Optimal thromboprophylaxis and anticoagulant strategies in patients with COVID-19 pneumonia. The PROTHROMCOVID Trial

Introduction: Hospitalized patients with COVID-19 are at increased risk of venous and arterial thrombosis, ARDS, and death. The optimal dosage of thromboprophylaxis in patients is unknown. Objective: To evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia.Design, Setting, and Participants: The PROTHROMCOVID multicenter randomized clinical trial enrolled noncritical hospitalized adult patients with COVID-19 pneumonia from February 1, 2021, to September 30, 2021, at 18 centers in Spain. Methods: Patients were randomized to prophylactic tinzaparin 4500IU or intermediate dose 100IU/kg or therapeutic tinzaparin 175IU/kg during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge. The patients were stratified at the time of randomization according to age, sex and the presence or absence of hypertension.The primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non invasive mechanical ventilation or not, including high-flow nasal cannula oxygen, or death within 30 days. The main safety outcome was major bleeding at 30 days. Data were collected and adjudicated locally by non-blinded investigators through imaging, laboratory, and health record data. Results: Of 311 patients randomized, 300 were included in the analysis (mean [SD]age, 56.7 [14.6] years;men, 182 [60.7%];women, 118 [39.3%]). 106 patients (35.33%) were assigned to the prophylaxis group, 91 patients (30.33%) were allocated to the intermediate dose group and 103 patients (34.33%) were randomized to the anticoagulant dose group. The composite endpoint thrombotic event, need for invasive (IMV) or noninvasive mechanical ventilation (NIV) or HFT via nasal cannula or death at 30 days from randomization occurred in 58 patients (19.3%) of the whole population, 19 patients (17.09%) in prophylactic group, 20 (21.98%) in intermediate group and 19 (18.45%) in therapeutic group (P=0.72). No major bleeding were reported in the trial and non-major bleeding occurred in 5 patients (4.71%) in prophilactic, in 3 patients (3.2%) in intermediate arm and in 3 patients (2.9%) in therapeutic, without significant differences in each group (P=0.31). Conclusions: In non-critically ill patients with COVID 19, intermediate or full-dose of tinzaparin do not appear to offer benefit over standard prophylactic doses IU in the likelihood of thrombotic event, non-invasive ventilation or high-flow oxygen, or death. Funding Acknowledgement: Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Leo Pharma

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.

Severity of Covid-19 Clinical Outcomes and Mortality in Multiple Myeloma Patients over Year 1 of the Pandemic

Introduction In the first weeks of the Covid-19 pandemic when healthcare systems in many areas were overstretched, we documented that hospital mortality in multiple myeloma (MM) patients infected by Sars-Cov-2 was 50% higher than in age matched Covid-19 patients without cancer. In the following months, the pressure on healthcare systems in Spain continued although it did not reach the extreme levels of the first weeks of the pandemic. In this study, we proposed to determine if the severity of Covid-19 outcomes in MM patients has changed over the first year of the pandemic. Patients and methods The Spanish MM Collaborative Group (Pethema-GEM) conducted a survey at national level on plasma cell disorder patients infected by SARS-Cov-2 between March 2020 and February 2021. Sixty-six (69%) out of 96 contacted healthcare centers, from all 17 regions in Spain, reported 502 patients. Data on Covid-19 acute and post-acute phase outcomes (hospitalization, oxygen requirements, severity of symptoms and mortality) were reported first in May 2020 (Martinez-Lopez et al, BCJ 2021) and updated in February 2021. In this study, we compared outcome occurrence between two study periods: P1, a period of extreme stress for the healthcare system in Spain, from March to mid-June 2020;and a second period, P2, up to mid-February 2021 with a sustained but lower burden on the national health care system. Results Among the 451 patients with plasma cell disorders and a Sars-Cov-2 infection documented with an rRT-PCR positive test, 377 (84%) were MM patients, 15 SMM (3%), 40 MGUS (9%) and 19 amyloidosis (4%). The number of MM weekly reported cases was 57% (95%CI, 48-65) lower in P2 (188 cases in 35 weeks) compared to P1 (189 cases in 15 weeks), p<0.001. The mean (SD) age and the proportion of men did not differ between P1 and P2, respectively 69.8 (10.9) vs 68.6 (11.0) years, p=0.6, and 53.3% vs 59.6%, p=0.2. MM patients with active or progressive disease at time of Covid-19 diagnosis were 24% in P1 and 34% in P2, p=0.05;patients on active treatment were more frequent in P1, 89%, than in P2, 79%, p=0.01. MM treatment was withheld in 78% and 82% of patients, p=0.4. Covid-19 treatment changed over time: MM inpatients received more remdesivir and corticoids in the second period (3% vs 31% p<0.001, and 49% vs 73%, p<0.001, respectively). In P1, 90% of the reported MM patients were hospitalized compared to 71% in P2, p<0.001. Thirty-one and 41% of patients did not require oxygen support during P1 and P2, respectively;non-invasive ventilation in 19% and 14%, and mechanical ventilation in 7% and 8%, p=0.12. Overall, acute clinical Covid-19 severity was reduced from P1 to P2: 75% to 51%, p<0.001: moderate/severe pneumonia was reduced from 68% to 36%, p<0.001 but severe distress syndrome increased from 7% to 15%, p=0.03. However, mortality in all reported patients was 30.7% in P1 vs 26.1% in P2, p=0.3;and no differences in mortality were observed in hospitalized patients, 32.2% in P1 and 35.3% in P2, p=0.6. We performed a multivariable adjustment with the predictors identified in our previous study (BCJ 2021) and confirmed that inpatient mortality was similar in both study periods, odds ratio (OR) 0.99 (95%CI 0.59-1.66). Independently of the study period, an increased mortality was observed in men (OR 1.81, 1.08-3.05), patients over 65 (OR 2.40, 1.33-4.36), and patients with active or progressive disease (OR 2.12, 1.24-3.62). The severity of Covid-19 clinical outcomes -besides mortality, was associated with increased age but not with active or progressive disease. Conclusions Although COVID-19 clinical severity has decreased over the first year of the pandemic in multiple myeloma patients, mortality remains high with no change between the initial weeks of the pandemic and the following months. Prevention and vaccination strategies should be strengthened in this vulnerable population, particularly in patients with active or progressive disease at time of Covid-19 diagnosis. Disclosures: Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfi er: Consultancy;Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees;Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Bluebird bio: Honoraria;GSK: Honoraria;Oncopeptides: Honoraria. López-Muñoz: Amgen: Consultancy. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Other: Support for attending meetings and/or travel;Mundipharma: Consultancy;Bluebird: Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Consultancy, Honoraria, Speakers Bureau;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Lahuerta: Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy;Celgene: Other: Travel accomodations and expenses. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.

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.