Case 121 – Summary!

This week we followed our patient with relapsed/refractory DLBCL through CAR T-cell therapy. We managed her cytokine release syndrome (CRS) and she is in remission thus far.

CAR T-cell therapy

Chimeric Antigen Receptor (CAR) T-cells are modified T cells in which the receptors are targeted against a specific tumour antigen. There a several ‘brands’ of CAR T-cells directed against CD19 which hold great promise in the treatment of relapsed/refractory B cell malignancies, including diffuse large B cell lymphoma (DLBCL), which has previously represented an area of unmet need.

Within the UK, eligibility and appropriateness for CAR T-cell therapy is discussed in MDT meetings at designated CAR T centres. Current products are licensed in DLBCL after two or more prior lines of treatment. Patients often require bridging therapy due to the timeframe of organising CAR T cell therapy (including MDT discussion, cell harvest, manufacture and production) and the therapy used is often down to clinician choice.

Patients receive lymphodepleting conditioning prior to infusion of CAR T-cell therapy. There is increasing recognition of specific toxicities related to CAR T-cell therapy:

 

Cytokine-release syndrome (CRS) is an escalated immune response triggered by CAR T-cell release of inflammatory mediators (cytokines) which often presents with fever, hypotension, hypoxia with or without evidence of end-organ dysfunction.

The severity of CRS can be graded according to the ASBMT Consensus Grading System

Table 1Table from Neelapu SS. Managing the toxicities of CAR T‐cell therapy. Hematological Oncology. 2019;37(S1):48–52. https://doi.org/10.1002/hon.2595

Centres which administer CAR T-cell therapy should have an algorithm for assessment and management of patients receiving CAR T-cell therapy to ensure early recognition and intervention of acute toxicities.

Management will often be guided by the grade of CRS. Supportive measures should be used including anti-pyretics, IV fluids and oxygen. It is vitally important to consider infection and treat accordingly.

Hypotension or hypoxia refractory to adequate fluid challenges or oxygen therapy, or those with Grade 2 CRS, can be considered for management with tocilizumab, an anti-IL-6 therapy. Depending on response patients may require intensive care admission with cardiovascular support. Corticosteroids can be considered for patients with Grade 3 or 4 CRS or those refractory to treatment above.

Patients receiving CAR T-cell therapy should be monitored closely with assessment of fluid balance, organ systems and CRS grade at least twice daily, or more frequently if there is a change in clinical status

 

Immune effector cell-associated neurotoxicity syndrome (ICANS) represents a toxic encephalopathic state and often presents with CNS signs including confusion, impaired higher cognitive function and delirium.

The severity of CRS is often graded using the ASBMT consensus grading system which incorporates the ICE score (Immune effector Cell‐associated Encephalopathy).

Table 2Table from Neelapu SS. Managing the toxicities of CAR T‐cell therapy. Hematological Oncology. 2019;37(S1):48–52. https://doi.org/10.1002/hon.2595

Management of ICANS is based on toxicity grade and options include supportive care, anti-IL-6 therapy (tocilizumab) when associated with CRS, or corticosteroids if not.

Patients receiving CAR T-cell therapy should be monitored closely with assessment of fluid balance, organ systems and ICANS grade at least 8 hourly, or more frequently if there is a change in clinical status. Both CRS and ICANS are reversible in most patients with the correct treatment, and so close monitoring and awareness of local policy is key.

There is also increasing recognition of medium term toxicities related to CAR T-cell therapy including prolonged cytopenias, risk for opportunistic infections, and B‐cell aplasia and hypogammaglobulinaemia.

 

References/further reading:

  • Neelapu SS. Managing the toxicities of CAR T‐cell therapy. Hematological Oncology. 2019;37(S1):48–52. https://doi.org/10.1002/hon.2595
  • Yakoub-Agha, I et al. Management of adults and children undergoing CAR t-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica Nov 2019, haematol.2019.229781; DOI: 10.3324/haematol.2019.229781

 

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