key: cord-0893590-rcoyhtzl authors: Jeyaraman, Preethi; Agrawal, Narendra; Bhargava, Rahul; Bansal, Divya; Ahmed, Rayaz; Bhurani, Dinesh; Bansal, Sachin; Rastogi, Neha; Bora, Pronamee; Naithani, Rahul title: Convalescent plasma therapy for severe Covid-19 in patients with hematological malignancies date: 2021-02-03 journal: Transfus Apher Sci DOI: 10.1016/j.transci.2021.103075 sha: 7e63f39ab6fe16ed1d6ba811ce481db52b117895 doc_id: 893590 cord_uid: rcoyhtzl Background Data on convalescent plasma therapy (CPT) in patients of hematological malignancies with severe Covid-19 is scarce. Objective To study 14-day mortality in patients who received CPT. Patients & Methods Retrospective multicentre observational study conducted in 4 centres treating haematological malignancies across Delhi-national capital region. Total 33 haematological malignancies patients with severe Covid-19 who received CPT were analysed. Results The median age of the study cohort was 62 years (18 to 80 years). Twenty one percent patients had 1 comorbidity, 18% had 2 comorbidities and 6% patients had 3 and 5 comorbidities each. Twenty four patients were on active therapy. Sixty nine percent of patients required ICU stay. Twenty five patients received plasma therapy within 7 days (early) of diagnosis of Covid-19 infection. Median day of plasma infusion from date of diagnosis of Covid-19 infection was 4 days (range: 2 to 25 days). Patient who had early initiation of plasma therapy had shorter duration of hospitalisation (12.7 vs 24.3 days, p = 0.000). Overall mortality in the cohort was 45.5%. There was no effect of disease status, active therapy, presence of comorbidity on mortality. There was no difference in the mortality in patients receiving early vs late initiation of plasma therapy or in patients receiving one versus two plasma therapy. Conclusions We provide a large series of patients with hematological malignancies and role of CPT in this group. The coronavirus (Covid-19) pandemic, with its origin in Wuhan, China, has ravaged the global population with 1.57 million deaths globally so far [1] . Various drugs starting from hydroxychloroquine (HCQs) and ivermectin to antiretrovirals like remdesivir and favipiravir have been tried with variable results and WHO has repeatedly pointed out on the lack of effectiveness of these repurposed drugs [2] . In the absence of an effective antiviral drug, and taking a clue from the effectiveness of convalescent plasma therapy (CPT) in treating other viral diseases like influenza [3] , H1N1 [4] , Ebola [5] convalescent plasma was tried in moderate to severe Covid-19 infections. The proposed mechanism of convalescent plasma is primarily through transfer of virusneutralizing antibodies against Covid -19 [6] . The adverse effects of plasma transfusion has been well studied and reported in the literature and are mostly non-lethal and rare but need close monitoring [7] . The ministry of health and family welfare (MoHFW), India approved convalescent plasma in June 2020 for off-label use in moderate and severe Covid-19 Patients with haematological malignancy pose specific issues like impairment of humoral immunity, defects in myeloid and lymphoid maturation, and increased susceptibility to cytokine storm, predisposing them to more severe disease and possibly increased morbidity and mortality [9] . These patients are also at increased risk of transmission due to frequent visits to the health care centres and their immunocompromised status [10] . Data on usefulness of convalescent plasma therapy (CPT) in patients with hematological malignancies is scarce. Herein, we describe the outcomes of 33 haematological malignancies patients who received convalescent plasma. Severe disease: patient having one or more of the following conditions: -Clinical signs of pneumonia plus one of the following: respiratory rate > 30/min or severe respiratory distress requiring ventilation or SPO2 < 90% on room air. status were excluded. Pregnant and lactating mothers were also excluded. Primary objective of the study was to study 14-day mortality in patients who received convalescent plasma therapy. This retrospective study was approved by institutional review board and conducted as per Helsinki declaration. J o u r n a l P r e -p r o o f 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. A total of 33 patients from 4 centres were included in the study. The median age of the study cohort was 62 years (18 to 80 years). Sixty percent of patients were above the age of 60 years. Majority of patients were males (69.7%). Nearly half the cohort (48.5%) did not have any comorbidities. Hypertension and diabetes were most common (Table I) (Table II) . shorter duration of hospitalisation as compared to patients who had late initiation (12.7 ± 6.5 days vs 24.3 ± 9.5 days, p=0.000). Patients receiving plasma within 3 days had shorter ICU stay (p=0.026). Overall mortality in the cohort was 45.5% (14-day mortality 24.2% and 28day mortality 33.3%). Overall mortality was higher in patients older than 60 years (13 vs 2, p=0.005). There was no effect of disease status, active therapy, presence of comorbidity on mortality. There was no difference in the mortality in patients receiving early vs late initiation of plasma therapy or in patients