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Published in: BMC Infectious Diseases 1/2021

Open Access 01-12-2021 | Micafungin | Case report

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report

Authors: Kai Rejeski, Wolfgang G. Kunz, Martina Rudelius, Veit Bücklein, Viktoria Blumenberg, Christian Schmidt, Philipp Karschnia, Florian Schöberl, Konstantin Dimitriadis, Louisa von Baumgarten, Joachim Stemmler, Oliver Weigert, Martin Dreyling, Michael von Bergwelt-Baildon, Marion Subklewe

Published in: BMC Infectious Diseases | Issue 1/2021

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Abstract

Background

Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications.

Case presentation

We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis.

Conclusions

This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.
Literature
1.
go back to reference Nahas GR, Komanduri KV, Pereira D, Goodman M, Jimenez AM, Beitinjaneh A, et al. Incidence and risk factors associated with a syndrome of persistent cytopenias after CAR-T cell therapy (PCTT). Leuk Lymphoma. 2020;61(4):940–3.CrossRef Nahas GR, Komanduri KV, Pereira D, Goodman M, Jimenez AM, Beitinjaneh A, et al. Incidence and risk factors associated with a syndrome of persistent cytopenias after CAR-T cell therapy (PCTT). Leuk Lymphoma. 2020;61(4):940–3.CrossRef
2.
go back to reference Cordeiro A, Bezerra ED, Hirayama AV, Hill JA, Wu QV, Voutsinas J, et al. Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol Blood Marrow Transplant. 2020;26(1):26–33.CrossRef Cordeiro A, Bezerra ED, Hirayama AV, Hill JA, Wu QV, Voutsinas J, et al. Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Biol Blood Marrow Transplant. 2020;26(1):26–33.CrossRef
3.
go back to reference Fried S, Avigdor A, Bielorai B, Meir A, Besser MJ, Schachter J, et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019;54(10):1643–50.CrossRef Fried S, Avigdor A, Bielorai B, Meir A, Besser MJ, Schachter J, et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019;54(10):1643–50.CrossRef
4.
go back to reference Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, JP MG, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45–56.CrossRef Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, JP MG, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45–56.CrossRef
5.
go back to reference Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31–42.CrossRef Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31–42.CrossRef
6.
go back to reference Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367–76. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367–76.
7.
go back to reference Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625–38.CrossRef Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625–38.CrossRef
8.
go back to reference Valand HA, Huda F, Tu RK. Chimeric Antigen Receptor T-Cell Therapy: What the Neuroradiologist Needs to Know. AJNR Am J Neuroradiol. 2019;40(5):766–8.CrossRef Valand HA, Huda F, Tu RK. Chimeric Antigen Receptor T-Cell Therapy: What the Neuroradiologist Needs to Know. AJNR Am J Neuroradiol. 2019;40(5):766–8.CrossRef
9.
go back to reference Saberi A, Roudbary SA, Ghayeghran A, Kazemi S, Hosseininezhad M. Diagnosis of Meningitis Caused by Pathogenic Microorganisms Using Magnetic Resonance Imaging: A Systematic Review. Basic Clin Neurosci. 2018;9(2):73–86.CrossRef Saberi A, Roudbary SA, Ghayeghran A, Kazemi S, Hosseininezhad M. Diagnosis of Meningitis Caused by Pathogenic Microorganisms Using Magnetic Resonance Imaging: A Systematic Review. Basic Clin Neurosci. 2018;9(2):73–86.CrossRef
10.
go back to reference Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol. 2018;36(30):3043–54.CrossRef Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol. 2018;36(30):3043–54.CrossRef
11.
go back to reference Sterner RM, Sakemura R, Cox MJ, Yang N, Khadka RH, Forsman CL, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697–709.CrossRef Sterner RM, Sakemura R, Cox MJ, Yang N, Khadka RH, Forsman CL, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697–709.CrossRef
12.
go back to reference Rodrigues CF, Silva S, Henriques M. Candida glabrata: a review of its features and resistance. Eur J Clin Microbiol Infect Dis. 2014;33(5):673–88.CrossRef Rodrigues CF, Silva S, Henriques M. Candida glabrata: a review of its features and resistance. Eur J Clin Microbiol Infect Dis. 2014;33(5):673–88.CrossRef
13.
go back to reference Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD. Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species. Front Microbiol. 2016;7:2173.PubMed Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD. Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species. Front Microbiol. 2016;7:2173.PubMed
14.
go back to reference Wudhikarn K, Pennisi M, Garcia-Recio M, Flynn JR, Afuye A, Silverberg ML, et al. DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality. Blood Adv. 2020;4(13):3024–33.CrossRef Wudhikarn K, Pennisi M, Garcia-Recio M, Flynn JR, Afuye A, Silverberg ML, et al. DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality. Blood Adv. 2020;4(13):3024–33.CrossRef
15.
go back to reference Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;131(1):121–30.CrossRef Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;131(1):121–30.CrossRef
16.
go back to reference Park JH, Romero FA, Taur Y, Sadelain M, Brentjens RJ, Hohl TM, et al. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells. Clin Infect Dis. 2018;67(4):533–40.CrossRef Park JH, Romero FA, Taur Y, Sadelain M, Brentjens RJ, Hohl TM, et al. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells. Clin Infect Dis. 2018;67(4):533–40.CrossRef
17.
go back to reference Haidar G, Dorritie K, Farah R, Bogdanovich T, Nguyen MH, Samanta P. Invasive Mold Infections After Chimeric Antigen Receptor-Modified T-cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis. Clin Infect Dis. 2020;71(3):672–6. Haidar G, Dorritie K, Farah R, Bogdanovich T, Nguyen MH, Samanta P. Invasive Mold Infections After Chimeric Antigen Receptor-Modified T-cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis. Clin Infect Dis. 2020;71(3):672–6.
18.
go back to reference Wudhikarn K, Palomba ML, Pennisi M, Garcia-Recio M, Flynn JR, Devlin SM, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020;10(8):79.CrossRef Wudhikarn K, Palomba ML, Pennisi M, Garcia-Recio M, Flynn JR, Devlin SM, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020;10(8):79.CrossRef
19.
go back to reference Luo H, Wang N, Huang L, Zhou X, Jin J, Li C, et al. Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy. J Immunother Cancer. 2019;7(1):271.CrossRef Luo H, Wang N, Huang L, Zhou X, Jin J, Li C, et al. Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy. J Immunother Cancer. 2019;7(1):271.CrossRef
20.
go back to reference Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233–47.CrossRef Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233–47.CrossRef
21.
go back to reference Chen L, Wang Y, Zhang T, Li Y, Meng T, Liu L, et al. Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis. BMC Infect Dis. 2018;18(1):155.CrossRef Chen L, Wang Y, Zhang T, Li Y, Meng T, Liu L, et al. Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis. BMC Infect Dis. 2018;18(1):155.CrossRef
22.
go back to reference Healey KR, Nagasaki Y, Zimmerman M, Kordalewska M, Park S, Zhao Y, et al. The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination. Antimicrob Agents Chemother. 2017;61(12):e01412–7. Healey KR, Nagasaki Y, Zimmerman M, Kordalewska M, Park S, Zhao Y, et al. The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination. Antimicrob Agents Chemother. 2017;61(12):e01412–7.
23.
go back to reference van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39(10):1407–16.CrossRef van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39(10):1407–16.CrossRef
24.
go back to reference Jimenez Rosales R, CAB AC, Ojeda Hinojosa M. The first reported case of colonic infection caused by Candida glabrata. Rev Esp Enferm Dig. 2019;111(8):648.PubMed Jimenez Rosales R, CAB AC, Ojeda Hinojosa M. The first reported case of colonic infection caused by Candida glabrata. Rev Esp Enferm Dig. 2019;111(8):648.PubMed
25.
go back to reference Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(4):251–61.CrossRef Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(4):251–61.CrossRef
26.
go back to reference Jung J, Hong HL, Lee SO, Choi SH, Kim YS, Woo JH, et al. Immune reconstitution inflammatory syndrome in neutropenic patients with invasive pulmonary aspergillosis. J Infect. 2015;70(6):659–67.CrossRef Jung J, Hong HL, Lee SO, Choi SH, Kim YS, Woo JH, et al. Immune reconstitution inflammatory syndrome in neutropenic patients with invasive pulmonary aspergillosis. J Infect. 2015;70(6):659–67.CrossRef
Metadata
Title
Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report
Authors
Kai Rejeski
Wolfgang G. Kunz
Martina Rudelius
Veit Bücklein
Viktoria Blumenberg
Christian Schmidt
Philipp Karschnia
Florian Schöberl
Konstantin Dimitriadis
Louisa von Baumgarten
Joachim Stemmler
Oliver Weigert
Martin Dreyling
Michael von Bergwelt-Baildon
Marion Subklewe
Publication date
01-12-2021

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