ABSTRACT
Background: Autoimmune haemolytic anaemia (AIHA) during pregnancy is a rare finding, and few is known about maternal and foetal outcomes. AIHA may either develop or relapse during gestation and postpartum or be an issue in a patient on active therapy who becomes pregnant. AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns. Aims: We studied AIHA impact on pregnancy focusing on disease severity, treatment need and maternal/foetal outcome. Methods: Through a multicentric retrospective cohort study, we identified 38 pregnancies occurred in 28 women from 1997 to 2021 in 10 European centres in Italy, Denmark, France, the Netherlands, USA, and Spain. All included patients had a previous AIHA history or developed/exacerbated AIHA during gestation or postpartum. AIHA was classified according to the direct antiglobulin test. Results: We registered 18 warm AIHA (10 IgG;8 IgG+C3d), 2 cold agglutinin disease, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 4. Mean age at AIHA diagnosis was 27 (3-39) and at pregnancy 32 (21-41) years. AIHA diagnosis predated pregnancy in 15 women and had required at least 1 therapy line in all of them, and >2 lines in 12 (rituximab, N=7;cytotoxic immunosuppressants, N=6;splenectomy, N=5). Among these 15 patients, 6 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=8;cyclosporine, N=1;azathioprine, N=1;the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenic purpura during pregnancy. Further 8 patients had an AIHA onset during gestation and 2 postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In the 20 women experiencing AIHA during pregnancy/postpartum, median Hb and LDH levels were 6,4 g/dL (3,1 - 8,7) and 588 UI/L (269-1631), respectively. Management consisted in blood transfusions (N=10) and prompt establishment of steroid therapy+/-IVIG (N=20), all with response (complete N=13, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 obstetric complications (10/38, 26%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Apart from the case of biliary colic and one of the two cases of preeclampsia, 8/10 complications occurred during active haemolysis and treatment for AIHA. Nine foetal adverse events (9/38, 24%) were reported: a transitory respiratory distress of the new-born in a mother with active AIHA, 3 cases of foetal growth restriction, a preterm birth, an infant reporting neurologic sequelae, a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange, and 2 perinatal deaths. The latter both occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. (Figure Presented ) Summary/Conclusion: AIHA developing/reactivating during pregnancy or postpartum is rare (about 5%) but mainly severe requiring steroid therapy and transfusions. Importantly, severe maternal and foetal complications may occur in up to 26% of cases mostly associated with active disease, pinpointing the importance of maintaining a high level of awareness. Passive maternal autoantibodies transfer to the foetus seems a rare event.
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We sought to determine parameters of the acute phase response, a feature of innate immunity activated by infectious noxae and cancer, deranged by Covid-19 and establish oncological indices' prognostic potential for patients with concomitant cancer and Covid-19. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive referrals of patients with cancer and Covid-19 aged 18 from the U.K., Spain, Italy, Belgium, and Germany. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values and the pre-established risk categorizations from literature utilized for the mGPS and PI. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of 1 comorbidity (52.1% TS, 49.8% VS), development of 1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P<0.0001) with a return to pre-Covid-19 diagnosis NLR, PNI, and mGPS categorizations following recovery (P<0.01). In the TS, higher mortality rates were associated with NLR>6 (44.6% vs 28%, P<0.0001), PNI<40 (46.6% vs 20.9%, P<0.0001), mGPS (50.6% for mGPS2 vs 30.4% and 11.4% for mGPS1 and 0, P<0.0001), and PI (50% for PI2 vs 40% for PI1 and 9.1% for PI0, P<0.0001). Findings were confirmed in the VS (P<0.001 for all comparisons). Patients in poor risk categories had shorter median overall survival [OS], (NLR>6 30 days 95%CI 1-63, PNI<40 23 days 95%CI 10-35, mGPS2 20 days 95%CI 8-32, PI2 23 days 95%CI 1-56) compared to patients in good risk categories, for whom median OS was not reached (P<0.001 for all comparisons). The PLR was not associated with survival. Analyses of survival in the VS confirmed the NLR (P<0.0001), PNI (P<0.0001), PI (P<0.01), and mGPS (P<0.001) as predictors of survival. In a multivariable Cox regression model including all inflammatory indices and pre-established prognostic factors for severe Covid-19 including sex, age, comorbid burden, malignancy status, and receipt of anti-cancer therapy at Covid-19 diagnosis, the PNI was the only factor to emerge with a significant hazard ratio [HR] in both TS and VS analysis (TS HR 1.97, 95%CI 1.19-3.26, P=0.008;VS HR 2.48, 95%CI 1.47- 4.20, P=0.001). We conclude that systemic inflammation drives mortality from Covid-19 through hypoalbuminemia and lymphocytopenia as measured by the PNI and propose the PNI as the OnCovid Inflammatory Score (OIS) in this context.
