Cycle threshold predicted mortality in a cohort of patients with hematologic malignancies infected with SARS-CoV-2.

When a SARS-CoV-2 RT-qPCR test is performed, it may determine an indirect measure of viral load called cycle threshold (Ct). Respiratory samples with Ct <25.0 cycles are considered to contain a high viral load. We aimed to determine whether SARS-CoV-2 Ct at diagnosis could predict mortality in patients with hematologic malignancies (lymphomas, leukemias, multiple myeloma) who contracted COVID-19. We included 35 adults with COVID-19 confirmed by RT-qPCR performed at diagnosis. We evaluated mortality due to COVID-19 rather than mortality due to the hematologic neoplasm or all-cause mortality. Twenty-seven (27) patients survived and 8 died. The global mean Ct was 22.8 cycles with a median of 21.7. Among the survivors, the mean Ct was 24.2, and the median Ct value was 22.9 cycles. In the deceased patients, the mean Ct was 18.0 and the median Ct value was 17.0 cycles. Using the Wilcoxon Rank Sum test, we found a significant difference (p=0.035). SARS-CoV-2 Ct measured in nasal swabs obtained at diagnosis from patients with hematologic malignancies may be used to predict mortality.

JAK inhibitors and COVID-19.

During SARS-CoV-2 infection, the innate immune response can be inhibited or delayed, and the subsequent persistent viral replication can induce emergency signals that may culminate in a cytokine storm contributing to the severe evolution of COVID-19. Cytokines are key regulators of the immune response and virus clearance, and, as such, are linked to the-possibly altered-response to the SARS-CoV-2. They act via a family of more than 40 transmembrane receptors that are coupled to one or several of the 4 Janus kinases (JAKs) coded by the human genome, namely JAK1, JAK2, JAK3, and TYK2. Once activated, JAKs act on pathways for either survival, proliferation, differentiation, immune regulation or, in the case of type I interferons, antiviral and antiproliferative effects. Studies of graft-versus-host and systemic rheumatic diseases indicated that JAK inhibitors (JAKi) exert immunosuppressive effects that are non-redundant with those of corticotherapy. Therefore, they hold the potential to cut-off pathological reactions in COVID-19. Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. Yet, only baricitinib is recommended in first line for severe COVID-19 treatment by the WHO, as it is the only JAKi that has proven efficient to reduce mortality in individual randomized clinical trials (RCT), especially the Adaptive COVID-19 Treatment Trial (ACTT-2) and COV-BARRIER phase 3 trials. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules.

Clinical Characteristics and Risk Factors of COVID-19 in 60 Adult Cancer Patients.

BACKGROUND: During the pandemic of COVID-19, cancer patients have been considered as one high-risk group in the morbidity and mortality of COVID-19. This study aimed to describe the clinical symptoms and risk factors of COVID-19 in cancer patients. METHOD: In a prospective cross-sectional study, during a year, all cancer patients who underwent chemotherapy and/or targeted therapy in our clinic (Kermanshah, Iran) were followed up in terms of getting COVID-19. We analyzed the effect of tumor features and demographic information on clinical manifestations, survival status, therapeutic outcomes, and severity of the disease COVID-19 in 2 categories of cancer (hematologic and solid cancers). RESULTS: Most of the patients (68%) were in the solid tumor category, including breast cancer (24.4%), colon cancer (22%), and gastric cancer (9.8%). There was a statistically significant difference between 2 categories of cancer in the clinical manifestations: the stage of cancer and survival status (P < .05). Logistic regression analysis showed that the risk of death in cancer patients with COVID-19 along with symptoms of diarrhea (odds ratio [OR] = 12.8, P = .004), the difficulty of breath (OR = 10.73, P = .034), drop of SO2 (OR = 1.334, P = .003), thrombocytopenia (OR = 1.022, P = .02), anemia (OR = 2.72, P = .011), requiring mechanical ventilation (OR = 9.24, P = .004), pleural infusion (OR = 10.28, P = .02), and intensive care unit (ICU) admission (OR = 7.389, P = .009) increases independent of other variables. The COVID-19 mortality rate in our cancer patients was 23%. CONCLUSIONS: Thrombocytopenia, anemia, and diarrhea are symptoms that, along with common symptoms such as lung involvement, difficulty breathing, and the need for a ventilator, increase the risk of death in cancer patients with COVID-19.

