Use of monoclonal antibody therapy in hematologic patients with mild-to-moderate COVID-19: A retrospective single-center experience.

INTRODUCTION: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. METHODS: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. RESULTS: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01). CONCLUSIONS: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients.

Current outcomes of SARS-CoV-2 Omicron variant infection in high-risk haematological patients treated early with antivirals.

OBJECTIVES: We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals. METHODS: We conducted a prospective observational study on high-risk haematological patients admitted in our hospital between December 2021 and March 2022. We performed detection techniques on viral subgenomic mRNAs until negative results were obtained to document active, prolonged viral replication. RESULTS: This analysis included 60 consecutive adults with high-risk haematological malignancies and COVID-19. All of these patients underwent early treatment with remdesivir. Thirty-two (53%) patients received combined antiviral strategies, with sotrovimab or hyperimmune plasma being added to remdesivir. The median length of viral replication-as measured by real-time RT-PCR and/or subgenomic RNA detection-was 20 (IQR 14-28) days. Prolonged viral replication (6 weeks after diagnosis) was documented in six (10%) patients. Only two patients had prolonged infection for more than 2 months. Overall mortality was 5%, whereas COVID-19-related mortality was 0%. CONCLUSIONS: Current outcomes of high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predminance are good with the use of early antiviral strategies. Persistent viral shedding is uncommon.

Systematic review and meta-analysis of the clinical effectiveness of tixagevimab/cilgavimab for prophylaxis of COVID-19 in immunocompromised patients.

Immunocompromised patients, such as those with a haematological malignancy, are at higher risk of SARS-CoV-2 infection, severe outcomes and mortality. Tixagevimab/cilgavimab is a monoclonal antibody combination which binds to the SARS-CoV-2 spike protein. The PROVENT phase III clinical trial reported that tixagevimab/cilgavimab prophylaxis significantly reduced the risk of COVID-19 infection in immunocompromised participants. However, the trial was conducted before the Omicron variant became prevalent. This systematic review and meta-analysis provide an up-to-date summary of the real-world effectiveness of tixagevimab/cilgavimab in immunocompromised patients, including patients with haematological malignancies. Clinical studies from 1 January 2021 to 1 October 2022, which reported breakthrough COVID-19 infections after tixagevimab/cilgavimab, were included. COVID-19-related hospitalisations, intensive care admissions and mortality were also assessed. A meta-analysis was performed to ascertain overall clinical effectiveness. Eighteen studies, with 25 345 immunocompromised participants, including 5438 patients with haematological pathologies, were included in the review. The overall clinical effectiveness of tixagevimab/cilgavimab against COVID-19 breakthrough infection, hospitalisation, intensive care admission and COVID-19-specific mortality was 40.54%, 66.19%, 82.13% and 92.39%, respectively. This review highlights the clinical effectiveness of tixagevimab/cilgavimab at reducing COVID-19 infection and severe outcomes for immunosuppressed individuals, including patients with a haematological malignancy, during the Omicron-predominant era. Real-world studies are important to provide ongoing certainty of the clinical benefit for immunocompromised patients against new SARS-CoV-2 variants.

Passive pre-exposure immunization by tixagevimab/cilgavimab in patients with hematological malignancy and COVID-19: matched-paired analysis in the EPICOVIDEHA registry.

Only few studies have analyzed the efficacy of tixagevimab/cilgavimab to prevent severe Coronavirus disease 2019 (COVID-19) and related complications in hematologic malignancies (HM) patients. Here, we report cases of breakthrough COVID-19 after prophylactic tixagevimab/cilgavimab from the EPICOVIDEHA registry). We identified 47 patients that had received prophylaxis with tixagevimab/cilgavimab in the EPICOVIDEHA registry. Lymphoproliferative disorders (44/47, 93.6%) were the main underlying HM. SARS-CoV-2 strains were genotyped in 7 (14.9%) cases only, and all belonged to the omicron variant. Forty (85.1%) patients had received vaccinations prior to tixagevimab/cilgavimab, the majority of them with at least two doses. Eleven (23.4%) patients had a mild SARS-CoV-2 infection, 21 (44.7%) a moderate infection, while 8 (17.0%) had severe infection and 2 (4.3%) critical. Thirty-six (76.6%) patients were treated, either with monoclonal antibodies, antivirals, corticosteroids, or with combination schemes. Overall, 10 (21.3%) were admitted to a hospital. Among these, two (4.3%) were transferred to intensive care unit and one (2.1%) of them died. Our data seem to show that the use of tixagevimab/cilgavimab may lead to a COVID-19 severity reduction in HM patients; however, further studies should incorporate further HM patients to confirm the best drug administration strategies in immunocompromised patients.

