush University Medical Center, one of the largest COVID-19 tertiary care hospitals in Chicago. Baseline characteristics, malignancy type and types of cancer treatment within the last 30 days were recorded. Measures of COVID-19 severity included hospital admission versus outpatient care, use of oxygen, intensive care unit (ICU) admission, and mechanical ventilation. The primary outcome was death. Statistical analysis was conducted using optimal discriminant analysis, a non-parametric exact machine-learning algorithm which identifies the relationship between independent and dependent variables that maximizes model predictive accuracy adjusted to remove the effect of chance. Analysis was performed separately for each attribute using the entire sample (“training” analysis), then one-sample jackknife analysis was conducted to estimate cross-generalizability of findings using the model to classify an independent random sample.Results: 378 total patients with a history of cancer tested positive for COVID-19 within the time frame of the study. Of these, 294 (78%) patients had ST malignancy and 84 (22%) patients had HM. Characteristics and outcomes are summarized in Table 1. ST patients were marginally older than HM patients (p<0.025). A significantly greater proportion of HM patients were male (p<0.0023). HM and ST patients did not differ with respect to percentage receiving active cancer treatment (p<0.81). Compared to ST patients, more HM patients had received corticosteroids in the 30 days prior to COVID-19 diagnosis (p<0.017), had higher rates of hospitalization (p<0.0013) and ICU requirement (p<0.0001) with a significantly longer length of ICU stay (p<0.0036). Compared to ST patients, HM patients also required oxygen (p<0.002) and mechanical ventilation (p<0.0005) more often and had a 3.88-fold statistically higher death rate (OR 3.88 [95% CI 1.62-9.29] p<0.003). Patients with HM are categorized by disease subtype and summarized in Table 2. The case fatality rate from COVID-19 was 33.3% for patients with myeloproliferative neoplasms/myelodysplastic syndromes (MPN/MDS), 21.4% for patients with chronic lymphocytic leukemia (CLL), 13.6% for patients with non-Hodgkin lymphoma, 10.5% for patients with plasma cell neoplasms, and 4.5% for patients with acute leukemia. When looking at outcomes, CLL had the highest percentage of patients requiring hospital admission, oxygen, and ICU admission, and MPN/MDS had the highest percentage of patients requiring mechanical ventilation.Conclusions: Patients with hematologic malignancies had more severe COVID-19 illness and hospitalization rates and a 3.88-fold higher rate of death than patients with solid tumors. The comparable proportion of patients on anti-cancer therapy despite differences in survival suggests that being on anti-cancer therapy is less important than the underlying diagnosis of HM versus ST as a determinant of poor outcomes. Clinicians should closely monitor and initiate early COVID-19 treatments for all patients with HM and COVID-19. Because HM are highly heterogenous group of cancers, it is important to look at subtypes in greater detail. Numerous patient-level, disease-specific, and therapy-related factors may impact outcomes of COVID-19 among patients with HM, and we are currently analyzing additional data to better understand the factors which make this disease group more susceptible to severe infection. [Display omitted] DisclosuresKuzel: Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.

Dnmt3a Mutations in the Hematopoietic System Promote Colitis-Associated Colon Cancer: A Model of Clonal Hematopoiesis in Solid Tumors

