The advent of chimeric antigen receptor (CAR) T-cell therapy offers a new therapeutic avenue for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia (B-ALL) up to the age of 25 years, or diffuse large B-cell lymphoma (DLBCL) in adult patients. However, CAR-T therapy is associated with significant and unique toxicities that require specialised monitoring and management.1 We spoke with Professor Simon Harrison, Director of the Centre of Excellence in Cellular Immunotherapy at the Peter MacCallum Cancer Centre (PMCC) in Melbourne, about some of the complexities involved in successfully delivering CAR-T therapy to these difficult-to-treat patients.
What is CAR-T therapy?
CAR-T therapy is a cellular immunotherapy that genetically reprograms T cells harvested from a patient. Each CAR construct is genetically modified to identify and destroy tumour cells.2 As Prof Harrison explains, “it essentially activates the patient’s own immune system to eliminate the cancer cells.”
Tisagenlecleucel (Kymriah®) contains a CAR that targets CD19-positive B cells and is the first CAR-T therapy approved in Australia for paediatric, adolescent and young adult (<25 years) patients with refractory or relapsed B-ALL, and for adults with relapsed or refractory DLBCL.2 Clinical trials with Kymriah in patients with B-ALL show an overall remission rate at 3 months of 81%, with an overall survival of 76% at 12 months.3 In patients with DLBCL, the best overall response rate (i.e. complete or partial response) was 54%, with a 24 and 36-month PFS of 33% and 31%, respectively.4,5 The relapse-free probability was 60% among all infused patients at 24 and 36 months, with the median duration of response not reached at the 40.3 month updated analysis.5 Studies show that the efficacy of Kymriah in patients with DLBCL may be affected by baseline tumour characteristics, with Myc overexpression and limited T-cell response associated with poorer outcomes.4,5
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Case 1: B-cell acute lymphoblastic leukaemia
Patient background
A 24-year-old man with CD19-positive B-ALL previously treated with the Australian Leukaemia and Lymphoma Group ALL06 protocol and blinatumomab was referred for consideration for CAR-T therapy after rising minimal residual disease (MRD) was identified on surveillance bone marrow biopsy. Clinical review showed no central nervous system (CNS) involvement and normal blood counts, and the patient met Medical Services Advisory Committee (MSAC) criteria for treatment with Kymriah.
Pre-infusion management
The patient travelled interstate for medical review, eligibility screening, consent and lymphocyte collection. He returned home for bridging therapy with one cycle of inotuzumab, during which he experienced an upper respiratory tract infection (URTI).
The patient’s CAR T-cells were successfully manufactured and returned to the PMCC, and he relocated to Melbourne with his carers for a total of 6 weeks.
During the restaging assessment, the patient’s bone marrow aspiration and trephine (BMAT) biopsy showed progressive disease (61% blasts vs 7% blasts recorded 3 weeks previously), with normal blood counts. Due to his recent URTI and hypogammaglobulinemia, the patient commenced intravenous immunoglobulin (IVIG). Lymphodepletion with fludarabine/cyclophosphamide was administered one week before the CAR-T infusion.
While most can be treated in the outpatient setting, this particular patient had a planned inpatient admission after receiving the CAR-T infusion due to his high disease burden (>50% blasts on BMAT).
Post-infusion toxicity management
Continued post-infusion monitoring for tumour lysis syndrome (TLS) and neurotoxicity (ICANS) was negative.
On day+2, the patient developed a fever with mild hypotension; tocilizumab was administered with a good response. On day+3, the Medical Emergency Team (MET) was called, as the patient’s hypotension was not responding to a second dose of tocilizumab. He was transferred to the intensive care unit (ICU), where noradrenaline was commenced, and a third dose of tocilizumab was administered. The patient’s haemodynamic status improved, and his fever resolved.
On day+5, the patient developed a new fever. A fourth dose of tocilizumab and dexamethasone 10 mg were administered, improving his haemodynamic status within 24 hours, at which point he was discharged from the ICU. The patient did not experience any further toxicities and was discharged from hospital on day+14.
Clinical response and follow-up
The patient was MRD-negative with complete molecular remission at 1, 3, 6, and 9 months after the Kymriah infusion (results at 12 months pending at time of publication).
As part of a shared model of care, the patient returned home for continued follow-up facilitated by telehealth visits.
Case 2: Diffuse large B-cell lymphoma
Background
A 68-year-old woman with CD19-positive DLBCL who had relapsed after two previous lines of therapy, including an autologous stem cell transplant, was referred for consideration for CAR-T therapy. Due to longer than normal wait time to receive finished product from the overseas manufacturing facility due to manufacturing constraints at this time (8 weeks at the time of referral), the patient was presented with alternate treatment options (inclusion in the BiTE trial or a CAR-T trial); however, standard of care Kymriah therapy was selected, based on the amount of supporting data, including follow-up. This was prior to approval of manufacturing in Australia. Manufacturing constraints are no longer a current consideration. Clinical review showed a history of hypertension but no CNS involvement, and the patient met MSAC criteria for treatment with Kymriah.
Pre-infusion management
After the patient considered the treatment options presented, she undertook screening and completed the consent process. The order for Kymriah cells was placed and the patient received bridging therapy locally with 2 cycles of chemotherapy with R-gemcitibine-oxaliplatin. She did not respond to bridging therapy and experienced deconditioning and grade 3 cytopenias during treatment. Her blood counts recovered, and she proceeded to lymphodepletion and Kymriah infusion. While most can be treated in the outpatient setting, this patient had a planned inpatient admission after the Kymriah infusion due to her extensive disease burden.
