key: cord-0913780-ln3cck9o
authors: Crees, Zachary D.; Stockerl-Goldstein, Keith
title: COVID-19 and Light Chain Amyloidosis, Adding Insult To Injury
date: 2022-01-23
journal: Am J Med
DOI: 10.1016/j.amjmed.2022.01.005
sha: 3a424dbfe9117f65ebc8d87b69c47ebdc5bdb53e
doc_id: 913780
cord_uid: ln3cck9o

Light chain amyloidosis (AL) is a potentially fatal disease of monoclonal plasma cells which leads to accumulation of light chain amyloid fibrils, organ damage and the manifestations of clinical disease. Meanwhile, COVID-19 is a disease caused by infection with the SARS-CoV-2 virus, with the potential to cause severe systemic illness and death. There is significant overlap in the demographics and comorbidities observed in AL and those associated with highest risk for severe morbidity and mortality due to COVID-19. This overlap creates unique challenges in caring for patients with AL which are further compounded by the immunosuppressive nature of anti-plasma cell therapies, the need for frequent clinical assessments and the exclusion of AL patients from initial COVID-19 vaccine trials. Herein, we highlight many of the relevant concerns related to COVID-19 and the treatment of AL, summarize a general approach for AL amyloidosis management amidst the ongoing COVID-19 pandemic and discuss current guidance regarding COVID-19 vaccination of patients with AL amyloidosis.

Light chain amyloidosis (AL) is a rare disease with an incidence of ~3,000-4,000 cases/year in the United States, although many cases likely go undiagnosed. [1] [2] [3] [4] The most common organ systems involved include the cardiovascular, renal, hepatic, gastrointestinal and nervous systems, as well as other lymphatic and soft tissues. 5 The current AL treatment paradigm centers on lymphocyte/plasma cell targeted therapies to suppress amyloid fibril production, as discussed in more detail elsewhere in this Issue. 2 Following early World Health Organization (WHO) reports in December 2019 describing a "pneumonia" of unknown etiology emerging in Wuhan China, COVID-19 has swept the globe leading to >260 million cases and >5.2 million deaths worldwide as well as >48 million cases and over 780,000 deaths in the United States. [6] [7] While little was known regarding COVID-19 as the pandemic began, we now understand that COVID-19 is a systemic disease caused by infection with SARS-CoV-2 virus. Striking overlap exists between the demographics and organ dysfunction associated with AL and severe COVID-19 infection. Here we discuss some of these factors while summarizing an evidence-based approach for AL management amidst the COVID-19 pandemic.

The incidence of AL increases with age, with a median age at diagnosis of 64 years and <5% of patients diagnosed at <40 years of age. [8] [9] Meanwhile, advanced age has been reported as a significant risk factor for severe COVID-19 and death. 10 According to CDC data, those aged 50-74 have a 2-fold increased risk of acquiring COVID-19 (relative to ages 5-17) but a 25-to 35-fold increased risk of hospitalization and a 400-to 1100-fold increased risk of death due to COVID. 11 Therefore, the large majority of patients with AL face notably increased risk of severe COVID-19 and death based on the age demographic alone.

Males account for ~65-70% of AL cases, and male sex is an independent risk factor for severe COVID-19 infection as well as mortality. 10 One recent meta-analysis including >3 million cases from 44 countries found that men were more likely to develop severe COVID-19 requiring admission to an intensive care unit (OR 2.84, 95% CI = 2.06-3.92) and also significantly more likely to die from COVID-19 (OR = 1.39; 95% CI = 1.31-1.47). 12 Notably, this same increased risk was seen in the prior SARS-CoV-1 and MERS viral outbreaks as well. These may be attributable to differences in the innate antiviral responses and adaptive immunity towards viral antigens in females compared to males, leading to more effective viral control, reduced risk of severe disease and decreased mortality due to COVID-19. Thus, the increased risk of severe COVID-19 in men represents a proportionally increased risk to AL patients, the majority of which are male.

AL is a systemic disease with deposition of amyloid fibrils leading to multi-system organ toxicity.

The organs most commonly affected by AL include the cardiovascular (50-70%), renal (50-60%), hepatic (10-30%), gastrointestinal (10-20%) and nervous systems (20-30%). 2, 5, 9 The presence of pre-existing organ dysfunction due to AL places such patients at markedly increased risk of severe COVID-19 infection, which has been documented to affect each of these organ systems. 13 This overlap in multi-system organ involvement between AL and COVID-19 has the effect of adding further insult to pre-existing injury for AL patients who contract SARS-CoV-2.

AL is characterized by a population of dysfunctional plasma cells, but can also be associated with an underlying hematologic malignancy of clonal B-cells (e.g. non-Hodgkin's lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) or of clonal plasma cells (e.g. multiple myeloma, lymphoplasmacytic lymphoma). Therefore, patients with AL are at increased baseline risk of infection, including from SARS-CoV-2. In addition, most plasma cell targeted therapies used for AL are inherently immunosuppressive and associated with increased risk of infection. A recent study found markedly prolonged shedding of live SARS-CoV-2 viral particles (>60 days) in patients who recently underwent hematopoietic cell transplantation (HCT), whereas the average period of viral shedding has been shown to be 10-15 days or less within the general population. [14] [15] Strategies to optimize treatment efficacy while mitigating risk during the COVID-19 pandemic

With the significant overlap between AL patient demographics and risk factors for severe COVID-19 and death, a comprehensive strategy is needed to mitigate risk from COVID-19 while providing standard of care AL therapy (Table 1) . This imperative is underscored by the observation that the risk of COVID-19 infection is frequently outweighed by the risk of amyloidrelated death, with <6 month median survival for symptomatic AL patients with cardiac involvement (Cardiac Stage IIIb-IV). 2 Such a comprehensive strategy may focus on several domains, and the overarching concept is generally applicable to a variety of diseases where the demographics, disease sequelae or disease treatments confer increased risk to COVID-19.