Clonal hematopoiesis (CH) is a condition wherein hematopoietic stem cells (HSCs) acquire mutations, often in presumed leukemia driver genes such as in DNMT3A, leading to clonal dominance and disproportionate contribution to peripheral blood without overt hematologic abnormalities (Jaiswal et al. 2014). In large cohorts of patients with solid tumors including colorectal cancer, presence of CH is associated with inferior overall survival due to progression of primary malignancy (Coombs et al. 2017). While potential involvement of CH in the pathogenesis of solid tumors driven by unrelated genetic alterations has far-reaching translational implications, the mechanistic understanding of this relationship is lacking.Colorectal cancer is a leading cause of cancer deaths worldwide and can arise from preceding inflammatory bowel disease. More than 20% of patients with colon cancer have detectable CH, which is notably more prevalent than in age-matched general population. We hypothesized that bone marrow-derived cells harboring alterations in DNMT3A, the most commonly disrupted gene in CH (up to 40% of cases), contribute to the pathogenesis of colorectal cancer. To address this, we combined a bone marrow transplantation-based model of CH driven by heterozygous loss of Dnmt3a with a well-established induction of colitis-associated colon cancer (CAC) by azoxymethane (AOM, a carcinogen) and dextran sodium sulfate (DSS, a colitogen). High resolution colonoscopy demonstrated increased colon wall opacity, visible bleeding, numerous fibrin patches and earlier onset of tumor formation with higher penetrance in animals with partial ablation of Dnmt3a in the hematopoietic compartment. Heightened colon pathology was reflected by modified murine endoscopic index of CAC severity (MEICS) (Fung and Putoczki 2018) (MEICS scores 7.5±2.0 in WT vs 10.0±3.2 in Dnmt3a +/-, p=0.05, n=14,13). We observed elevated incidence of tumors >2mm in diameter (40.2±22.2% in WT vs 74.2±15.7% in Dnmt3a +/-, p=0.03, in 5 independent trials) and a higher tumor burden in Dnmt3a +/- chimerae (7.4±7.8 mm 3 in WT vs 14.5±13.9 mm 3 in Dnmt3a +/-, p=0.0017, n=53,55) at end point. Histopathological analysis revealed marked immune infiltration, extensive ulceration and dysplasia of colonic epithelium, and more frequent adenocarcinoma formation with occasional submucosal invasion (histology score 20.2±4.4 in WT vs 24.6±6.9 in Dnmt3a +/-, p=0.03, n=10,9). To uncover signaling pathways deregulated by experimental Dnmt3a-driven CH, we surveyed the auto- and paracrine stimulatory loops by multiplex cytokine/chemokine assays and profiled transcriptomes of colon tumors by bulk RNA-seq. These studies identified gene signatures commonly associated with colon carcinogenesis including accentuated epithelial-to-mesenchymal transition (gene set enrichment analysis (GSEA) NES=2.42, padj=0.0096), Wnt/b-catenin (NES=2.07, padj=0.0096), and Vegf/angiogenesis (NES=1.83, padj=0.0096). Elevated proliferation (Ki67) and increased vascularization (CD31) were validated by immunohistochemistry. These aspects of tumor pathophysiology along with the composition and functional characteristics of the tumor-infiltrating leukocytes derived from animals with and without hematopoietic-specific Dnmt3a partial loss are being further investigated. Preliminary data showed bone marrow-derived macrophages (BMDMs) from Dnmt3a +/- chimera exhibit impaired ability to phagocytose syngeneic MC38 colon tumor cells, compared to WT.Our study provides new insights into the non-tumor-cell-autonomous mechanisms of carcinogenesis effected by alterations in the hematopoietic system and into the interplay between the immune system and the aggressive phenotype of colorectal cancer. Our findings may aid the development of novel therapeutic options to improve outcomes in solid tumor patients with CH. [Display omitted] DisclosuresBowman: Mission Bio: Honoraria, Speakers Bureau. Levine: Ajax: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Prelude: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Zentalis: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Lilly: Honoraria; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Roche: Honoraria, Research Funding.

