Poor Hematopoietic Reserve at the Time of CD19 CAR T-Cell Infusion Is Associated with Long Term B-Cell Aplasia
Background: On-target off-tumor toxicities of anti-CD19 CAR T-cell therapy include B-cell aplasia and hypogammaglobulinemia. Long term B-cell aplasia is hypothesized to represent functional CAR T-cell engraftment (Melenhorst, Nature 2022), while peripheral blood B-cell recovery represents the loss o...
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| Veröffentlicht in: | Blood 2023-11, Vol.142 (Supplement 1), p.3512-3512 |
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| creator | Johnson, Grace Patel, Kedar Arciola, Brian Perez Perez, Ariel Wood, Anthony Ionescu, Filip Logue, Jennifer M Albanyan, Omar Yasin, Hassaan Bachmeier, Christina A Reid, Kayla Menges, Meghan Corallo, Salvatore Shah, Bijal D. Chavez, Julio C Khimani, Farhad Nishihori, Taiga Faramand, Rawan Liu, Hien Lazaryan, Aleksandr Rejeski, Kai Subklewe, Marion Perna, Fabiana Davila, Marco Mhaskar, Rahul Locke, Frederick L. Jain, Michael D. |
| description | Background: On-target off-tumor toxicities of anti-CD19 CAR T-cell therapy include B-cell aplasia and hypogammaglobulinemia. Long term B-cell aplasia is hypothesized to represent functional CAR T-cell engraftment (Melenhorst, Nature 2022), while peripheral blood B-cell recovery represents the loss of functional CAR-T cells against target over time. Patients with large B-cell lymphoma (LBCL) who are clinical responders have a 50-70% chance of B-cell recovery in the first year, with the remainder experiencing longer term B-cell aplasia (Logue, Haematologica 2021). Here, we sought to identify factors associated with long term B-cell aplasia using a cohort of responding patients who received CAR T-cell therapy for LBCL.
Methods:This retrospective cohort study included 57 patients with LBCL treated with CD19-targeted CAR T-cell therapy between June 2016 and August 2020 at Moffitt Cancer Center who exhibited complete or partial response at six months after CAR T-cell infusion. Patients were treated with with axicabtagene ciloleucel (axi-cel; n=50) or tisagenlecleucel (tisa-cel; n=7), either as standard-of-care therapy (n=47) or as part of a previously published clinical trial (n=10; NCT02348216, NCT03391466, NCT03153462). Peripheral blood B-cells were measured by flow cytometry using CD19 expression as part of routine clinical care at baseline and periodically after infusion. Prolonged B-cell aplasia was defined as a CD19+ B cell count comprising less than 1% of peripheral blood mononuclear cells during a minimum of two separate time points beyond 6 months of follow-up. Patients were defined as having B cell recovery if >1% B-cells were observed in peripheral blood at any time after CAR T-cell infusion.
Results: At a median follow up of 33 months (95% CI: 28.7, 37.3 months), 29 (51%) patients had persistent B-cell aplasia and 28 (49%) had recovery of peripheral B-cell counts. Median B-cell count at 12 months in the recovery group was 84/µL (IQR 2.5-197) compared to 0/µL (IQR 0-1) in the aplasia group. Patients with long-term B-cell aplasia had lower CD4 T-cell counts prior to CAR T-cell infusion [median 200/µL (IQR 136-278) vs. 330/µL (IQR 224-451); P= 0.008] and over time compared to patients with B-cell recovery (Fig. A). Patients with long-term B cell aplasia also had lower pre-infusion absolute neutrophil counts (2.3K/µL (IQR 1.4-4.15) vs. 3.5K/µL (IQR 2.8-4.2); P |
| doi_str_mv | 10.1182/blood-2023-185097 |
| format | Article |