Differential Impact of a Multicomponent Goals-of-Care Program in Patients with Hematologic and Solid Malignancies.

We recently reported that an interdisciplinary multicomponent goals-of-care (myGOC) program was associated with an improvement in goals-of-care (GOC) documentation and hospital outcomes; however, it is unclear if the benefit was uniform between patients with hematologic malignancies and solid tumors. In this retrospective cohort study, we compared the change in hospital outcomes and GOC documentation before and after myGOC program implementation between patients with hematologic malignancies and solid tumors. We examined the change in outcomes in consecutive medical inpatients before (May 2019-December 2019) and after (May 2020-December 2020) implementation of the myGOC program. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included GOC documentation. In total, 5036 (43.4%) patients with hematologic malignancies and 6563 (56.6%) with solid tumors were included. Patients with hematologic malignancies had no significant change in ICU mortality between 2019 and 2020 (26.4% vs. 28.3%), while patients with solid tumors had a significant reduction (32.6% vs. 18.8%) with a significant between-group difference (OR 2.29, 95% CI 1.35, 3.88; p = 0.004). GOC documentation improved significantly in both groups, with greater changes observed in the hematologic group. Despite greater GOC documentation in the hematologic group, ICU mortality only improved in patients with solid tumors.

Descriptive analysis of Cycle Threshold in patients with hematologic malignancies infected with SARS-COV-2.

INTRODUCTION: SARS-CoV-2 has caused over 200 million documented infections, more than 4 million deaths, and unprecedented consequences worldwide. The cycle threshold (Ct), the number of amplification cycles required to obtain a product detectable through fluorescence during a quantitative RT-PCR test, is an indirect measurement of viral load. Patients with hematologic malignancies have an increased risk of death by the SARS-CoV-2. CASES PRESENTATION: We conducted a retrospective, observational, descriptive analysis of the Ct obtained from patients with history of hematologic malignancies who tested positive for SARS-CoV-2 in our hospital, from March 3rd, 2020, to August 17th, 2021. We used the mean Ct at diagnosis. 15 adults, with previous diagnosis of lymphomas, acute leukemias and chronic lymphocytic leukemia, were included. 9 of the 15 patients (60 %) developed pneumonia, 6 of them required supplementary oxygen and 5 mechanical ventilation. 5 patients died between 7-86 days from symptom onset. Ct was lower among the group of patients who died (15.5 cycles; SD= 2.28, CI95%= 9.17-21.86) compared with those who survived (20.2 cycles; SD= 8.87, CI95%= 13.9-26.6). Ct was also lower in the pneumonia group (18.2 cycles; SD= 2.28, CI95%= 12.98-23.51) than in the no-pneumonia group (19.3 cycles; SD= 4.11; CI95%= 8.73-29.9). DISCUSSION: Ct was lowest in severe forms of CoViD-19. Further studies with larger populations of patients with hematologic malignancies could establish the validity of Ct as a quantitative laboratory determination as a course-prediction and infectivity tool.

Introducción: SARS-CoV-2 ha causado más de 200 millones de infecciones documentadas, más de 4 millones de muertes, y consecuencias sin precedentes globalmente. El umbral de ciclado (Ct), número de ciclos de amplificación requerido para obtener un producto detectable durante una prueba cuantitativa de RT-PCR, es una medida indirecta de la carga viral. Los pacientes con enfermedades oncohematológicas tienen mayor riesgo de muerte por SARS-CoV-2. Presentación de casos: Realizamos un estudio observacional, retrospectivo y descriptivo de los valores de Ct obtenidos de pacientes con enfermedades oncohematológicas que resultaron positivos para SARS-CoV-2 en nuestro hospital, desde el 3 de marzo de 2020, hasta el 17 de agosto de 2021. Empleamos el Ct promedio al diagnóstico. Fueron incluidos 15 adultos, con diagnóstico de linfomas, leucemias agudas y leucemia linfocítica crónica. 9 pacientes (60 %) desarrollaron neumonía, 6 requirieron oxígeno suplementario y 5 ventilación mecánica. 5 murieron a los 7-86 días desde el inicio de síntomas. Ct fue menor entre los pacientes que murieron (15.5 ciclos; DS= 2.28, IC95%= 9.17-21.86), comparado con los que sobrevivieron (20.2 ciclos; DS= 8.87, IC95%= 13.9-26.6). La misma tendencia se observó en el grupo de los que desarrollaron neumonía (18.2 ciclos; DS= 2.28, IC95%= 12.98-23.51), comparado con lo que no tuvieron neumonía (19.3 ciclos; DS= 4.11; IC95%= 8.73-29.9). Discusión: El valor de Ct fue más bajo en las formas más graves de CoViD-19. Estudios adicionales con poblaciones mayores de pacientes con enfermedades oncohematológicas podrían establecer la validez de Ct como determinación cuantitativa de laboratorio útil como predictora de evolución e infectividad.

