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Case history

image A 22-year-old man with relapsed B cell acute lymphoblastic leukaemia (B-ALL) had exhausted all available treatment options, including combination chemotherapy, myeloablative allogenic bone marrow transplant and monoclonal antibody therapy. At the time of his most recent relapse he had isolated bone marrow disease with only 1% B-ALL cells by immunophenotyping, expressing cluster of differentiation (CD) 19, and consistent with minimal residual disease. He was enrolled into a phase I anti-CD19 chimeric antigen receptor (CAR) T cell trial.

He received 5 days of lymphodepleting chemotherapy with fludarabine, cyclophosphamide and alemtuzumab. Bone marrow biopsy following lymphodepletion showed 69% blasts, representing progressive disease. He was then infused with a single dose of anti-CD19 CAR T cells at a total dose of 6 × 106 cells.

Three days after CAR T cell infusion he developed fevers and was empirically treated for febrile neutropenia. Blood cultures showed no bacterial growth. By day 7 he had persistent fevers up to 39°C, and he was tachycardic with a systolic blood pressure of 100 mmHg. He continued to be managed for neutropenic sepsis; supportive measures including intravenous fluids and paracetamol had been deployed in the intervening days. As he was clinically deteriorating and there was no obvious septic source, the working diagnosis was cytokine release syndrome (CRS). The decision was made to give him the interleukin (IL)-6 receptor (IL-6R) antagonist tocilizumab.

Initially, his blood pressure and heart rate normalized, although he continued to spike fevers. By day 9 he was again hypotensive and a second dose of tocilizumab was administered. Despite intravenous fluid resuscitation his systolic blood pressure fell to 80 mmHg; on day 10 he received his third dose of tocilizumab and intravenous corticosteroids. He was transferred to the intensive care unit but stabilized without any requirement for inotropes or other organ support. He was stepped down to the ward a day later prior to being managed in ambulatory care. Expansion of CAR T cells in the blood tracked the clinical course of fevers as did a rise in the cytokines IL-6, interferon (IFN)-γ and IL-10 (Figure 1.1). His bone marrow biopsy on day 14 showed CAR T cells with no evidence of residual B-ALL.

Why did CAR T cell therapy cause CRS in this patient?

What was the aim of treatment for the CRS?

What evidence is there for the use of tocilizumab?

When should corticosteroid therapy be administered?

Can we prevent or ameliorate CRS in patients receiving CAR T cell therapy?

Figure 1.1

Fold increase from baseline of IL-6, IFN-γ and IL-10 following CAR T cell infusion. Cytokines peaked at day 10 when the patient clinically was most unwell from CRS.

Why did CAR T cell therapy cause CRS in this patient?

Anti-CD19 CAR T cells express a single-chain variable fragment of a monoclonal antibody directed against CD19. This ...

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