Optimal Upfront CLL Treatment during the COVID-19 Pandemic
Here, we report the optimal upfront CLL treatment during the COVID-19 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has challenged our healthcare systems and threatened individuals worldwide, particularly the most vulnerable elderly and those with medical comorbidities. The emergence of the new virus variant with its increased infectivity threats requires a quick response before the availability of evidence on managing patients with chronic lymphocytic leukemia (CLL) in this pandemic. Accordingly, this document prepared to provide informed opinions based on available evidence on how CLL patients were treated during the pandemic period.
CLL and COVID-19 Infection Risk
Several factors linked to CLL contribute to the high risk of recurrent infections, including cellular and humoral immune defects (hypogammaglobulinemia, qualitative and quantitative B and T cell defects, CD4+ lymphopenia, innate immune dysfunction, and neutropenia). This immune dysfunction resulted in the impaired immune response to infection and vaccination . These immune defects can be exacerbated further by chemoimmunotherapy (CIT), with an associated risk of viral infections . Thus, exiting and or treatment induce immune dysfunction might also prevent or delay CLL patients’ ability to react against the SARS-CoV-2 virus or cope with COVID-19 infection severity.
It is uncertain whether cancer patients, including CLL, have a higher prevalence of COVID-19 infection than matched age and gender normal populations . However, there is accumulating evidence that cancer conveys a more unsatisfactory outcome in patients with COVID-19 infection . CLL is a disease of the elderly population more often associated with pre-existing medical comorbidities, which have a detrimental effect on COVID-19 morbidity and mortality. The typical patient with CLL may already have background risk factors for life-threatening COVID-19 that apply to the general population . Accordingly, around 70% of patients with CLL are male, 70% are older than 65 years, 25% harbour >2 comorbidities, 21% have hypertension, 13% cardiovascular disease, 26% diabetes, and 5% chronic respiratory disease .
COVID-19 Infection Prevention Strategy and CLL
Until the COVID-19 vaccine becomes available, public health and non-pharmaceutical interventions aimed at reducing population contact rate and ultimately reducing virus transmission which are the most effective prevention measures for SARS-CoV-2 infection . The spread of SARS-CoV-2 across patients and healthcare professionals is a serious concern and COVID-19 free environments are the ultimate goal for safely taking care of CLL patients . The same will also imply using treatment options if indicated with less risk of further suppressing the immune systems and requiring less frequent hospital visits during both endemic and future epidemic outbreaks.
Management of CLL Patients Needing Therapy during the Pandemic
Unless specific treatment initiation criteria are met, clinicians should defer the CLL treatment initiation. In general, during the COVID-19 pandemic, commencing of therapy is postponed until the epidemic trajectory is decreasing. When treatment cannot be deferred, we should use the systemic treatment that requires fewer hospital visits and less immune suppressive to reduce the risk of nosocomial SARS-CoV-2 infection. In our practice, only Chemoimmunotherapy (CIT) is licensed in the upfront line setting for most CLL patients (~90%) (lacking p53 gene alterations), while targeted therapies (Ibrutinib & Venetoclax) only approved for patient harbouring p53 disruptions (~10%). With these limitations, CLL treatment during the COVID-19 pandemic has proven to be a challenging task, further complicated with CIT, which increases the risk of infection.
Optimal Upfront CLL Treatment Options during the COVID-19 Pandemic
Ibrutinib as monotherapy for upfront treatment for CLL patients is considered as the ideal if not the best treatment option during the COVID-19 pandemic. The rationale of this recommendation is based on the following evidence:
i. Several well-designed clinical trials confirmed targeted therapies (Ibrutinib & Venetoclax) are associated with prolonged progression-free and overall survival, in comparison with the standard of care (CIT) [8-11].
ii. Ibrutinib therapy is associated with a lower risk of infections and less frequent hospital care than CIT . The reported risk of opportunistic infections for Ibrutinib is low (4.1%), compared favourably to CIT . Also, Ibrutinib does not produce significant lymphopenia, a known risk factor for severe COVID-19 .
iii. Ibrutinib treatment requires a few routine hospital visits and lab assessments with low neutropenia risk . It also enhances the T cell immune reconstitution, which decreases the infection rate after the first six months of therapy [12, 14]. Although Ibrutinib is a continuous therapy not allowing treatment-free intervals during the pandemic. However, for patients in remission, treatment interruption for side effects, the achieved response may last for a prolonged period before an alternative therapy is required .
