key: cord-0691245-7jt41iww
authors: Langerbeins, Petra; Hallek, Michael
title: COVID-19 in patients with hematologic malignancy
date: 2022-05-13
journal: Blood
DOI: 10.1182/blood.2021012251
sha: adcb4f4dd3e41912157b3a0b97adfc12cd07d158
doc_id: 691245
cord_uid: 7jt41iww

The coronavirus infectious disease (COVID-19) shows a remarkable symptomatic heterogeneity. Several risk factors including advanced age, previous illnesses and a compromised immune system contribute to an unfavorable outcome. In patients with hematologic malignancy, the immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is significantly reduced explaining why the mortality rate of hematologic patients hospitalized for a SARS-CoV-2 infection is about 34%. Active immunization is an essential pillar to prevent SARS-CoV-2 infections in patients with hematologic malignancy. However, the immune response to SARS-CoV-2 vaccines may be significantly impaired, as only half of patients with hematologic malignancy develop a measurable anti-viral antibody response. The subtype of hematologic malignancy and B-cell depleting treatment predict a poor immune response to vaccination. Recently, antiviral drugs and monoclonal antibodies for pre-exposure or post-exposure prophylaxis and for early treatment of COVID-19 have become available. These therapies should be offered to patients at high risk for severe COVID-19 and vaccine non-responder. Importantly, as the virus evolves, some therapies may lose their clinical efficacy against new variants. Therefore, the ongoing pandemic will remain a major challenge for patients with hematologic malignancy and their caregivers who need to constantly monitor the scientific progress in this area.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) was identified as 50 the causative agent of the coronavirus infectious disease in early 2020. Since 51

December 2020, variants of concerns with increased transmissibility or with an escape to 52 prior immunization have been reported. [1] [2] [3] [4] [5] Since November 2021, variant B. 1.1.529 53 (Omicron) was discovered in Botswana. This variant of concern encodes the largest number 54 of genomic mutations reported so far, including 32 mutations in the spike protein alone. 6 55

It has become apparent that the clinical course of COVID-19 is more severe in patients with 56 hematologic malignancy (HM). Therefore, we wished to summarize the current knowledge 57 on COVID-19 in these diseases and performed a systematic literature search using the 58 terms "hematologic malignancy", "immunosuppressive" and "COVID-19". 59 60

In light of the complex and profound immune dysfunction of patients with HM, already the 62 first reports from Wuhan, China demonstrated a more severe course of COVID-19 and a 63 higher case fatality rate for patients with HM. 7 Although hospitalized patients with HM had a 64 similar case rate of COVID-19 compared with normal health care providers (10 and 7%), the 65 case fatality rate was significant higher with 62% for patients with HM as compared to 0%, 66 respectively. Thereafter, cohort studies and surveys from Europe, North America, South 67

America and Asia evaluated larger case series of patients with HM with COVID-19 and 68 searched for risk factors associated with an adverse outcome (Table 1) . Summarizing all 69 studies reporting on more than 50 HM patients with COVID-19, the overall hospitalization 70 rate ranged from 56.4 to 73.8%, the ICU admission rate was 9.8 to 24.1%, mechanical 71 ventilation was applied to 13.8 to 29.2%, and 14.1 to 51.5% of all patients died. 8-42 72 Among the most common risk factors for an adverse outcome were -in the order of their 73 frequency -age, comorbidities, active HM, type of HM, ICU stay, mechanical ventilation, and 74

severe [11] [12] [13] [14] [15] [16] 20, 22, 26, 29, 30, 37, 39, 42 In a pooled meta-analysis the estimated risk of 75 death was 34% (95% CI 28-39; N=3240) in HM patients with The analysis of individual patient trajectories demonstrated shifting age and sex profiles of 77 hospitalized patients, as well as large scale fluctuations in patient mortality with the ongoing 78 progression of the pandemic. 43 The results suggest that in HM patients vaccination, more 79 frequent testing with identification of less symptomatic patients and usage of COVID-19 80 directed interventions may have improved outcome. 44 81