Tocilizumab, an IL6-receptor antibody, proved effective as adjuvant therapy for cytokine storm induced by severe infection in patients with hematologic malignancy.

Patients with hematological malignancies who experience severe infections are at risk of developing dangerous complications due to excessive inflammatory cytokines. To improve the prognosis, it is crucial to identify better ways to manage the systemic inflammatory storm after infection. In this study, we evaluated four patients with hematological malignancies who developed severe bloodstream infections during the agranulocytosis phase. Despite receiving antibiotics, all four patients presented elevated serum IL-6 levels as well as persistent hypotension or organ injury. Adjuvant therapy with tocilizumab, an IL-6-receptor antibody, was administered, and three of the four patients showed significant improvement. Unfortunately, the fourth patient died due to multiple organ failure caused by antibiotic resistance. Our preliminary experience suggests that tocilizumab, as an adjuvant therapy, may help alleviate systemic inflammation and reduce risk of organ injury in patients with elevated IL-6 levels and severe infection. Further randomized controlled trials are needed to confirm the effectiveness of this IL-6 targeting approach.

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.

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies.

Bruton's tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

Patients with Hematological Malignancies Treated with T-Cell or B-Cell Immunotherapy Remain at High Risk of Severe Forms of COVID-19 in the Omicron Era.

BACKGROUND: Patients with hematological malignancies are at greater risk of severe COVID-19 and have been prioritized for COVID-19 vaccination. A significant proportion of them have an impaired vaccine response, both due to the underlying disease and to the treatments. METHODS: We conducted a prospective observational study to identify the specific risks of the outpatient population with hematological diseases. RESULT: Between 22 December 2021 to 12 February 2022, we followed 338 patients of which 16.9% (n = 57) developed SARS-CoV-2 infection despite previous vaccination (94.7%). COVID-19 patients were more likely to have received immunotherapy (85.5% vs. 41%, p < 10-4), and particularly anti-CD20 monoclonal antibodies (40% vs. 14.9%, p < 10-4) and Bruton's tyrosine kinase inhibitors (BTKi) (7.3% vs. 0.7%, p < 10-2). There was no significant difference in demographic characteristics or hematological malignancies between COVID-19-positive and non-positive patients. Patients hospitalized for COVID-19 had more frequently received immunotherapy than patients with asymptomatic or benign forms (100% vs. 77.3%, p < 0.05). Hospitalized COVID-19 patients had a higher proportion of negative or weakly positive serologies than non-hospitalized patients (92.3% vs. 61%, p < 0.05). Patients who received tixagevimab/cilgavimab prophylaxis (n = 102) were less likely to be COVID-19-positive (4.9 vs. 22%, p < 0.05) without significant difference in hospitalization rates. CONCLUSION: In the immunocompromised population of patients with hematological malignancies, the underlying treatment of blood cancer by immunotherapy appears to be a risk factor for SARS-CoV-2 infection and for developing a severe form.

Supportive care and symptom management in patients with advanced hematological malignancies: a literature review.

