Risk factors and outcome of COVID-19 in patients with hematological malignancies

Piñanaetal. Exp Hematol Oncol (2020) 9:21 https://doi.org/10.1186/s40164-020-00177-z RESEARCH Risk factors andoutcome ofCOVID-19 inpatients withhematological malignancies José Luis Piñana1,2,36* , Rodrigo Martino3, Irene García‑García4, Rocío Parody5, María Dolores Morales6, Gonzalo Benzo7, Irene Gómez‑Catalan8, Rosa Coll9, Ignacio De La Fuente10, Alejandro Luna4, Beatriz Merchán6, Anabelle Chinea4, Dunia de Miguel6, Ana Serrano8, Carmen Pérez10, Carola Diaz11, José Luis Lopez12, Adolfo Jesús Saez4, Rebeca Bailen13, Teresa Zudaire14, Diana Martínez15, Manuel Jurado16, María Calbacho17, Lourdes Vázquez18, Irene Garcia‑Cadenas3, Laura Fox19, Ana I. Pimentel20, Guiomar Bautista21, Agustin Nieto22, Pascual Fernandez23, Juan Carlos Vallejo24, Carlos Solano25, Marta Valero26, Ildefonso Espigado27, Raquel Saldaña28, Luisa Sisinni29, Josep Maria Ribera30, Maria Jose Jimenez30, Maria Trabazo31, Marta Gonzalez‑Vicent32, Noemí Fernández33, Carme Talarn34, Maria Carmen Montoya8, Angel Cedillo35 and Anna Sureda5 on behalf of Infectious Complications Subcommittee of the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH) Abstract Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID‑19 are poorly defined. Patients and methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory‑confirmed SARS‑CoV‑2 infection through PCR assays from March 1st 2020 to May 15th 2020. Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo‑SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1–93.8). Recipients of ASCT and allo‑SCT showed lower mortality rates (17% and 18%, respectively) compared to non‑SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% con‑ fidence interval (CI) 1.2–3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6–5.2, p < 0.0001); ECOG 3–4 (OR, 2.56, 95% CI 1.4–4.7, p = 0.003); neutropenia (< 0.5 × 109/L) (OR 2.8, 95% CI 1.3–6.1, p = 0.01); and a C‑reactive protein (CRP) > 20 mg/dL (OR 3.3, 95% CI 1.7–6.4, p < 0.0001). In multivariate analysis of 216 patients with very severe COVID‑19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2–0.89 and OR 0.31, 95% CI 0.11–0.87, respectively, p = 0.02) whereas the use of hidroxycloroquine did not show significant improvement in OM (OR 0.64, 95% CI 0.37–1.1, P = 0.1). © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Open Access Experimental Hematology & Oncology *Correspondence: [email protected] 36 Division of Clinical Hematology, Hospital Universitario la Fe de Valencia, Avda Fernando Abril Martorell, 106 CP 46026 Valencia, Spain Full list of author information is available at the end of the article Page 2 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 Background The coronavirus infectious disease 2019 (COVID- 19) pandemic caused by the new zoonotic coronavirus (SARS-CoV-2) is causing a massive impact globally. Mortality can be as high as 15% in elderly patients, and/ or in patients with comorbidities [1, 2]. Risk factors for COVID-19 severity and death include older age, diabetes, hypertension, or cardiac disease [1–4]. Prior experience with seasonal community-acquired respiratory virus (CARV) infections showed that, in immunocompromised patients, these infections are notable for prolonged viral shedding, higher rates of pneumonia and mortality [5, 6]. Thus, it would be expected that COVID-19 be particularly life threatening in patients with hematological malignancies. In fact, initial reports suggested that patients with cancer had an estimated two-fold increased risk of contracting SARS-CoV-2 than the general population and, if infected, also had a higher risk of severe events [intensive care unit (ICU) admission, invasive ventilation, or death] compared to patients without cancer [7–9]. The outcomes of COVID-19 in patients with hematological disorders such as