Assessment, Grading and Management of Acute Toxicities From CAR-T-Cell Therapy

Recommendations of the CAR T cell-therapy-associated TOXicity (CARTOX) Working Group

Chimeric antigen receptor (CAR)-T‑cell therapy is a promising approach for the treatment of refractory malignancies, but is associated with unique acute toxicities that need specialised monitoring and management, however, algorithms are lacking. To address this unmet need, the investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR‑T‑cell therapy products formed a CAR‑T‑cell-therapy-associated TOXicity (CARTOX) Working Group. In an article published in the Nature Reviews Clinical Oncology they describe the multidisciplinary approach adopted at their institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR‑T‑cell therapy.

Durable remissions have been noted, suggesting that this immunotherapeutic strategy can be cura­tive. The feasibility of central manufacturing of CAR‑T‑cell therapies and the safety of treatment with cryopreserved CAR‑T‑cell products has been demon­strated in multicentre clinical trials.

On 30th August 2017, the US FDA approved the first anti-CD19 CAR‑T‑cell product, tisagenlecleucel, for the treatment of paediatric and young adult patients with relapsed and/or refractory B-cell precursor acute lymphoblastic leukaemia. At same time, the FDA also approved tocilizumab for the treatment of patients 2 years of age or older with cytokine-release syndrome (CRS) that occurs with CAR-T-cell therapy. On 18 October 2017, the FDA granted regular approval to CAR-T-cell therapy axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

The two most commonly observed toxicities with CAR‑T‑cell therapies are CRS, characterised by high fever, hypotension, hypoxia, and/or multiorgan tox­icity; and a CAR‑T‑cell‑related encephalopathy syndrome (CRES), typically characterised by a toxic encephalopathic state with symptoms of confusion and delirium, and occasionally seizures and cerebral oedema. Rare cases of fulminant haemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS), which is characterised by severe immune activation, lymphohistiocytic tissue infiltration, and immune-mediated multiorgan failure, have also been reported.

Such toxicities have also been observed in patients treated with other redirected-T‑cell therapies, such as TCR-gene therapies and bispecific T‑cell-engaging antibodies (BiTEs), and preclinically with CAR natural killer (NK) cells.

Both CRS and HLH/MAS have been observed in patients treated with blinatumomab, an anti‑CD19/CD3 BiTE. These toxicities are manageable in most patients, although some require monitoring and treatment in the intensive-care setting, and fatalities can occur.

The CARTOX Working Group representatives from multiple medical disciplines, including haemato-oncology, solid tumours, stem‑cell transplantation, neurology, critical care, immunology, and pharmaceutical sciences, have been involved in treating more than 100 adult patients with leukaemia or lymphoma, using at least four different anti‑CD19 CAR‑T‑cell plat­forms that were originally developed at academic institutions and subsequently licensed to commercial entities for further clinical development in multicentre trials. The CARTOX Working Group discussed the available evidence in the literature and their collective experience in treating these patients, and collectively developed recommendations and a prac­tical guide for monitoring, grading, and management of CRS, CRES, and HLH/MAS in adult patients.

In the paper, the authors present and discuss the CARTOX management and treatment algorithms, with reference to a representative clinical case.

Supportive-care considerations for CAR‑T‑cell therapy

Before and during CAR-T‑cell infusion:

  • Baseline brain MRI to rule out any central nervous system (CNS) disease
  • Central venous access, preferably with double or triple lumen catheter, for intravenous fluid and other infusions in case of toxicities
  • Cardiac monitoring by telemetry starting on the day of CAR‑T‑cell infusion and continued until CRS resolves, in order to detect arrhythmias
  • Tumour lysis precautions for patients with bulky tumours, as per standard institutional guidelines
  • Seizure prophylaxis with levetiracetam at 750 mg orally every 12 h for 30 days, starting on the day of infusion for CAR‑T‑cell therapies known to cause CRES
  • Hospitalization recommended for at least 7 days after CAR-T‑cell therapy

Patient monitoring after CAR-T‑cell infusion:

  • Assess vital signs every 4 h, close monitoring of oral and intravenous fluid input and urine output, and daily measurement of bodyweight
  • Daily review of patient history and physical examination
  • Daily blood counts, complete metabolic profiling, and coagulation profiling
  • C‑reactive protein and ferritin levels measured daily, starting on the day of infusion
  • Assessment and grading of CRS should be done at least twice daily, and whenever the patient’s status changes
  • Assessment and grading of CRES using the CAR‑T‑cell-therapy-associated toxicity 10‑point neurological assessment (CARTOX‑10) should be done at least every 8 h
  • Maintenance intravenous fluids with normal saline to ensure adequate hydration

Notifications and contingency orders:

  • The physician should be notified on detection of any of the following: systolic blood pressure (SBP) >140 mmHg or <90 mmHg; heart rate >120 bpm or <60 bpm, or arrhythmia; respiratory rate >25 breaths per min or <12 breaths per min; arterial oxygen saturation <92% on room air; urine output <1,500 ml per day; upward trend in blood creatinine levels or the results of liver function tests; tremors or jerky movements in extremities; change in mental status (alertness, orientation, speech, ability to write a sentence, or CARTOX‑10 score)
  • For patients with a temperature ≥38.3 °C, order blood cultures (central and peripheral), urinalysis and urine cultures, portable chest radiography, and notify physician
  • For patients with neutropenia and fever, start empiric broad-spectrum antibiotics
  • Corticosteroids should not be administered unless approved by physician
  • If patient develops CRES, withhold oral intake of food, fluids, and medicine, and notify physician
  • Pro re nata (as needed) medications, acetaminophen (first choice) or ibuprofen (second choice, if not contraindicated), and cooling blanket for fever ≥38.3 °C; normal saline 500–1,000 ml bolus for SBP <90 mmHg, with one repeat if SBP remains <90 mmHg after first bolus
  • Anti‑IL‑6 therapy with tocilizumab or siltuximab to be initiated only on physician order

Furthermore, the authors provide in their article very useful recommendations for the management of different grades of CRS symptoms and signs, CRES, status epilepticus after CAR‑T‑cell therapy, raised intracranial pressure and CAR‑T‑cell-related HLH/MAS.

Reference

Neelapu S, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T‑cell therapy — assessment and management of toxicities. Nature Reviews Clinical Oncology; Published online 19 Sep 2017. doi:10.1038/nrclinonc.2017.148