COVID-19 induces prolonged immunological exhaustion leading to relapse of hematological malignancies except in hematopoietic cell transplant recipients
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Keywords
Covid-19, Relapse, Cancer, immune exhaustion, NKG2A, PD-1, acute leukemia
Abstract
We studied the impact of COVID-19 on relapse in patients with hematological malignancies who had achieved complete remission (CR) and were either treatment-free or maintained on uninterrupted therapy over a 24-month period, excluding patients who relapsed or succumbed to the infection within 30 days.
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[1] T.P. Hanna, G.A. Evans, and C.M. Booth, Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic. Nat Rev Clin Oncol (2020).
[2] J. Jee, M.B. Foote, M. Lumish, A.J. Stonestrom, B. Wills, V. Narendra, V. Avutu, Y.R. Murciano-Goroff, J.E. Chan, A. Derkach, J. Philip, R. Belenkaya, M. Kerpelev, M. Maloy, A. Watson, C. Fong, Y. Janjigian, L.A. Diaz, Jr., K.L. Bolton, and M.S. Pessin, Chemotherapy and COVID-19 Outcomes in Patients With Cancer. J Clin Oncol 38 (2020) 3538-3546.
[3] P. Fedele, V. Sanna, A. Fancellu, A. Marino, N. Calvani, and S. Cinieri, De-escalating cancer treatments during COVID 19 pandemic: Is metronomic chemotherapy a reasonable option? Crit Rev Oncol Hematol 157 (2021) 103148.
[4] C. Nunez-Torron, V. Garcia-Gutierrez, M.C. Tenorio-Nunez, G. Moreno-Jimenez, F.J. Lopez-Jimenez, and P. Herrera-Puente, Poor outcome in patients with acute leukemia on intensive chemotherapy and COVID-19. Bone Marrow Transplant 56 (2021) 267-269.
[5] E. Brissot, M. Labopin, F. Baron, A. Bazarbachi, G. Bug, F. Ciceri, J. Esteve, S. Giebel, M.H. Gilleece, N.C. Gorin, F. Lanza, Z. Peric, A. Ruggeri, J. Sanz, B.N. Savani, C. Schmid, R. Shouval, A. Spyridonidis, J. Versluis, A. Nagler, and M. Mohty, Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 56 (2021) 532-535.
[6] F. Martin-Moro, C. Nunez-Torron, L. Perez-Lamas, C. Jimenez-Chillon, J. Marquet-Palomanes, F.J. Lopez-Jimenez, and P. Herrera-Puente, The impact of lockdown during the COVID-19 pandemic on newly acute myeloid leukemia patients: Single-centre comparative study between 2019 and 2020 cohorts in Madrid. Leuk Res 101 (2021) 106518.
[7] H. Zalpoor, A. Akbari, N. Nayerain Jazi, M. Liaghat, and M. Bakhtiyari, Possible role of autophagy induced by COVID-19 in cancer progression, chemo-resistance, and tumor recurrence. Infect Agent Cancer 17 (2022) 38.
[8] J. Xie, W. Qi, L. Cao, Y. Tan, J. Huang, X. Gu, B. Chen, P. Shen, Y. Zhao, Y. Zhang, Q. Zhao, H. Huang, Y. Wang, H. Fang, Z. Jin, H. Li, X. Zhao, X. Qian, F. Xu, D. Ou, S. Wang, C. Xu, M. Li, Z. Jiang, Y. Wang, X. Huang, and J. Chen, Predictors for Fear of Cancer Recurrence in Breast Cancer Patients Referred to Radiation Therapy During the COVID-19 Pandemic: A Multi-Center Cross-Section Survey. Front Oncol 11 (2021) 650766.
[9] I. Rahimmanesh, L. Shariati, N. Dana, Y. Esmaeili, G. Vaseghi, and S. Haghjooy Javanmard, Cancer Occurrence as the Upcoming Complications of COVID-19. Front Mol Biosci 8 (2021) 813175.
