B-CELL MALIGNANCIES TREATED WITH TARGETED DRUGS AND SARS-COV-2 INFECTION. A EUROPEAN HEMATOLOGY ASSOCIATION SURVEY (EPICOVIDEHA)

Background: Patients with lymphoproliferatie diseases (LPD) appear particularly ulnerable to SARS-CoV-2 infection, partly because of the effects of the anti-neoplastic regimens (chemotherapy, signaling pathway inhibitors, and monoclonal antibodies) on the immune system. The real impact of COVID-19 on the life expectancy of patients with different subtypes of lymphoma and targeted treatment is still unknown. Aims: The aim of this study is to describe and analyse the outcome of COVID-19 patients with underlying LPD treated with targeted drugs such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, niolumab or pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib), PI3K inhibitors (idelalisib), BCL2 inhibitors (enetoclax) and IMIDs, (lenalidomide). Methods: The surey was supported by EPICOVIDEHA registry. Adult patients with baseline CLL or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between January 2020 and January 2022 were selected. Results: The study included 368 patients (CLL n=205, 55.7%;NHL n=163, 44.3%) treated with targeted drugs (Table 1). Median follow-up was 70.5 days (range 19-159). Most used targeted drugs were ITKs (51.1%), anti-CD20 other than rituximab (16%), BCL2 inhibitors (7.3%) and lenalidomide (7.9%). Of note, only 16.0% of the patients were accinated with 2 or more doses of accine at the onset of COVID-19. Pulmonary symptoms were present at diagnosis in 244 patients (66.2%). Seere COVID-19 was obsered in 47.8 % patients while 21.7% were admitted to to intensie care unit (ICU), being 55 (26.8%) CLL patients and 25 (15.3%) NHL patients. More comorbidities were reported in patients with seere-critical COVID-19 compared to those with mild- asymptomatic infection (p=0.002). This difference was releant in patients with chronic heart diseases (p=0.005). Oerall, 134 patients (36.4%) died. Primary cause of death was COVID-19 in 92 patients (68.7%), LPD in 14 patients (10.4%), and a combination of both in 28 patients (20.9%).Mortality was 24.2% (89/368) at day 30 and 34.5%(127/368) at day 200. After a Cox multiariable regression age >75 years (p<0.001, HR 1.030), actie malignancy (p=0.011, HR 1.574) and admission to ICU (p<0.00, HR 4.624) were obsered as risk factors. Surial in patients admitted to ICU was 33.7% (LLC 38.1%, NHL 24%). Mortality rate decreased depending on accination status, being 34.2% in not accinated patients, 15.9-18% with one or two doses, decreasing to 9.7% in patients with booster dose (p<0.001). There was no difference in OS in NLH s CLL patients (p=0.344), nor in ITKs s no ITKs treated patients (p=0.987). Additionally, mortality rate dropped from the first semester 2020 (41.3%) to last semester 2021 (25%). Summary/Conclusion: - Our results confirm that patients with B--mallignancies treatted with targeted drugs hae a high risk off seere infection (47.8%) and mortality (36.4%) from COVID-19. - Pressence of comorbidities,, especially heart disease,, is a risk factor for seere COVIID--19 infection in ourr series. - Age >75 years,, actie mallignancy att COVIID--19 onset and ICU admission were mortality risk factors. - COVIID--19 acination was a protectie factor for mortality,, een iin this popullation wiitth humorall immunity impairment. - The learning cure in the management of the infection throughout the pandemiic and the deelopmentt off COVIID--19 treatments showed benefit in this partticullarlly ullnerablle popullation? (Table Presented).

