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CAR T-cell therapies, have shown efficacy across a range of hematologic and solid tumors, are standard of care for certain types of lymphoma. As with other therapies, patients may report CAR T-cell treatment-related adverse events (AE). Cytopenia has been reported following lymphodepletion and CAR T-cell infusion with axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel).1-3 During the 2nd European CAR T Meeting, Sitges, ES session dedicated to the management of the side effects, Marion Subklewe, from the Ludwig Maximilian University of Munich, DE, discussed cytopenia in patients who received CAR T- cell therapy. This article summarizes the key messages from the presentation.
Marion Subklewe started the presentation by describing the grading of cytopenia by Common Terminology Criteria for Adverse Events (CTCAE) presented in Table 1.
Table 1. Grading of cytopenia according to the CTCAE version 3.0 (values per mm3 unless otherwise stated)4
N/A, not available *transfusion indicated |
|||||
|
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
Grade 5 |
Anemia |
> 10 g/dL |
> 8 g/dL |
< 8 g/dL* |
Life-threatening |
Death |
Neutropenia |
> 1500 |
> 1000 |
> 500 |
< 500 |
N/A |
Thrombocytopenia |
> 75000 |
> 50000 |
> 25000 |
< 25000 |
N/A |
Lymphocytes |
> 800 |
> 500 |
> 200 |
< 200 |
N/A |
CD4 lymphocytes |
> 500 |
> 200 |
> 50 |
< 50 |
|
She then followed with an overview of the CAR-T clinical trials in lymphoma and multiple myeloma (MM) (Table 2).
Table 2. Overview of clinical trials evaluating CAR T-cell therapies in lymphoma and MM1,4-7
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; axi-cel, axicabtagene ciloleucel; benda, bendamustine; cy, cyclophosphamide; DLBCL, diffuse large B-cell lymphoma; HGBCL, high grade B-cell lymphoma (double/triple hit lymphomas); FL3B, follicular lymphoma Grade 3B; flu, fludarabine; HSCT, hematopoietic stem cell transplant; MM, multiple myeloma; liso-cel, lisocabtagene maraleucel; NR, Not reported; PMBCL, primary mediastinal B-cell lymphoma; PTL, platelet count; R/R relapsed or refractory; tCLL, transformed chronic lymphocytic leukemia, tis-cel, tisagenlecleucel; tFL, transformed follicular lymphoma; tMZL, marginal zone lymphoma *pediatric and young adult patients |
||||
|
JULIET1,4 (N = 111) |
ZUMA4 (N = 108) |
TRANSCEND4-6 (N = 269) |
EVOLVE4,7,8 (N = 44) |
CAR T-cell therapy |
tis-cel |
axi-cel |
liso-cel |
JCARH125 |
NCT number |
||||
Disease area |
R/R DLBCL |
R/R DLBCL PMBCL tFL HGBCL |
DLBCL PBMCL tFL tCLL tMZL MCL FL3B HGBCL |
R/R MM |
Patient characteristics |
||||
Median age, years |
56 (22–76) |
58 (23–76) |
63 (18–86) |
62 (36–79) |
HGBCL, % |
27 |
NR |
13 |
100 |
Refractory to last therapy, % |
55 |
74 |
67 |
100 |
≥ 3 prior therapies, % |
52 |
76 |
26 |
100 |
Prior HSCT, % |
49 |
NR |
35 |
|
Blood count threshold |
ANC < 1000/ul PLT < 50000 g/L |
ANC < 1000/ul PTL < 75000 g/L ALC < 1000/ul |
No threshold for blood count |
No threshold for blood count |
Lymphodepletion |
Flu 25 mg/m2 + Cy 250 mg/m2 for 3 days or benda 90 mg/m2 for 2 days |
Flu 30 mg/m2 + Cy 500 mg/m2 for 3 days |
Flu 30 mg/m2 + Cy 300 mg/m2 for 3 days |
Flu 30 mg/m2 + Cy 300 mg/m2 for 3 days |
Cytopenia (most frequently neutropenia) is the most common AE, seen in patients across different hematological tumors who underwent lymphodepletion and infusion with any CAR T-cell therapy
In the ZUMA-1 trial, cytopenia was the most frequent AE, reported in 93% of patients:
Table 3. Incidence of late cytopenia with axi-cel, liso-cel, and JCARH125*, 4
*cytopenia present on Day 30 |
|||
|
ZUMA-1 (N = 108) |
TRANSCEND (N = 269) |
EVOLVE (N = 44) |
Neutropenia, n (%) All Grade Grade ≥ 3 |
39 (36) 28 (26) |
169 (63) 161 (60) |
NA 38 (86) |
Anemia, n (%) All Grade Grade ≥ 3 |
31 (29) 11 (10) |
129 (48) 101 (38) |
NA 22 (50) |
Thrombocytopenia, n (%) All Grade Grade ≥ 3 |
44 (41) 26 (24) |
84 (31) 72 (27) |
NA 19 (43) |
In JULIET trial, prolonged cytopenia, defined as Grade 3/4 cytopenia not resolved to Grade ≤ 2 by Day 28, was reported in
In the ZUMA trial
Table 4. Prolonged cytopenia at 1 and 2 years4
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; HGB, hemoglobulin count; PLT, platelet count |
||
Treatment-emergent cytopenia |
At 1 year |
At 2 years |
ANC/HGB/PLT < Grade 3, % |
75 |
85 |
ALC (> 1x 109/L), % |
80 |
100 |
CD4 (> 200 cells/mm3), % |
63 |
86 |
CD8 (> 82 cells/mm3), % |
100 |
100 |
CD56 (> 0 cells/mm3), % |
100 |
100 |
Patients on CAR T-cell therapies are at risk of infections and the presence of cytopenia can further increase susceptibility and reduce the ability to fight pathogens.
ZUMA-1
TRANSCEND
Infectious complications after anti-CD19 CAR T-cell therapy at Fred Hutchinson Cancer Research Center, Seattle, US
In total 133 patients were analyzed for incidence of infection in first 100 days post CAR-T (n = 62 with lymphoma, n = 24 with CLL, and n = 47 with acute lymphoblastic leukemia).
Infectious prophylaxis at Ludwig Maximilian University of Munich Hospital
CART-cell therapies are becoming established in clinical practice, increasing the treatment options available to patients with refractory or relapsed disease. As with many treatment regiments, CAR-Ts are associated with an increased risk of cytopenia and higher susceptibility to infections. However, clinical benefits outweigh the risks, which can be reduced with appropriate prophylaxis.
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