[10] D. Bagautdinova, K.C. Bacharz, C.L. Bylund, M. Sae-Hau, E.S. Weiss, M. Rajotte, G. Lincoln, T.S. Vasquez, N.D. Parker, K.B. Wright, and C.L. Fisher, Understanding the Impact of COVID-19 on Chronic Lymphocytic Leukemia (CLL) Caregiving and Related Resource Needs. J Clin Med 12 (2023).
[11] S.R. Jaiswal, J. Arunachalam, A. Bhardwaj, A. Saifullah, R. Lakhchaura, M. Soni, G. Bhagawati, and S. Chakrabarti, Impact of adaptive natural killer cells, KLRC2 genotype and cytomegalovirus reactivation on late mortality in patients with severe COVID-19 lung disease. Clin Transl Immunology 11 (2022) e1359.
[12] S.R. Jaiswal, J. Arunachalam, A. Saifullah, R. Lakhchaura, D. Tailor, A. Mehta, G. Bhagawati, H. Aiyer, B. Khamar, S.V. Malhotra, and S. Chakrabarti, Impact of an Immune Modulator Mycobacterium-w on Adaptive Natural Killer Cells and Protection Against COVID-19. Front Immunol 13 (2022) 887230.
[13] S.R. Jaiswal, P. Malhotra, D.K. Mitra, and S. Chakrabarti, Focusing On A Unique Innate Memory Cell Population Of Natural Killer Cells In The Fight Against COVID-19: Harnessing The Ubiquity Of Cytomegalovirus Exposure. Mediterr J Hematol Infect Dis 12 (2020) e2020047.
[14] S.R. Jaiswal, A. Saifullah, J. Arunachalam, R. Lakhchaura, D. Tailor, A. Mehta, G. Bhagawati, H. Aiyer, S. Biswas, B. Khamar, S.V. Malhotra, and S. Chakrabarti, Augmenting Vaccine Efficacy against Delta Variant with 'Mycobacterium-w'-Mediated Modulation of NK-ADCC and TLR-MYD88 Pathways. Vaccines (Basel) 11 (2023).
[15] S.R. Jaiswal, S. Chakraborty, R. Lakhchaura, P. Shashi, A. Mehta, M. Soni, and S. Chakrabarti, Early and Sustained Expansion of Adaptive Natural Killer Cells Following Haploidentical Transplantation and CTLA4Ig-Primed Donor Lymphocyte Infusions Dissociate Graft-versus-Leukemia and Graft-versus-Host Effects. Transplant Cell Ther 27 (2021) 144-151.
[16] C. Phetsouphanh, B. Jacka, S. Ballouz, K.J.L. Jackson, D.B. Wilson, B. Manandhar, V. Klemm, H.X. Tan, A. Wheatley, A. Aggarwal, A. Akerman, V. Milogiannakis, M. Starr, P. Cunningham, S.G. Turville, S.J. Kent, A. Byrne, B.J. Brew, D.R. Darley, G.J. Dore, A.D. Kelleher, and G.V. Matthews, Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection. Nat Commun 15 (2024) 3315.
[17] E. Untersmayr, C. Venter, P. Smith, J. Rohrhofer, C. Ndwandwe, J. Schwarze, E. Shannon, M. Sokolowska, C. Sadlier, and L. O'Mahony, Immune Mechanisms Underpinning Long COVID: Collegium Internationale Allergologicum Update 2024. Int Arch Allergy Immunol 185 (2024) 489-502.
[18] K. Yin, M.J. Peluso, X. Luo, R. Thomas, M.G. Shin, J. Neidleman, A. Andrew, K.C. Young, T. Ma, R. Hoh, K. Anglin, B. Huang, U. Argueta, M. Lopez, D. Valdivieso, K. Asare, T.M. Deveau, S.E. Munter, R. Ibrahim, L. Standker, S. Lu, S.A. Goldberg, S.A. Lee, K.L. Lynch, J.D. Kelly, J.N. Martin, J. Munch, S.G. Deeks, T.J. Henrich, and N.R. Roan, Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat Immunol 25 (2024) 218-225.