BACKGROUND AND OBJECTIVE: Recent advances have led to cure or long-term disease control for patients with hematological malignancy (HM). Unfortunately, some of them still have poor prognoses and are often associated with significant symptom burden and poor quality of life for patients and families. These patients usually require supportive care including red blood cell and platelet transfusion, due to disease itself and the oncological treatment, apart from their symptom management. However, there is currently lack of the literatures review in these aspects. The objective of this review is to summarize practical supportive care recommendations for physicians or nurses practicing in palliative care (PC)/hematology-oncology unit, starting with core approaches in use of blood products for anemia and thrombocytopenia, management of tumor lysis syndrome, PC and oncology nursing care. METHODS: Evidence for this review was obtained from a search of the Cochrane database, PubMed, guidelines of European Society of Medical Oncology, British society of Hematology, American Society of Clinical Oncology, National Comprehensive Cancer Network and peer-reviewed journal articles. KEY CONTENT AND FINDINGS: For asymptomatic cancer patients who are anaemic, a threshold of haemoglobin level of 7 g/dL is considered to be safe and generally favored for blood transfusion. 'Single-unit' red cell transfusion is safer and at least as effective as 'double-unit' transfusion. Prophylactic platelet transfusion should be given to stable patients without bleeding and with platelet count less than 10×109/L. In febrile patients, the threshold is lifted to 20×109/L. There are also recommendations for the use of blood products during COVID-19 pandemic. In general, HM patients were more prone to painful infections when compared with solid cancer patients. Thus, antibiotics to treat underlying infections should be applied whenever possible and as required to control pain. CONCLUSIONS: This narrative review showed the recent literatures in the supportive care and symptom management of advanced HM patients. However, it is limited by some of the 'evidence-based' recommendations for interventions (including symptom management) based on early phase of HM populations rather than those receiving end-of-life care.

COVID-19 in pediatric cancer patients is associated with treatment interruptions but not with short-term mortality: a Polish national study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently constitutes the leading and overwhelming health issue worldwide. In comparison with adults, children present milder symptoms, with most having an asymptomatic course. We hypothesized that COVID-19 infection has a negative impact on the continuation of chemotherapy and increases nonrelapse mortality. MATERIAL AND METHODS: This study was performed to assess the course of SARS-CoV-2 among children with hematological or oncological malignancies and its impact on cancer therapy. Records of SARS-CoV-2 infection in 155 children with malignancies from 14 Polish centers for pediatric hematology and oncology were collected and analyzed. RESULTS: SARS-CoV-2 replication was observed in 155 patients. Forty-nine patients were symptomatic, with the following being the most common manifestations: fever (31 patients), gastrointestinal symptoms (10), coryza (13), cough (13) and headache (8). In children who were retested, the median time of a positive PCR result was 16 days (range 1-70 days), but 12.7% of patients were positive beyond day + 20. The length of viral PCR positivity correlated with the absolute neutrophil count at diagnosis. Seventy-six patients did not undergo further SARS-CoV-2 testing and were considered convalescents after completion of isolation. Antibiotic therapy was administered in 15 children, remdesivir in 6, convalescent plasma in 4, oxygen therapy in 3 (1-mechanical ventilation), steroids in 2, intravenous immunoglobulins in 2, and heparin in 4. Eighty patients were treated with chemotherapy within 30 days after SARS-CoV-2 infection diagnosis or were diagnosed with SARS-CoV-2 infection during 30 days of chemotherapy administration. Respiratory symptoms associated with COVID-19 and associated with oxygen therapy were present in 4 patients in the study population, and four deaths were recorded (2 due to COVID-19 and 2 due to progressive malignancy). The probability of 100-day overall survival was 97.3% (95% CI 92.9-99%). Delay in the next chemotherapy cycle occurred in 91 of 156 cases, with a median of 14 days (range 2-105 days). CONCLUSIONS: For the majority of pediatric cancer patients, SARS-CoV-2 infection does not result in a severe, life-threatening course. Our data show that interruptions in therapy are common and can result in suboptimal therapy.

A Canadian Perspective: Monoclonal Antibodies for Pre- and Post-Exposure Protection from COVID-19 in Vulnerable Patients with Hematological Malignancies.

Patients with hematological malignancies have an increased risk of serious outcomes following COVID-19 infection, suggesting broader protection is needed beyond vaccination. Monoclonal antibodies such as sotrovimab, casirivimab-imdevimab, and bamlanivimab have provided valuable options for the treatment of COVID-19 disease. More recently, monoclonal antibodies have been examined for the prevention of COVID-19 infection. The monoclonal antibody combination, tixagevimab-cilgavimab, was recently approved by Health Canada as pre-exposure prophylaxis against COVID-19 in individuals who are immunocompromised or where vaccination is not recommended. Prophylactic approaches such as the use of tixagevimab-cilgavimab, in addition to COVID-19 vaccination, may provide additional protection for patients with hematological malignancies who are at greater risk of serious outcomes from COVID-19 infection.

[Impact of Coronavirus Disease 2019 on Prognosis and Treatment Strategies in Patients with Hematological Malignancy--Review].

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide since outbreak in December 2019, and become a global public health crisis. Patients with hematological malignancy concurrently infected with COVID-19 are often associated with severe even fatal complications, due to low basic immune function, high intensity of chemotherapy and radiotherapy, and slow immune reconstruction post hematopoietic stem cell transplantation, and their treatment strategies, such as anti-infective therapy, blood transfusion, and the use of granulocyte colony stimulating factor need to be adjusted. The characteristics of patients, chemotherapy, hematopoietic stem cell transplantation, and other clinical factors may affect the prognosis of patients with hematological malignancy concurrently infected with COVID-19. Herein, the latest research progress is reviewed.

Use of the ONCO-TreC electronic diary compared with a standard paper diary to improve adherence to oral cancer therapy in patients with solid and haematological tumours: protocol for a randomised controlled trial.

INTRODUCTION: ONCO-TreC platform consists of a mobile application delivered to patients as electronic diary and a web-based dashboard managed by healthcare professionals. We aim to compare the effectiveness of ONCO-TreC electronic diary with a standard paper diary, in improving adherence to oral cancer therapy in patients with solid and haematological tumours. METHODS AND ANALYSIS: This is an open label, superiority, randomised controlled trial conducted in two Italian oncology units. Patients will be randomised with a 1:1 ratio to electronic or paper diary. For both groups a counsellor will be responsible for drug and diary delivery. The evaluation period will end after six cycles of therapy. The primary aim is to compare the proportion of non-adherent patients in the two arms. Adherence will be measured through pill count; anyone who takes less than 90% of the total prescribed drug dose will be considered non-adherent. Assuming a percentage of non-adherent patients to oral therapy of 40% in arm B, and a 60% reduction in this percentage in arm A, a sample of 124 patients will provide 80% power to identify an absolute difference greater than 24 percentage points using a bilateral Fisher's exact test with a significance level of 0.05. Considering a dropout rate of 10%, approximately 136 patients will have to be enrolled. The primary analysis will be performed on the intention-to-treat population. Secondary aims are to describe the reasons for non-adherence, the level of satisfaction of patients and healthcare professionals with the paper and electronic diary, and the impact of non-adherence in terms of healthcare costs. ETHICS AND DISSEMINATION: Ethical approval was obtained from Romagna Ethics Committee (CEROM), study ID 2108, prot. n. IRST 100.28 of 10/04/2020. Informed consent will be obtained from all study participants. Findings will be disseminated through peer-reviewed journals, conferences and event presentations. PROTOCOL VERSION: Version 2, 6 April 2021. TRIAL REGISTRATION NUMBER: NCT04826458.

Antibiotic Management of Patients with Hematologic Malignancies: From Prophylaxis to Unusual Infections.

PURPOSE OF REVIEW: Patients with hematological malignancies are recognized for their high susceptibility and increased risk of developing infections associated with immunosuppression that can be caused by the infection itself or by the treatments that condition a decrease in the humoral and T lymphocyte response, so this review attempts to gather the main bacterial, viral, parasitic, and fungal agents that affect them and give recommendations for their approach and diagnosis. RECENT FINDINGS: In recent years, with the discovery and use of new therapies including immunological and targeted treatments, it has been possible to improve the survival and response of patients with hematological malignancies; however, antimicrobial resistance has also increased; we have faced new and unknown microorganisms, such as the SARS-CoV-2 that caused the COVID-19 pandemic in the past year, and therefore, new risks and more severe infections are presented. We present a review of the different circumstances where hematological malignancies increased the risk of infections and which microorganisms affect these patients, their characteristics, and the suggested prophylaxis.

COVID 19 and febrile neutropenia: Case report and systematic review.