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Introduction. MPN-COVID is a European LeukemiaNet cohort study, launched in March 2020 in patients with myeloproliferative neoplasms (MPN) with COVID-19. The first cohort of 175 cases was analyzed at the end of first wave (July 2020) and results provided estimates and risk factors of overall mortality (Barbui T. Leukemia, 2021), thrombosis incidence (Barbui T. Blood Cancer J, 2021), and post-COVID outcomes (Barbui T. Blood Cancer J, 2021). In the second wave of pandemic (June 2020 to June 2021), case-fatality risk in the general population has been found variable across different countries, and no information is available in MPN patients with COVID-19 diagnosed during the second wave in comparison with those of the first wave. Methods. In an electronic case report form, we registered a total of 479 cases of ET (n=161, 34%), PV (n=135, 28%), pre-PMF (n=49, 10%) and overt MF (n=134, 28%), from 39 European hematology units (Italy, Spain, Germany, France, UK, Poland, Croatia). Of these, 304 were diagnosed COVID-19 during the second wave. Results. Patients in the second wave were significantly different from those in the first wave, including parameters such as age (median: 63 vs. 71 years, p<.001), sex (females: 52% vs. 42%, p=0.037), MPN category (MF 24% vs. 34%, p=0.020), comorbidity (at least one comorbidity 63% vs. 74%, p=0.012), disposition (home: 68% vs. 23%, regular ward: 29% vs. 66%, ICU: 3% vs. 11%, p<.001), need of respiratory support (28% vs. 59%, p<.001) and degree of systemic inflammation (C-Reactive Protein: 51% vs. 74%, p=0.008;Neutrophil to Lymphocyte Ratio: 4.1 vs. 5.4, p=0.038). In regard to COVID-19-directed therapy, in the second wave steroids were more frequently prescribed (28% vs. 40%, p=0.007), while the use of antibiotics, antivirals, hydroxychloroquine and experimental therapies was significantly less frequent (p<.001 for all the differences). Interestingly, only 4 out of 46 patients (8.7%) discontinued Ruxolitinib during second-wave acute COVID (all MF admitted to regular ward). In the two waves, distribution probability of COVID-19 incidence by Kernel method showed a substantially similar shape, whereas the two incidence peaks were associated with very different mortality, as reported in Fig. 1A. The difference between the probability of death was highly significant during the first (n=175) vs. second (n=304): 31% vs. 9% at 60 days from COVID-19 diagnosis, respectively (p<.001) (Fig. 1B). Of note, among 26 deaths, 4 (15%) occurred at home, 19 (73%) on regular wards and 3 (12%) in the ICU, and death more frequently afflicted patients with (n=17, 65%) than ET (n=5, 19%) and PV (n=4. 15%) (p<.001). Independent risk factors for death in a multivariate Cox regression model fitted on the whole cohort and adjusted for the wave to which patients belonged, were age over 70 years (HR=5.2, 95% CI 1.8-15.1, p=0.002), male sex (HR=1.9, 95% CI 1.1-3.1, p=0.016), COVID-19 severity revealed by the need for respiratory support (HR=4.5, 95% CI 1.9-10.7, p=0.001), and Ruxolitinib discontinuation (HR=3.0, 95% CI 1.3-6.9, p=0.011). Conversely, in patients who continued this drug, no risk was documented (HR=1.21, p=0.566). Taking into account death as competing event, the second outcome of interest was the incidence of thrombosis, wich occurred in a significantly lower proportion of patients in the second wave compared to the first one (n=5 [1.6%] vs. n=14 [8.0%] at +60 days, respectively, SHR=0.20, p=0.002) (Fig. 1C). All the events, but one (n=4/5) were