Risk of Venous Thromboembolism and Survival Outcomes in Patients with Lymphoma

Background: The relationship between venous thromboembolism (VTE) and lymphoma is well established. In recent years, direct oral anticoagulants (DOACs) have been adopted as a treatment option for cancer associated thrombosis, however the majority of data using DOACs is in solid tumor patients. Here, we report the risk of recurrent VTE, bleeding outcomes, and effect of VTE on survival among lymphoma patients treated in a large centralized cancer associated thrombosis clinic.Methods: We prospectively followed lymphoma patients referred to our clinic from 8/2014-01/2021. VTE events including deep venous thrombosis (DVT), pulmonary embolism (PE), and visceral vein thrombosis (VVT), were noted. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Cumulative incidence rate of VTE was estimated and compared using Gray's method.Results: A total of 103 patients were referred to our clinic due to clinical suspicion of VTE, of whom 40 (38.8%) were diagnosed with an acute VTE. The median age of the study population was66 (range 19-88), 61.2% were male and 16.5% had prior VTE. Non-Hodgkin Lymphoma (NHL) compromised 87.4%, with diffuse large b-cell lymphoma (DLBCL) being the most common subtype. Most patients had stage 4 disease (55.34%), had high grade lymphoma (defined as grade 3-4) (51.46%), and were on antineoplastic treatment (71.67%) at the time of VTE diagnosis. Site of VTE was DVT in 35.9%, PE in 5.8%, both DVT and PE in 2.9% and VVT in 0.97% of patients. Of these, 21 (20.39%) received a (DOAC), 14(13.59%) received enoxaparin, and 2(1.94) had IVC filter placed due to contraindication to anticoagulation. VTE recurrence occurred in 10% patients (total n=4; 2 were on enoxaparin and 2 were on rivaroxaban). Cumulative incidence of VTE in all patients at 6 months was 1% (95% CI: 0-2.9%), at 1 year was 3% (95% CI: 0-6.4%) with no significant difference in VTE or bleeding rates between lymphoma types or grade groups (P >0.05) (Table 1). Of 37 patients on anticoagulation, 10.8% experienced bleeding events (n=4) , of which 1 (2.7%) had major bleeding on IVC filter and 3 (8.1%) had CRNMB (2 on enoxaparin and 1 on rivaroxaban) at 6 month follow-up. Median follow-up was 35.9 months (range: 0.4-77.7 months) and median 2 year OS was 76%, 95% CI (68-85%). Overall survival was negatively impacted by age (patients over age 65 had a 2 year OS rate of 67%95% CI (0.56-0.81), p=0.01). Lymphoma grade had no impact on OS (2-year OS rate= 0.69, 95% CI (0.57-0.84), P=0.1132)Conclusion: High grade and low grade lymphoma patients treated in our centralized cancer thrombosis clinic had a 10% chance of VTE recurrence when treated with DOAC or enoxaparin. Bleeding rates were low in both groups; however, we saw decreased overall survival in those treated with DOACs. This data adds to the growing knowledge of treating hematologic malignancies with direct oral anticoagulants, but larger studies are needed to study the safety and efficacy of these agents in lymphoma patients. [Display omitted] DisclosuresKhorana: Halozyme: Consultancy, Honoraria; Anthos: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Angelini: Sanofi: Membership on an entity's Board of Directors or advisory committees.

Impact of ABO Blood Group Type on Risk of Venous Thromboembolism in Patients with Cancer

