Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition - A Descriptive Observational Retrospective Multicenter Analysis.

Introduction: Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.
Methods: This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).
Results: In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4-49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.
Conclusion: Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.
Competing Interests: AZ received travel support from Novartis, Sanofi Genzyme, and Bristol-Myers Squibb, outside the submitted work. RK has received speaker fees by NG-Akademie GmbH and Hollister Incorporated, outside the submitted work. MS is an honoraria and/or travel grants from Abbvie, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer and Sanofi-Aventis. AG: Speaker´s honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp & Dohme, Pfizer and Roche. BB received speaker fees for BMS, MSD, Novartis. Travel accomodation: BMS, Pierre Fabre. MS is an honoria for advisory board for Sanofi/Regneron and speaker fees für Novartis Pharma AG. GM has received speaker fees from PharmaMar, outside the submitted work. DJ received advisory board honoraria from BMS, Catalyst, Iovance, Jansen, Merck, Novartis, Oncosec, and Pfizer, and research funding from BMS and Incyte. LS is an honoraria for advisory boards & speaker fees from BMS. CaL received Advisory board: Roche, Novartis, BMS, MSD, SunPharma, Biontech, Kyowa Kirin, Sanofi, Pierre Fabre, Merck; Speakers fee: Roche, Novartis, BMS, MSD, SunPharma, Biontech, Kyowa Kirin, Sanofi, Pierre Fabre, Merck; Travel reimbursement: Roche, Novartis, BMS, MSD, SunPharma, Biontech, Kyowa Kirin, Sanofi, Pierre Fabre, Merck. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, Pierre Fabre, SUNPHARMA and LEO. GL is a consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., Specialised Therapeutics Australia Pty Ltd. AM is an honoraria for advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. MC is a consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD, and Novartis. CeL received Honoraria: Roche; BMS; Novartis; Amgen; MSD; Pierre Fabre; Pfizer; Incyte; Consulting or Advisory Role: BMS; MSD; Novartis; Amgen; Roche; Merck Serono; Sanofi; Pierre Fabre; Speakers’ Bureau: Roche; BMS; Novartis; Amgen; MSD; Research Funding: Roche; BMS; Travel, Accommodations, Expenses: BMS; MSD; Novartis; Sanofi; Pierre Fabre; Other Relationship: Avantis Medical Systems (board). MT received grants and personal fees from MSD, Ono Pharmaceutical, BMS, Bayer, Eisai, Novartis, Pfizer, Rakuten Medical, Merck Biopharma, personal fees from LOXO, Celgene, Amgen, outside the submitted work. PB received research funding from BeiGene, BMS, MSD and Takeda; advisory board honoraria from Takeda; speakers honoraria from BMS and travel support from Celgene, all outside the submitted work. TEi received speaker fees from Novartis, Pierre Fabre, MSD, Sanofi Genzyme, Alirall Hermal and Bristol-Myers Squibb, outside the submitted work. KK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. RG: Invited speaker: Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre. Advisory board: BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, Bayer, MerckSerono, Pfizer, Immunocore. Research grants: Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi. Travel/meeting support: Roche, BMS, SUN, Merck-Serono, Pierre-Fabre, outside the submitted work. CB received advisory board honoraria and/or speaker´s fees from Amgen, BMS, Immunocore, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, and Sanofi-Aventis. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. JB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. EL served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Medac, Pierre Fabre, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. JH received research support from BMS; advisory board honoraria from Pierre Fabre, Sanofi, Sun Pharma and MSD; speakers honoraria from GSK, Amgen, BMS, MSD, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre and 4SC. DS reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. LH reports Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Curevac, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Roche, Amgen, GSK, Curevac and Novartis. LZ reports being a consultant and/or receiving honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sunpharma and Sanofi; research funding to institution from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Zaremba, Kramer, De Temple, Bertram, Salzmann, Gesierich, Reinhardt, Baroudjian, Sachse, Mechtersheimer, Johnson, Weppler, Spain, Loquai, Dudda, Pföhler, Hepner, Long, Menzies, Carlino, Lebbé, Enokida, Tahara, Bröckelmann, Eigentler, Kähler, Gutzmer, Berking, Ugurel, Stadtler, Sucker, Becker, Livingstone, Meier, Hassel, Schadendorf, Hanoun, Heinzerling and Zimmer.)