| fullrecord | <record><control><sourceid>elsevier_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1182_blood_2023_185097</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006497123101145</els_id><sourcerecordid>S0006497123101145</sourcerecordid><originalsourceid>FETCH-LOGICAL-c947-119dc2cb1bc15fc28a458e8ae36f6d86ac93ca9f25d4aa61531730baa6cdbd883</originalsourceid><addsrcrecordid>eNp9kMtOwzAQRS0EEqXwAez8AwaP83LEKoRHK1UCVdlbjj2hRklc2QHE39MS1qzmLuZcXR1CroHfAEhx2_beWya4SBjIjJfFCVlAJiTjXPBTsuCc5ywtCzgnFzG-cw5pIrIFGV-9D3SFg5783jucnKFbjBg-keqJTjukjRuQ-o7WD1DSutrShtXY93Q9dh_R-ZGuI61i9MbpCS39ctOObvz4RhsMA72fn6t9r6PTl-Ss033Eq7-7JM3TY1Ov2ObleV1XG2bKtGAApTXCtNAayDojpE4ziVJjkne5lbk2ZWJ02YnMplrnkCVQJLw9RGNbK2WyJDDXmuBjDNipfXCDDt8KuDr6Ur--1NGXmn0dmLuZwcOuT4dBReNwNGhdQDMp690_9A-rmHKX</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Poor Hematopoietic Reserve at the Time of CD19 CAR T-Cell Infusion Is Associated with Long Term B-Cell Aplasia</title><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Johnson, Grace ; Patel, Kedar ; Arciola, Brian ; Perez Perez, Ariel ; Wood, Anthony ; Ionescu, Filip ; Logue, Jennifer M ; Albanyan, Omar ; Yasin, Hassaan ; Bachmeier, Christina A ; Reid, Kayla ; Menges, Meghan ; Corallo, Salvatore ; Shah, Bijal D. ; Chavez, Julio C ; Khimani, Farhad ; Nishihori, Taiga ; Faramand, Rawan ; Liu, Hien ; Lazaryan, Aleksandr ; Rejeski, Kai ; Subklewe, Marion ; Perna, Fabiana ; Davila, Marco ; Mhaskar, Rahul ; Locke, Frederick L. ; Jain, Michael D.</creator><creatorcontrib>Johnson, Grace ; Patel, Kedar ; Arciola, Brian ; Perez Perez, Ariel ; Wood, Anthony ; Ionescu, Filip ; Logue, Jennifer M ; Albanyan, Omar ; Yasin, Hassaan ; Bachmeier, Christina A ; Reid, Kayla ; Menges, Meghan ; Corallo, Salvatore ; Shah, Bijal D. ; Chavez, Julio C ; Khimani, Farhad ; Nishihori, Taiga ; Faramand, Rawan ; Liu, Hien ; Lazaryan, Aleksandr ; Rejeski, Kai ; Subklewe, Marion ; Perna, Fabiana ; Davila, Marco ; Mhaskar, Rahul ; Locke, Frederick L. ; Jain, Michael D.</creatorcontrib><description>Background: On-target off-tumor toxicities of anti-CD19 CAR T-cell therapy include B-cell aplasia and hypogammaglobulinemia. Long term B-cell aplasia is hypothesized to represent functional CAR T-cell engraftment (Melenhorst, Nature 2022), while peripheral blood B-cell recovery represents the loss of functional CAR-T cells against target over time. Patients with large B-cell lymphoma (LBCL) who are clinical responders have a 50-70% chance of B-cell recovery in the first year, with the remainder experiencing longer term B-cell aplasia (Logue, Haematologica 2021). Here, we sought to identify factors associated with long term B-cell aplasia using a cohort of responding patients who received CAR T-cell therapy for LBCL.
Methods:This retrospective cohort study included 57 patients with LBCL treated with CD19-targeted CAR T-cell therapy between June 2016 and August 2020 at Moffitt Cancer Center who exhibited complete or partial response at six months after CAR T-cell infusion. Patients were treated with with axicabtagene ciloleucel (axi-cel; n=50) or tisagenlecleucel (tisa-cel; n=7), either as standard-of-care therapy (n=47) or as part of a previously published clinical trial (n=10; NCT02348216, NCT03391466, NCT03153462). Peripheral blood B-cells were measured by flow cytometry using CD19 expression as part of routine clinical care at baseline and periodically after infusion. Prolonged B-cell aplasia was defined as a CD19+ B cell count comprising less than 1% of peripheral blood mononuclear cells during a minimum of two separate time points beyond 6 months of follow-up. Patients were defined as having B cell recovery if >1% B-cells were observed in peripheral blood at any time after CAR T-cell infusion.