Introduction: Venous thromboembolism (VTE) is common in patients with cancer. Non-O blood type is associated with higher levels of factor FVIII activity and von Willebrand factor compared to blood type O, and has been identified as a risk factor for VTE in the general population. However, the impact of ABO blood type on risk of cancer-associated VTE has not been clarified.Methods: To determine the influence of non-O blood type on risk of cancer-associated VTE, we utilized the dataset of the Vienna Cancer and Thrombosis Study (CATS), which is a single center, prospective observational cohort study including patients with newly diagnosed or recurrent cancer. Patients were followed for objectively diagnosed, independently adjudicated VTE for a maximum of 2 years. VTE was quantified in competing risk analysis, accounting for all-cause mortality as competing outcome event. A proportional sub-hazard regression model according to Fine & Gray was used for between-group comparisons. Based on the violation of the proportional sub-hazard assumption, we explored potential time-dependent effects of non-O blood type on VTE risk in a restricted cubic spline analysis, modeling differences in risk estimates over follow-up time. Further, time-restricted subdistribution hazard ratios (SHR) were obtained specifically for the <3 months and ≥3 months follow-up intervals. In a subgroup analysis, differences in VTE risk according to ABO-blood type were analyzed for patients with very high thrombotic risk tumor types (pancreatic, gastric, glioblastoma), compared to the remainder of patients.Results: In total, 1,708 patients were included in our analysis (46% female, median age: 61 years [interquartile range, IQR: 52-68]). The most common tumor types were lung (19%), breast (16%), and brain (14%) cancer, with 32% of solid tumor patients having metastatic disease at study inclusion. Over a median follow-up of 24 months (IQR: 10-24), 151 patients were diagnosed with VTE (cumulative 2-year incidence: 9.2%, 95% confidence interval [CI]: 7.9-10.7) and 649 patients died (2-year mortality: 38%). Overall, blood type O was present in 38% of patients, A in 40%, B in 15%, and AB in 7%. The cumulative incidence of VTE at 3-, 6-, 12-, and 24-months for patients with blood type O was 3.8% (95% CI: 2.5-5.5), 5.7% (95% CI: 4.1-7.7), 7.0% (95% CI: 5.1-9.1), and 7.6% (95% CI: 5.7-9.9), compared to 3.4% (95% CI: 2.4-4.7), 6.5% (95% CI: 5.1-8.1), 8.4% (95% CI:6.8-10.2), and 10.2% (95% CI: 8.4-12.2) in patients with non-O blood type (Gray´s test: p=0.103, Figure 1). Upon visual inspection of cumulative incidence functions, a violation of the proportional sub-hazard assumption was suspected. In restricted cubic spline analysis, estimating hazard ratio (HR) for VTE of patients with non-O compared to O blood type, a time-varying effect of non-O blood type towards an increased VTE risk was observed (Figure 2). Based on that, time-restricted competing risk regression models were performed. During the first 3 months of follow-up, no differences in VTE risk were found (SHR for non-O vs. O blood type: 1.00, 95% CI: 0.60-1.67, p=0.992). Beyond the first 3-month follow-up, patients with non-O blood type had an increased VTE risk compared to patients with blood type O (SHR 1.79, 95%CI: 1.12-2.85, p=0.015). In a subgroup analysis, no association with VTE risk was found in patients with very high thrombotic risk tumor types (SHR 0.94, 95% CI: 0.55-1.61, p=0.824). In contrast, in patients with low/intermediate risk cancer, non-O blood type was associated with increased risk of VTE (SHR 1.73, 95% CI: 1.09-2.73, p=0.019).Conclusion: Non-O blood type was identified as a time dependent risk factor for cancer-associated VTE. In the first 3 months after study inclusion, characterized as the highest VTE risk period in our cancer cohort, no differences in VTE risk between blood types were found. Afterwards, beyond the first 3 months of follow-up, an increased VTE-risk in non-O blood types was observed, comparably in magnitude to the risk difference in the general non-cancer population. Further, an association of non-O blood type with VTE risk in patients with low/intermediate thrombotic risk cancers was observed, whereas no effect was present in those with very high-risk tumors. These findings indicate non-O blood type as a putative risk factor for VTE in patients with cancer in comparably low thrombotic risk scenarios. [Display omitted] DisclosuresPabinger: Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; NovoNordisk: Consultancy, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding.

Venous Thromboembolism Is Associated with Inferior Survival after Allogeneic Hematopoietic Cell Transplant

