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Cytopenias after CAR T-cell therapy
Figure 1. Cohort description. *Early deaths after chimeric antigen receptor T (CAR T) therapy included death due to fusarium infection in the central nervous system at day 39, hemophago- cytic lymphohistiocytosis at day 38, and candidemia at day 40.19
Table 2. Cytopenias following axicabtagene ciloleucel (axi-cel).
Grade 3-4 Leukopenia
Any Grade Leukopenia Grade 3-4 Neutropenia Any Grade Neutropenia Grade 3-4 Anemia
Any Grade Anemia
Grade 3-4 Thrombocytopenia
Any Grade Thrombocytopenia
Any Grade 3-4 Cytopenia
Any Grade Cytopenia
Apheresis
3.5% (3/85)
23.5% (20/85)
3.5% (3/85)
14.1% (12/85)
7.1% (6/85)
57.6% (49/85)
5.9% (5/85)
28.2% (24/85)
14.1% (12/85)
72.9% (62/85)
Day 30
28.6% (20/70)
85.7% (60/70) 30.0% (21/70) 71.4% (50/70) 7.1% (5/70) 87.1% (61/70) 25.7% (18/70) 80% (56/70) 44.3% (31/70)
100.0% (70/70)
Day 90
10.7% (6/56)
64.3% (36/56) 12.5% (7/56) 37.5% (21/56) 3.6% (2/56) 44.6% (25/56) 5.4% (3/56) 51.8% (29/56) 14.3% (8/56)
83.9% (47/56)
Day 180
16.7% (7/42)
64.3% (27/42)
11.9% (5/42)
42.9% (18/42)
7.1% (3/42)
31.0% (13/42)
4.8% (2/42)
45.2% (19/42)
19.0% (8/42)
81.0% (34/42)
Day 270
9.4% (3/32)
56.3% (18/32)
9.4% (3/32)
37.5% (12/32)
3.1% (1/32)
31.3% (10/32)
3.1% (1/32)
43.8% (14/32)
9.4% (3/32)
71.9% (23/32)
Day 360
3.2% (1/31)
51.6% (16/31)
9.7% (3/31)
25.8% (8/31)
3.2% (1/31)
22.6% (7/31)
3.2% (1/31)
38.7% (12/31)
9.7% (3/31)
67.7% (21/31)
Clinical complete blood count and differential results were
grade 3-4 neutropenia = neutrophil (N) count <1,000/mm3;
any grade cytopenia, patients had at least grade 1 leukopenia, neutropenia, anemia, or thrombocytopenia, defined as WBC <4,000/mm3, N <1,800/mm3, Hb <11.4 g/dl, and PLT <143,000/mm3,based on the lower limits of normal set by the clinical laboratory at our institution. Information is shown as % (#patients/total number of non-relapsing patients with follow-up at that time point).
because they followed up outside of our institution (Figure 1). Median follow-up from time of axi-cel infusion was 12.8 months (range: 0.8-42.4). The median time from apheresis to axi-cel infusion was 27 days (range: 20-42). Patient characteristics are shown in Table 1. Severe (grade 3 or higher) CRS occurred in 9.4% of patients, and severe neurotoxicity occurred in 30.6%. Median duration of cor- ticosteroid treatment for toxicity was 7 days (range: 1–62). ORR at day 30 was 80%, and CR at day 30 was 48.2%. Kaplan-Meier curves of PFS and OS are shown in the Online Supplementary Figure S1.
In order to describe cytopenias after axi-cel, we graded cytopenias based on the clinical CBC and differential using clinical trial criteria (CTCAE v4.03; Table 2). At baseline (time of apheresis) prior to axi-cel, 14.1% of patients had grade 3 or 4 cytopenias. At day 30 after axi- cel, grade 3 or 4 leukopenia, neutropenia, or thrombocy- topenia was found in 28.6%, 30%, and 25.7% of patients, respectively, for a cumulative grade 3 or 4 cytopenia rate of 44.3%. All patients at day 30 had at least one grade 1 cytopenia. Most patients recovered counts over subse- quent months, although a proportion of patients (3 of 31; 9.7%) still had neutrophil counts below 1,000/mL at 1 year after axi-cel infusion.
Cellular and humoral reconstitution was evaluated over time using the clinical CBC and a flow cytometry panel that quantifies B-, T-, and NK-cell subsets (Figure 2).
Median leukocyte and neutrophil counts decreased after axi-cel therapy and remained significantly below baseline levels at 1 year after therapy. Similarly, peripheral blood CD4 T cells were low at a median of 220 cells/mL (range: 34–1,720) prior to axi-cel and remained persistently low after axi-cel, with a median CD4 count of 155 cells/mL (range: 33–269) at 1 year. Multiple comparison testing and means are provided in the Online Supplementary Table S1. CD19 positive B cells were detectable in 28 of 58 (48.3%) patients at baseline prior to axi-cel and in 4 of 34 (11.8%) patients at day 30. The proportion of patients with detectable levels at day 90, 180, and 360, were 22.6% (7 of 31), 46.2% (12 of 26), and 57.9% (11 of 19), respectively; B cells had significantly increased from baseline by 1 year (P=0.05). At baseline 9 of 58 (15·5%) patients had IgG <300 mg/dL, 16 of 58 (27.6%) patients had IgG <400 mg/dL, and 27 of 58 (46.6%) patients had IgG <500 mg/dL. IgG levels decreased after axi-cel infusion with a nadir at 6 months. By 1 year, excluding patients censored for receipt of IVIG, 9 of 17 (52.9%) had IgG levels above 400 mg/dL and 7 of 17 (41·2%) patients had IgG levels above 500 mg/dL. Of the patients with IgG ≥500 mg/dL at baseline, new hypogammaglobulinemia occurred in 10 of 17 (58.8%) that were measured at day 30 and 20 of 27 (74.1%) in total at any time. We also followed quantitative titers of HSV antibodies in 17 patients (Online Supplementary Figure S2). While quantitative levels
graded using clinical trial criteria (CTCAE v4.03).Grade 3-4 leukopenia = white blood cell count (WBC) <2,000/mm3; grade 3-4 anemia = hemoglobin (Hb) <8 g/dL; grade 3-4 thrombocytopenia = platelet (PLT) count <50,000/mm3. For
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