Results: At a median follow up of 33 months (95% CI: 28.7, 37.3 months), 29 (51%) patients had persistent B-cell aplasia and 28 (49%) had recovery of peripheral B-cell counts. Median B-cell count at 12 months in the recovery group was 84/µL (IQR 2.5-197) compared to 0/µL (IQR 0-1) in the aplasia group. Patients with long-term B-cell aplasia had lower CD4 T-cell counts prior to CAR T-cell infusion [median 200/µL (IQR 136-278) vs. 330/µL (IQR 224-451); P= 0.008] and over time compared to patients with B-cell recovery (Fig. A). Patients with long-term B cell aplasia also had lower pre-infusion absolute neutrophil counts (2.3K/µL (IQR 1.4-4.15) vs. 3.5K/µL (IQR 2.8-4.2); P<0.001) and higher baseline CAR-HEMATOTOX scores [2 (IQR 1-3.25) vs 1 (IQR 0-1)], consistent with poor baseline hematopoietic reserve (Rejeski, Blood 2021). While disease-related mortality did not significantly differ between groups, non-relapse mortality was markedly higher in patients with long-term B-cell aplasia due to infection: all 8 patient deaths in the aplasia group were due to infections occurring beyond day 30 post-infusion, with 6 of the 8 deaths due to COVID-19. However, no patients in the B-cell recovery group died of late infection (Fig. B).
Conclusions: Long term B-cell aplasia is hypothesized to represent ongoing CAR T-cell activity against normal B-cells. However, our results demonstrate that B-cell aplasia is associated with low baseline hematopoietic reserve and subsequent poor immune reconstitution of multiple lineages including B-cells, T-cells, and myeloid cells. Further studies are warranted to assess whether poor immune reconstitution and B-cell aplasia are related to long term CAR T-cell activity or other processes. These patients are at higher risk for non-relapse mortality from infection, and mitigation strategies are needed.
Perez Perez:Gilead Kite: Speakers Bureau. Bachmeier:Kite Pharma: Consultancy. Shah:Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Moffitt Cancer Center: Current Employment; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Chavez:Epizyme: Speakers Bureau; Cellectar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Merck: Research Funding; Morphosys: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Nishihori:Medexus: Speakers Bureau; Moffitt Cancer Center: Other: Personal fees from Karyopharm and Novartis outside the submitted work. Faramand:Gilead: Research Funding; Kite: Research Funding. Liu:BioLineRx: Membership on an entity's Board of Directors or advisory committees. Lazaryan:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rejeski:Novartis: Honoraria; BMS/CELGENE: Consultancy, Honoraria; Kite/Gilead: Other: Travel Support, Research Funding; Pierre-Fabre: Other: Travel Support. Subklewe:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte Biosciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; AvenCell: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; Ichnos Sciences: Consultancy, Honoraria; Seagen: Research Funding; Molecular Partners: Consultancy, Honoraria, Research Funding; GSK: Speakers Bureau; LAWG: Speakers Bureau; Springer Healthcare: Speakers Bureau; AbbVie: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; advesya (CanCell Therapeutics): Consultancy, Honoraria; Genmab US: Consultancy, Honoraria; Interius BioTherapeutics: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Orbital Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Scare: Consultancy, Honoraria. Davila:Precision Biosciences: Other: Ownership interest (stock, stock options in a publicly owned company); Legend Biotech: Consultancy; Kite Pharma Inc.: Other: Teaching and Speaking; Caribou Biosciences: Consultancy; Capstan: Other: Advisor or review panel participant; CRISPR (CRSP): Patents & Royalties: Intellectual property rights (Royalties or patent sales); Bellicum Pharmaceuticals, Inc.: Other: Advisor or review panel participant; Ownership interest (stock, stock options in a publicly owned company); Adicet: Consultancy; Atara Biotherapeutics: Consultancy; Adaptive Biotechnologies: Other: Ownership interest (stock, stock options in a publicly owned company); Syncopation Life Sciences: Consultancy; Synthekine: Consultancy. Locke:Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cowen: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Daiichi Sankyo: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions: Consultancy, Other; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Other; Leukemia and Lymphoma Society: Other; National Cancer Institute: Other; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioPharma Communications CARE Education: Other: Institutional; Clinical Care Options Oncology: Other; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy; Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellular Medicine Group: Consultancy; Imedex: Other; Calibr: Consultancy; CERo Therapeutics: Other: (Institutional); EcoR1: Consultancy; ASH: Other: Travel Support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Other: Travel Support; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Gerson Lehrman Group (GLG): Consultancy; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Jain:Kite/Gilead: Consultancy, Honoraria, Research Funding; Loxo@</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2023-185097</identifier><language>eng</language><publisher>Elsevier Inc</publisher><ispartof>Blood, 2023-11, Vol.142 (Supplement 1), p.3512-3512</ispartof><rights>2023 The American Society of Hematology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids></links><search><creatorcontrib>Johnson, Grace</creatorcontrib><creatorcontrib>Patel, Kedar</creatorcontrib><creatorcontrib>Arciola, Brian</creatorcontrib><creatorcontrib>Perez Perez, Ariel</creatorcontrib><creatorcontrib>Wood, Anthony</creatorcontrib><creatorcontrib>Ionescu, Filip</creatorcontrib><creatorcontrib>Logue, Jennifer M</creatorcontrib><creatorcontrib>Albanyan, Omar</creatorcontrib><creatorcontrib>Yasin, Hassaan</creatorcontrib><creatorcontrib>Bachmeier, Christina A</creatorcontrib><creatorcontrib>Reid, Kayla</creatorcontrib><creatorcontrib>Menges, Meghan</creatorcontrib><creatorcontrib>Corallo, Salvatore</creatorcontrib><creatorcontrib>Shah, Bijal D.</creatorcontrib><creatorcontrib>Chavez, Julio C</creatorcontrib><creatorcontrib>Khimani, Farhad</creatorcontrib><creatorcontrib>Nishihori, Taiga</creatorcontrib><creatorcontrib>Faramand, Rawan</creatorcontrib><creatorcontrib>Liu, Hien</creatorcontrib><creatorcontrib>Lazaryan, Aleksandr</creatorcontrib><creatorcontrib>Rejeski, Kai</creatorcontrib><creatorcontrib>Subklewe, Marion</creatorcontrib><creatorcontrib>Perna, Fabiana</creatorcontrib><creatorcontrib>Davila, Marco</creatorcontrib><creatorcontrib>Mhaskar, Rahul</creatorcontrib><creatorcontrib>Locke, Frederick L.</creatorcontrib><creatorcontrib>Jain, Michael D.</creatorcontrib><title>Poor Hematopoietic Reserve at the Time of CD19 CAR T-Cell Infusion Is Associated with Long Term B-Cell Aplasia</title><title>Blood</title><description>Background: On-target off-tumor toxicities of anti-CD19 CAR T-cell therapy include B-cell aplasia and hypogammaglobulinemia. Long term B-cell aplasia is hypothesized to represent functional CAR T-cell engraftment (Melenhorst, Nature 2022), while peripheral blood B-cell recovery represents the loss of functional CAR-T cells against target over time. Patients with large B-cell lymphoma (LBCL) who are clinical responders have a 50-70% chance of B-cell recovery in the first year, with the remainder experiencing longer term B-cell aplasia (Logue, Haematologica 2021). Here, we sought to identify factors associated with long term B-cell aplasia using a cohort of responding patients who received CAR T-cell therapy for LBCL.
Methods:This retrospective cohort study included 57 patients with LBCL treated with CD19-targeted CAR T-cell therapy between June 2016 and August 2020 at Moffitt Cancer Center who exhibited complete or partial response at six months after CAR T-cell infusion. Patients were treated with with axicabtagene ciloleucel (axi-cel; n=50) or tisagenlecleucel (tisa-cel; n=7), either as standard-of-care therapy (n=47) or as part of a previously published clinical trial (n=10; NCT02348216, NCT03391466, NCT03153462). Peripheral blood B-cells were measured by flow cytometry using CD19 expression as part of routine clinical care at baseline and periodically after infusion. Prolonged B-cell aplasia was defined as a CD19+ B cell count comprising less than 1% of peripheral blood mononuclear cells during a minimum of two separate time points beyond 6 months of follow-up. Patients were defined as having B cell recovery if >1% B-cells were observed in peripheral blood at any time after CAR T-cell infusion.