An Unusual Case of Autoantibody-Negative KetosisProne Diabetes (KPD) Secondary to Marked Insulin Resistance

KPD is classically regarded as an atypical form of diabetes caused by near-complete beta-cell failure. A 37-year-old Egyptian man (BMI: 27.7 Kg/m2) presented with hyperglycemia (362 mg/dL) and DKA (arterial pH 7.20, ketonemia 5.0 mmol/L, ketonuria 80 mg/dL) . He was afebrile, with recent polyuria, polydipsia and weight loss. HbA1c was 107 mmol/mol (11.9%) and blood tests excluded diabetes secondary to endocrinopathies. SARS-CoV-2 RT-PCR test was negative. IV insulin infusion (0.1 IU/kg/h) and IV fluid therapy were started. He was shortly transitioned to a sc basal-bolus insulin regimen (0.7 IU/kg/day) . Mixed-meal tolerance test (MMTT) revealed a peak 120-min stimulated C-peptide of 12.3 ng/mL, suggesting marked insulin resistance. Islet autoantibodies (ICA, IAA, GADA, IA-2A, ZnT8A) and insulin receptor autoantibodies (IgG/IgM) were negative. HLA genotyping detected the following haplotypes: DRB1∗01, ∗04;DQA1∗01:01P, ∗03:01P;DQB1∗03:02P, ∗05:01P. Insulin dose was gradually reduced and insulin therapy was discontinued after 4 months in favor of metformin (2550 mg/day) plus sc semaglutide (up to 1 mg/week) . After one year, MMTT revealed a peak 60-min stimulated C-peptide of 8.25 ng/mL. During the 18-month follow-up period, fasting capillary beta-hydroxybutyrate values were <0.2 mmol/L and HbA1c remained <48 mmol/mol (<6.5%) , indicating disease remission. This case suggests the existence of an autoantibody-negative KPD subtype driven by marked insulin resistance rather than by insulinopenia.

Impaired antibody response after mRNA COVID-19 vaccination in patients with chronic lymphocytic leukemia

Introduction: Patients with hematological malignancies have a higher susceptibility to develop severe COVID-19 and their humoral response to vaccination is usually impaired due to the immunosuppression caused by treatments or the disease itself. A recent prospective study that analyzed the humoral response to the BNT162b messenger RNA (mRNA) COVID-19 vaccine in patients with CLL showed an antibody response rate of 39.5%, significantly lower than that of sex- and agematched healthy controls. Patients with active disease or under treatment, especially with targeted agents were the ones with the worst humoral response (Herinashu et al., 2021). More data are needed to validate these results and enhance protective strategies in those patients. In this study, we aimed to assess the humoral response following vaccination with the mRNA SARS-CoV-2 vaccine in a cohort of CLL patients from routine clinical practice and compared it with patients with other hematological neoplasms. Methods: Twenty-two CLL patients underwent blood sampling 2-4 weeks after the second dose of BNT162b2 (Pfizer- BioNTech) or mRNA-1273 (Moderna) vaccine. A control group was composed of 65 patients with other hematological cancers that also received mRNA vaccines. IgG antibodies against SARS-CoV-2 Spike antigen were measured using electrochemiluminescent assay (ADVIA Centaur XPT, Siemens), and responses reported as index inferior or superior to 1 (range 0.50-150.00), being index <1.00 informed as no reactive and index >1.00 as reactive. Statistical analyses were performed using SPSS, version 22.0 (IBM SPSS Statistics, IBM Corporation). Results: CLL patient's characteristics are shown in Table 1. Antibody-response to the vaccine was only obtained in 54.5% of the patients with CLL (12/22) and was significantly lower than that observed in the control group, in which 77.8% of the patients with other malignancies seroconverted (p=0.03), Figure 1. The other malignancies group was composed of multiple myeloma (N=21);indolent non-Hodgkin lymphoma (NHL) (N=12), Hodgkin lymphoma (N=5);acute myeloblastic leukemia (N=1);myeloproliferative neoplasms (N=12);myelodysplastic syndromes (N=7) and aggressive NHL (N=7). Antibody titers in patients with CLL showed a trend to be lower than the control group [median 3.16 (0-150) vs. 52.95 (0-150), p=0.133]. Focusing on CLL patients, antibody response rate was higher when disease was not active (75 vs. 43%, p=0.1) and in treatment-naïve patients (66.7 vs. 52.6%, p=0.6). Moreover, we observed similar responses in patients who obtained clinical remission after treatment (56.6 vs. 50%, p=0.8%). In patients under treatment with targeted drugs (Bruton's tyrosine kinase inhibitors (BTKi) or venetoclax based regimens) at the time of vaccination, antibody response rates were significantly lower (33 vs. 80%, p=0.03). Specifically, 40% of patients under BTKi showed a serologic response, and only 25% of patients under venetoclax-based regimens. Of note, at the moment of the study, the disease was controlled in all patients under continuous treatment. Conclusions: Antibody-mediated response to mRNA COVID-19 vaccines in CLL patients is significantly impaired in comparison to other onco-hematological diseases. Our series confirms better response rates when the disease is controlled and in treatment-naïve patients, showing slightly better responses than published to date (54.5 vs. 39.5%), which reinforces the need to vaccine CLL patients as some of them will benefit. Special concern must be taken to patients treated with targeted drugs, who show very low humoral responses. Therefore, in this vulnerable population, preventive measures, such as masks wearing, social distancing, and co-habitants vaccination should be reinforced.

Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalized men with COVID-19.

OBJECTIVE: Evidence supports a sex disparity in clinical outcomes of COVID-19 patients, with men exhibiting higher mortality rates compared to women. We aimed to test the correlation between serum levels of sex hormones [total testosterone, estradiol (E2), estradiol to testosterone (E2/T) ratio, progesterone), prolactin and 25-hydroxyvitamin D [25(OH)D] and markers of inflammation, coagulation and sepsis at admission in hospitalized men with COVID-19. PATIENTS AND METHODS: We conducted an exploratory retrospective study including symptomatic men with confirmed SARS-CoV-2 infection who were consecutively admitted to our Institution between April 1 and May 31, 2020. RESULTS: Patients were divided into survivors (n=20) and non-survivors (n=39). As compared to survivors, non-survivors showed significantly higher median neutrophil-to-lymphocyte ratio (NLR) values, D-dimer and procalcitonin (PCT) levels, along with significantly lower median 25(OH)D levels and total testosterone levels. Non-survivors exhibited significantly higher median values of E2/T ratio (a marker of aromatase activity). Spearman's correlation analysis revealed that total testosterone levels were significantly and inversely correlated with NLR, high-sensitivity C-reactive protein (hsCRP), interleukin-6, D-dimer and PCT. Conversely, E2/T ratio values were significantly and positively correlated with the aforementioned markers and with white blood cell (WBC) count. In a multivariate analysis performed by a logistic regression model after adjusting for major confounders (age, body mass index, hypertension and cardiovascular disease, diabetes mellitus and malignancy), total testosterone levels were significantly and inversely associated with risk of COVID-19-related in-hospital mortality. CONCLUSIONS: Low total testosterone levels and elevated E2/T ratio values at admission are associated with hyperinflammatory state in hospitalized men with COVID-19. Low total testosterone levels at admission represent an independent risk factor for in-hospital mortality in such patients. Therefore, total testosterone and E2/T ratio may serve as prognostic markers of disease severity in this population.

Infection Risk in Lymphoproliferative Diseases (LPD) Treated with Targeted Drugs. Geltamo Real-Life Experience

