Management of the toxicities commonly associated with chimeric antigen receptor (CAR) T-cell therapy, including cytokine release syndrome (CRS) and neurotoxicity, can require stays in the intensive care unit (ICU) or treatment with corticosteroids and tocilizumab – both of which can increase patients’ risk for infection. According to a study of adult patients with hematologic malignancies treated with lymphodepletion chemotherapy and anti-CD19 CAR T-cell therapies, the incidence of infections was similar to that observed with other chemotherapy regimens, although the researchers identified several patient- and treatment-related factors associated with an increased infection risk in patients treated with CAR T-cells.
Joshua A. Hill, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and co-authors conducted a retrospective, open-label, phase I/II study of 133 patients with hematologic malignancies, evaluating the incidence, distribution, and severity of infectious events occurring within 90 days of CAR T-cell administration. The results were published in Blood.
“The incidence and type of infections after CD19 CAR T-cell immunotherapy were consistent with those seen in patients with relapsed/refractory B-cell malignancies receiving salvage chemoimmunotherapies,” the authors wrote, adding that life-threatening and fatal infections were rare. “Patients with greater immunosuppression and CAR T-cell–associated toxicities had the highest risk for infection, identifying a targeted group to study improved prophylactic strategies.”
The study included adult patients (median age = 54 years; range = 20-73 years) who were treated at the Fred Hutchinson Cancer Research Center. All patients had relapsed/refractory CD19-positive B-cell malignancies, including acute lymphocytic leukemia (ALL; n=47; 35%), chronic lymphocytic leukemia (n=24; 18%), and non-Hodgkin lymphoma (n=62; 47%). Patients had received a median of four prior therapies (range = 1-11 therapies), and 38 percent (n=50) had undergone prior autologous or allogeneic hematopoietic cell transplantation.
All patients received lymphodepletion chemotherapy (most commonly cyclophosphamide and fludarabine) and CAR T-cell therapy at one of three dose levels (2×105 cells/kg, 2×106 cells/kg, or 2×107 cells/kg).
Supportive care after lymphodepletion consisted of subcutaneous granulocyte colony-stimulating factor and antimicrobial prophylaxis, which consisted of: acyclovir 800 mg or valacyclovir 500 mg twice daily for herpes simplex or varicella zoster virus–seropositive individuals; levofloxacin 750 mg daily and fluconazole 400 mg daily during severe neutropenic episodes; and trimethoprim 160 mg/sulfamethoxazole 800 mg twice-daily for two days each week starting after neutrophil recovery until ≥3 months after CAR-T cell infusion.
During the first 28 days after CAR T-cell infusion, the investigators analyzed 3,615 patient days-at-risk. The first instances of infections were identified a median of six days (range = 1-27 days) following treatment, with 80 percent of first infections occurring within the first 10 days after CAR T-cell infusion. During the first 28 days, 43 infections were identified in 30 patients (23%), for an “infection density” of 1.19 infections per 100 days-at-risk.
The most common types of infections were bacterial (24 events in 22 patients; 17%), followed by viral (13 events in 11 patients; 8%).
Twenty-eight patients developed both CRS and infection, but CRS was preceded by infection in only three patients. The median time to onset of CRS and first infection were 1.9 and six days (ranges not provided), respectively. “Most infections occurred after the onset of CRS and did not appear to precipitate or exacerbate CRS,” the authors wrote.
Among the 119 patients who were evaluable for infection risk between 29 and 90 days after CAR T-cell infusion (contributing to 3,431 days-at-risk), the infection density dropped to 0.67 infections per 100 days-at-risk, “which was significantly lower than the infection density in the first 28 days (relative risk [RR] = 0.56; 95% CI 0.33-0.93; p=0.02),” the authors noted. Twenty-three infections occurred in 17 patients (14%) during that period, most commonly viral (13 infections in 11 patients; 9%). Among patients who experienced late infections, persistent disease and neutropenia were reported in 48 percent and 22 percent, respectively.
Half of infections occurring up to 90 days after CAR T-cell administration were mild (requiring no treatment) or moderate (requiring oral treatment only): 33 of 66 events in 23 patients. Severe infections accounted for 41 percent of events (27 of 66 events in 19 patients). Four infections (6%) were deemed life-threatening (occurring in 3 patients; 2%), and two deaths were reportedly related to infection.
Univariate analyses identified more severe CRS, more severe neurotoxicity, treatment with tocilizumab, and ICU admission as being associated with an increased risk for infection. After the researchers adjusted for baseline characteristics, the following factors remained predictive of an increase in infection density: diagnosis of ALL, four or more prior cancer treatments, an absolute neutrophil count <500 cells/mm3 before CAR T-cell infusion, and CAR T-cell doses of 2×107 cells/kg.
“Any treatment with corticosteroids was not associated with infection, and there were insufficient events to determine whether duration or dose of tocilizumab or corticosteroids independently increased risk,” the authors added. “Overall, the data show that most infections occurred during periods of neutropenia, and patients with more severe CRS had higher risk of infection.”
When the investigators looked at the infection risk according to type of lymphodepletion chemotherapy received, they found that, among the 90 patients who received the “preferred” regimen of cyclophosphamide and fludarabine plus an optimized CAR T-cell dose (determined by disease type and tumor burden), there were only 17 infections in 14 patients (16%). The infection density was “lower than in patients receiving a non-preferred regimen (0.69; RR=0.30 [p<0.001]),” the authors reported, adding that there were no life-threatening or fatal infections in that group.
“Future studies will be required to identify lymphodepletion regimens that have limited hematopoietic toxicity while still enabling robust CAR-T cell engraftment,” the researchers concluded, adding that “identification of [other] risk factors for infection might enhance the development of infection prophylaxis regimens.”
The study is limited by its single-center, retrospective design, and that the interpretation of late infection rates may be misconstrued based on a potential bias of patients who required follow-up beyond day 28. In addition, “the incidence of bacterial infections in our study may be overestimated by [the] inclusion of patients treated for single positive bacterial blood cultures with possible skin contaminants in whom it was not possible to distinguish between infection and CRS as a cause of fever,” the authors wrote.
Juno Therapeutics contributed to the funding of this study.
The authors report receiving funding from Chimerix Inc., Nohla Therapeutics Inc., Shire, and Juno Therapeutics.
Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T cell immunotherapy. Blood. 2017 October 16. [Epub ahead of print]