leukemia, lymphoma, myeloma and recipients of autologous (ASCT) or allogeneic hematopoietic stem cell transplantation (allo-SCT) are of utmost interest due to their high degree of humoral and cellular immunosuppression status. Recent studies have reported an overall COVID-19 related mortality of 32 to 40% in hematological patients [10–14]. Future challenges include the identification of prognostic factors that could help in risk assessment and decision-making for effective supportive care and antiviral therapy or in cases of limited access to ICU. The current study addresses the COVID-19 clinical course, outcome and risk factors for severe disease and mortality in a large series of patients with hematological disorders, including recipients of ASCT and allo-SCT. Patients andmethods Study population This is a retrospective multicenter cohort study of the Infectious Complications Subcommittee (GRUCINI) of the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH). Inclusion criteria anddata preparation This series included patients (pediatric and adult) with PCR-documented SARS-CoV-2 infection diagnosed from March 1st 2020 to May 15th 2020 in 41 participating Spanish centers. The status of all patients (and thus the study database) was updated on May 21th 2020. During the study period, hematological patients from participating centers with COVID-19 were prospectively registered through REDcap on-line platform in the GETH database by completing an essential medical data form, and more detailed baseline and outcome data were retrospectively requested afterwards with follow-up forms. The information collected included respiratory symptoms (rhinorrhea, cough, dyspnea, oxygen requirement, sinusitis, otitis, and fever), SARS-COV-2-related hospital admission, oxygen requirement, ICU admission, antiviral COVID-19 therapy given for at least 3 consecutive days, corticosteroid use and anti-cytokine therapy. The dose of corticosteroids was divided in 2 groups, ≤ or > 0.5mg/kg/ day of methylprednisolone (or equivalent doses of prednisone, dexamethasone or hydrocortisone). Details on the underlying disease and its treatment(s) were also captured (details not shown). Baseline laboratory variables, if available [absolute lymphocyte and neutrophil counts, C-reactive protein (CRP), IL6, ferritin and D-dimer levels], were also requested at the time or within 3days after SARS-CoV-2 detection. Detailed microbiological findings and radiological pulmonary patterns were also required for each episode. Definitions We classified COVID-19 stages according to the recent published staging proposal [15]. Briefly, stage 1 refers to early establishment of disease (symptomatic infection of the upper respiratory tract only, with or without fever and generalized malaise). In stage 1 we included patients reported as being asymptomatic by the registering physician, as well as patients with upper respiratory symptoms (rhinorrhea, sinusitis, otitis, or pharyngitis) and/or systemic symptoms (fever, diarrhea, nausea or vomiting, fatigue and myalgia) in the absence of lower respiratory tract disease (LRTD) symptoms and/or any indication of pulmonary infiltrates by radiology, either chest X-ray or computed tomography (CT) scan. Stage II was divided into IIA and IIB. Stage IIA refers to patients with LRTD with radiological proof of pulmonary involvement but without requirements for oxygen support to maintain an oxygen saturation > 92%. Stage IIB included patients meeting the IIA criteria but who required oxygen support (i.e., patients with acute respiratory failure). Finally, Conclusions: In most patients with hematological malignancies COVID‑19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of inflammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID‑19. Page 3 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 we did not classify cases as stage III since