Question 1

Which of the following statements about cytokine-release syndrome and neurotoxicity after tisagenlecleucel infusion is correct?

Correct answer: B. The median time to onset of cytokine-release syndrome is 3 days.

Expert Perspective

Following tisagenlecleucel infusion, cytokine-release syndrome occurred in 79% of pediatric and young adult patients with relapsed or refractory ALL¹ and 74% of adults with relapsed or refractory large B-cell lymphomas,² including ≥ grade 3 in 49% of patients with relapsed or refractory ALL and in 23% of patients with relapsed or refractory large B-cell lymphomas. Toxicity was graded according to the “Penn criteria” which scores hypoxia as grade 3 (among other factors). The median time to onset of cytokine-release syndrome was 3 days (range: 1–51 days), and in only two patients was the onset seen after 10 days of infusion. The median time to resolution of cytokine-release syndrome was 8 days (range: 1–36 days).

Neurologic toxicities including severe or life-threatening reactions occurred in 72% of patients with relapsed or refractory ALL¹ and in 58% of patients with relapsed or refractory large B-cell lymphomas,² including ≥ grade 3 in 21% of patients with relapsed or refractory ALL¹ and in 18% of patients with relapsed or refractory large B-cell lymphomas. Among patients who had a neurologic toxicity, 88% occurred within 8 weeks following infusion. The median time to the first event was 6 days from infusion (range: 1–359 days), and the median duration was 6 days for patients with relapsed or refractory ALL and 14 days for patients with relapsed or refractory large B-cell lymphomas. Resolution occurred within 3 weeks in 79% of patients with relapsed or refractory ALL and in 61% of patients with relapsed or refractory large B-cell lymphomas. Encephalopathy lasting up to 50 days was noted.^1,2

Question 2

Which of the following statements about cytokine-release syndrome and neurotoxicity after axicabtagene ciloleucel infusion is correct?

Correct answer: D. The median time to onset of neurotoxicity was 4 days.

Expert Perspective

With axicabtagene ciloleucel, the median time to onset of cytokine-release syndrome is 2 days (range: 1–12 days), and the median duration of cytokine-release syndrome was 7 days (range: 2–58 days).³ Cytokine-release syndrome was graded according to the “Lee scale,” making its incidence difficult to compare with that of tisagenlecleucel (for instance, patients with hypoxia could be considered grade 2 cytokine-release syndrome with the Lee scale). Neurologic toxicities occurred in 87% of patients.³ About 88% of all neurologic toxicities occurred within the first 8 weeks of axicabtagene ciloleucel infusion, with a median time to onset of 4 days (range: 1–43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities occurred in 31% of patients. Serious events including leukoencephalopathy and seizures occurred with axicabtagene ciloleucel. Fatal and serious cases of cerebral edema have occurred in patients treated with axicabtagene ciloleucel.

Question 3

Approximately what proportion of patients develop infection(s) after the first month of CAR T-cell therapy platform (lymphodepleting therapy plus anti-CD 19 CAR T-cell infusion) despite being on appropriate antimicrobial prophylaxis?

Correct answer: B. 20% to 40%.

Expert Perspective

The majority of recipients of CAR T-cell therapy received lymphodepleting chemotherapy several days before T-cell infusion.^1-3 The lymphodepleting chemotherapy frequently leads to neutropenia and by design, T-cell lymphopenia, placing patients at risk for both bacterial and opportunistic infections. The immune-suppressive environment caused approximately 20% to 40% of patients to develop infections within the first month after CAR T-cell platform despite appropriate antimicrobial prophylaxis.^1-5 Bacterial and viral infections are the most common, although invasive fungal infections have also been reported. Clinically significant reactivation of latent DNA viruses (eg, cytomegalovirus, Epstein-Barr virus, BK polyomavirus) is not a common occurrence, although prospective screening studies are lacking.

Question 4

Which statement about the diagnosis and management of cytokine-release syndrome after CAR T-cell infusion is correct?

Correct answer: C. Careful and timely exclusion of an alternative diagnosis is important.

Expert Perspective

Early and aggressive supportive care and timely therapy with tocilizumab (humanized monoclonal antibody that acts as an interleukin-6 receptor antagonist) are of paramount importance to mitigate life-threatening cytokine-release syndrome. Although prospective clinical trials evaluating the timing of intervention are lacking, retrospective analyses suggest that tocilizumab does not abrogate the antitumor response, at least when such therapies are implemented once cytokine-release syndrome is well under way (≥ grade 2).^6-8 How the use of preemptive or prophylactic tocilizumab or corticosteroids affects the antitumor response or alters the natural history of other immune effector cell–associated toxicities, such as neurotoxicity, remains an open question that merits further exploration in well-controlled studies, some of which are underway.

Infectious illness concurrent with cytokine-release syndrome predicts for poor outcomes and may exacerbate cytokine-release syndrome, highlighting the critical importance to exclude ongoing/active infection(s) and to consider the use of prophylactic or preemptive antimicrobial strategies. A reasonable temporal relationship to CAR T-cell therapy must be present before the diagnosis of cytokine-release syndrome, and exclusion of other competing diagnoses (such as infection, allergic reactions, heart failure, and disease progression) is important. Steroids may be useful in selected individuals with cytokine-release syndrome (eg, tocilizumab for refractory or progressive disease or life -threatening cytokine-release syndrome [but not in all patients with cytokine-release syndrome]).The FDA has approved tocilizumab for severe or life-threatening cytokine-release syndrome in adults and in pediatric patients 2 years of age and older.⁸

Question 5

Which of the following statements about anti-CD19 CAR T-cell–associated chronic hypogammaglobulinemia is correct?