[19] A. Horowitz, Z. Djaoud, N. Nemat-Gorgani, J. Blokhuis, H.G. Hilton, V. Beziat, K.J. Malmberg, P.J. Norman, L.A. Guethlein, and P. Parham, Class I HLA haplotypes form two schools that educate NK cells in different ways. Sci Immunol 1 (2016).
[20] V. Beziat, B. Hervier, A. Achour, D. Boutolleau, A. Marfain-Koka, and V. Vieillard, Human NKG2A overrides NKG2C effector functions to prevent autoreactivity of NK cells. Blood 117 (2011) 4394-6.
[21] D. Bortolotti, V. Gentili, S. Rizzo, A. Rotola, and R. Rizzo, SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway. Cells 9 (2020).
[22] L. Antonioli, M. Fornai, C. Pellegrini, and C. Blandizzi, NKG2A and COVID-19: another brick in the wall. Cellular & Molecular Immunology (2020).
[23] S.R. Jaiswal, P. Bhakuni, G. Bhagawati, H.M. Aiyer, M. Soni, N. Sharma, R.R. Jaiswal, A. Chakrabarti, and S. Chakrabarti, CTLA4Ig-primed donor lymphocyte infusions following haploidentical transplantation improve outcome with a distinct pattern of early immune reconstitution as compared to conventional donor lymphocyte infusions in advanced hematological malignancies. Bone Marrow Transplant 56 (2021) 185-194.
[24] R. Zeiser, and L. Vago, Mechanisms of immune escape after allogeneic hematopoietic cell transplantation. Blood 133 (2019) 1290-1297.
[1] T.P. Hanna, G.A. Evans, and C.M. Booth, Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic. Nat Rev Clin Oncol (2020).
[2] J. Jee, M.B. Foote, M. Lumish, A.J. Stonestrom, B. Wills, V. Narendra, V. Avutu, Y.R. Murciano-Goroff, J.E. Chan, A. Derkach, J. Philip, R. Belenkaya, M. Kerpelev, M. Maloy, A. Watson, C. Fong, Y. Janjigian, L.A. Diaz, Jr., K.L. Bolton, and M.S. Pessin, Chemotherapy and COVID-19 Outcomes in Patients With Cancer. J Clin Oncol 38 (2020) 3538-3546.
[3] P. Fedele, V. Sanna, A. Fancellu, A. Marino, N. Calvani, and S. Cinieri, De-escalating cancer treatments during COVID 19 pandemic: Is metronomic chemotherapy a reasonable option? Crit Rev Oncol Hematol 157 (2021) 103148.
[4] C. Nunez-Torron, V. Garcia-Gutierrez, M.C. Tenorio-Nunez, G. Moreno-Jimenez, F.J. Lopez-Jimenez, and P. Herrera-Puente, Poor outcome in patients with acute leukemia on intensive chemotherapy and COVID-19. Bone Marrow Transplant 56 (2021) 267-269.
[5] E. Brissot, M. Labopin, F. Baron, A. Bazarbachi, G. Bug, F. Ciceri, J. Esteve, S. Giebel, M.H. Gilleece, N.C. Gorin, F. Lanza, Z. Peric, A. Ruggeri, J. Sanz, B.N. Savani, C. Schmid, R. Shouval, A. Spyridonidis, J. Versluis, A. Nagler, and M. Mohty, Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 56 (2021) 532-535.
[6] F. Martin-Moro, C. Nunez-Torron, L. Perez-Lamas, C. Jimenez-Chillon, J. Marquet-Palomanes, F.J. Lopez-Jimenez, and P. Herrera-Puente, The impact of lockdown during the COVID-19 pandemic on newly acute myeloid leukemia patients: Single-centre comparative study between 2019 and 2020 cohorts in Madrid. Leuk Res 101 (2021) 106518.
