Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients
Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We...
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-10-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000957 |
| _version_ | 1797280232666824704 |
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| author | Victoria Panagiota Johanna Franziska Kerschbaum Olaf Penack Catarina M. Stein Christopher M. Arends Christian Koenecke Paulina M. Strzelecka Arnold Kloos Laura Wiegand Alina Lasch Robert Altwasser Adriane Halik Razif Gabdoulline Julia Thomson Konstantin Weibl Georg-Nikolaus Franke Carolina Berger Justin Hasenkamp Francis Ayuk Il-Kang Na Gernot Beutel Ulrich Keller Lars Bullinger Gerald Georg Wulf Nicolaus Kröger Vladan Vucinic Michael Heuser Frederik Damm |
| author_facet | Victoria Panagiota Johanna Franziska Kerschbaum Olaf Penack Catarina M. Stein Christopher M. Arends Christian Koenecke Paulina M. Strzelecka Arnold Kloos Laura Wiegand Alina Lasch Robert Altwasser Adriane Halik Razif Gabdoulline Julia Thomson Konstantin Weibl Georg-Nikolaus Franke Carolina Berger Justin Hasenkamp Francis Ayuk Il-Kang Na Gernot Beutel Ulrich Keller Lars Bullinger Gerald Georg Wulf Nicolaus Kröger Vladan Vucinic Michael Heuser Frederik Damm |
| author_sort | Victoria Panagiota |
| collection | DOAJ |
| description | Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome. |
| first_indexed | 2024-03-07T16:37:14Z |
| format | Article |
| id | doaj.art-3ee53a5fe55248a48a4f66fd724ad837 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T16:37:14Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
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| series | HemaSphere |
| spelling | doaj.art-3ee53a5fe55248a48a4f66fd724ad8372024-03-03T09:26:57ZengWileyHemaSphere2572-92412023-10-01710e95710.1097/HS9.0000000000000957202310000-00009Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated PatientsVictoria Panagiota0Johanna Franziska Kerschbaum1Olaf Penack2Catarina M. Stein3Christopher M. Arends4Christian Koenecke5Paulina M. Strzelecka6Arnold Kloos7Laura Wiegand8Alina Lasch9Robert Altwasser10Adriane Halik11Razif Gabdoulline12Julia Thomson13Konstantin Weibl14Georg-Nikolaus Franke15Carolina Berger16Justin Hasenkamp17Francis Ayuk18Il-Kang Na19Gernot Beutel20Ulrich Keller21Lars Bullinger22Gerald Georg Wulf23Nicolaus Kröger24Vladan Vucinic25Michael Heuser26Frederik Damm271 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany4 Department of Hematology and Medical Oncology, University Medicine Göttingen, Germany5 Medical Clinic and Policlinic 1, Hematology, Cellular Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany5 Medical Clinic and Policlinic 1, Hematology, Cellular Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany6 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany4 Department of Hematology and Medical Oncology, University Medicine Göttingen, Germany6 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany4 Department of Hematology and Medical Oncology, University Medicine Göttingen, Germany6 Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany5 Medical Clinic and Policlinic 1, Hematology, Cellular Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany1 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany2 Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, GermanyRecent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.http://journals.lww.com/10.1097/HS9.0000000000000957 |
| spellingShingle | Victoria Panagiota Johanna Franziska Kerschbaum Olaf Penack Catarina M. Stein Christopher M. Arends Christian Koenecke Paulina M. Strzelecka Arnold Kloos Laura Wiegand Alina Lasch Robert Altwasser Adriane Halik Razif Gabdoulline Julia Thomson Konstantin Weibl Georg-Nikolaus Franke Carolina Berger Justin Hasenkamp Francis Ayuk Il-Kang Na Gernot Beutel Ulrich Keller Lars Bullinger Gerald Georg Wulf Nicolaus Kröger Vladan Vucinic Michael Heuser Frederik Damm Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients HemaSphere |
| title | Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients |
| title_full | Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients |
| title_fullStr | Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients |
| title_full_unstemmed | Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients |
| title_short | Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients |
| title_sort | clinical implications and dynamics of clonal hematopoiesis in anti cd19 car t cell treated patients |
| url | http://journals.lww.com/10.1097/HS9.0000000000000957 |
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