Introduction:Recently there has been a renewal of therapeutic tools for the treatment of lymphoid neoplasms to increase the antitumor efficacy and reduce the toxicity generated by conventional chemotherapies, which adds to the intrinsic immunological dysfunction of the disease itself. To date, few data are published about infection risk of these new drugs, and the need for infectious prophylaxis is unknown. The aim of the study is to analyze the infectious complications in patients with LPD treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab and pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib) and PI3K inhibitors (idelalisib). Methods: Multicenter retrospective study in patients with LPD treated with targeted therapies (single agents or combination) in 18 Hematology centers in Spain, from the time of their commercial availability to March 2020. Patients in clinical trials were excluded as well as patients with active infections at the beginning of treatment. Results:During the study period, 380 patients were included.Baseline characteristics of the entire cohort are shown in Table 1.Median follow-up was 17.3 months (range 0-103), the longest follow-up corresponding to CLL patients (24 months, range 0-98) and the shortest to LBCL (5 months, range 0-25). Median exposure to target drugs was 8 months (range 0-72).Ibrutinib was administered to 219 patients(1 FL, 147 CLL, 27 MCL, 10 DLBCL, 1 TL and 32 WM, 1 HL),Brentuximab to 49(31 HL, 14 TL and 4 DLBCL) andIdelalisibto 35 patients (16 affected by chronic lymphocytic leukemia - CLL, 15 FL and 1 DLBCL, 1 WM, 1MCL, 1HL).Obinutuzumabcombinations were used in 10 (6 CLL, 3 FL, 1 MCL) and 5 HL patients (of which 4/5 underwent previous BMT) receivedNivolumab. A total number of 237 infectious events occurred in 148/380 patients (38.9%), 39% of which were grade 3 and 54/148 (36.4%) experienced 2 or more infective episodes: of those 54, 21 (38%) had underwent 3 or more lines of therapy and 28 (51%) had hypogammaglobulinemia. Hospitalization was required in 59.2% events. A bacterial cause of infection was reported in 40% of cases, and viral in 16%, including 11/237 (4,6%) SARS-CoV-2 infection. Invasive fungal infection (IFI) occurred in 3.3% (8/237). Noteworthy, no case of PJP was identified. Lung was the most frequent site of infection in 24% of cases (57/237) while the upper respiratory tract was involved in 17% of events (41/237). Urinary tract infections were diagnosed in 10% (24/237). Other sites involved were skin and soft tissue 7%, gastrointestinal tract 5,4%, bloodstream infections 3% and catheter related infections 2,5%. Considering drugs individually, 86 patients that receivedIbrutinib(39.2 %)experienced a total of 137 infectious episodes: 30% bacterial, 19% viral, 5% fungal and 45% clinical and image-based infections;the 17(34.6%of those who received Brentuximab, experienced a total of 16 infectious episodes: 56% bacterial, 37.5% viral infections and one catheter-related sepsis. Of those who receivedIdelalisib,18 (51.4%)experienced a total of 28 episodes: 42% bacterial, 14% viral and 7% fungal. Four patients treated withObinutuzumabcombinations (40%) experienced one infection during treatment (25% bacterial and 75% viral). Only one patient treated withNivolumabexperienced more than three infections, he was also under corticosteroid treatment. Focusing on IFI (Table 2): 7/8 infections were identified in CLL patients, 6 out 7 being on ibrutinib treatment and 1/7 on Idelalisib.Aspergilluswas the fungus most frequently isolated. The targeted drug was discontinued temporarily in 4 patients and indefinitely in 3. Twenty three (6%) patients died due to infection in our series. Conclusions: 1. We identified 38.7% infections in our LPD patients treated with targeted drugs, with a median drug-exposure time of 8 months (range 0-72), with a non-negligible incidence of bacterial infections. 2. The highest rates of infection were found in patients treated with with Idelalisib and Ibrutinib (51.4% and 39.2% respectively). 3. IFI (3.3%) occurr d with low frequency, mostly in CLL patients during ibrutinib treatment, leading to its temporal discontinuation in most of the cases. 4. No case of PJP was identified in our cohort. 5. An analysis to determine risk factors for infection and the optimal monitoring and prophylaxis for these patients is ongoing. [Formula presented] Disclosures: Hernandez-Rivas:Janssen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Membership on an entity's Board of Directors or advisory committees;Gilead:Membership on an entity's Board of Directors or advisory committees;Celgene/BMS:Membership on an entity's Board of Directors or advisory committees;Rovi:Membership on an entity's Board of Directors or advisory committees.Lopez-Guillermo:novartis:Consultancy;celgene:Consultancy, Research Funding;roche:Consultancy, Research Funding;gilead:Consultancy, Research Funding.

Outcomes of patients with lymphoma and COVID-19: An observational cohort study from geltamo spanish group