Results: At a median follow up of 33 months (95% CI: 28.7, 37.3 months), 29 (51%) patients had persistent B-cell aplasia and 28 (49%) had recovery of peripheral B-cell counts. Median B-cell count at 12 months in the recovery group was 84/µL (IQR 2.5-197) compared to 0/µL (IQR 0-1) in the aplasia group. Patients with long-term B-cell aplasia had lower CD4 T-cell counts prior to CAR T-cell infusion [median 200/µL (IQR 136-278) vs. 330/µL (IQR 224-451); P= 0.008] and over time compared to patients with B-cell recovery (Fig. A). Patients with long-term B cell aplasia also had lower pre-infusion absolute neutrophil counts (2.3K/µL (IQR 1.4-4.15) vs. 3.5K/µL (IQR 2.8-4.2); P<0.001) and higher baseline CAR-HEMATOTOX scores [2 (IQR 1-3.25) vs 1 (IQR 0-1)], consistent with poor baseline hematopoietic reserve (Rejeski, Blood 2021). While disease-related mortality did not significantly differ between groups, non-relapse mortality was markedly higher in patients with long-term B-cell aplasia due to infection: all 8 patient deaths in the aplasia group were due to infections occurring beyond day 30 post-infusion, with 6 of the 8 deaths due to COVID-19. However, no patients in the B-cell recovery group died of late infection (Fig. B).
Conclusions: Long term B-cell aplasia is hypothesized to represent ongoing CAR T-cell activity against normal B-cells. However, our results demonstrate that B-cell aplasia is associated with low baseline hematopoietic reserve and subsequent poor immune reconstitution of multiple lineages including B-cells, T-cells, and myeloid cells. Further studies are warranted to assess whether poor immune reconstitution and B-cell aplasia are related to long term CAR T-cell activity or other processes. These patients are at higher risk for non-relapse mortality from infection, and mitigation strategies are needed.
Perez Perez:Gilead Kite: Speakers Bureau. Bachmeier:Kite Pharma: Consultancy. Shah:Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Moffitt Cancer Center: Current Employment; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Chavez:Epizyme: Speakers Bureau; Cellectar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Merck: Research Funding; Morphosys: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Nishihori:Medexus: Speakers Bureau; Moffitt Cancer Center: Other: Personal fees from Karyopharm and Novartis outside the submitted work. Faramand:Gilead: Research Funding; Kite: Research Funding. Liu:BioLineRx: Membership on an entity's Board of Directors or advisory committees. Lazaryan:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rejeski:Novartis: Honoraria; BMS/CELGENE: Consultancy, Honoraria; Kite/Gilead: Other: Travel Support, Research Funding; Pierre-Fabre: Other: Travel Support. Subklewe:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte Biosciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; AvenCell: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; Ichnos Sciences: Consultancy, Honoraria; Seagen: Research Funding; Molecular Partners: Consultancy, Honoraria, Research Funding; GSK: Speakers Bureau; LAWG: Speakers Bureau; Springer Healthcare: Speakers Bureau; AbbVie: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; advesya (CanCell Therapeutics): Consultancy, Honoraria; Genmab US: Consultancy, Honoraria; Interius BioTherapeutics: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Orbital Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Scare: Consultancy, Honoraria. Davila:Precision Biosciences: Other: Ownership interest (stock, stock options in a publicly owned company); Legend Biotech: Consultancy; Kite Pharma Inc.: Other: Teaching and Speaking; Caribou Biosciences: Consultancy; Capstan: Other: Advisor or review panel participant; CRISPR (CRSP): Patents & Royalties: Intellectual property rights (Royalties or patent sales); Bellicum Pharmaceuticals, Inc.: Other: Advisor