key: cord-0970990-aazy4d43
authors: Borah, Pronamee; Mirgh, Sumeet; Sharma, Sanjeev Kumar; Bansal, Sachin; Dixit, Ashish; Dolai, Tuphan Kanti; Lunkad, Sweta; Gupta, Naveen; Singh, Gurmeet; Jain, Aditi; Bansal, Divya; Choudhary, Dharma; Khandelwal, Vipin; Doval, Divya; Kumar, Meet; Bhargava, Rahul; Chakrabarti, Amrita; Kalashetty, Mallikarjun; Rauthan, Amit; Kazi, Bilal; Mandal, Prakas Kumar; Jeyaraman, Preethi; Naithani, Rahul
title: Effect of age, comorbidity and remission status on outcome of COVID-19 in patients with hematological malignancies
date: 2020-12-08
journal: Blood Cells Mol Dis
DOI: 10.1016/j.bcmd.2020.102525
sha: 1ec5894d6b32e22ee8f71d481100325196eb32a1
doc_id: 970990
cord_uid: aazy4d43

Background There is scarcity of data on outcome of COVID-19 in patients with hematological malignancies. Primary objective of study was to analyse the 14-day and 28-day mortality. Secondary objectives were to correlate age, comorbidities and remission status with outcome. Methods Retrospective multicentre observational study conducted in 11 centres across India. Total 130 patients with hematological malignancies and COVID-19 were enrolled. Results Fever and cough were commonest presentation. Eleven % patients were incidentally detected. Median age of our cohort was 49.5 years. Most of our patients had a lymphoid malignancy (n = 91). One-half patients (52%) had mild infection, while moderate and severe infections contributed to one-fourth each. Sixty seven patients (52%) needed oxygen For treatment of COVID-19 infection, half(n = 66) received antivirals. Median time to RT-PCR COVID-19 negativity was 17 days (7–49 days). Nearly three-fourth (n = 95) of our patients were on anticancer treatment at time of infection, of which nearly two-third (n = 59;64%) had a delay in chemotherapy. Overall, 20% (n = 26) patients succumbed. 14-day survival and 28-day survival for whole cohort was 85.4% and 80%, respectively. One patient succumbed outside the study period on day 39. Importantly, death rate at 1 month was 50% and 60% in relapse/refractory and severe disease cohorts, respectively. Elderly patients(age ≥ 60)(p = 0.009), and severe COVID-19 infection (p = 0.000) had a poor 14-day survival. The 28-day survival was significantly better for patients in remission (p = 0.04), non-severe infection (p = 0.00), and age < 60 years (p = 0.05). Conclusions Elderly patients with hematological malignancy and severe covid-19 have worst outcomes specially when disease is not in remission.

Corona virus disease 2019 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which originated in Wuhan, China. With the 2 nd wave of COVID being reported in a lot of countries, better understanding of disease is very important. The spectrum of COVID-19 varies from asymptomatic cases to acute respiratory distress syndrome (ARDS) and death. 1 Secondary bacterial pneumonias, thrombotic complications, myocarditis, and gastrointestinal involvement are more prevalent in those with co morbidities such as hypertension, diabetes, cardiac disease, cancer and age > 70 years. 2 Patients with hematological malignancies present a group of vulnerable patients. Hirsch etal has demonstrated that patients with hematological malignancies are at a higher risk of respiratory tract infections and severe complications. 3 These patients are often immunocompromised because of the disease, chemotherapy and hematopoietic stem cell transplant (HSCT) used for the treatment of these diseases. This further adds to the increased risk of complications and mortality. 4 Various studies have reported a higher mortality of 32-40% in patients with hematological malignancies and concomitant COVID infection. 5 , 6 , 7 , 8 As more and more cases are being reported our understanding of disease is improving. However, we are still in dilemma with regards to various aspects of COVID infections in hematological diseases. With 55 million people affected and 1.3 million mortalities as of 17 November 20, India has second highest number of patients affected worldwide. 9 We present the largest retrospective series from India with an aim to identify risk factors, associated with more severe disease and mortality.

Objectives: Primary objective of study was to analyse the 14-day and 28-day mortality in this population. Secondary objectives were to correlate age, comorbidities and remission status J o u r n a l P r e -p r o o f Journal Pre-proof with severity and outcome.