iv. Emerging data reporting anti-inflammatory effects in COVID-19 patients using BTK inhibitors are also undergoing investigation in clinical trials (NCT04346199) . By targeting BTK and other kinases and intermediates, Ibrutinib can minimize inflammation and prevent acute lung injury or ARDS and reduce viral replication during the COVID-19 pandemic .
v. In CLL patients, the serologic response post-SARS-CoV-2 infection is impaired, and with only one-third of patients developing detectable immunoglobulin G antibodies after a median of ∼2 months . This inadequate immune response could be compromised further by CIT and the addition of anti-CD20 monoclonal antibodies. The addition of anti-CD20 monoclonal antibodies failed to improve PFS when combined with Ibrutinib . Therefore, Ibrutinib monotherapy is a less immunosuppressive and very effective treatment without the immune response impact of anti-CD20 monoclonal antibody therapy on COVID-19 infection and vaccination. The CLL research community has already developed a COVID-19/CLL consortium and presented inferior outcomes in this population .
According to these considerations and reasons addressed above, we recommend Ibrutinib monotherapy for all CLL patients requiring treatment during the COVID-19 pandemic considering the cost-effectiveness of this approach.
Article TypeLetter to the Editor
Publication historyReceived: Mon 22, Feb 2021
Accepted: Mon 08, Mar 2021
Published: Wed 17, Mar 2021
Copyright© 2021 Ezzat Elhassadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository. All rights reserved.
Corresponding AuthorEzzat Elhassadi
Consultant Haematologist, Honorary Clinical Lecturer for UCC & RCSI, Clinical Director for Haematology and transfusion services, University Hospital Waterford, Ireland
Figures & Tables
1. Teh BW, Tam CS, Handunnetti S, Worth LJ, Slavin MA (2018) Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies. Blood Rev 32: 499-507. [Crossref]
2. Chen G, Wu D, Guo W, Cao Y, Huang D (2020) Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 130: 2620-2629. [Crossref]
3. Baumann T, Delgado J, Montserrat E (2020) CLL and COVID-19 at the Hospital Clinic of Barcelona: an interim report. Leukemia 34: 1954-1956. [Crossref]
4. Wu Z, McGoogan JM (2020) Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 323: 1239-1242. [Crossref]
5. Leung K, Wu JT, Liu D, Leung GM (2020) First-wave COVID-19 transmissibility and severity in China outside Hubei after control measures, and second-wave scenario planning: a modelling impact assessment. Lancet 395: 1382-1393. [Crossref]
6. Cowling BJ, Ali ST, Ng TWY, Tsang TK, Li JCM et al. (2020) Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study. Lancet Public Health 5: e279-e288. [Crossref]
7. National University Cancer Institute of Singapore (NCIS) Workflow Team (2020) A segregated-team model to maintain cancer care during the COVID-19 outbreak at an academic center in Singapore. Ann Oncol 31: 840-843. [Crossref]
8. Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S et al. (2019) Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med 381: 432-443. [Crossref]
9. Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM et al. (2018) Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med 379: 2517-2528. [Crossref]
10. Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B et al. (2019) Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20: 43-56. [Crossref]
11. Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW et al. (2019) Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: Post-treatment follow-up of the Murano phase III study. J Clin Oncol 37: 269-277. [Crossref]
12. Burger JA, Barr PM, Robak T, Owen C, Ghia P et al. (2020) Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 34: 787-798. [Crossref]
13. Davids MS, Hallek M, Wierda W, Roberts AW, Stilgenbauer S et al. (2018) Comprehensive safety analysis of Venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res 24: 4371-4379. [Crossref]
14. Sun C, Tian X, Lee YS, Gunti S, Lipsky A et al. (2015) Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood 126: 2213-2219. [Crossref]
15. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA et al. (2020) Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res 26: 3918-3927. [Crossref]
16. Treon SP, Castillo JJ, Skarbnik AP, Soumerai JD, Ghobrial IM et al. (2020) The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19 infected patients. Blood 135: 1912-1915. [Crossref]
17. Ernst M, Inglese M, Scholz GM, Harder KW, Clay FJ et al. (2002) Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. J Exp Med 196: 589-604 [Crossref]
18. Roeker LE, Knorr DA, Pessin MS, Ramanathan LV, Thompson MC et al. (2020) Anti-SARS-CoV-2 antibody response in patients with chronic lymphocytic leukemia. Leukemia 34: 3047-3049. [Crossref]
19. Burger JA, Sivina M, Jain N, Kim E, Kadia T et al. (2019) Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 133: 1011-1019. [Crossref]
Mato AR, Roeker LE, Lamanna N, Allan JN, Leslie L et al. (2020) Outcomes of COVID-19 in patients with CLL: a multicenter international experience. Blood 136: 1134-1143. [Crossref]