Correct answer: D. All of the above.

Expert Perspective

B-cell aplasia with anti-CD19 CAR T-cell therapy is due to “on target, off-tumor” effect. As long as anti-CD19 CAR-modified T cells persist, B-cell aplasia continues, which provides what appears to be a highly accurate pharmacodynamic marker of CAR function¹. It is more common after tisagenlecleucel infusion for the treatment of relapsed or refractory ALL than for large B-cell lymphoma. It was reported in 43% of patients treated with tisagenlecleucel for relapsed or refractory ALL (ELIANA study¹), 14% of patients with relapsed or refractory large B-cell lymphoma (JULIET study²), and 15% of patients treated with axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma (ZUMA 1 study³). It is important to monitor for infections, consider prophylactic medications, and use immunoglobulin wisely after treatment with anti-CD19 CAR T-cell therapy. Some experts consider intravenous immunoglobulin replacement when IgG levels are extremely low (especially < 200 mg/dL), especially when associated with extremely low concurrent IgA levels. Others replace intravenous immunoglobulin in patients with hypogammaglobulinemia and recurrent infections. Additional studies will be needed to best define how to manage B-cell aplasia and hypogammaglobulinemia.

Question 6

Which of the following statements about the diagnosis and management of neurotoxicity after CAR T-cell infusion is correct?

Correct answer: C. Neurotoxicity may occur without preceding cytokine-release syndrome.

Expert Perspective

Neurotoxicity associated with cellular therapy is now termed “immune effector cell–associated neurologic syndrome (previously referred to as CAR T-cell–related encephalopathy syndrome).”⁶ The earliest manifestations of this CAR T-cell–associated syndrome (neurotoxicity) are tremor, dysgraphia, mild difficulty with expressive speech, impaired attention, apraxia, and mild lethargy. In one trial,⁹ expressive aphasia was identified as the most characteristic feature, occurring in 19 of 22 patients who went on to develop severe neurotoxicity. Expressive aphasia, starting as impaired naming of objects, paraphasic errors, hesitant speech, and verbal perseveration, may progress to global aphasia, characterized by expressive and receptive difficulty. Patients with global aphasia may appear wide awake but are mute and unable to follow commands (akinetic).⁶ In general, mild clinical findings are self-limited and resolve within days, whereas more severe symptoms may require 4 or more weeks to resolve and can result in mortality. The tempo of progression to severe neurotoxicity may vary from hours to days.¹⁰

It is important to rule out other important (reversible) neurotoxicity or encephalopathy causes such as hepatic disease, severe uncontrolled hypertension, infection/sepsis, electrolyte abnormalities, immunosuppressive medications, antiseizure medication(s), and cytotoxic drug(s). Brain imaging and cerebrospinal fluid evaluation may be useful to rule out bleeding, infection, and disease progression. Immune effector cell–associated neurologic syndrome (neurotoxicity) can occur concurrently with cytokine-release syndrome, following resolution of cytokine-release syndrome, or it may occur without preceding cytokine-release syndrome. Intriguing preclinical data suggest blocking granulocyte-macrophage colony-stimulating factor may be effective for neurotoxicity.¹¹ The mainstay of treatment for this type of neurotoxicity is the use of steroids, usually given to patients with ≥ grade 2 American Society of Transplantation and Cellular Therapy–defined neurotoxicity⁶; however, there is no FDA-approved therapy for immune effector cell–associated neurologic syndrome. 

The authors would like to acknowledge Olha Huzo, MD, for participating in the preparation of this article.

DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca. Dr. Porter holds IP and is a patent holder for CTL019 (CAR T cells for CD19+ malignancies), licensed by the University of Pennsylvania to Novartis, and may receive Royalty and milestone payments for tisagenlecleucel (Kymriah). COI is managed by, and according to COI policies of the University of Pennsylvania. He has received research support from Novartis, and has received honoraria for advisory board participation from Novartis, Kite, Incyte, Glenmark, and Janssen; spouse receives salary, stock/options, and employment compensation from Genentech. Dr. Hashmi reported no conflicts of interest.

REFERENCES

1. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014.

2. Schuster SJ, Svoboda J, Chong EA, et al: Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 377:2545-2554, 2017.

3. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.

4. Park JH, Romero FA, Taur Y, et al: Cytokine release syndrome grade as a predictive marker for infections in patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with chimeric antigen receptor T cells. Clin Infect Dis 67:533-540, 2018.

5. Hill JA, Li D, Hay KA, et al: Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood 131:121-130, 2018.

6. Lee DW, Santomasso BD, Locke FL, et al: ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 25:625-638, 2019.

7. Locke FL, Neelapu SS, Bartlett NL, et al: Preliminary results of prophylactic tocilizumab after axicabtagene ciloleucel treatment for patients with refractory, aggressive non-Hodgkin lymphoma (NHL). 2017 ASH Annual Meeting & Exposition. Abstract 1547.

8. Le RQ, Li L, Yuan W, et al: FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 23:943-947, 2018.

9. Santomasso BD, Park JH, Salloum D, et al: Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov 8:958-971, 2018.

10. Frey N, Porter D: Cytokine release syndrome with chimeric antigen receptor T cell therapy. Biol Blood Marrow Transplant 25:e123-e127, 2019.

11. Ahmed O: CAR-T-cell neurotoxicity: Hope is on the horizon. Blood 133:2114-2116, 2019.