receiving one versus two plasma therapy (Table III) . No severe adverse effect was reported. We report a real life experience of severe Covid-19 patients with hematological malignancies treated with convalescent plasma therapy. Studies evaluating the efficacy of CPT in haematological malignancies are scarce. Wright et. al reported a case of follicular lymphoma on maintenance rituximab with prolonged course of Covid-19 who responded in 3-5 days after CPT [13] . A 63-year-old female with non-hodgkin lymphoma in remission and on maintenance therapy with Obinutuzumab had a persistent positive PCR for Covid-19 over 12 weeks with negative antibody response. Her symptoms resolved rapidly after the administration of convalescent plasma [14] . Another 55-year-old female with B cell acute lymphoblastic leukemia(ALL) has J o u r n a l P r e -p r o o f been reported who developed reactivation of Covid-19 after receiving rituximab, cytarabine, and dasatinib. A dramatic response within 48 hours of CPT was observed [15] . Shankar et.al. reported a 4 year femalewith case of Covid-19 pneumonia and ALL who was treated with CPT, IVIG and steroids [16] . These few case reports mostly highlight good outcome with CPT. It is possible that CPT has been used in lot many situations but only positive reports are published. In a study of 24 cancer patients (including 14 hematological malignancies) receiving CPT by Tremblay et al, a mortality rate of 41.7% was observed, similar to our results [17] . A significant decrease in C-reactive protein and rise in lymphocyte count were observed. Altuntas et al have documented benefit of CPT in large series of 1776 community (noncancer) patients where CPT was shown to reduce duration in the ICU, the rate of mechanical ventilation support and vasopressor support. There was no difference in mortality [18] . We have earlier shown benefit of CPT in patients with severe Covid-19 in general population with reduction in mortality [19] . Yigenoglu et al have reported a large database of 740 patients with hematological malignancy. This study revealed an increased risk of need for ICU admission, mechanical ventilation and death compared with Covid-19 patients without cancer [20] . We have earlier documented a high 60% mortality rate in patients with hematological malignancies with severe Covid-19 [21] . Mortality in present study with use of CPT is 45.5%. This difference may be due to benefit of CPT or could be due to present study being limited to 4 larger centres with better infrastructure to manage Covid-19 complications compared to previous study which was spread-out in 11 centres across India. Lack of control arm in present study makes it difficult to evaluate efficacy of CPT in this group. However, it was difficult to deny benefit of convalescent plasma to this high risk subgroup of patients for a disease where treatment is still evolving. A large randomised phase II trial of CPT in J o u r n a l P r e -p r o o f moderate Covid-19 documented 15% mortality in moderate subgroup with no benefit of CPT in general population [12] . Thirteen of the 15 patients who died were on invasive mechanical ventilation and only 2 were not (p=0.000). This is similar to the results observed by another study [22] . This suggests that patients with advanced respiratory involvement may not benefit much out of plasma therapy. Timing of initiation of plasma therapy is critical for its efficacy. In a multicentre study of 35322 patients, mortality was lower in patients receiving plasma therapy within 3 days of diagnosis [23] . Most of the patients in our study received plasma therapy within 7 days of diagnosis (75%). We did not find any difference in mortality in patients receiving early versus late plasma therapy. Similarily, there was no difference in mortality if patients received plasma within 3 days or later in our study. The median duration of hospital stay in our study was 11 days similar to Tremblay et.al [17] . We did notice a shorter duration of hospital stay on patients receiving early plasma (<7 days) therapy. Patients receiving plasma within 3 days had shorter ICU stay in our study. This has not been reported in literature. Covid-19 related mortality in elderly patients and/or patients with co-morbidities can be 15% higher than in general younger population [19, 21, 24] . The median age of patients included in our study was 62 years and > 60% of patients were above the age of 60 years. More than half these patients had concomitant comorbidities. Of the 15 patients who died only 2 were less than 60 years (p=0.005). This could be one of the reasons for high mortality in our study. Adverse effect of age and comorbidity in patients with haematological malignancy was previously demonstrated by our group [21] . In this cohort of patients, disease status, active therapy and presence of comorbidity J o u r n a l P r e -p r o o f Early plasma initiation < 7 days Late plasma initiation ≥ 7 days 12.7 ± 6.5 days 24.3 ± 9.5 days 0.000 WHO coronavirus disease (COVID-19 -19 ) dashboard. Geneva: World Health Organization WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment? Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Ministry of Health & family Welfare. 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