we did not have sufficient inflammatory blood markers in all cases, which are required for upgrading a stage IIB to a stage III. Patients with stage IIB thus comprise all patients with severe COVID-19, while stage IIA can be considered to have moderate COVID-19. We considered very severe COVID-19 those who developed stage IIB and those who required ICU admission due to respiratory failure and/or hemodynamic instability. Disease status at the time of SARS-CoV-2 detection was defined according to each specific disease’s revised criteria for leukemia, myeloproliferative neoplasm, multiple myeloma and lymphoma [16–18]. Performance status at the time of COVID-19 was graded according to the Eastern Cooperative Oncology Group (ECOG) [19]. Cardiomyopathy was defined by the patient’s medical history or when the left ventricular ejection fraction was < 50%, as were moderate to severe valvular disease, prior or current history of coronary artery disease, or heart failure. Technical anddiagnostic considerations Patients with URTD and/or LRTD symptoms underwent nasopharyngeal aspiration, nasopharyngeal swabs, or an induced sputum test, while BAL was performed very rarely and only in patients with negative PCR in the upper airway with radiology-proven LRTD and whenever an alternative diagnosis for the patient was deemed possible by each treating team. Most patients underwent weekly PCR test monitoring until negativity of SARS-CoV-2, especially when the patients improved and discharge was being considered, or for epidemiological reasons. The specific method used for performing the PCR was not captured. During this pandemic, GETH published online recommendations on the diagnosis, management, testing and infectious control measures (available in the following website; https ://www.geth.es/). Endpoints andstatistical analysis The primary objective of the study was to describe clinical characteristics of COVID-19 in onco-hematological patients. We also analyzed potential risk factors (RFs) for the development of severe COVID-19 (stage IIB) and day 45 mortality after SARS-CoV-2 detection. Lastly, we explored the effect of antiviral and anti-cytokine therapy on mortality in patients with very severe COVID-19. The main characteristics of patients were reported by descriptive statistics on the total of the available information. Median and range were used for continuous variables, while absolute and percentage frequencies were used for categorical variables. Univariate and multivariate analyses of clinical, laboratory and therapeutic variables associated with outcomes were calculated using logistic regression models. For multivariate analysis, only variables with parameter estimates showing a p value ≤ 0.10 in the univariate analysis were finally included. Two-sided exact P values were reported and p values ≤ 0.05 were considered statistically significant. COVID-19 related mortality according to different clinical and biological variables was estimated from time of SARS-CoV-2 detection using Kaplan–Meier curves and univariate comparisons were made with the log-rank test. All the analyses were performed using the statistical software SPSS v. 20. Results Patient characteristics Overall, 388 pediatric and adult patients with hematological malignancies were initially registered. However, 21 cases were excluded due to negative results for SARS-CoV-2 PCR testing, irrespective of being classified as “probable COVID-19” by their hospital or regional epidemiologists based on a compatible clinical presentation and the large numbers of infections in the community. Thus, the study includes 367 patients with laboratory-confirmed SARS-CoV-2. Patient and disease characteristics according to whether they received or not a hematopoietic stem cell transplant (ASCT or allo-SCT) are detailed in Table1. The median age was 64 years (range 1–93.8). Overall, the