or review panel participant; Ownership interest (stock, stock options in a publicly owned company); Adicet: Consultancy; Atara Biotherapeutics: Consultancy; Adaptive Biotechnologies: Other: Ownership interest (stock, stock options in a publicly owned company); Syncopation Life Sciences: Consultancy; Synthekine: Consultancy. Locke:Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cowen: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Daiichi Sankyo: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions: Consultancy, Other; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Other; Leukemia and Lymphoma Society: Other; National Cancer Institute: Other; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioPharma Communications CARE Education: Other: Institutional; Clinical Care Options Oncology: Other; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy; Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellular Medicine Group: Consultancy; Imedex: Other; Calibr: Consultancy; CERo Therapeutics: Other: (Institutional); EcoR1: Consultancy; ASH: Other: Travel Support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Other: Travel Support; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Gerson Lehrman Group (GLG): Consultancy; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Jain:Kite/Gilead: Consultancy, Honoraria, Research Funding; Loxo@</description><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kMtOwzAQRS0EEqXwAez8AwaP83LEKoRHK1UCVdlbjj2hRklc2QHE39MS1qzmLuZcXR1CroHfAEhx2_beWya4SBjIjJfFCVlAJiTjXPBTsuCc5ywtCzgnFzG-cw5pIrIFGV-9D3SFg5783jucnKFbjBg-keqJTjukjRuQ-o7WD1DSutrShtXY93Q9dh_R-ZGuI61i9MbpCS39ctOObvz4RhsMA72fn6t9r6PTl-Ss033Eq7-7JM3TY1Ov2ObleV1XG2bKtGAApTXCtNAayDojpE4ziVJjkne5lbk2ZWJ02YnMplrnkCVQJLw9RGNbK2WyJDDXmuBjDNipfXCDDt8KuDr6Ur--1NGXmn0dmLuZwcOuT4dBReNwNGhdQDMp690_9A-rmHKX</recordid><startdate>20231102</startdate><enddate>20231102</enddate><creator>Johnson, Grace</creator><creator>Patel, Kedar</creator><creator>Arciola, Brian</creator><creator>Perez Perez, Ariel</creator><creator>Wood, Anthony</creator><creator>Ionescu, Filip</creator><creator>Logue, Jennifer M</creator><creator>Albanyan, Omar</creator><creator>Yasin, Hassaan</creator><creator>Bachmeier, Christina A</creator><creator>Reid, Kayla</creator><creator>Menges, Meghan</creator><creator>Corallo, Salvatore</creator><creator>Shah, Bijal D.</creator><creator>Chavez, Julio C</creator><creator>Khimani, Farhad</creator><creator>Nishihori, Taiga</creator><creator>Faramand, Rawan</creator><creator>Liu, Hien</creator><creator>Lazaryan, Aleksandr</creator><creator>Rejeski, Kai</creator><creator>Subklewe, Marion</creator><creator>Perna, Fabiana</creator><creator>Davila, Marco</creator><creator>Mhaskar, Rahul</creator><creator>Locke, Frederick L.</creator><creator>Jain, Michael D.</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20231102</creationdate><title>Poor Hematopoietic Reserve at the Time of CD19 CAR T-Cell Infusion Is Associated with Long Term B-Cell Aplasia</title><author>Johnson, Grace ; Patel, Kedar ; Arciola, Brian ; Perez Perez, Ariel ; Wood, Anthony ; Ionescu, Filip ; Logue, Jennifer M ; Albanyan, Omar ; Yasin, Hassaan ; Bachmeier, Christina A ; Reid, Kayla ; Menges, Meghan ; Corallo, Salvatore ; Shah, Bijal D. ; Chavez, Julio C ; Khimani, Farhad ; Nishihori, Taiga ; Faramand, Rawan ; Liu, Hien ; Lazaryan, Aleksandr ; Rejeski, Kai ; Subklewe, Marion ; Perna, Fabiana ; Davila, Marco ; Mhaskar, Rahul ; Locke, Frederick L. ; Jain, Michael D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c947-119dc2cb1bc15fc28a458e8ae36f6d86ac93ca9f25d4aa61531730baa6cdbd883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johnson, Grace</creatorcontrib><creatorcontrib>Patel, Kedar</creatorcontrib><creatorcontrib>Arciola, Brian</creatorcontrib><creatorcontrib>Perez Perez, Ariel</creatorcontrib><creatorcontrib>Wood, Anthony</creatorcontrib><creatorcontrib>Ionescu, Filip</creatorcontrib><creatorcontrib>Logue, Jennifer M</creatorcontrib><creatorcontrib>Albanyan, Omar</creatorcontrib><creatorcontrib>Yasin, Hassaan</creatorcontrib><creatorcontrib>Bachmeier, Christina A</creatorcontrib><creatorcontrib>Reid, Kayla</creatorcontrib><creatorcontrib>Menges, Meghan</creatorcontrib><creatorcontrib>Corallo, Salvatore</creatorcontrib><creatorcontrib>Shah, Bijal D.