Shafer, Danielle

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

Abstract The detection of recurrent genetic abnormalities in acute myeloid leukemia (AML), including RUNX1T1/RUNX1 gene fusion, is critical for optimal medical management. Herein, we report a 45 year old woman with newly diagnosed AML and conventional chromosome studies that revealed an apparently balanced t(8;20)(q22;p13) in all 20 metaphases analyzed. A RUNX1T1/RUNX1 dual-color dual-fusion fluorescence in situ hybridization (FISH) probe set was subsequently performed and revealed a RUNX1T1/RUNX1 gene fusion. Metaphase FISH studies performed on abnormal metaphases revealed a cryptic, complex translocation resulting in RUNX1T1/RUNX1 fusion, t(8;20;21)(q22;p13;q22). This case study shows the importance of performing FISH studies or other high-resolution genetic testing concurrently with conventional chromosome studies for the detection of cryptic recurrent gene fusions in AML, particularly a focused genetic evaluation such as RUNX1T1/RUNX1 gene fusion, when specific abnormalities involving 8q22 are identified.

BACKGROUND: Malignant lymphomatous involvement of the eye and its surrounding structures is a rare phenomenon. Due to the unique location, non-specific symptomatology, limitations for invasive procedures, physician experience, and significant effect on the quality of life related to vision, it poses many challenges in the diagnosis and management. Ocular involvement can be primary or secondary in lymphoma. Primary ocular lymphoma, based on its clinical and pathological characteristics, has been divided into 2 main groups: those involving the orbit and adnexal tissues including lacrimal gland, conjunctiva and cornea and, those affecting intra-ocular structures mainly vitreous and retina. We aim to evaluate the SEER database to assess patterns and outcomes in patients with primary ocular involvement with lymphoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients (≥18 years) diagnosed with primary ocular lymphomas between 1975 and 2016. B-cell and T-cell lymphomas with stage I disease and primary site labeled as ocular (orbital, retina, conjunctiva, cornea, choroid, ciliary, lacrimal gland) were included. Treatment effect (surgery, radiation, systemic therapy) was analyzed when available.Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the Log-Rank test. Cox proportional hazards models were used for adjusted survival analyses. RESULTS: We identified 3610 patients with primary lymphoma of the eye and adnexa. The median age was 66 years (18-103). 70% of the patients were Caucasians, followed by Hispanic (10%). Slight female preponderance was noted (55%). Most common site of involvement was orbit (n = 2063; 57%) followed by conjunctiva (n = 986; 27.3%). 8% (n = 292) of the patients were noted to have bilateral involvement. MALT (n = 2208; 61.2%) was the most common histology followed by DLBCL (n = 576; 16%) and follicular lymphoma (n = 519; 14.4%). Other histologies were rare (see Table 1). Most common treatment modality was radiation (n = 2117; 58.6%). Systemic therapy was utilized in only about 25% of the patients. Radiation treatment was associated with improved survival HR = 0.44 (0.23-0.83 95%CI, p = 0.01). Interestingly, patients that received systemic therapy had worse survival in univariate analysis (p<0.05) but was not significant in multivariate analysis. Site-specific survival suggested conjunctiva had the best median OS (19 years [16.3 - 21.7 95% CI]), followed by orbital and lacrimal gland involvement (median OS 12 years [10.92-13.23 95% CI]) - Figure 1. Retina (median OS 1.9 years) and choroid/ ciliary body (median OS 6.3 years) involvement were associated with shorter survival (p<0.05). DISCUSSION: Ocular lymphoma is a rare occurrence. Overall MALT was the most common subtype followed by DLBCL and FL. Very few instances of Burkitt's lymphoma, T-cell, and CLL were identified. Site-specific data in our subset, albeit with low numbers, suggest worse survival in the ciliary body and choroid similar to what is seen within vitreoretinal involvement. Due to small numbers in our subset, this requires confirmation in a larger dataset to identify potential change in management similar to primary vitreoretinal lymphoma, which is now recognized and managed as primary CNS lymphoma. Patients receiving systemic therapy showed a trend towards worse survival, which may be explained by a selection bias for more aggressive disease. Our study highlights the small but relevant prevalence of primary ocular lymphomas and reports the interesting observation of different survival patterns based on the site of involvement. Disclosures Yazbeck: Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: Primary extranodal lymphomas of the salivary glands constitute 12% of head and neck lymphomas, and less than 5% of salivary gland neoplasms. Parotid gland is the most commonly involved structure. Mucosa-associated lymphoid tissue (MALT) lymphoma is considered the most common histology in parotid lymphomas and carry a favorable prognosis. In this study, we sought to explore the impact of histologic subtype on survival. Methods: The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients (≥18 years) diagnosed with primary parotid lymphomas between 1975 and 2016. B-cell, T-cell, and Hodgkin's lymphomas were included. Treatment effect (surgery, radiation, chemotherapy) was analyzed when available. Only stage I lymphomas by Ann-Arbor staging system were included to ensure parotid gland as the primary site. Overall survival was estimated using the Kaplan-Meier method, and compared using Log-Rank test. Cox proportional hazards models were used for adjusted survival analyses. Results: A total of 1482 patients were included in the analysis. Median age was 66 years (18-102), and the majority were female (n=904, 61%) and Caucasian (n=1074, 72.5%). MALT was the most common histology (N=681, 46%), followed by follicular lymphoma (FL; N=407, 27.5%), and diffuse large B-cell lymphoma (DLBCL; N=310, 21%). Small lymphocytic lymphoma was the least common histology (CLL/SLL; N=3, 0.8%). A total of 1084 patients (73%) had surgery, 433 (29%) had systemic therapies and 691 (47%) had radiation. Median overall survival was 13 years [12-14.5; 95% CI]. Survival was different by histological type (Figure 1, P<0.001). Compared with MALT, DLBCL was associated with higher mortality (HR 2.05 [1.60-2.63], P <0.001), while FL was not significantly different (HR 1.11 [0.89-1.40], P=0.32); independent of other variables. In a multivariate model; surgery (HR 0.81 [0.66-0.99], P=0.042) and radiation (HR 0.67 [0.56-0.82], P <0.001), but not systemic therapies (HR 0.93 [0.76-1.15], P=0.55) were associated with lower mortality (Figures 2-4). Adjusted mortality decreased by a relative 3% annually (HR 0.97 [0.95-0.99], P=0.03). Conclusion: Primary parotid lymphomas are rare extranodal lymphomas affecting mostly elderly Caucasian women. Using a large population database, MALT was still the most common histology and carried a favorable prognosis with a median overall survival of greater than 10 years despite the high median age at diagnosis. DLBCL histology did significantly worse which highlights the need for potentially more aggressive interventions to improve outcomes. Surgery and radiation were associated with improved outcomes. Disclosures Yazbeck: Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Acute leukemias of ambiguous lineage (ALAL), including acute undifferentiated leukemia and mixed phenotype acute leukemia (MPAL), are rare hematologic malignancies, accounting for only 2-5% of cases of acute leukemia. Outcomes are generally poor, and retrospective studies have suggested that patients have better outcomes when treated with regimens used for acute lymphoblastic leukemia (ALL) rather than acute myeloid leukemia (AML). Due to heterogeneous definitions and rarity of these leukemias, no single ALL regimen has been studied extensively. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) is one of the most widely used adult ALL regimens in the United States. We retrospectively examined the effectiveness of this regimen as initial therapy in patients with ALAL. Methods: We retrospectively reviewed records from adult patients treated initially with hyperCVAD-based chemotherapy for ALAL as defined by the World Health Organization at five academic institutions. Only patients whose diagnosis was verified at a participating institution were examined. Philadelphia (Ph) chromosome-positive ALAL patients treated concurrently with tyrosine kinase inhibitors were included. The primary objective of the study was to determine the overall response rate (ORR) and median overall survival (OS). Descriptive statistics were used for baseline characteristics and responses, and Kaplan-Meier estimates were used to calculate all time-to-event outcomes. Results: Twenty-two patients were identified, and pre-treatment characteristics are shown in the Table. Median age was 50 years (range, 22-69), with an even distribution of male and female patients (50% each). The majority (77%) were Caucasian. Two patients (9%) had acute undifferentiated leukemia, 11 (50%) T/myeloid MPAL, 8 (36%) B/myeloid MPAL, and 1 (5%) B/T MPAL. Seven (32%) had a complex karyotype (at least 3 abnormalities), 6 (27%) had a normal karyotype, 3 (14%) were Ph-positive and were treated concurrently with dasatinib, and 1 (5%) had an 11q23 rearrangement. FLT3-ITD was detected in 5 of 8 patients (63%) with an available mutation panel. Three (15%) had central nervous system (CNS) involvement at presentation, and one additional patient developed CNS disease during the course of therapy. There were no deaths within the first 30 days, and the median number of cycles given was 4 (range, 1-8). The CR rate was 73% (n=16) and an additional 14% (n=3) had CR with incomplete count recovery (CRi), for an ORR rate of 86%. One patient had a partial response, and 2 patients had no response. Of the 19 patients achieving CR or CRi, median number of cycles to CR was 1.5, and 12 (63%) proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT). Of the 7 responders who did not receive alloHSCT, 3 relapsed shortly after initial CR and 4 are alive and in remission 77, 39, 37 and 10 months from treatment initiation. All 3 patients with Ph-positive disease achieved CR. Only 1 proceeded with alloHSCT and all 3 patients are alive and in remission at 51, 39, and 10 months. With a median follow up of 37 months, 14 (64%) patients were alive and in remission, including 11 who had undergone alloHSCT. Four of the 6 patients who died had a complex karyotype. Median overall survival for the entire cohort was not reached (Figure). Conclusions: HyperCVAD results in high remission rates in patients with ALAL, with low incidence of early mortality and high ability to proceed to allogeneic transplantation following response. HyperCVAD can be considered an effective front-line therapy for patients with ALAL. Additionally, hyperCVAD may be a backbone for incorporation of novel immunotherapies and targeted therapies, which may improve results in patients with appropriate targets. Disclosures Sweet: Astellas: Consultancy; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria; Phizer: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; BMS: Honoraria. Wang:Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy. Al-Kali:Novartis: Research Funding.