most common hematological disease was non-Hodgkin’s lymphoma (n = 91, 25%) followed by plasma cell disorders (n = 81, 22%). As expected, patients who did not receive SCT were older, had been diagnosed more recently of their hematological malignancy and/or had received chemotherapy less than 40days before the SARS-CoV-2 infection, and thus they also had higher rates of uncontrolled hematological disease (not in partial or complete remission). Of note, they had higher comorbidities such as hypertension, cardiomyopathy and dyslipidemia (p < 0.01 for all comparisons). In contrast, recipients of SCT had received more prior lines of therapy, while allo-SCT recipients were commonly receiving immunosuppressive drugs at the time of COVID-19 diagnosis (p < 0.01 for all comparisons). Clinical characteristics ofCOVID‑19 innon‑transplant andtransplant patients Detailed clinical and laboratory characteristics of COVID-19 by patient category (non-SCT, ASCT and allo-SCT recipients) are shown in Table2. Most patients (n = 250, 68%) were diagnosed from March 19th to April 8th (see Fig.1). Out of the 367 cases, 285 (78%) were diagnosed in the outpatient or emergency units, and non-SCT patients were more commonly diagnosed during a hospital admission for treatment of their hematological disease or its complications (23% vs. 12% in SCT recipients). Page 4 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 Table 1 Patient’s characteristics SCT: stem cell transplantation; ASCT: autologous stem cell transplantation; allo-SCT: allogeneic hematopoietic stem cell transplantation; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; MDS: myelodysplastic syndrome; cMPD: chronic myeloproliferative disease; NHL: non-Hodgkin lymphoma; CLL: chronic lymphocytic leukemia; AA: aplastic anemia; CR: complete remission; PR: partial remission; Rel: relapse; Ref: refractory; Prog: progression; CNI: calcineurin inhibitors; MMF: mycophenolate mophetil acid; F/U: follow-up Characteristics Hematological disease, non‑SCT (n = 244) ASCT (n = 58) Allo‑SCT (n = 65) p value Age (years), median (range) 71 (7–93) 61 (34–75) 48 (1–70) < 0.0001 0–40 years, n (%) 20 (8) 1 (2) 25 (39) < 0.0001 41–60 years, n (%) 51 (22) 22 (38) 21 (32) 61–70 years, n (%) 45 (18) 30 (52) (17) (26) >71 years, n (%) 128 (52) 5 (8) 2 (3) Male, n (%) 132 (54) 34 (59) 40 (61) 0.5 Baseline disease, n (%) < 0.0001 AML 44 (19) 0 23 (35) ALL 12 (5) 1 (2) 12 (18) MDS 12 (5) 0 10 (15) CMPD 27 (11) 0 2 (3) NHL 68 (28) 17 (30) 6 (9) CLL 2 (10) 0 2 (3) Plasmatic cell disorder 40 (16) 38 (66) 3 (5) AA or auto‑immune disorders 13 (6) 1 (2) 5 (8) Disease status, n (%) < 0.0001 CR/PR 81 (33)/45 (18) 28 (48)/16 (28) 56 (86)/0 Not in remission (Rel/Ref/Prog) 10 (4)/8 (3)/23 (9) 5 (8)/1 (2)/6 (10) 6 (9)/0/2 (3) Active disease not requiring therapy 22 (9) 0 0 Prior lines of therapy 0–1 189 (77) 21 (36) 26 (40) < 0.001 > 1 55 (23) 37 (64) 39 (60) Allo‑SCT, n (%) HLA identical sibling 29 (45) Unrelated Donor 22 (34) Haplo‑identical family donor 14 (21) Time from transplant to COVID‑19, days (range) 790 (10–10661) 441 (6–7597) 0.1 Prior therapy/conditioning 40 days before COVID‑19, n (%) 102 (42) 24 (41) 10 (15) < 0.0001 Disease diagnosed within 40 days of COVID‑19, n (%) 60 (25) 0 0 < 0.0001 Under immunosuppressive drugs before COVID‑19 CNI or sirolimus or MMF 0 0 28 (43) < 0.0001 Performance status, n (%) 0.2 ECOG 0–1 166 (68) 48 (82) 50 (77) ECOG 2/ECOG 3–4 45 (18)/28 (11) 7 (12)/2 (3) 7 (11)/5 (8) Pulmonary/cardiovascular risk factors, n (%) Active smoking 27 (11) 4 (7) 2 (3) 0.12 Arterial hypertension 118 (48) 12 (21) 12 (18) < 0.0001 Cardiomyopathy 51 (21) 10 (17) 4 (6) 0.021 Dyslipidemia 78 (32) 11 (19) 5 (8) < 0.0001 Diabetes 9 (4) 3 (5) 3 (5) Median F/U after COVID‑19, days (range) 21 (0–74) 30 (0–72) 35 (0–72) 0.2 Median F/U in survivors, days (range) 33 (10–74) 34 (11–72) 40 (12–72) 