This was a retrospective multicentre observational study conducted in 11 centres treating haematological malignancies across India. Patients with malignant hematological disorders either newly diagnosed, or on ongoing therapy or follow-up at any of the participating centres were included. Patients were included irrespective of COVID-19 severity, need for hospitalisation or outpatient management and remission status of primary hematological disorder. Patients diagnosed with COVID 19 infection from 15 March to 30

Sep 2020 were enrolled in the study. A diagnosis of SARS-CoV-2infection was based on quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) of nasal and/ or oropharyngeal swabs. Repeat testing was performed based on institutional protocols.

Baseline demographic data including comorbidities, severity of illness, remission status, ongoing therapy were extracted from electronic/manual health records and entered in common Microsoft Excel spreadsheet format. All centres submitted their data in anonymised form to central repositor (RN). Any follow-up queries were sent on email and sheet modified accordingly. One centre with 4 patients was excluded due to inability to respond to queries generated. Figure 1 shows the CONSORT diagram. Data was coded centrally and sent to SM for statistical analysis. Patients received various treatment regimens as per physician discretion or institutional protocol in accordance with the national guidelines for the management of COVID-19, issued by the government from time to time. 10 

Data was described in percentages for categorical variables and as the mean ± standard deviation and median in case of continuous variables. For categorical data, comparisons were made by using the Chi square/Fisher exact test, for quantitative data by t test/F-test and for non-normally distributed quantitative variables by the Mann-Whitney/Kruskal Wallis test.

Data was analysed with SPSS v 23 software. P value ≤0.05 was considered significant in all statistical evaluations.

J o u r n a l P r e -p r o o f

One hundred and thirty patients with hematological malignancies diagnosed with COVID -19 were analysed. Baseline characteristics are enlisted in Table 1 . Median age of our cohort was 49.5 years (2-84) years, with a male predominance (2.5:1). Importantly, one-third of our patients with hematological cancers were elderly (≥65years) and more than two-fifth patients 

Most common symptom at time of presentation was fever (77%) followed by cough (50.7%) and breathlessness (49.2%). Fifteen (11%) asymptomatic patients with newly diagnosed Overall, 20% (n=26) patients succumbed. 14-day survival and28-day survival for whole cohort was 85.4% and 80%, respectively. One patient succumbed outside the study period on day 39. Importantly, death rate at 1month was 50% and 60% in relapse/refractory and severe disease cohorts, respectively. One-month OS for mild, moderate and severe COVID-19 infection was 95.6%, 92.8% and 38.2% respectively. Elderly patients(age≥60)(p=0.009), and severe COVID-19 infection (p=0.000) had a poor 14-day survival. The 28-day survival was significantly better for patients in remission (p=0.04), non-severe infection (p=0.00), and age < 60years (p=0.05).

Amongst various hematological disorders, one-month survival was 67% in AML, 86% in ALL, 93% in MDS / MPN, and 78.4% in lymphoma, and plasma cell dyscrasias, respectively. . Interestingly, amongst those on active treatment, 36% (n=4) patients on immunotherapy alone/ combinations (n=11) (I, C+I, C+I+O) succumbed, versus 19.7% of those on chemotherapy (n=71) (C, C+O). Amongst those with severe disease, administration of remdesivir (55% vs 68%;p=0.49) and/or steroids (66% vs 28.5%;p=0.09) did not improve survival.

Being a novel virus, there is scarcity of data on how corona virus impacts the management of patients with hematological malignancies. Patients with hematologic malignancies appear to have a greater risk of COVID-19 infection and severe disease due to myelosuppression and lymphopenia. 12 In this study, 130 patients with various hematological malignancies were assessed retrospectively from 11 centres in India. About one-third of our patients were >65 years age.

About 25-50% of people exposed to COVID-19 are asymptomatic. 13 Eleven percent of our patients were asymptomatic and were detected as part of routine screening for COVID-19 J o u r n a l P r e -p r o o f Journal Pre-proof before starting chemotherapy. Fever was the most common manifestation of COVID-19 infection in our cohort, followed by cough and breathlessness. These patients may be screened for COVID-19, including a baseline computed tomography of the chest without contrast due to the potential for false-negative PCR from the nasopharyngeal swab, regardless of symptoms. 14 Ninety percent of patients in our cohort had radiological findings of COVID-19 pneumonia.

