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Immune reconstitution after axi-cel in lymphoma
trend for higher baseline ferritin levels in these patients also suggests a potential role for chronic inflammation in its eti- ology.
Consistent with prior studies in patients with B-acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 CAR T-cell therapy, we observed that viral infections, especially herpes zoster, were a later event, as compared to other infections.19,20 This is likely explained by the delayed recovery of CD4+ T cells, a well-established risk factor for the development of both common and oppor- tunistic infections, which in this series occurred inde- pendently of age.21 These data suggest that effective long- term monitoring and prophylaxis against opportunistic infections needs to be considered in a subset of patients receiving CAR T-cell therapy. Although the baseline char- acteristics of patients enrolled in the ZUMA-9 study mir- rored those of patients treated in the real world setting, the subset of patients included in this analysis had an apparently higher incidence of grade >3 infections as compared to the 2-year follow-up of the ZUMA-1 trial (42% vs. 28%). It is important to highlight that this may be due to differences in baseline characteristics and co- morbid health conditions of the subset of patients select- ed for this single institution analysis, as compared to the previously reported multi-center results.2
While pre-conditioning IgG levels were not available in this study, and prior treatment with anti-CD20 mono- clonal antibodies and/or chemotherapy may have affect- ed their levels before CAR T-cell infusion, hypogamma- globulinemia was observed in a subset of patients early after axi-cel therapy. Similar to what was reported with the use of tisagenlecleucel, recovery of IgG to normal lev- els was observed in more than half the patients in this series.22 In contrast to children where prophylactic IVIG is recommended with IgG <400 mg/dL, in adults it is usual- ly used in cases with concomitant frequent or severe infections.23 Consistent with this, we did not observe sig- nificant differences in infections between patients receiv- ing prophylactic IVIG or not (P=0.10).
Finally, a strong and positive correlation between platelet count and CD56 cell count was observed in our study. NK cells are among the first hematopoietic cells that recover during bone marrow reconstitution, based
on data from stem cell transplant recipients.24,25 The asso- ciation observed here between platelet count and NK cell numbers might reflect the dynamics of bone marrow recovery, although a mechanistic relation may still be possible and is under evaluation at our institution.
In conclusion, our study suggests that patients with prolonged cytopenias after CAR T-cell therapy may be managed conservatively with supportive care. Importantly, our results suggest the potential need for antimicrobial prophylaxis against opportunistic infections because of delayed CD4+ T-cell recovery following axi- cabtagene ciloleucel therapy in a subset of patients.
Disclosure
SSN reports honoraria and research support from Kite, a Gilead Company, Merck, Celgene, Allogene, and Unum Therapeutics; research support from Bristol-Myers Squibb, Poseida, Cellectis, Karus, and Acerta Pharma; and honoraria from Novartis, Pfizer, Precision Biosciences, Cell Medica, Calibr, Incyte, and Legend Biotech. FS reports honoraria from Celgene. LN reports honoraria from Celgene, Genentech, Gilead, Janssen, Juno, Novartis, Spectrum, TG Therapeutics and research support from Celgene, Genentech, Janssen, Karus Therapeutics, and Merck. NF reports honoraria from Celgene, Gilead Sciences, Pharmacyclics, Roche Pharma AG, research support from Celgene, Gilead Sciences, Pharmacyclics, and Roche Pharma AG.
Contributions
PS designed the study, analyzed data, and wrote the paper; LN, JW, FH, NF, HJL, LEF, FS, SA, PK, VEM and EAH pro- vided clinical care to patients and coauthored the paper; YC, SH, SA, AV, SA, and SJ collected clinical data and co-authored the paper; SN designed the study, analyzed the data, provided clinical care to patients, and wrote the paper.
Acknowledgments
This research is supported in part by the MD Anderson Cancer Center Support Grant P30 CA016672 and Kite Pharma. PS salary is supported by the Lymphoma Research Foundation Career Development Award. We thank Adrian Bot, John Rossi and Jenny Kim from Kite Pharma for data and man- uscript review.
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