Screening for SARS-COV-2 Using RT-qPCR in Patients with Hematologic Neoplasms Receiving Chemotherapy.

It has been recommended that patients with leukaemias and lymphomas undergo universal screening for SARS-COV-2 using RT-qPCR before each treatment on the grounds of their high risk of experiencing severe forms of COVID-19. This raises a conflict with different recommendations which prioritise testing symptomatic patients. We found that among 56 RT-qPCR obtained in asymptomatic patients with hematologic neoplasms before chemotherapy administration, 2 (3.5%) were positive. A negative result did not exclude SARS-COV-2 infection in 1 patient (1.8%). It is unclear what the benefit of screening for SARS-COV-2 using RT-qPCR in patients with hematologic neoplasms who receive chemotherapy is.

SARS-CoV-2 infections in pediatric and young adult recipients of chimeric antigen receptor T-cell therapy: an international registry report.

BACKGROUND: Immunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%-40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited. METHODS: We created an international retrospective registry of CAR T recipients aged 0-30 years infected with SARS-CoV-2 within 2 months prior to or any time after CAR T infusion. SARS-CoV-2-associated illness was graded as asymptomatic, mild, moderate, or severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C). To assess for risk factors associated with significant SARS-CoV-2 infections (infections requiring hospital admission for respiratory distress or supplemental oxygen), univariate and multivariable regression analyses were performed. RESULTS: Nine centers contributed 78 infections in 75 patients. Of 70 SARS-CoV-2 infections occurring after CAR T infusion, 13 (18.6%) were classified as asymptomatic, 37 (52.9%) mild, 11 (15.7%) moderate, and 6 (8.6%) severe COVID-19. Three (4.3%) were classified as MIS-C. BCA was not significantly associated with infection severity. Prior to the emergence of the Omicron variant, of 47 infections, 19 (40.4%) resulted in hospital admission and 7 (14.9%) required intensive care, while after the emergence of the Omicron variant, of 23 infections, only 1 (4.3%) required admission and the remaining 22 (95.7%) had asymptomatic or mild COVID-19. Death occurred in 3 of 70 (4.3%); each death involved coinfection or life-threatening condition. In a multivariable model, factors associated with significant SARS-CoV-2 infection included having two or more comorbidities (OR 7.73, CI 1.05 to 74.8, p=0.048) and age ≥18 years (OR 9.51, CI 1.90 to 82.2, p=0.014). In the eight patients infected with SARS-CoV-2 before CAR T, half of these patients had their CAR T infusion delayed by 15-30 days. CONCLUSIONS: In a large international cohort of pediatric and young adult CAR-T recipients, SARS-CoV-2 infections resulted in frequent hospital and intensive care unit admissions and were associated with mortality in 4.3%. Patients with two or more comorbidities or aged ≥18 years were more likely to experience significant illness. Suspected Omicron infections were associated with milder disease.

Features of COVID-19 infection among patients with hematological malignancies

Background: COVID-19 infection can be especially severe in certain risk populations such as patients with hematologic malignancies. Aim(s): To describe the characteristics and clinical outcomes of a population of patients with hematologic malignancies and COVID-19. Material(s) and Method(s): Review of medical records of patients with COVID-19 and hematologic malignancies, treated in Hematology Service of a regional hospital in Chile, between April 1 and October 30, 2020. Demographic characteristics, chronic comorbidities and clinical characteristics related to the underlying disease and COVID-19 infection were recorded. Result(s): Thirty adults aged 17 to 73 years (67% men) with COVID-19 confirmed by RT-PCR, were evaluated. Forty percent had comorbidities, mainly hypertension (30%), obesity (27%) and diabetes (10%). Two thirds of cases came from a nosocomial outbreak and 77% were symptomatic. Half of the cases had mild disease and 20% required mechanical ventilation. Five patients (17%) died from COVID 19. Female sex, the presence of comorbidities and obesity were more common among deceased patients. Only 1 of 5 deceased patients were in complete remission. No differences were found in the mean survival according to requirement for intubation or the presence of complete remission. Conclusion(s): This population with hematologic malignancies and COVID-19 had special characteristics leading to a greater fatality rate which, in this series, does not increase with the use of mechanical ventilation. Copyright © 2022 Sociedad Medica de Santiago. All rights reserved.