</creatorcontrib><creatorcontrib>Chavez, Julio C</creatorcontrib><creatorcontrib>Khimani, Farhad</creatorcontrib><creatorcontrib>Nishihori, Taiga</creatorcontrib><creatorcontrib>Faramand, Rawan</creatorcontrib><creatorcontrib>Liu, Hien</creatorcontrib><creatorcontrib>Lazaryan, Aleksandr</creatorcontrib><creatorcontrib>Rejeski, Kai</creatorcontrib><creatorcontrib>Subklewe, Marion</creatorcontrib><creatorcontrib>Perna, Fabiana</creatorcontrib><creatorcontrib>Davila, Marco</creatorcontrib><creatorcontrib>Mhaskar, Rahul</creatorcontrib><creatorcontrib>Locke, Frederick L.</creatorcontrib><creatorcontrib>Jain, Michael D.</creatorcontrib><collection>CrossRef</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johnson, Grace</au><au>Patel, Kedar</au><au>Arciola, Brian</au><au>Perez Perez, Ariel</au><au>Wood, Anthony</au><au>Ionescu, Filip</au><au>Logue, Jennifer M</au><au>Albanyan, Omar</au><au>Yasin, Hassaan</au><au>Bachmeier, Christina A</au><au>Reid, Kayla</au><au>Menges, Meghan</au><au>Corallo, Salvatore</au><au>Shah, Bijal D.</au><au>Chavez, Julio C</au><au>Khimani, Farhad</au><au>Nishihori, Taiga</au><au>Faramand, Rawan</au><au>Liu, Hien</au><au>Lazaryan, Aleksandr</au><au>Rejeski, Kai</au><au>Subklewe, Marion</au><au>Perna, Fabiana</au><au>Davila, Marco</au><au>Mhaskar, Rahul</au><au>Locke, Frederick L.</au><au>Jain, Michael D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poor Hematopoietic Reserve at the Time of CD19 CAR T-Cell Infusion Is Associated with Long Term B-Cell Aplasia</atitle><jtitle>Blood</jtitle><date>2023-11-02</date><risdate>2023</risdate><volume>142</volume><issue>Supplement 1</issue><spage>3512</spage><epage>3512</epage><pages>3512-3512</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Background: On-target off-tumor toxicities of anti-CD19 CAR T-cell therapy include B-cell aplasia and hypogammaglobulinemia. Long term B-cell aplasia is hypothesized to represent functional CAR T-cell engraftment (Melenhorst, Nature 2022), while peripheral blood B-cell recovery represents the loss of functional CAR-T cells against target over time. Patients with large B-cell lymphoma (LBCL) who are clinical responders have a 50-70% chance of B-cell recovery in the first year, with the remainder experiencing longer term B-cell aplasia (Logue, Haematologica 2021). Here, we sought to identify factors associated with long term B-cell aplasia using a cohort of responding patients who received CAR T-cell therapy for LBCL.
Methods:This retrospective cohort study included 57 patients with LBCL treated with CD19-targeted CAR T-cell therapy between June 2016 and August 2020 at Moffitt Cancer Center who exhibited complete or partial response at six months after CAR T-cell infusion. Patients were treated with with axicabtagene ciloleucel (axi-cel; n=50) or tisagenlecleucel (tisa-cel; n=7), either as standard-of-care therapy (n=47) or as part of a previously published clinical trial (n=10; NCT02348216, NCT03391466, NCT03153462). Peripheral blood B-cells were measured by flow cytometry using CD19 expression as part of routine clinical care at baseline and periodically after infusion. Prolonged B-cell aplasia was defined as a CD19+ B cell count comprising less than 1% of peripheral blood mononuclear cells during a minimum of two separate time points beyond 6 months of follow-up. Patients were defined as having B cell recovery if >1% B-cells were observed in peripheral blood at any time after CAR T-cell infusion.
