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PAPER SPOTLIGHT
Examining Infection Risk in Patients Treated With Anti-CD19 CAR T-Cell Therapies
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 , openlabel , 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 ( 2x10 5 cells / kg , 2x10 6 cells / kg , or 2x10 7 cells / kg ).
Supportive care after lymphodepletion consisted of subcutaneous granulocyte colonystimulating 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 daysat-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 / mm 3 before CAR T-cell infusion , and CAR T-cell doses of 2x10 7 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 .
REFERENCE
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 ]
44 ASH Clinical News December 2017