venous and were reported in patients with ET (SHR=4.4, 95% CI 1.8-10.7, p=0.001). Conclusions. This is the largest series of MPN patients who incurred COVID-19 from June 2020 onward, namely during the 'second COVID-19 wave'. Compared to the first wave, the second one recorded a lower overall COVID-19 severity, but Ruxolitinib discontinuation still remained a risk factor for a dismal outcome. Greater vulnerability of ET than PV in developing venous thrombosis was confirmed also during the second wave. This finding suggests that ET warrants a specific antithrombo ic prophylaxis in addition to heparin.
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Background: Little is known about natural anti-SARS-CoV-2 antibody seroprevalence post COVID-19 and safety of vaccines in COVID-19 survivors with cancer. Methods: Among 2795 consecutive patients (pts) with COVID-19 and cancer registered to OnCovid between 01/2020 and 02/2021, we examined natural seroprevalence of anti-SARS-CoV-2 Antibodies (SC2Ab, IgM or IgG) in pts tested post-infection. We analysed prevalence and safety of SARS-Cov-2 vaccine administration in pts who underwent clinical re-assessment at participating institutions. Results: Out of 350 pts tested for SC2Ab, 318 (90.9%) had a positive SC2Ab titre post-convalescence. Neither baseline features (sex, age, comorbidities, smoking history, tumour stage/status, anticancer-therapy and primary tumour) nor COVID-19-specific features (complications, hospitalization, sequelae) were significantly associated SC2Ab status. Receipt of COVID-19 specific therapy was higher among SC2Ab+ pts (62.6% vs 40.6%, p=0.0156). Out of 593 pts with known vaccination status, 178 (30%) had received 1 dose, whilst 38 pts (6.4%) received 2 doses of mRNA based (70.2%) or viral vector vaccine (17.4%). Vaccinated pts were more likely aged ≥65 years (59% vs 48.3%, p=0.0172), with loco-regional tumour stage (56% vs 40.8%, p=0.0014), on anti-cancer therapy at COVID-19 (49.1% vs 38.2%, p=0.0168) and history of prior hospitalisation due to COVID-19 (61.8% vs 48.3%, p=0.0029). Vaccine-related adverse events were reported for 18/56 evaluable pts (32.1%) and included injection site reactions (50%), fever (44.4%), arthralgias (33.3%), fatigue (33.3%) and allergy (5.5%). No long-term vaccine-related morbidity was reported. Conclusions: We report high seroprevalence (>90%) of SC2Ab in convalescent cancer pts who survived COVID-19 irrespective of baseline demographics, oncological characteristics and COVID-19 severity. COVID-19 vaccines appear to be safe in cancer pts with history of prior infection. Clinical trial identification: NCT04393974. Legal entity responsible for the study: Imperial College London. Funding: Has not received any funding. Disclosure: D.J. Pinato: Financial Interests, Personal, Invited Speaker: ViiV Healthcare;Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Personal, Advisory Board: Eisai;Financial Interests, Personal, Advisory Board: Amgen;Financial Interests, Personal, Advisory Board: BMS;Financial Interests, Personal, Advisory Board: Pfizer;Financial Interests, Personal, Advisory Board: Nanostring tech. A. Cortellini: Financial Interests, Personal, Advisory Board: MSD;Financial Interests, Personal, Advisory Board: BMS;Financial Interests, Personal, Advisory Board: Roche;Financial Interests, Personal, Invited Speaker: Novartis;Financial Interests, Personal, Advisory Board: SunPharma;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Invited Speaker: Astellas. All other authors have declared no conflicts of interest.
