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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 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.

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 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.

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

 

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

Table 1: ASBMT grading system for CRS

 

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

Table 2: ASBMT immune effector cell-associated neurotoxicity syndrome (ICANS) grading system for NE in adults 

References
  1. Maziarz R. Consensus CRS and neurological events regrading of “JULIET”: Phase II prospective study of tisagenlecleucel therapy in patients with relapsed/refractory diffuse large B-cell lymphoma. Abstract OS-4-6. 2019 March 26. 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE
  2. Schuster S. J. et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Blood. 2017 Dec 7. http://www.bloodjournal.org/content/130/Suppl_1/577
  3. Porter D. et al. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol. Oncol. 2018 March 2. DOI: 10.1186/s13045-018-0571-y
  4. Lee D.W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 May 29. DOI: 10.1182/blood-2014-05-552729

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