Page 69 - 2021_04-Haematologica-web

Cytopenias after CAR T-cell therapy
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CD19/CD28/CD3z CAR in R/R B-ALL treated through a phase I trial and found that 42% of patients had infections during the first 30 days after axi-cel infusion, while 31% of surviving patients had infections between day 31 and day 180.15 Overall, infection rates in our cohort were sim- ilar to that reported on these trials, although we character- ized most of these infections as non-severe.
In the cohort of lymphoma patients described here, most of the infections in the first 30 days were due to Clostridium difficile colitis or respiratory viruses and were manageable. The rate of Clostridium difficile is likely influ- enced by our choice of fluoroquinolone prophylaxis for all CAR T patients. Severe infections occurred in 12.9% of patients, and in 3.5% of patients, infection was a contrib- utor to death. We find that early severe infections almost always occur in patients that have severe CRS and/or neu- rotoxicity and receive treatment with tocilizumab, corti- costeroids, and/or had bridging therapy. At baseline, total WBC and neutrophil counts were counterintuitively high- er in patients with infection compared to those who do not experience infection. Speculatively, patients with higher neutrophil counts at baseline may have adverse lymphoma biology and a greater degree of tumor-related immunosuppression.16,17 We also noted that the majority of bacterial isolates in severe infection were gram positive, which may also be related to our use of fluoroquinolone prophylaxis to prevent gram negative infections. The two fungal infections were not susceptible to our prophylactic fluconazole. Clinically, patients who require steroids for toxicity management are at a higher infection risk. There is an overall lack of data to guide prophylaxis policies fol- lowing treatment with CAR T-cell therapy, and further study is needed to optimize infection prophylaxis and pre- vent infection in this group.
We also report that CD4 T-cell levels remain persistent- ly low for months after axi-cel. Indeed, we observed that CD4 counts remain significantly low even at 1 year after treatment. Despite profound and prolonged T-cell immunosuppression, severe infections remain rare. Our low rate of severe infection is in agreement with the smaller study published by Kochenderfer and colleagues, in which only 1 of 7 patients (14·3%) had a severe infec- tion requiring hospitalization after treatment with CD19 CAR T-cells for LBCL.10 Longer follow-up is needed to determine how CD4 counts recover beyond 1 year and the degree to which prophylaxis and vigilance for CD4 recovery are necessary. In our institution we currently pro- vide PJP prophylaxis and VZV reactivation prophylaxis for a minimum of 6 months or until recovery of CD4 count over 200 cells/mL, although there is physician variability in duration of prophylaxis and also with respect to the pro- vision of IVIG to clinically asymptomatic patients. While we did not observe any PJP or Mycobacterium avium-intra- cellulare in our cohort, the level of CD4 suppression after CAR T-cell therapy may provide an impetus for prolonged or alternative prophylaxis in some patients. During the dates of this cohort study we typically revaccinated patients starting at 3 months post-CAR T-cell therapy in a manner analogous to our practice after autologous stem cell transplant. However, in this study we found that immunoglobulin levels nadir at 6 months and recover thereafter and we also noted recovery of B-cell aplasia and immunoglobulin levels while maintaining lymphoma remission, as is reported in other studies.1,10,11 This suggests that CD19 CAR T-cell therapy does not lead to a perma-
Figure 4. Infections occurring post-axi-cel. (A) Incidence rate of infection over time per 1,000 person-days, with time from axi-cel infusion on the X-axis. (B) Competing risk plot of the cumulative incidence of a patient’s first infection. Death or progression were considered as competing events. axi-cel: axicabtagene ciloleucel.
nent loss of humoral immunity, which may account for a lower rate of opportunistic infections. Moreover, the available data presented here on HSV titers suggests that patients may not lose full protection against some infec- tions. Similarly, Hill et al.18 recently reported on antiviral humoral immunity in 39 adults receiving CD19 CAR-T cell therapy and found that anti-measles IgG levels remained stable over time, possibly because long-lived plasma cells do not express CD19.18 Further study is required on the efficacy and optimal timing of infectious prophylaxis and vaccination after CAR T therapy.
Given the low rate of severe infections, this study is lim- ited in that it cannot generate a risk prediction model for severe infection using baseline factors. A larger, ideally multicenter, cohort is needed to identify patients at risk of infection and to consider modifying treatment. Another issue is that we censored patients at the time of disease progression in order to reduce confounding introduced by subsequent therapy. However, cytopenias and poor immune reconstitution may interfere with therapies given for post-CAR T relapse and further study is needed to
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