T cell responses against SARS-CoV-2 and its Omicron variant in a patient with B cell lymphoma after multiple doses of a COVID-19 mRNA vaccine.

Anti-SARS-CoV-2 antibodies are crucial for protection from future COVID-19 infections, limiting disease severity, and control of viral transmission. While patients with the most common type of hematologic malignancy, B cell lymphoma, often develop insufficient antibody responses to messenger RNA (mRNA) vaccines, vaccine-induced T cells would have the potential to 'rescue' protective immunity in patients with B cell lymphoma. Here we report the case of a patient with B cell lymphoma with profound B cell depletion after initial chemoimmunotherapy who received a total of six doses of a COVID-19 mRNA vaccine. The patient developed vaccine-induced anti-SARS-CoV-2 antibodies only after the fifth and sixth doses of the vaccine once his B cells had started to recover. Remarkably, even in the context of severe treatment-induced suppression of the humoral immune system, the patient was able to mount virus-specific CD4+ and CD8+ responses that were much stronger than what would be expected in healthy subjects after two to three doses of a COVID-19 mRNA vaccine and which were even able to target the Omicron 'immune escape' variant of the SARS-CoV-2 virus. These findings not only have important implications for anti-COVID-19 vaccination strategies but also for future antitumor vaccines in patients with cancer with profound treatment-induced immunosuppression.

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study.

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.

Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study.

BACKGROUND: Patients with cancer have been shown to have a higher risk of clinical severity and mortality compared to non-cancer patients with COVID-19. Patients with hematologic malignancies typically are known to have higher levels of immunosuppression and may develop more severe respiratory viral infections than patients with solid tumors. Data on COVID-19 in patients with hematologic malignancies are limited. Here we characterize disease severity and mortality and evaluate potential prognostic factors for mortality. METHODS: In this population-based registry study, we collected de-identified data on clinical characteristics, treatment and outcomes in adult patients with hematologic malignancies and confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection within the Madrid region of Spain. Our case series included all patients admitted to 22 regional health service hospitals and 5 private healthcare centers between February 28 and May 25, 2020. The primary study outcome was all-cause mortality. We assessed the association between mortality and potential prognostic factors using Cox regression analyses adjusted for age, sex, comorbidities, hematologic malignancy and recent active cancer therapy. RESULTS: Of 833 patients reported, 697 were included in the analyses. Median age was 72 years (IQR 60-79), 413 (60%) patients were male and 479 (69%) and 218 (31%) had lymphoid and myeloid malignancies, respectively. Clinical severity of COVID-19 was severe/critical in 429 (62%) patients. At data cutoff, 230 (33%) patients had died. Age ≥ 60 years (hazard ratios 3.17-10.1 vs < 50 years), > 2 comorbidities (1.41 vs ≤ 2), acute myeloid leukemia (2.22 vs non-Hodgkin lymphoma) and active antineoplastic treatment with monoclonal antibodies (2·02) were associated with increased mortality; conventional chemotherapy showed borderline significance (1.50 vs no active therapy). Conversely, Ph-negative myeloproliferative neoplasms (0.33) and active treatment with hypomethylating agents (0.47) were associated with lower mortality. Overall, 574 (82%) patients received antiviral therapy. Mortality with severe/critical COVID-19 was higher with no therapy vs any antiviral combination therapy (2.20). CONCLUSIONS: In this series of patients with hematologic malignancies and COVID-19, mortality was associated with higher age, more comorbidities, type of hematological malignancy and type of antineoplastic therapy. Further studies and long-term follow-up are required to validate these criteria for risk stratification.

Managing haematology and oncology patients during the COVID-19 pandemic: interim consensus guidance.

INTRODUCTION: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. MAIN RECOMMENDATIONS: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. ENDORSED BY: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia.