Akhtari, Mojtaba

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

e18506 Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin <1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL+ ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.