[7] H. Zalpoor, A. Akbari, N. Nayerain Jazi, M. Liaghat, and M. Bakhtiyari, Possible role of autophagy induced by COVID-19 in cancer progression, chemo-resistance, and tumor recurrence. Infect Agent Cancer 17 (2022) 38.
[8] J. Xie, W. Qi, L. Cao, Y. Tan, J. Huang, X. Gu, B. Chen, P. Shen, Y. Zhao, Y. Zhang, Q. Zhao, H. Huang, Y. Wang, H. Fang, Z. Jin, H. Li, X. Zhao, X. Qian, F. Xu, D. Ou, S. Wang, C. Xu, M. Li, Z. Jiang, Y. Wang, X. Huang, and J. Chen, Predictors for Fear of Cancer Recurrence in Breast Cancer Patients Referred to Radiation Therapy During the COVID-19 Pandemic: A Multi-Center Cross-Section Survey. Front Oncol 11 (2021) 650766.
[9] I. Rahimmanesh, L. Shariati, N. Dana, Y. Esmaeili, G. Vaseghi, and S. Haghjooy Javanmard, Cancer Occurrence as the Upcoming Complications of COVID-19. Front Mol Biosci 8 (2021) 813175.
[10] D. Bagautdinova, K.C. Bacharz, C.L. Bylund, M. Sae-Hau, E.S. Weiss, M. Rajotte, G. Lincoln, T.S. Vasquez, N.D. Parker, K.B. Wright, and C.L. Fisher, Understanding the Impact of COVID-19 on Chronic Lymphocytic Leukemia (CLL) Caregiving and Related Resource Needs. J Clin Med 12 (2023).
[11] S.R. Jaiswal, J. Arunachalam, A. Bhardwaj, A. Saifullah, R. Lakhchaura, M. Soni, G. Bhagawati, and S. Chakrabarti, Impact of adaptive natural killer cells, KLRC2 genotype and cytomegalovirus reactivation on late mortality in patients with severe COVID-19 lung disease. Clin Transl Immunology 11 (2022) e1359.
[12] S.R. Jaiswal, J. Arunachalam, A. Saifullah, R. Lakhchaura, D. Tailor, A. Mehta, G. Bhagawati, H. Aiyer, B. Khamar, S.V. Malhotra, and S. Chakrabarti, Impact of an Immune Modulator Mycobacterium-w on Adaptive Natural Killer Cells and Protection Against COVID-19. Front Immunol 13 (2022) 887230.
[13] S.R. Jaiswal, P. Malhotra, D.K. Mitra, and S. Chakrabarti, Focusing On A Unique Innate Memory Cell Population Of Natural Killer Cells In The Fight Against COVID-19: Harnessing The Ubiquity Of Cytomegalovirus Exposure. Mediterr J Hematol Infect Dis 12 (2020) e2020047.
[14] S.R. Jaiswal, A. Saifullah, J. Arunachalam, R. Lakhchaura, D. Tailor, A. Mehta, G. Bhagawati, H. Aiyer, S. Biswas, B. Khamar, S.V. Malhotra, and S. Chakrabarti, Augmenting Vaccine Efficacy against Delta Variant with 'Mycobacterium-w'-Mediated Modulation of NK-ADCC and TLR-MYD88 Pathways. Vaccines (Basel) 11 (2023).
[15] S.R. Jaiswal, S. Chakraborty, R. Lakhchaura, P. Shashi, A. Mehta, M. Soni, and S. Chakrabarti, Early and Sustained Expansion of Adaptive Natural Killer Cells Following Haploidentical Transplantation and CTLA4Ig-Primed Donor Lymphocyte Infusions Dissociate Graft-versus-Leukemia and Graft-versus-Host Effects. Transplant Cell Ther 27 (2021) 144-151.