The SARS-CoV-2 viral load as assessed by cycle threshold (CT) values from RT-PCR 82 assays seems significantly higher in patients with HM (CT = 25.0) than in patients without 83 HM (CT = 29.2; p = 0.0039). This seems to apply particularly those who had received 84 chemotherapy or targeted therapies. 45 In a retrospective observational study of HM patients, 85 median time to RT-PCR negativity for SARS-CoV-2 was 17 days (7-49 days). 26 B cells for patients with HM as compared to COVID-19 patients without HM. 50 51 These data 100 emphasize the significant alterations in the relative distribution of specific innate and 101 adaptive cell types in patients with HM, possibly compromising an initial response to COVID-102

A prospective study monitored the kinetic of immune response to SARS-CoV-2 in 45 104 patients with HM. Antibody levels (Ab) to the SARS-CoV-2 nucleocapsid (N) and spike (S) 105 protein were measured at +1, +3, +6 months after nasal swabs became PCR-negative. 52 106

Mean anti-N and anti-S-Ab levels were similar between patients with HM and controls, and 107 shared the same behavior, with anti-N Ab levels declining at +6 months and anti-S-Ab 108 remaining stable. However, seroconversion rates both for anti-N and anti-S-Ab and at all 109 time points were significant lower in patients with HM than in controls. All rituximab pre-110 treated patients failed to produce anti-N and anti-S-Ab. 111

A small case series of 25 patients with HM confirmed the short lasting protection with 112 declination of antibody titers from 4 months following COVID-19. 53 113

The ITA-HEMA-COV project (NCT04352556) investigated patterns of seroconversion in a 114 large case series of 237 SARS-CoV-2 infected patients with HM. 54 Overall, 69% of patients 115 had detectable IgG SARS-CoV-2 serum antibodies. In a multivariable logistic regression analysis, chemoimmunotherapy [odds ratio (OR), 3·42; 95% confidence interval (CI), 1·04-117 11·21; P = 0·04] was associated with a lower rate of seroconversion, indicating that 118 treatment-mediated immune dysfunction represents a main driver of impaired 119 immunogenicity. Smaller case series confirmed the impaired immune response to SARS-120

CoV-2 in patients with HM and reported a range of seroconversion of 16.6 to 84%. 53,55 121

Evaluating cellular immune response, newly generated CD4 T cell responses to SARS-CoV-2 in patients with HM. 56 In this study, 123 patients with HM presented with reduced prevalence of pre-existing SARS-CoV-2 cross-124 reactive CD4+ T cell responses and signs of T cell exhaustion when compared to patients 125 with solid cancer or healthy volunteers. The intensity, expandability, and diversity of SARS-126

CoV-2 T cell responses were profoundly reduced and a potential determinant for a dismal 127 outcome of COVID-19 in patients with HM. 128

Lacking T cell immunity even in the setting of humoral response was demonstrated in the 129 prospective monocentric COV-CREM trial (NCT04365322) evaluating 39 SARS-CoV-2 130 infected cancer patients, including 11 patients with HM. 57 Only 36.4% of patients with HM 131 exhibited T cell responses against at least one of the SARS-CoV-2 proteins (S, M or N). Of 132 note, two patients without peripheral SARS-CoV-2 specific T cells had prolonged virus RNA 133 detection after symptoms resolution. The lack of T cell responses suggests patients with HM 134 fail to mount a protective T cell response. Therefore, a specific immunoglobulin monitoring 135 alone may not be sufficient to characterize anti-SARS-CoV-2 immunity. 136

Higher rates of SARS-CoV-2 specific T cells (77%) were reported in an observational study 137 of 100 patients with HM who were hospitalized for COVID-19. Flow cytometric and serologic 138 analyses demonstrated that their B cell response was impaired and levels of SARS-CoV-2 139 specific antibodies were reduced as compared to patients with solid cancer. 58 It is important to note that many anti-cancer therapies are immunosuppressive. In particular 156 anti-CD20 antibodies may result in a prolonged depletion of normal B cells. This inevitably 157 impairs the humoral response, and patients may fail to respond not only to influenza 158

vaccines, but also to other, common vaccines. 64 159

Patients with HM display the most pronounced impairment of SARS-CoV-2 cross-reactive 160 CD4 T cells, in parallel with highest expression of PD-1 on CD4 T cells. 56 As opposed to 161 anti-CD20 antibody treatment, PD-1 blockade (immune checkpoint treatment) may therefore 162 enhance vaccination response. 163