Those domains include following universal precautions for COVID-19 risk reduction, increasing the use of tele-medicine and technology-assisted clinical assessments to reduce in-person exposures, developing patient-specific evidence-based strategies to deliver optimal treatment while mitigating risk and, finally, developing standardized approaches to managing treatment in the event of an acute COVID-19 infection. 16 For patients with AL, mask-wearing, maintaining physical distance, good hand hygiene and vaccination represent high-yield universal precautions that should be employed to the fullest extent possible. Meanwhile, a multi-faceted, deliberate and individualized approach to patient care should balance the considerable risks associated with AL alongside the immunosuppressive nature AL therapies, the ongoing risks of COVID-19 and the evolving nature of the COVID-19 pandemic.

There are currently 3 separate COVID-19 vaccinations that have attained FDA Emergency Use Authorization, including the Pfizer-BioNTech COVID-19 Vaccine, the Moderna COVID-19 Vaccine and the Janssen COVID-19 Vaccine. 17 However, it is important to note that the pivotal studies that led to these FDA authorizations excluded patients on active chemotherapy treatments, including AL patients. Therefore, the effectiveness of these vaccines in immunocompromised patients and those receiving active therapies for AL is unknown. Prior data found highly variable vaccine responses (to influenza, pneumococci, varicella zoster, haemophilus influenza B, etc.) in patients receiving treatment for hematologic malignancies , with seroconversion rates ranging from 20-70%. 18 An observational retrospective cohort study of 261 cancer patients who contracted COVID-19 found similarly variable seroconversion rates of 33-60% in patients receiving anti-CD20 therapy, chimeric antigen receptor T-cell therapy and HCT. 19 These data suggest seroconversion to COVID-19 vaccination among AL patients on active therapies may be significantly attenuated when compared to those subjects included in the trials leading to the vaccine authorizations. vaccination for patients with underlying hematologic malignancies, including AL, with whichever COVID-19 vaccine formulation is most readily available, unless contraindicated. [20] [21] The timing of vaccination may be tailored to the patient's individual clinical situation, but in general should be performed as soon as is reasonable. Of note, vaccination should not delay the initiation of induction chemotherapy for patients with newly diagnosed and symptomatic AL. Patients who have recovered from a prior COVID-19 infection should still receive COVID-19 vaccination, as natural immunity to COVID-19 following infection is variable, can wane over time and may not be protective to alternative COVID-19 variant strains.

When scheduling the COVID-19 vaccination, one should ideally target a goal absolute neutrophil count of >500/uL and platelets >50,000/uL to optimize the chances of vaccine response and minimize the risk of an intramuscular hematoma, respectively. For patients in a very good partial remission or complete remission for whom a brief treatment delay is not a concern, one may reasonably hold treatment 7 days before the first vaccine dose through 7 days after the second vaccine dose (~5-6 weeks). If such a delay is not feasible, holding treatment 2-7 days before the first dose and waiting 10 days before restarting therapy (~2 weeks), while administering the second dose at the appropriate interval without treatment interruption may be reasonable. Patients receiving lenalidomide monotherapy may be able to continue treatment without interruption, given that the available data suggest lenalidomide may either have no effect or may have a beneficial effect on vaccine responses. [22] [23] Following auto-HCT, these authors recommend waiting a minimum of 3 months post-transplant to administer COVID-19 vaccination based on data suggesting diminished vaccine responsiveness in the months immediately post-HCT. 18 If a patient has been vaccinated prior to auto-HCT, data is not currently available regarding if or when to revaccinate post-HCT. Therefore, it may be reasonable to delay COVID-19 vaccination until after completion of auto-HCT if the timing of auto-HCT is imminent. Furthermore, there are no clinically validated tests to verify vaccine seroconversion among immunocompromised patients receiving COVID-19 vaccination.

Patients with AL carry a significantly increased risk of severe COVID-19 infection and death due to age, sex, comorbidities, and disease-and treatment-related immunosuppression. However, in most cases, the risk of morbidity and mortality from untreated AL exceeds that of COVID-19.

Therefore, current guidance supports continued treatment for AL during the COVID-19 pandemic with risk mitigation precautions including universal COVID-19 precautions (maskwearing, physical distancing, etc.), increased tele-medicine care, and evidence-based adjustments to the treatment regimen. COVID-19 vaccination is generally recommended for all patients with AL by major professional societies, despite potential for lower seroconversion rates in patients with hematological malignancies undergoing active therapy.

 AL amyloidosis is associated with significant organ dysfunction that increases risk of COVID-19 morbidity and mortality.  Anti-plasma cell therapies for AL amyloidosis are immunosuppressive and further increase risk associated with COVID-19 infection.  Therapy for symptomatic AL amyloidosis should not be unnecessarily delayed and modifications to standard therapies should be evidence-based, whenever possible.  COVID-19 vaccination with an FDA emergency use authorized vaccine is strongly recommended, along with standard risk mitigation measures.

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