Introduction: COVID-19 is thought to be more frequent and severe in patients with cancer. Lymphoma patients may be especially vulnerable, due to the immunodeficiency and immune dysregulation caused by the lymphoma itself and the antitumor treatments. This study describes the characteristics and outcomes of lymphoma patients after developing COVID-19. Methods: This is a retrospective multicentre study carried out in the hospitals of the GELTAMO group, which included patients with a histological diagnosis of lymphoma and confirmed SARS-COV-2 infection before June 30th, 2020. The primary outcome was overall survival (OS) 60 days after a COVID-19 diagnosis. Results: A total of 218 patients (median sage 69.5 [21-94] years, 54% male) were included;100 patients had an indolent B-cell non-Hodgkin's lymphoma (NHL), 67 aggressive B-cell NHL, 19 mantlecell lymphoma, 15 peripheral T-cell lymphoma, and 17 Hodgkin's lymphoma. Patients had received a median of 1 line (0-7) of therapy, and 44.9% were on active treatment at the time of COVID-19 diagnosis. Only 6.4%, 1.8% and 0.9% of patients had received previously autologous stem-cell transplantation, allogeneic SCT and CAR-T cell therapy, respectively. 89% of patients were hospitalized, 71% required oxygen, and 15% mechanical ventilation. With a median follow-up of 91.5 days (13-203), 65 patients have died (60 from COVID-19, 4 from lymphoma, 1 due to other causes), with an estimated 60-day OS of 68.6% (95% CI 62.1-75.1) (figure 1A). In univariate analysis, baseline characteristics associated with decreased OS were age ≥70 years, hypertension, diabetes, other cancer, active disease and hypogammaglobulinemia, but only age ≥70 years maintained independent influence in the multivariate analysis (HR 3.29, 95% CI 1.86-5.83, p < 0.001). Active treatment did not significantly impact OS (figure 1B). Univariate analysis revealed different prognostic factors, apart from age, for patients with DLBCL (N = 60) and FL (N = 69). While the presence of active disease had a prognostic impact on DLBCL (60-day OS 56% vs 79%, p = 0.038) but not on FL (60-day OS 65% vs 78%, p = 0.181) patients, the opposite occurred in the case of active treatment, which seemed to have a negative influence only in patients with FL, as shown in figures 1C and 1D. Conclusions: Our results confirm a high mortality in patients with lymphoma and COVID-19, especially in those ≥70 years old. In patients with DLBCL, disease control seems essential to reduce the risk of mortality in the event of contracting the infection. By contrast, in patients with FL, delaying the start of treatment until it is not strictly necessary should be considered, and these patients should be prioritized to be vaccinated before starting antitumor treatment. This study provides initial data to develop recommendations for the management of lymphoma patients during the COVID-19 pandemic.

How covid-19 pandemic impacted integrated care pathways for lung cancer: the experience of two Italian centers in veneto region

Background: COVID-19 pandemic has represented a historic challenge to healthcare systems. The management of cancer care has become a crucial issue for clinical services to cancer patients. During the COVID-19 pandemic, raising evidence has been published on lung cancer care but no data have been presented on the integrated care pathways (ICP) impact. Materials and methods: We retrospectively reviewed the ICPs of consecutive lung cancer patients who accessed two Centres before and after COVID-19 pandemic: the Veneto Institute of Oncology (IOV)/University Hospital of Padua and University Hospital of Verona. Sixteen indicators about oncology, radiaton therapy, thoracic surgery, pathology and pneumology were developed using groupfacilitation techniques taking into account their reproducibility, significance, measurability. We report data extracted from electronic medical records and linked softwares, about MDT performance at the two participating Centres, and preliminary data about pathological and oncological indicators in Padua. Additional data about both complete ICPs will be presented at the Conference. Results: We compared data about ICP performance in two window periods: 1/3/2019-30/4/2019 and 1/3/2020- 30/4/2020. MDT meetings were reshaped in order to discuss those cases where more than two specialists were required and whenever possible on a web-basis;therefore, it determined an average reduction of patients discussed of 57.5%. Preliminary data from Padua showed that median time between diagnostic procedure and diagnosis was reduced from 11 days in 2019 to 7.5 days in 2020, mostly due to a prioritization of oncological procedures over any other. Moreover, a 39% reduction of first oncological visits was observed between the two time frames;this was linked to a reduction of out of region second opinion and to optimization of outpatient access. Among patients under oncological treatment, 12(4%) and 8(2%) patients received treatment within 30 days from death in 2019 and 2020, respectively. Conclusions: Based on the experience the two Centres went through, we identified the key steps in ICP impacted by a pandemic such COVID-19 so to proactively put in place robust service provision in thoracic oncology.