That treatment modality may impact the vaccination response was shown by an evaluation 164 of seroconversion rates against SARS-CoV-2 spike protein following FDA-approved COVID-165 19 vaccines. 65 While patients with solid tumors had adequate immune response in 98%, this 166 response was only 85% in patients with HM, and particularly impaired in patients having 167 received immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell 168 Several other prospective studies confirmed the low antibody response following SARS-181

CoV-2 vaccination in patients with HM (Table 2) Multivariable analysis showed that the only factor independently related to the risk of death 198 was age. 199

The first prospective evaluation of a booster dose was reported in a well described cohort of Results of several studies indicate that the time from last rituximab infusion (< 6 months, < 222 12 months) is associated with rates of serological conversion 66, 69, 70, 73, 75, 79, 81 and hardly any 223 HM patients treated with rituximab in the 6 months prior to vaccination had detectable 224 neutralizing antibodies. 85 As up to 80% of anti-CD20 treated HM patients were able to mount 225 a specific T-cell response, 73 it is possible that SARS-CoV2 vaccines may generate a cellular 226 protection even at the time of anti-CD20 antibody induced B-cell depletion. 227

After a two-dose vaccination, the antibody persistence was reported to hold up to 6 months 228 in healthy individuals. 86 The duration of protection from reinfection and severe disease after 229 booster vaccination is currently the subject of extensive debate. Cellular immunity might 230 provide long-term protection (in contrast to waning humoral immunity) and as recently 231 Molnupiravir is an oral, small-molecule antiviral prodrug that is active against SARS-CoV-2 284 by increasing the frequency of viral RNA mutations and impairing SARS-CoV-2 replication. 97 A double-blind, placebo-controlled phase 3 trial (MOVe-OUT) evaluated molnupiravir therapy 286 starting within 5 days after onset of symptoms in non-hospitalized, unvaccinated patients 287 with confirmed SARS-CoV-2 (including 2.2% patients with active cancer) and demonstrated 288 a relative risk reduction of hospitalization or death of 30% (relative risk 0.70; 95% CI: 0.49, 289 0.99). 98 Due to the mechanism of action an increased teratogenicity is of concern, 290 particularly in younger, childbearing, pregnant and lactating patients. Molnupiravir is 291 indicated for the treatment of COVID-19 in HM patients who do not require supplement 292 oxygen to reduce the risk of progression to severe COVID-19. The neutralizing antibody sotrovimab binds to the receptor-binding motif that engages the 326 ACE2 receptor and demonstrated activity against several variants of concern including 327 alpha, beta, gamma, delta and lambda. 113 The COMET-ICE trial demonstrated that 328 sotrovimab reduces the risk of severe COVID-19 in high-risk, ambulatory patients with mild-329 to-moderate COVID-19 (relative risk reduction, 85%; 97.24% CI, 44 to 96; P=0.002). 114 330

Following these results, sotrovimab has been approved for the treatment of COVID-19 in 331 patients who do not require oxygen supplementation but are at increased risk of progressing 332 to severe COVID-19. Sotrovimab retained activity against Omicron BA.1 sublineages, but its 333 activity against BA.2 has remarkably dropped. 112 Following these findings, the FDA has 334 For patients with hematologic malignancy the current SARS-CoV-2 pandemic represents a 385 particular challenge for at least two reasons. First, their immune system may be impaired by the interaction of cancer cells with different immune cell subsets, inducing a state of anergy. 387

Second, the anti-neoplastic therapies themselves, and in particular anti-CD20 antibodies or 388 chemotherapies act as potent immunosuppressive agents. As a consequence, patients with 389 HM have an increased risk for a severe course of COVID-19 with a hospitalization rate of 390 more than 50% and a case fatality rate of approximately 30%. Advanced age, comorbidities 391 and type of hematologic malignancy seem to be additional risk factors. 392

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