0.2 Page 5 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 Table 2 Clinical andlaboratory characteristics Characteristics Hematological disease, non‑SCT (n = 244) ASCT (n = 58) Allo‑HCT (n = 65) p value Place of SARS‑CoV‑2 infection, n (%) 0.1 Outpatient 180 (74) 50 (86) 55 (85) Inpatient in specialized hospital 55 (23) 7 (12) 8 (12) Hospice institution 9 (4) 1 (2) 2 (3) COVID‑related hospital admission, n (%) 163 (67) 42 (72) 44 (68) 0.079 Symptoms, n (%) Asymptomatic 19 (8) 6 (10) 5 (8) 0.9 Fever 178 (73) 40 (69) 41 (63) 0.6 Rhinorrhea 29 (12) 11 (19) 14 (22) 0.3 Pharyngitis 15 (6) 3 (5) 9 (14) 0.09 Fatigue 140 (57) 24 (41) 32 (49) 0.25 Myalgia 51 (21) 9 (16) 13 (20) 0.38 Cough 175 (72) 30 (52) 39 (60) 0.069 Diarrhea 54 (22) 15 (26) 12 (18) 0.5 Emesis 23 (9) 8 (14) 6 (9) 0.46 COVID‑19 stagea, n (%) Stage 1 41 (17) 15 (26) 18 (28) 0.075 Stage 2A 70 (29) 22 (38) 19 (29) 0.38 Stage 2B 133 (55) 21 (36) 28 (43) 0.027 Oxygen support, n (%) 136 (56) 24 (41) 32 (49) 0.021 Abnormal radiological pulmonary finding, n (%) 200 (82) 44 (76) 46 (71) 0.35 Antiviral COVID‑19 therapy, n (%) 0.05 None 49 (20) 16 (28) 13 (20) HCQ 15 (6) 0 11 (17) HCQ + AZT 36 (15) 5 (9) 8 (12) HCQ + AZT + lop/rit 14 (5) 3 (5) 1 (1) lop/rit 29 (12) 4 (9) 5 (8) HCQ + lop/rit 32 (13) 14 (24) 8 (12) AZT + lop/rit 39 (16) 6 (12) 8 (12) AZT 24 (10) 5 (7) 7 (11) Remdesivir 3 (1) 3 (5) 2 (3) Other 4 (2) 3 (5) 3 (5) Corticosteroid therapy 0.029 No 132 (54) 40 (69) 45 (69) ≤0.5 mg/kg/dayb29 (12) 7 (12) 9 (14) >0.5 mg/kg/dayb83 (34) 11 (19) 11 (17) Anti‑cytokine supportive therapy, n (%) Tocilizumab 26 (11) 10 (17) 14 (21) 0.05 Anakinra 10 (4) 3 (5) 5 (8) Baricitinib 6 (2) 1 (2) 0 Laboratory characteristics at the time of SARS‑CoV‑2 detection ANC < 0.5 × 109/L, n (%) 36 (15) 4 (7) 4 (6) 0.089 ALC < 0.5 × 109/L, n (%) 99 (41) 22 (38) 19 (29) 0.27 Platelet count (× 109/L), median (range) 109 (1–1075) 127 (5–410) 115 (10–548) 0.4 < 20 × 109/L 28 (13) 2 (4) 4 (7) 21–50 × 109/L 27 (12) 7 (14) 9 (15) > 50 × 109/L 166 (75) 42 (82) 46 (78) CRP > 20 mg/dL (n/evaluable, %) 152/217 (70) 23/48 (48) 25/54 (46) 0.001 IL‑6 > 50 pg/mL (n/evaluable, %) 28/70 (40) 6/15 (40) 11/25 (44) 0.9 Page 6 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 During follow-up, 30 patients (8%) who were asymptomatic at the time SARS-CoV-2 infection was made did not develop symptoms during follow-up (no differences by patient type). Otherwise, the most common clinical features were fever (n = 259, 71%) cough (n = 244, 66%), fatigue (n = 192, 53%) and diarrhea (n = 81, 22%). COVID-19 was in stage I in 74 cases (20%), stage IIA in 111 patients (30%) and stage IIB in 182 cases (50%). We did not observe significant variations in clinical symptoms among groups. Although pulmonary involvement was not significantly different amongst groups (83%, 74% and 72% of non-SCT, ASCT and allo-SCT, respectively, p = 0.2), non-SCT and allo- SCT patients had higher rates of acute respiratory failure (stage IIB) than ASCT (55% vs. 48% vs. 36%, respectively, p = 0.027). Regarding the available laboratory data, non- SCT patients had higher rates of severe neutropenia (< 0.5 × 109/mL) and high CRP (> 20mg/dL) as compared to ASCT and allo-SCT (p < 0.0001), whereas high IL-6, ferritin and D-dimer levels were similar among groups, although these latter laboratory values were available in less than half of the patients (see Table2). Table 2 (continued) Characteristics Hematological disease, non‑SCT (n = 244) ASCT (n = 58) Allo‑HCT (n = 65) p value Ferritin > 500 µg/mL, (n/evaluable, %) 80/104 (77) 14/21 (67) 25/29 (86) 0.4 D dimer > 500 ng/mL (n/evaluable, %) 127/197 (64) 20/42 (48) 25/46 (54) 0.085 Recovery from COVID‑19 (n/evaluable, %) 107/218 (49) 42/57 (74) 33/59 (56) 0.001 PCR negativity documented (n/evaluable, %) 49/131 (37) 15/30 (50) 13/27 (48) 0.01 Median time from diagnosis to negativity, days (range) 20 (4–48) 26 (7–53) 26 (7–43) 0.5 Overall mortality, n (%) 80 (33) 12 (21) 13 (20) 0.1 COVID‑19 related mortality, n (%) 76 (31) 10 (17) 12 (18) 0.02 Median time from diagnosis to death, days (range) 7.5 (0–38) 13 (0–51) 8 (0–42) 0.18 Admission to the ICU, n (%) 28 (11) 8 (14) 7 (11) 0.8 ICU mortality rate, n (%) 16 (57) 2 (25) 3 (43) 0.2 SCT: stem cell transplantation; ASCT: autologous stem cell transplantation; allo-SCT: allogeneic hematopoietic stem cell transplantation; HCQ: hydroxi-cloroquine; AZT: azithromycin; lop/rit, lopinavir/ritonavir; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; CRP: C-reactive protein; IL: interleukin; PCR: polymerase chain reaction; ICU: intensive care unit a As suggested in Siddiqi etal. [15] b Refers to dose of IV methylprednisolone or an equivalent dose of another corticosteroid Fig. 1 Number of cases and mortality rate according to the severity of COVID‑19 and the date of diagnostic Page 7 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 Outcome andmortality The overall median follow-up after SARS-CoV-2 infection was 25 days (range 0-74) for the entire cohort (see Table1). At the time of the last follow-up, centers reported a higher proportion of full clinical recovery from COVID-19 in ASCT recipients (74%) as compared to allo-SCT (56%) and non-SCT patients (48%) (p < 0.0001). The proportion of documented SARS- CoV-2 PCR negativity during follow-up screening was also higher in SCT patients (ASCT 50% and allo-SCT 48%) as compared to non-SCT (37%) (p = 0.01) without any significant differences in time to negativity (see Table2). Overall mortality at day 45 after SARS-CoV-2 detection was 29% (n = 105), whereas day 45 COVID-19-related mortality was 27% (n = 98). The COVID-19-related mortality was higher in non-SCT (31%) as compared to ASCT (17%) and allo-SCT (18%) (p = 0.02). Median time to death was similar among groups (see Table 2). Overall mortality in patients who were considered suitable candidates for the ICU (n = 43) was high (n = 21, 49%) without differences between groups. Overall mortality rate according to the date of COVID-19 diagnosis is shown in Fig. 1. Overall mortality according to the COVID-19 stage in the entire cohort and by patient groups is shown in Fig.2a–d. Risk factors forsevere COVID‑19 (stage IIB) andmortality Logistic regression univariate and multivariate analyses of conditions associated with COVID-19 stage IIB and related mortality in all 367 patients are shown in Table3. By multivariate analysis we identified 3 conditions associated with stage IIB or severe COVID-19; history of hypertension [Odds ratio (OR) 2, 95% confidence interval (CI) 1.3–3.2, p = 0.02], baseline lymphopenia (< 0.5 × 109/ mL) (OR 1.7, 95% CI 1.1–2.7, p = 0.015) and baseline CRP > 20mg/dL (OR 2.67, 95% CI 1.6–4.3, p < 0.0001). Finally, 5 conditions were associated with increased COVID-19-related mortality: (i) age > 70years (OR 2.1, 95% CI 1.2–3.8, p = 0.011); (ii) uncontrolled hematological disease (OR 2.9, 95% CI 1.6–5.2, p < 0.0001); (iii) ECOG 3–4 (OR, 2.56, 95% CI 1.4–4.7, p = 0.003); (iv) neutropenia (< 0.5 × 109/L) (OR 2.8, 95% CI 1.3–6.1, p = 0.01); and (v) CRP > 20mg/dL (OR 3.3, 95% CI 1.7– 6.4, p < 0.0001). Mortality rates progressively increased according to the presence of 0–1, 2 or > 2 of these 5 RFs, as shown in Fig.3a. Rising mortality by number of RFs was also observed in patients with stages IIA-IIB only, in patients with or without uncontrolled malignancy, and in non-SCT patients or SCT recipients (shown in Fig.3b–f). Effect ofanti‑viral andanti‑cytokine supportive therapy onday 45 COVID‑19‑related mortality Most patients (n = 289, 79%) received therapy against SARS-CoV-2, with azithromycin (n = 156, 42%) and hidroxycloroquine (n = 147, 40%) being the most common agents prescribed (details are shown in Table2). However, each center established