ABSTRACT
To our knowledge, there is no information on long-term follow-up of recovered patients with chronic myeloproliferative neoplasms (MPN) with COVID-19. It can be hypothesized that cytokine storm of the acute phase and the post-COVID persistence of a residual inflammatory state may contribute to elicit hematopoietic stem cell insults and continuous vascular endothelial damage, leading to MPN disease progression and persistent high risk of thrombosis. Aims: To describe sequelae of COVID-19 in surviving patients with MPN following COVID-19. Methods: MPN-COVID study involved 38 European blood centers, and accrued 180 patients with MPN diagnosed with COVID-19 from Feb to Jun 2020, assessing mortality and incidence of thrombosis and bleeding during the acute phase of the pandemic [Barbui T et al. Leukemia. 2021;35(2):485-493. Barbui T et al. Blood Cancer J. 2021;11(2):21]. One-hundred-twenty-five (69%) of these patients survived and were followed up for at least 6 months. Centers were asked to update symptoms, treatments, hematological changes, major outcomes (i.e., thrombosis, disease evolution and death). Results: Among the 125 surviving patients, all eligible for the follow-up update, with a median age 70 years (IQR: 58-79), the following phenotypes were registered: PV (n=38, 30%), ET (n=37, 30%), early PMF (n=14, 11%) and MF (n=36, 29%). During the acute phase of infection, 38 (30%) were managed at home, 80 (64%) in a regular ward and 7 (6%) in ICU. Symptoms (i)The 3 prevalent symptoms during the acute phase of the disease were fever (79%), cough (56%) and dyspnea (53%), while gastrointestinal, neurological, musculoskeletal symptoms, as well as fatigue and anosmia/ dysgeusia, were present in a minor proportion, ranging from 1.6% to 17%. (ii) In the post-acute COVID-19 phase, 36 of 125 patients (32%) declared the persistence of some of these symptoms, fatigue being the most frequent (19%), while none presented persistence of fever and only 10% of dyspnea. Major outcomes (i) Major thrombosis was documented in 5 patients and involved 3 patients with MF (one fatal intestinal ischemia, two non-fatal events: splenic infarction and peripheral artery thrombosis), one case in PV (acute myocardial infarction) and one with ET (DVT of the legs with pulmonary embolism). Age varied from 61 to 80 years. The first event occurred five months after COVID-19 recovery and the Kaplan Meier thrombosis-free survival probability after 9 months was 82%. (ii) Acute myelogenous leukemia (AML) was ascertained in 3 patients (1 in MF, 1 in early-PMF, 1 in ET);one was fatal and occurred in a 49-yearold patient, the other 2 in 78- and 82-year-old patients, respectively. One non-Hodgkin′s lymphoma (in ET) and one progression of a previous parotid carcinoma (in MF) were seen in two patients aged 60 and 77 years, respectively. (iii) Deaths were reported in 8 patients (6.4%), due to AML (n=1), thrombosis (n=1), progression to prior carcinoma (n=2, 1 suspected), multi organ failure (n=1) and heart failure (n=2);the cause was unknown in a single patient. Five deaths (63%) occurred in MF patients. (iv) Overall, the event-free survival pooling together thrombosis, disease evolution and death reached 66% after 9 months from COVID- 19 recovery, indicating that, during this time of observation, 1 out of 3 patients died or have experienced at least one of the other two severe events. Summary/Conclusion: These results indicate that MPN patients who have survived SARS-CoV-2 infection continue to experience severe events suggesting an increased vigilance in the post-COVID period.