Results: At a median follow up of 33 months (95% CI: 28.7, 37.3 months), 29 (51%) patients had persistent B-cell aplasia and 28 (49%) had recovery of peripheral B-cell counts. Median B-cell count at 12 months in the recovery group was 84/µL (IQR 2.5-197) compared to 0/µL (IQR 0-1) in the aplasia group. Patients with long-term B-cell aplasia had lower CD4 T-cell counts prior to CAR T-cell infusion [median 200/µL (IQR 136-278) vs. 330/µL (IQR 224-451); P= 0.008] and over time compared to patients with B-cell recovery (Fig. A). Patients with long-term B cell aplasia also had lower pre-infusion absolute neutrophil counts (2.3K/µL (IQR 1.4-4.15) vs. 3.5K/µL (IQR 2.8-4.2); P<0.001) and higher baseline CAR-HEMATOTOX scores [2 (IQR 1-3.25) vs 1 (IQR 0-1)], consistent with poor baseline hematopoietic reserve (Rejeski, Blood 2021). While disease-related mortality did not significantly differ between groups, non-relapse mortality was markedly higher in patients with long-term B-cell aplasia due to infection: all 8 patient deaths in the aplasia group were due to infections occurring beyond day 30 post-infusion, with 6 of the 8 deaths due to COVID-19. However, no patients in the B-cell recovery group died of late infection (Fig. B).
Conclusions: Long term B-cell aplasia is hypothesized to represent ongoing CAR T-cell activity against normal B-cells. However, our results demonstrate that B-cell aplasia is associated with low baseline hematopoietic reserve and subsequent poor immune reconstitution of multiple lineages including B-cells, T-cells, and myeloid cells. Further studies are warranted to assess whether poor immune reconstitution and B-cell aplasia are related to long term CAR T-cell activity or other processes. These patients are at higher risk for non-relapse mortality from infection, and mitigation strategies are needed.
Perez Perez:Gilead Kite: Speakers Bureau. Bachmeier:Kite Pharma: Consultancy. Shah:Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Moffitt Cancer Center: Current Employment; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Chavez:Epizyme: Speakers Bureau; Cellectar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Merck: Research Funding; Morphosys: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Nishihori:Medexus: Speakers Bureau; Moffitt Cancer Center: Other: Personal fees from Karyopharm and Novartis outside the submitted work. Faramand:Gilead: Research Funding; Kite: Research Funding. Liu:BioLineRx: Membership on an entity's Board of Directors or advisory committees. Lazaryan:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rejeski:Novartis: Honoraria; BMS/CELGENE: Consultancy, Honoraria; Kite/Gilead: Other: Travel Support, Research Funding; Pierre-Fabre: Other: Travel Support. Subklewe:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte Biosciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; AvenCell: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; Ichnos Sciences: Consultancy, Honoraria; Seagen: Research Funding; Molecular Partners: Consultancy, Honoraria, Research Funding; GSK: Speakers Bureau; LAWG: Speakers Bureau; Springer Healthcare: Speakers Bureau; AbbVie: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; advesya (CanCell Therapeutics): Consultancy, Honoraria; Genmab US: Consultancy, Honoraria; Interius BioTherapeutics: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Orbital Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Scare: Consultancy, Honoraria. Davila:Precision Biosciences: Other: Ownership interest (stock, stock options in a publicly owned company); Legend Biotech: Consultancy; Kite Pharma Inc.: Other: Teaching and Speaking; Caribou Biosciences: Consultancy; Capstan: Other: Advisor or review panel participant; CRISPR (CRSP): Patents & Royalties: Intellectual property rights (Royalties or patent sales); Bellicum Pharmaceuticals, Inc.: Other: Advisor or review panel participant; Ownership interest (stock, stock options in a publicly owned company); Adicet: Consultancy; Atara Biotherapeutics: Consultancy; Adaptive Biotechnologies: Other: Ownership interest (stock, stock options in a publicly owned company); Syncopation Life Sciences: Consultancy; Synthekine: Consultancy. Locke:Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cowen: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Daiichi Sankyo: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions: Consultancy, Other; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Other; Leukemia and Lymphoma Society: Other; National Cancer Institute: Other; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioPharma Communications CARE Education: Other: Institutional; Clinical Care Options Oncology: Other; Pfizer: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy; Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellular Medicine Group: Consultancy; Imedex: Other; Calibr: Consultancy; CERo Therapeutics: Other: (Institutional); EcoR1: Consultancy; ASH: Other: Travel Support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Other: Travel Support; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Gerson Lehrman Group (GLG): Consultancy; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Jain:Kite/Gilead: Consultancy, Honoraria, Research Funding; Loxo@</abstract><pub>Elsevier Inc</pub><doi>10.1182/blood-2023-185097</doi><tpages>1</tpages></addata></record> |
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| title | Poor Hematopoietic Reserve at the Time of CD19 CAR T-Cell Infusion Is Associated with Long Term B-Cell Aplasia |
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