its own treatment algorithms, which also probably varied on a patient by patient basis according to the stage and progression of COVID- 19. Unfortunately, we did not capture the exact date of start and end of these therapeutic interventions. Thus, in order to evaluate the potential effect of therapy, we performed a second multivariate analysis of COVID-19-re- lated mortality including only the 216 patients (59%) with very severe disease. Results of these univariate and multivariate analyses are shown in Table4. Treatments which led to lower mortality in multivariate analysis were (i) the use of azithromycin (OR 0.42, 95% CI 0.2–0.89, p = 0.02), and (ii) the use of corticosteroids at doses ≤ 0.5 mg/kg/day (OR 0.31, 95% CI 0.11–0.87, p = 0.02); higher doses of corticosteroids (> 0.5 mg/kg/day) did not show any effect on mortality. Of note, the use of hidroxycloroquine did not show significant improvement in OM. Other variables associated with higher mortality in this subset analysis of severely ill patients were; (iii) age > 70years (OR 2.54, 95% CI 1.2–5.2, p = 0.011); (iv) uncontrolled hematological disease (OR 3.5, 95% CI 1.6–7.5, p = 0.001); (v) platelet count ≤ 20 × 109/L (OR, 5.66, 95% CI 1.44–22, p = 0.013); (vi) platelet count 21–0 × 109/L (OR 3.3, 95% CI 1.2–9.2, p = 0.021); (vii) history of arterial hypertension (OR, 2, 95% CI 1.3–3.2, p = 0.002); and (viii) CRP > 20 mg/dL (OR 2.7, 95% CI 1.1–6.5, p = 0.029). Discussion We report herein a real-life experience with COVID- 19 diagnosed in a large number of Hematology units in Spain over a two-month period during the first pandemic wave of the SARS-CoV-2 infection. Our results show an overall mortality rate at day 45 after diagnosis of 29% (27% COVID-19-related according to the treating physicians). Of note, a lower mortality was seen in recipients of a SCT (including allo-SCT recipients) as compared to non-SCT patients. For its simplicity and the ability to classify cases into moderate or severe cases of pneumonia, we used the COVID-19 stages classification, as developed by Siddiqi etal. [15], and as expected found that stage IIB (pneumonia with acute respiratory failure) significantly correlated with higher mortality (shown in different study groups in Fig.1a–d). This easy-to-implement classification could be of value for future observational studies and for the design of future randomized clinical trials. Page 8 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 Additionally, we found that hypertension, lymphopenia and high CRP predicted for the development of stage IIB COVID-19. Although hypertension and lymphopenia were not found to independently increase mortality in our study, both variables have been shown to be strong predictors of mortality in the general population and we can thus postulate that with larger patient numbers they would also have had an impact on survival. On the other hand, higher mortality was linked with age > 70 years, uncontrolled hematological malignancy, baseline poor Fig. 2 Day 45 overall mortality. a In the entire cohort, according to the COVID‑19 stage, mortality was 8% in patients with stage I, 18% in those with stage IIA and 53% in those who evolved to stage IIB ((p < 0.0001). b Mortality rate in non‑SCT patients was 10% vs. 23% vs. 53% in patients with stage I, stage IIA and Stage IIB, respectively (p < 0.0001). c Mortality in autologous SCT recipients was 13%, 11% and 50% in patients with stage I, stage IIA and Stage IIB, respectively (p < 0.09). d Mortality in allo‑SCT recipients was 0%, 17% and 47% in patients with stage I, stage IIA and Stage IIB, respectively (p < 0.01) Page 9 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 Table 3 Univariate andmultivariate analysis ofrisk factors forstage IIB COVID-19 andCOVID-19-related mortality SCT: stem cell transplantation; ASCT: autologous stem cell transplantation; allo-SCT: allogeneic hematopoietic stem cell transplantation; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; MDS: myelodysplastic syndrome; cMPD: chronic myeloproliferative disease; NHL: non-Hodgkin lymphoma; CLL: chronic lymphocytic leukemia; AA: aplastic anemia; CR: complete remission; PR: partial remission; Rel: relapse; Ref: refractory; Prog: progression; Dx: diagnostic; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; CRP: C-reactive protein; IL: interleukin; ns: not significant; NT: not tested a Stage IIB refers to severe disease, with pulmonary involvement and acute respiratory failure, as suggested in Siddiqi etal. [15] b These variables were not included in the multivariate analyses due to the low number of patients with complete data Variables Log. Regr. COVID‑19 Stage II Ba (n = 367) Log. Regr. COVID‑19 Mortality (n = 367) Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis OR (95% CI) p OR (95% CI) p OR (95% CI) p R (95% CI) p value Patient age > 70 years old 2.25 (1.45–3.5) < 0.0001 ns 3.1 (1.9–5) < 0.0001 2.1 (1.2–3.8) 0.011 Patient age ns ns 0–20 1 1 21–70 5.6 (1.2–25) 0.02 0.7 (0.22–2.3) 0.59 >70 11.5 (2.5–52) 0.002 2.3 (0.7–7.5) 0.16 Sex male 1.41 (0.93–2.1) 0.09 ns 0.95 (0.6–1.5) 0.8 Baseline disease ns ns AML 1 1 ALL 0.8 (0.3–2) 0.68 0.6 (0.22–1.67) 0.3 MDS 1.3 (0.5–3.4) 0.5 0.69 (0.25–1.9) 0.47 CMPD 2.7 (1.1–6.8) 0.032 0.6 (0.23–1.5) 0.3 NHL 1.37 (0.7–2.6) 0.3 0.63 (0.3–1.2) 0.3 CLL 2.9 (1.12–7.6) 0.03 0.7 (0.35–1.06) 0.06 Plasmatic cell disorder 0.98 (0.5–1.8) 0.9 0.7 (0.35–1.4) 0.3 AA or auto‑immune disorders 0.3 (0.09–1.1) 0.07 0.08 (0.01–0.69) 0.02 Disease status ns CR/PR/not requiring therapy 1 1 Rel/Ref/Prog 1.49 (0.96–2.3) 0.076 3.78 (2.3–6) < 0.0001 2.9 (1.6–5.2) < 0.0001 Procedure ns ns Allo‑SCT 1 1 ASCT 0.75 (0.37–1.5) 0.4 1.04 (0.43–2.5) 0.9 Non‑SCT 1.57 (0.92–2.6) 0.09 1.95 (1.03–3.7) 0.048 ns Chemotherapy 40 days before COVID‑19 1.18 (0.7–1.8) 0.4 ns 1.76 (1.1–2.79) 0.016 ns Disease Dx within 40 days of COVID‑19 1.1 (0.6–1.9) 0.7 ns 2.2 (1.24–3.9) 0.007 ns ECOG 3–4 1.8 (1.14–2.98) 0.012 ns 3.7 (2.2–6.1) < 0.0001 2.56 (1.4–4.7) 0.003 Active smoking 1.88 (0.89–3.9) 0.094 ns 1.3 (0.6–2.79) 0.4 Arterial hypertension 2.26 (1.4–3.49) < 0.0001 2 (1.3–3.2) 0.002 2.6 (1.6–4.16) < 0.0001 ns Cardiomyopathy 1.98 (1.1–3.4) 0.015 ns 1.6 (0.9–2.88) 0.089 ns Dyslipidemia 1.6 (1–2.59) 0.049 ns 1.86 (1.1–3) 0.015 ns Place of SARS‑CoV‑2 infection ns Outpatient 1 1 Inpatient in specialized hospital 1.1 (0.6–1.8) 0.69 1.05 (0.3–3.6) 0.9 ALC < 0.5 × 109/L 1.7 (1.1–2.68) 0.014 1.7 (1.1–2.7) 0.015 2.25 (1.6–3.6) 0.001 ns ANC < 0.5 × 109/L 1.4 (0.7–2.7) 0.27 ns 3.4 (1.8–6.67) < 0.0001 2.8 (1.3–6.1) 0.01 Platelet count (× 109/L) ns < 20 × 109/L 1.7 (0.8–3.66) 0.16 4.44 (2.1–9.4) < 0.0001 21–50 × 109/L 1.18 (0.6–2.26) 0.6 3.6 (1.8–7.05) < 0.0001 > 50 × 109/L 1 1 CRP > 20 mg/dL 3.1 (1.9–4.9) < 0.0001 2.67 (1.6–4.3) < 0.0001 4 (2.2–7.18) < 0.0001 3.3 (1.7–6.4) < 0.0001 IL‑6 > 50 pg/mLb3.2 (1.38–7.35) 0.007 NT 2.7 (1.1–6.59) 0.028 NT Ferritin levelsbNT NT <500 µg/mL 1 1 501–1000 µg/mL 1.18 (0.4–3.2) 1 (0.24–4.1) 0.99 >1001 µg/mL 2.4 (1.1–5.35) 0.03 2.8 (1–7.9) 0.05 D dimer > 500 ng/mLb1.6 (1.02–2.6) 0.04 NT 1.34 (0.8–2.3) 0.2 NT Page 16 of 16 Piñanaetal. Exp Hematol Oncol (2020) 9:21 • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year • At BMC, research is always in progress. Learn more biomedcentral.com/submissions Ready to submit your research ? Choose BMC and benefit from: es‑death ‑by‑up‑to‑one‑third ‑in‑hospi talis ed‑patie nts‑with‑sever e‑respi rator y‑compl icati ons‑of‑covid ‑19. Accessed June 23, 2020. 47. Actualización nº 130. Enfermedad por el coronavirus (COVID‑19). 08.06.2020. https ://www.mscbs .gob.es/profe siona les/salud Publi ca/ccaye s/ alert asAct ual/nCov‑China /docum entos /Actua lizac ion_130_COVID ‑19.pdf. 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