There is scare data on the prevalence of COVID-19in patients with hematological malignancies. One-hundred and twenty-eight patients with hematologic malignancies, hospitalized at two centers in Wuhan, China were evaluated in a cohort study; 13 (10%) developed COVID-19. 15 In a data from 3 Italian surveys the prevalence of COVID-19 was 0.4% (1 of 267 patients) in adult Ph+ acute lymphoblastic leukemia patients, 0.5% (47 of 9,339 patient) in chronic lymphocytic leukemia patients, and 0.17% (12 of 6,883 patients) in chronic myeloid leukemia patients. 16 , 17 , 18 In a study from Italy, the prevalence of COVID-19 in hematologic patients, mainly affected by malignancies, was not significantly higher compared to that of the general population. 19 However, another report from China suggested that patients with cancer had an estimated two-fold increased risk of contracting COVID-19 than the general population and, if infected, also had a higher risk of severe events (ICU admission, invasive ventilation, or death) compared to patients without cancer. 15 Another study reported higher rates of severe illness (intensive care unit admissions, invasive ventilation, or death) in patients with cancer when compared with others (39 vs. 8%; p = 0.0003)(8). Patients with cancer also developed severe disease symptoms more rapidly compared with others (median 13 vs. 43 days; p< 0.001). 20 In a Spanish multicenter retrospective observational study which included 367 pediatric and J o u r n a l P r e -p r o o f Journal Pre-proof adult patients with hematological malignancies, prognostic factors identified for day 45 overall mortality included age > 70 years, uncontrolled hematological malignancy, ECOG 3-4, neutropenia (< 0.5 × 10 9 /L) and a C-reactive protein (CRP) > 20 mg/dL (9). 14 In a multicenter, retrospective, cohort study from Italy, 536 patients with COVID-19 and hematological malignancies were compared with the non-COVID-19 cohort with hematological malignancies, and the standardized mortality ratio was 41·3 (38·1-44·9). 21 Older age, progressive disease status, diagnosis of AML, aggressive NHL or plasma cell neoplasms and severe COVID-19 were associated with worse overall survival 8,18 suggesting that hematological malignancies have worse outcomes than both the general population with COVID-19 and patients with hematological malignancies without COVID-19. In another retrospective metacentric cohort study from France studying the outcome in Covid-19 hospitalized patients with lymphoma, 30-day mortality was associated with being older (age >70 years) and relapsed/refractory nature of lymphoma. 22 In our cohort, outcome in patients with comorbidities was not different from those without. Median age in our cohort was much younger than other reported studies and half the patients had mild illness. This may have accounted for this lack of association. Similar to our results A European study documented higher mortality (45% vs 11%) in patients more than 60 years age. 23 Patients not in remission had higher mortality compared to patients in remission. Kuderer et al have also demonstrated worse outcomes in elderly and people whose disease was not in remission. 24 They also established increased all-cause mortality in patients with cancer vs general population.

Similarily, Garcia-Suarez et al observed higher mortalities in elderly patients >60 years age and with more than 2 comorbidities 25 In spite the available literature till date, when to treat, how to treat, when to wait, how long to wait, how to predict and manage toxicities, and how to avoid compromising cure rates remains unknown. 12 There have been expert panel recommendations on how best to manage J o u r n a l P r e -p r o o f Journal Pre-proof these patients in current pandemic. 26 In the absence of more specific data, potential risk factors for a severe course of the disease should be assumed as for other viral infections: severe immunodeficiency, lymphopenia, long and profound neutropenia, and older age. 27 , 28 Patients in remission for their hematological malignancy had better survival and recovery from COVID-19 compared to those patients who were not in remission.

Cancer patients generally shed respiratory viruses longer than immunocompetent people and this is probably true for this novel coronavirus as well. 29 Our median time to negative PCR was 17 days (7-49 days) while one patient was still positive till day 105 at last follow-up.

This needs to be kept in mind while devising therapy for these patients. Such long waits may not be feasible sometimes. Limitations This is a retrospective study. Therefore, complete data was not available for all patients.

COVID-19 being a new disease, national guidelines for testing and need for hospitalisation/home isolation were dynamic. Hence, many patients in this study were hospitalised, who at the time of writing the manuscript could have been managed as J o u r n a l P r e -p r o o f outpatients. Study duration was wide and treatment guidelines were dynamic over this time period. Data was collected from multiple centres with different expertise and facilities to handle complications.

These limitations not withstanding we are able to identify important prognostic markers in relatively large cohort of hemato-oncology patients across different regions of India.

Conclusions: Elderly patients with hematological malignancy and severe covid-19 have worst outcomes specially when disease is not in remission. J o u r n a l P r e -p r o o f 

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