IntroductionVenous thromboembolism (VTE) is a common complication of both solid and hematologic malignancies. Risk factors for VTE and standard recommendations for prevention and treatment primarily pertain to solid tumor patients. There are fewer data in patients who have undergone allogeneic hematopoietic cell transplant (HCT). Therefore, we studied the incidence, risk factors, and impact of VTE on post-HCT outcomes.MethodsWe retrospectively reviewed 431 patients who underwent allogeneic HCT between 1/2014 and 8/2019 to identify patients with VTE. VTE was estimated with cumulative incidence methods. Risk factors for VTE were identified with Fine and Gray regression and results are reported as hazard ratio (HR) with a 95% confidence interval (CI). An apriori list of potential risk factors for VTE included age, gender, race, performance status, co-morbidity index, number of prior chemotherapy regimens, history of VTE, disease risk, donor/graft source, transplant conditioning regimen, and acute or chronic graft vs. host disease (GVHD). VTE was analyzed as a time-dependent covariate relative to other post-HCT outcomes.ResultsPatient characteristics are shown in the Table. The median age at time of transplant was 59 years, (range 18-76); 55.5% were male, the majority (90.7%) were White. The most common indication for transplant was acute myelogenous leukemia and myelodysplastic syndrome (70.3%). Within our cohort, 64 patients (14.8%) developed VTE after allogeneic HCT. The cumulative incidence of VTE at 1 year was 9% (CI 7-12%). Median time to VTE was 9.8 months (range 0.7-74.0) (Figure). Thrombosis site breakdown included the following: lower deep vein thrombosis (DVT) n=47 (74%), catheter related DVT n=12 (19%), DVT and pulmonary embolism (PE) n=12 (19%), PE alone n=4 (6%). Patients were most commonly treated with a direct oral anticoagulant (n=27, 42%), followed by enoxaparin (n=15, 23.4%). The majority of patients (n=38, 58%) were treated with anticoagulation for more than 6 months. Six (9.4%) patients had recurrent thrombosis after completion of anticoagulation therapy from the time of transplant until last known follow-up. Only 9 (14%) had an inferior vena cava filter placed due to contraindications for anticoagulation. In patients treated with anticoagulation, there was a low overall incidence of clinically significant bleeding (n=3, 5%). In multivariable analysis, age (HR 1.36 per 10-year increase, CI 1.09-1.70, P=0.006), history of VTE (HR 1.95, CI 1.09-3.48, P=0.024), and grade 2-4 acute GVHD (HR 1.75, CI 1.05-2.94, P=0.033) were significantly associated with VTE. VTE was not associated with relapse mortality (HR 0.95, CI 0.44-2.04, P=0.89), however VTE was significantly associated with an increased risk of non VTE-associated non-relapse mortality (NRM) (HR 4.09, CI 2.47-6.74, P<0.001) and decreased overall survival (OS) (HR 2.19, CI 1.48-3.24, P<0.001).DiscussionVTE is an important complication after allogeneic HCT and is associated with significantly increased NRM and inferior OS. Older patients, those with a prior history of VTE, and patients with acute GVHD are at increased risk for development of VTE after HCT. We found an overall low risk of bleeding with anticoagulation and further study to investigate the role of prophylaxis in this high-risk cohort is needed. [Display omitted] DisclosuresSobecks: CareDX: Membership on an entity's Board of Directors or advisory committees. Majhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Angelini: Sanofi: Membership on an entity's Board of Directors or advisory committees. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Extended Use of Romiplostim Treatment for Chemotherapy-Induced Thrombocytopenia

Background: Chemotherapy induced thrombocytopenia (CIT) is common, adversely impacts chemotherapy relative dose intensity, and may adversely impact cancer control. There is no approved therapy for CIT. In our recent phase II study of solid tumor patients with CIT (Soff et al, J. Clin. Onc., 2019), romiplostim lead to correction of platelet counts in 85% of participants within 3 weeks. While on romiplostim maintenance, only 6.8% of participants experienced chemotherapy dose reduction or delay as a result of recurrent CIT within a minimum of two cycles of chemotherapy or 8 weeks. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT.Objectives: This is an extension analysis of the phase II study for patients receiving romiplostim maintenance for 12 months or longer.Patients/Methods: In the phase II study, 44 patients successfully met the primary endpoint of correction of their platelet count within 3 weeks and resumed chemotherapy with romiplostim maintenance. 21 patients (48%) remained on romiplostim for 12 months or longer. Data were collected from one month prior to initiation of romiplostim to one month after the last dose of drug. Data extracted included complete blood count, chemotherapy doses and dates, romiplostim doses and dates, body weight, cancer diagnosis, age, gender, date of death and thrombotic events. Efficacy was demonstrated by persistent maintenance of platelet counts during long-term chemotherapy and avoidance of episodes of reduced chemotherapy dose intensity. Safety was assessed by two methods: tracking the rates of venous or arterial thrombosis; as well as development of marrow fibrosis and/or secondary hematologic malignancy. The mean romiplostim doses and lab values are calculated by month of study participation.Results: All participants had metastatic disease. Breast (N=6) and colorectal (N=6) were the most common cancers. No participant discontinued romiplostim therapy due to an adverse event or futility. One patient received romiplostim at our institution, but chemotherapy at an outside hospital; details of his chemotherapy were not available for this analysis. 14 of the 20 (70%) of the analyzable participants experienced no episode of CIT; 4 subjects experienced a single chemotherapy dose delay due CIT. No patient experienced multiple delays in chemotherapy due to CIT. Two patients required a chemotherapy dose reduction.The mean monthly platelet counts remained controlled throughout the period of analysis. (Figure 1A). The mean romiplostim doses were in the range of 3-5 mcg/kg through 35 months. There were insufficient participants beyond month 36 to allow meaningful interpretation of platelet counts or mean romiplostim doses. There was no evidence of adverse impact on absolute neutrophil count or hemoglobin levels (Figure 1B). No patient developed leukoerythroblastic changes indicative of marrow fibrosis, and no cases of secondary hematologic malignancy were identified. Two participants experienced thrombosis. One individual experienced a deep vein thrombosis. A second participant with an established history of congenital thrombophilia, experienced multiple tumor associated infarctions. The thrombotic events did not lead to discontinuation of participation in the trial for either participant. Of the 44 patients in the phase 2 study who resumed chemotherapy, 21 were alive at 12 months (48%) and 12 were alive at 24 months (27%).Conclusions: In this long-term analysis, romiplostim was effective and safe in the treatment of CIT with no evidence of drug resistance, marrow fibrosis, or secondary hematologic malignancy. The rates of thrombosis were no higher than expected for this patient demographic. There are some limitations to our analysis which includes our inability to accurately capture non-parenteral chemotherapy (oral or investigational agents) which were excluded from our analysis. We are unable to assess an impact on overall survival or cancer progression. However, the fact that half the participants were alive at 12 months and a quarter at 24 months is a reassuring signal. The analysis also is limited to the patients who were eligible for the initial phase 2 trial and corrected their platelet count within 3 weeks. Within these limitations, the extension study provides reassurance for long-term efficacy and safety of romiplostim treatment for CIT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Romiplostim is approved to increase platelet counts in ITP and pre-surgery. We are describing the results of a clinical trial.

