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I. Yakoub-Agha et al.
Epstein-Barr virus or adenoviruses are significant clinical problems after CAR T-cell therapy. Little is known regard- ing the risk of hepatitis B and C virus reactivation as patients with these infections were specifically excluded from the trials. It is not possible to provide recommenda- tions regarding the use of CAR T-cell therapy in patients with human immunodeficiency virus infection as seropos- itive individuals were also excluded. The pharmaceutical companies may, however, manufacture a drug product for a patient positive for hepatitis B, hepatitis C or human immunodeficiency virus if the viral load is below the level of detection following treatment. For patients with a his- tory of hepatitis B infection, prophylaxis with tenofovir is recommended.66
Medium-term complications and management: day +28 to day +100
Potential toxicities during this period include delayed tumor lysis syndrome, delayed hemophagocytic lympho- histiocytosis/macrophage activation syndrome and CRS, B-cell aplasia, hypogammaglobulinemia, graft-versus-host disease (GvHD), and infections. Neutropenia, thrombocy- topenia and anemia are common but generally resolve slowly over several months. Growth factor support may be indicated in the early stages.
Table 11 summarizes tests to be performed during this period and their recommended frequency.
Delayed macrophage activation syndrome and cytokine release syndrome
In the experience of CAR T-cell therapy for ALL, CRS typically occurred between 1 and 14 days after the CAR T- cell infusion, whereas in patients with chronic lymphocyt- ic leukemia, CRS usually occurred later, between 14 and 21 days after the infusion.42 Regardless of the timing, delayed macrophage activation syndrome and CRS are managed using standard approaches.
detection of flow cytometry, whereas CTL019 remained detectable by means of quantitative polymerase chain reaction analysis.42 B-cell aplasia can therefore serve as a marker for monitoring CD19-specific CAR T-cell activity over time.42,67
Persistent B-cell lymphopenia is associated with sino- pulmonary infections, notably with encapsulated bacteria; consideration can be given to vaccination although there is no evidence and immunoglobulin levels should be moni- tored.43 It has therefore been standard practice in pediatric centers to administer empiric immunoglobulin replace- ment following the administration of CAR T cells. Children with B-cell aplasia should receive immunoglobu- lin replacement to maintain IgG levels according to insti- tutional guidelines for IgG substitution (i.e. ≥500mg/dL).42 In some cases, this may be a long-term requirement.
There is no consensus regarding systematic supplemen- tation in adults who have been shown to have long-lived CD19-negative plasma cells that continue to confer humoral immunity in patients who were successfully treated with CAR T cells targeting CD19. Nevertheless, intravenous immunoglobulin replacement is recommend- ed in patients with hypogammaglobulinemia and recur- rent infections with encapsulated bacteria. Patients may transition to home-administered subcutaneous immunoglobulins after 6 months.
Graft-versus-host disease
Donor-derived CAR T cells may rarely trigger GvHD if
harvested from, and then returned to, patients who have undergone allogeneic HCT. Current evidence suggests that the risk of inducing GvHD with the use of donor- derived CAR T cells is low.68-70 However, vigilance is required as this complication is potentially severe and life- threatening. If suspected, GvHD should be diagnosed and managed using standard protocols, balancing the potential benefit of introducing systemic immunosuppression against its effect on anti-tumor CAR T-cell function.
Infections
Beyond 30 days, viral infections predominate including respiratory viral infections, cytomegalovirus viremia and pneumonia. Later infections may reflect prolonged immunoglobulin deficiency (up to 46% at day 90) as well as lymphopenia.71 Severe co-infections with CRS include respiratory virus infections (some nosocomial),
B-cell aplasia and hypogammaglobulinemia
B-cell aplasia is an almost universal on-target, off-tumor toxicity and results in hypogammaglobulinemia. It occurs in all responding patients and can persist for several years. This absence of CD19-positive cells correlated with func- tional persistence of CTL019 cells below the limits of
Table 11. Monitoring of patients during medium-term follow-up.
Test
FBC, biochemistry panel, LDH, fibrinogen, CRP
CMV, EBV, adenovirus
Quantitative immunoglobulins
or serum protein electrophoresis
Peripheral blood immunophenotyping – CD3/4/8/16+56/19+
CAR T-cell monitoring where kits are available for routine
monitoring of anti-CD19 CAR T cells
Purpose
Standard follow-up
Viral reactivation Immune reconstitution
Immune recovery
CAR T-cell persistence
Frequency
At every visit and as clinically indicated
As clinically indicated Monthly
Once monthly for first 3 months, three monthly thereafter in first year
Peripheral blood flow cytometry or transgene by molecular methods as clinically indicated
Comment
Consider IV immunoglobulins
Guide to anti-infective prophylaxis
Not recommended by CAR T-cell manufacturers
FBC: full blood count; LDH: lactate dehydrogenase; CRP: C-reactive protein; CMV: cytomegalovirus; EBV; Epstein-Barr virus; IV: intravenous; CAR: chimeric antigen receptor.
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haematologica | 2020; 105(2)