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Treating classical Hodgkin lymphoma: Spotlight on targeted therapies
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A new grading system for use in chimeric antigen receptor (CAR) T-cell trials was presented on Tuesday 26 March 2019, during the 45th Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Frankfurt, Germany, by Richard Maziarz, Oregon Health and Science University, Portland, US.1
Currently there is a lack of uniformity of the scales used to grade cytokine release syndrome (CRS) and neurological events (NE) in CAR T trials. This poses difficulties when attempting to assess toxicities across different trials.
This phase II retrospective study aimed to analyse if the established grading scales for CRS (Penn scale and Lee Scale) and NE (CTCAE and CARTOX-10) were concordant, by regrading the CRS and NE events reported in the JULIET study2* (NCT02445248) using alternative scales, and then, using a new consensus system.
Four experts with experience in CAR T therapy independently reviewed and re-evaluated adverse event data extracted from the JULIET study. The Penn scale and the CTCAE (v4.03) scale were used in JULIET to identify and grade CRS and NE, respectively and so regrading was performed using the Lee scale and a modified CARTOX-10 CRES (mCRES) system.3,4 If a consensus was not reached, the most conservative assessment was used.
The experts then developed a consensus grading system (ASBMT) for CRS and NE which can be seen in the tables below. A key difference in the CRS grading compared to the other scales, is the requirement to have a fever (temperature 38oC or higher for grades 1–4).
The JULIET data was then regraded according to the ASBMT criteria, with a first-look, shown during the presentation.
Using different toxicity assessments between studies yields contrasting data in the reporting of CRS and NEs. A unified grading scale for both CRS and NE will allow comparisons between trials using different CAR T-cell and immune effector cell therapy products.
|
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
---|---|---|---|---|
Fever |
Temperature ≥38oC |
Temperature ≥38oC |
Temperature ≥38oC |
Temperature ≥38oC |
With either: |
|
|
|
|
Hypotension requiring: |
None |
No vasopressors required |
One vasopressor +/- vasopressin |
Multiple vasopressors required (excluding vasopressin) |
And/or: |
|
|
|
|
Hypoxia requiring: |
None |
Low-flow nasal cannula or blow-by |
High-flow nasal cannula, facemask, non-rebreather mask, or Venturi mask |
Positive pressure e.g. CPAP, BiPAP, intubation and mechanical ventilation |
|
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
---|---|---|---|---|
Immune effector cell-associated encephalopathy (ICE) Score |
7–9 |
3-6 |
0–2 |
0 |
Depressed level of consciousness |
Awakens spontaneously |
Awakens to voice |
Awakens to tactile stimulus |
Patient unarousable or requires vigorous/repetitive tactile stimuli. Stupor or coma |
Seizure |
Not applicable (N/A) |
N/A |
Any clinical seizure that resolves rapidly or non-conclusive seizures on EEG that can be resolved without intervention |
Prolonged seizure that is life threatening (>5 minutes)/repetitive clinical or electrical seizures without return to baseline |
Motor findings |
N/A |
N/A |
N/A |
Deep focal motor weakness e.g. hemiparesis or paraparesis |
Raised intracranial pressure (ICP) or cerebral edema |
N/A |
N/A |
Focal or local edema |
Diffuse cerebral edema. Decerebrate or decorticate posturing or cranial nerve VI palsy, or papilledema, or Cushing’s triad |
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