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.

To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity. From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies. Ninety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study. These results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.

The Intensive care outcome of patients with a solid tumor in a tertiary care hospital in Saudi Arabia: Results of a prospective ICU Registry

Objective: There is a paucity of research on the factors predicting mortality and a length of stay in the Intensive Care Unit (ICU) with solid tumor patients. This study will assess the characteristics and predictors of outcomes of patients with solid tumors in medical ICU.&#x0D; Material and Methods: This research has been designed as a retrospective observational study using an ICU database. Patients who have a solid tumor were included in the study (May 2015 to July 2018). Post-surgical and those with a length of stay of more than one day are excluded from the study. We identified the predictors for ICU mortality and ICU long stay (≥21 days).&#x0D; Results: Out of 2883 patients, 364 patients with solid tumors were enrolled. The commonest sites for solid tumors were breast (15.9%), colorectal (11.5%), and lung (9.9%). 158 (43.4%) had metastatic disease, and 264 (72.5%) with progressive disease. The major reasons for ICU admission were a respiratory failure (52.7%) and severe sepsis (52.2%). The ICU and hospital mortality rates were 32.4% and 47%, respectively. Fifty patients (13.7%) had long stayed (≥ 21 days) in ICU. The independent predictors for mortality were Sequential Organ Failure Assessment (SOFA) score (OR, 1.2; 95% CI, 1.1–1.3; P=.000), invasive ventilation (OR, 3.5; 95% CI, 1.5–8.3; P=.004) and vasopressor (OR, 2.6; 95% CI, 1.1–5.9; P=.018), while the independent predictors of long-stay were ICU infections (odds ratio [OR], 18.9; 95% CI, 5.3 – 66.7; P=.0001), SOFA score (OR, 1.5; 95% CI, 1.2–1.8; P=.0001), invasive ventilation (OR, 8.2; 95% CI, 1.6–40.4; P=.009), bilirubin (OR, .5; 95% CI .2–.9; P=.049).&#x0D; Conclusion: Irrespective of the cancer stage, patients had a reasonable survival, and most do not require a long stay in the ICU. Flexibility in admission should be considered as disease progression and metastatic disease were not independent predictors of ICU mortality or long stay in this study.

Clonal hematopoiesis is associated with risk of severe Covid-19

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Study protocol for NCCH1908 (UPFRONT-trial): a prospective clinical trial to evaluate the feasibility and utility of comprehensive genomic profiling prior to the initial systemic treatment in advanced solid tumour patients.

This study, initiated in June 2020, has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (registration number: UMIN000040743). We plan to enrol a total of 200 patients over a period of 21months.