EBMT 2019 | A consensus grading system for toxicities in CAR T trials

A new grading system for use in chimeric antigen receptor (CAR) T-cell trials was presented on Tuesday 26 March 2019, during the 45^th 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.

Regraded CRS (from Penn to Lee):

• Patients regraded: 58% (64/111)
  • Moved to a lower grade (Lee < Penn): 31% (n = 20)
  • Stayed the same (Lee = Penn): 61% (n = 39)
  • Moved to a higher grade (Lee > Penn): 8% (n = 5)
• Using the Lee scale, fewer grade ≥2 CRS events were identified

Regraded NE (from CTCAE to mCRES):

• More NEs were identified using the CTCAE scale than mCRES (given as CTCAE versus mCRES):
  • Grade 1–2 NE: 34 vs 5 patients
  • Grade 3: 11 vs 6 patients
  • Grade 4: 5 vs 8 patients
• The CTCAE scale includes any nervous system or psychiatric event
• Analysis shows diversity of the two grading systems
• Looking at NE in patients with CRS (n = 64) versus no CRS (n = 47) as totals:
  • CTCAE scale: 30 vs 20 patients
  • mCRES scale: 15 vs 4 patients
  • Both scales identified more patients with NE who also had CRS

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 38^oC 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.

Regraded CRS using ASBMT:

• Previously reported cases of CRS: 64
• Downgraded: 7
  • One patient from grade 4 to grade 0 due to the lack of fever
• Upgraded: 3
• Breakdown of CRS events by ASBMT criteria (n = 60):
  • Grade 1: 21
  • Grade 2: 23
  • Grade 3: 8
  • Grade 4: 8

Regraded NE using ASBMT ICANS:

• Previously reported NEs: 19
  • Downgraded: 2
    • Grade 4 to grade 3
    • Grade 1/2 to grade 0
  • Upgraded: 1
    • Grade 1/2 to grade 2
• No chaages to the numbers in patients without CRS

Conclusion

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.

ASBMT grading systems