[16] C. Phetsouphanh, B. Jacka, S. Ballouz, K.J.L. Jackson, D.B. Wilson, B. Manandhar, V. Klemm, H.X. Tan, A. Wheatley, A. Aggarwal, A. Akerman, V. Milogiannakis, M. Starr, P. Cunningham, S.G. Turville, S.J. Kent, A. Byrne, B.J. Brew, D.R. Darley, G.J. Dore, A.D. Kelleher, and G.V. Matthews, Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection. Nat Commun 15 (2024) 3315.
[17] E. Untersmayr, C. Venter, P. Smith, J. Rohrhofer, C. Ndwandwe, J. Schwarze, E. Shannon, M. Sokolowska, C. Sadlier, and L. O'Mahony, Immune Mechanisms Underpinning Long COVID: Collegium Internationale Allergologicum Update 2024. Int Arch Allergy Immunol 185 (2024) 489-502.
[18] K. Yin, M.J. Peluso, X. Luo, R. Thomas, M.G. Shin, J. Neidleman, A. Andrew, K.C. Young, T. Ma, R. Hoh, K. Anglin, B. Huang, U. Argueta, M. Lopez, D. Valdivieso, K. Asare, T.M. Deveau, S.E. Munter, R. Ibrahim, L. Standker, S. Lu, S.A. Goldberg, S.A. Lee, K.L. Lynch, J.D. Kelly, J.N. Martin, J. Munch, S.G. Deeks, T.J. Henrich, and N.R. Roan, Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat Immunol 25 (2024) 218-225.
[19] A. Horowitz, Z. Djaoud, N. Nemat-Gorgani, J. Blokhuis, H.G. Hilton, V. Beziat, K.J. Malmberg, P.J. Norman, L.A. Guethlein, and P. Parham, Class I HLA haplotypes form two schools that educate NK cells in different ways. Sci Immunol 1 (2016).
[20] V. Beziat, B. Hervier, A. Achour, D. Boutolleau, A. Marfain-Koka, and V. Vieillard, Human NKG2A overrides NKG2C effector functions to prevent autoreactivity of NK cells. Blood 117 (2011) 4394-6.
[21] D. Bortolotti, V. Gentili, S. Rizzo, A. Rotola, and R. Rizzo, SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway. Cells 9 (2020).
[22] L. Antonioli, M. Fornai, C. Pellegrini, and C. Blandizzi, NKG2A and COVID-19: another brick in the wall. Cellular & Molecular Immunology (2020).
[23] S.R. Jaiswal, P. Bhakuni, G. Bhagawati, H.M. Aiyer, M. Soni, N. Sharma, R.R. Jaiswal, A. Chakrabarti, and S. Chakrabarti, CTLA4Ig-primed donor lymphocyte infusions following haploidentical transplantation improve outcome with a distinct pattern of early immune reconstitution as compared to conventional donor lymphocyte infusions in advanced hematological malignancies. Bone Marrow Transplant 56 (2021) 185-194.
[24] R. Zeiser, and L. Vago, Mechanisms of immune escape after allogeneic hematopoietic cell transplantation. Blood 133 (2019) 1290-1297.
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Published
Apr 30, 2025
Article Details
How to Cite
CHAKRABARTI, S. (2025) “COVID-19 induces prolonged immunological exhaustion leading to relapse of hematological malignancies except in hematopoietic cell transplant recipients”, Mediterranean Journal of Hematology and Infectious Diseases, 17(1), p. e2025042. doi: 10.4084/MJHID.2025.042.
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Scientific Letters
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Author Biography
SUPARNO CHAKRABARTI, Immunology and Cellular Therapy, Manashi Chakrabarti Foundation
PROGRAM DIRECTOR, DEPT OF BMT AND HEMATOLOGY