OBJECTIVES: In pandemic conditions, patients with febrile neutropenia are also at risk of COVID-19. Aim of this systematic review is to evaluate COVID-19 cases presented with febrile neutropenia and provide information regarding incidence, clinical course and prognosis. METHODS: We systematically searched on COVID-19 and febrile neutropenia cases in PubMed, SCOPUS and Web of Science. RESULTS: A total of 19 febrile neutropenic patients were analyzed. A male predominance was noted. Eleven cases had hematological malignancies. Fourteen of the cases were previously received chemotherapy. Five patients had severe neutropenia: 3 had hematologic cancer and none died. 17 (89.5%) cases have pulmonary involvement and seven of them had severe disease with acute respiratory distress syndrome (ARDS). Three cases with ARDS were died. 12 of them received G-CSF for treatment. Five cases were developed respiratory failure after G-CSF use. Overall mortality was 15.8%, while death was not observed in patients without malignancy and solid organ tumors, the mortality rate was 27% in cases with hematological malignancies. CONCLUSION: In ongoing pandemic, febrile neutropenic patients should be precisely evaluated for COVID-19 disease. It should be remembered that there may not be typical signs and symptoms and laboratory findings of COVID-19 disease because of the immunosuppression.

Patterns of neutralizing humoral response to SARS-CoV-2 infection among hematologic malignancy patients reveal a robust immune response in anti-cancer therapy-naive patients.

Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients following infection is crucial to inform vaccination strategies for this highly vulnerable population. This cross-sectional study documents the anti-SARS-CoV-2 humoral response and serum neutralizing activity in 189 HM patients recovering from a PCR-confirmed infection. The overall seroconversion rate was 85.7%, with the lowest values in patients with lymphoid malignancies or undergoing chemotherapy. Therapy-naive patients in the "watch and wait" status were more likely to seroconvert and display increased anti-s IgG titers. Enhanced serum neutralizing activity was observed in the following SARS-CoV-2-infected HM patient groups: (i) males; (ii) severe COVID-19; and (iii) "watch and wait" or "complete/partial response". The geometric mean (GeoMean) ID50 neutralization titers in patients analyzed before or after 6 months post-infection were 299.1 and 306.3, respectively, indicating that >50% of the patients in either group had a neutralization titer sufficient to provide 50% protection from symptomatic COVID-19. Altogether, our findings suggest that therapy-naive HM patients mount a far more robust immune response to SARS-CoV-2 infection vs. patients receiving anti-cancer treatment, raising the important question as to whether HM patients should be vaccinated before therapy and/or receive vaccine formats capable of better recapitulating the natural infection.

Efficacy and safety of heterologous booster vaccination with Ad26.COV2.S after BNT162b2 mRNA COVID-19 vaccine in haemato-oncological patients with no antibody response.

Patients with haemato-oncological malignancies are one of the high-risk groups for a severe course in case of COVID-19 infections. Furthermore, vaccination results in significantly lower response rates in haematological malignancies and lower antibody levels in patients with solid cancer. We investigated efficacy and safety of a heterologous booster vaccination with Ad26.COV2.S DNA vector vaccine in haemato-oncological patients without antibody response after double-dose BNT162b2 messenger (m-)RNA COVID-19 vaccine. A total of 32 haemato-oncological non-responders to double-dose BNT162b2 received a heterologous booster vaccination with Ad26.COV2.S. Blood samples were assessed directly before the vaccination (T0) and four weeks after (T1). Safety assessment was performed using a standardised questionnaire. The overall response rate was 31%, with a mean (SD) antibody titre of 693·79 (1 096·99) binding activity units (BAU)/ml. Patients with chronic lymphocytic leukaemia or lymphoma showed a significantly lower response rate (P = 0·048). Adverse events were reported in 29·6% of patients, of which 7·1% were graded as severe, including grade III and IV events following the Common Terminology Criteria of Adverse Events (CTCAE). The heterologous booster vaccination with Ad26.COV2.S led to a serological response in nine out of 29 patients without response after double-dose BNT162b2. Furthermore, the vaccination was safe in our cohort, leading to mainly mild local and systemic reactions. Overall, this vaccination regimen should be further evaluated to increase the response rate in the highly vulnerable population of haemato-oncological patients.