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Background: The severity of SARS-CoV-2 infection (COVID-19) is predicted by advancing age and co-morbidities. The relative contribution of cancer in influencing the course of COVID-19 is poorly understood. We designed the OnCOVID study to investigate natural history of COVID-19 disease in cancer patients. Methods: This retrospective, multi-center observational study conducted across 8 tertiary centers in Europe recruited cancer patients aged >/= 18 and diagnosed with COVID-19 between February 26th and April 1st, 2020. Descriptive statistics, univariable and multivariable Cox regression models were used to assess patient’s main characteristics and to evaluate the factors associated to COVID-19 related mortality. Results: We identified 204 patients from United Kingdom (n=97, 48%), Italy (n=56, 27%) and Spain (n=51, 25%). Most patients were male (n=127, 62%) had a diagnosis of solid malignancy (n=184, 91%) and 103 (51%) had non-metastatic disease. Mean (±SD) patient age was 69±13 years, and 161 (79%) had >/= 1 co-morbidity, most commonly hypertension (n=88, 43%) and diabetes (n=46, 23%). Commonest presenting symptoms were fever (n=136, 67%) and cough (n=119, 58%), beginning 3.8 (±4.5 SD) days before diagnosis. Most patients (n=141, 69%) had >/= 1 complication from COVID-19, including respiratory failure (n=128, 63%) and acute respiratory distress syndrome (n=49, 24%). In total, 36 patients (19%) patients were escalated to high-dependency or intensive care. At time of analysis, 59 patients had died (29%), 53 were discharged from hospital (26%) and 92 (45%) were in-hospital survivors. Mortality was higher in patients aged >/= 65 (36% versus 16%), in those with >/= 2 co-morbidities (40% versus 18%) and developing >/= 1 complication from COVID-19 (38% versus 4%, p=0.004). Multi-variable analyses confirmed age >/= 65 and >/= 2 co-morbidities to predict for patient mortality independent of tumor stage, active malignancy or anti-cancer therapy. Conclusions: In the early outbreak of SARS-CoV-2 infection in Europe co-morbid burden and advancing age predicted for adverse disease course in cancer patients. Risk stratification based on these factors should inform personalized oncological decision making during the COVID-19 pandemic. Legal entity responsible for the study: Imperial College London. Funding: Has not received any funding. Disclosure: D.J. Pinato: Speaker Bureau/Expert testimony, received lecture fees : ViiV Healthcare;Speaker Bureau/Expert testimony, received lecture fees : Bayer Healthcare;Travel/Accommodation/Expenses: BMS;Advisory/Consultancy: Mina Therapeutics;EISAI;Roche;Astra Zeneca;Research grant/Funding (institution): MSD;BMS. A. Patriarca: Advisory/Consultancy: Takeda;Sanofi. G. Gaidano: Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen;Abbvie;Advisory/Consultancy: AstraZeneca;Sunesys. J. Brunet: Advisory/Consultancy: MSD;AstraZeneca. J. Tabernero: Advisory/Consultancy: Array Biopharma;Astra Zeneca;Bayer;Beigene;Boehringer Ingelheim;Chugai;Genentech;GenMab;Halozyme;Inflection Biosciences Limited;Ipsen;Kura;Lilly;MSD;Menarini;Merck Serono;Merrimack;Merus;Molecular Partners;Novartis;Peptomics;Pfizer;Pharmacyclics;Rafael Pharmaceuticals;ProteoDesign SL;F. Hoffmann-La Roche Ltd;Sanofi;Servier;Seagen;Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. A. Prat:Honoraria (self), Advisory/Consultancy: Pfeizer;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis;Roche;Honoraria (self): MSD Oncology;Lilly;Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo;Advisory/Consultancy: BMS;Amgen;NanoString Technologies. A. Gennari: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche;Eli Lilly;EISAI;Advisory/Consultancy: Pierre Fabre;MSD;Novartis;Advisory/Consultancy, Speaker Bureau/Expert testimony: Daiichi Sankyo;Speaker Bureau/Expert testimony: Teva;Gentili;Pfizer;AstraZeneca;Celgene. All other authors have declared no onflicts of interest.