Post-infusion toxicity management
On day+1 after the Kymriah infusion, the patient developed fever and neutropenia; management according to the recommended septic pathway was initiated (antibiotics, IV tocilizumab, and supportive care). The fever persisted for 8 days with no haemodynamic instability. The septic screen was negative, and no intervention was required. No ICANS developed.
The patient developed cytopenia that persisted for 6 months after the Kymriah infusion, initially managed with regular platelet transfusions and then with red cell transfusions plus granulocyte colony-stimulating factor (GCSF) support administered as required.
Response
Positron emission tomography at 1, 3, and 6 months after the CAR-T infusion showed that the patient was in complete remission, with BMAT showing hypocellular bone marrow.
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Toxicities associated with CAR-T therapy
The two most common toxicities associated with CAR-cell therapy are cytokine release syndrome (CRS) and neurotoxicity. Prof Harrison describes CRS as “a systemic inflammatory response that usually develops during the first week after the CAR-T infusion, when the rapid CAR antitumour expansion occurs and causes a substantial proinflammatory cytokine response.” CRS can cause fever, hypoxia, and hypotension, and in rare cases can lead to organ toxicity. The incidence and severity of CRS can be influenced by the type of malignancy and the tumour burden, with Prof Harrison noting that “patients with B-ALL, a high bone marrow disease burden, or an early onset of fever within the first three days after infusion are at higher risk of developing more severe CRS.” 1,6
Neurotoxicity, termed immune effector cell-associated neurotoxicity syndrome (ICANS) or CAR T-cell-related encephalopathy syndrome (CRES), can occur during, after, or in the absence of CRS. “Patients who develop neurotoxicity after CAR-T infusion usually first present with handwriting impairment, and can also suffer language impairment characterised by word-finding or naming difficulties, confusion and attention deficits,” Prof Harrison explains, “but more severe neurotoxicity can cause global aphasia and reduced consciousness, and even progress to seizures and cerebral oedema.” 1,6
Other toxicities that are associated with CAR-T therapy include cytopenias, hypogammaglobulinaemia and sepsis. Rarely, CRS can progress to haemophagocytic lymphohistiocytosis or macrophage activation syndrome (HLH/MAS).1,6
Good patient management can reduce the impacts of CAR-T toxicities
While these toxicities can be severe and in rare cases life-threatening, appropriate patient management before and during the CAR-T infusion, as well as accurate and timely monitoring and intervention after the infusion, can help minimise the risk of adverse outcomes.1 Guidelines for appropriate monitoring and detailed grading systems have been developed for both CRS and ICANS/CRES, which in turn guide management of these toxicities based on their presentation and severity.1,7
“As we see in the previous case study of a patient with B-ALL who developed early-onset CRS, early intervention with tocilizumab is critical for relieving symptoms of CRS. Tocilizumab may be administered as needed every 8 hours, with a maximum of 3 doses in 24 hours and a maximum of 4 doses in total. For persistent or higher grades of CRS, corticosteroids such as methylprednisolone or dexamethasone can also be considered and administered with the second dose of tocilizumab,” Prof Harrison explains.1,2
An important caveat that Prof Harrison notes is that “the symptoms of CRS are not unique to CRS and overlap with those of sepsis, so it’s important to assess each patient carefully to rule out other causes of fever and haemodynamic instability, including infection.” 1
Individualisation is critical to successful CAR-T therapy
Factors that can affect the onset, severity, duration, and type of toxicity include the type of lymphodepleting chemotherapy used, the dose of CAR T-cell infused, and patient characteristics such as age and disease burden.1,6 As Prof Harrison explains, “the great variability between patients, and the limited number we have actually treated with CAR-T therapy, highlights the importance of our ongoing national data collection process. By tracking the characteristics of each patient – their disease burden, previous therapies and complications, response and toxicities after the infusion – we can help identify factors that affect successful delivery of CAR-T therapy and which patients may need more support to achieve those good outcomes.”
Supporting improved outcomes through greater access and shared care
The out-of-pocket expenses often incurred by patients for interstate travel are becoming less of a concern for patients hoping to access CAR-T therapy. A growing network of CAR-T centres has been established across Australia to provide more local services and access for patients remote from Melbourne, facilitated by weekly national meetings and the provision of telehealth services. Prof Harrison notes that “by supporting this shared model of patient care, we can keep the patients near their home – reducing the costs and stress of travel to the patients and their families during an already challenging time.”
Another win for patients is the recent approval from TGA for Cell Therapies Pty Ltd, located at the PMCC in Melbourne, as the first commercial manufacturing facility for CAR T-cell therapies (Kymriah) in Australia. “Local manufacturing means that patients’ cells can stay in Australia, rather than needing to be shipped overseas – eligible patients can now expect quicker timelines to access Kymriah,” explains Prof Harrison. “The shorter shipment-turnaround times reduce the need for bridging therapies and also limit the time for potential problems such as deconditioning, cytopenias or infections to develop that could negatively affect the outcomes of the CAR-T therapy.”
REFERENCES
- Neelapu SS, et al. Nat Rev Clin Oncol. 2018;15(1):47-62.
- Kymriah® (tisagenleclecuel) Approved Product Information.
- Maude SL, et al. N Engl J Med. 2018;378(5):439-448.
- Schuster SJ, et al.N Engl J Med. 2017;377(26):2545-2554.
- Jaeger U, et al. Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Feb 8-12, 2021; Poster 212.
- Selim AG, et al.Pathology. 2021;53(3):408-415.
- Lee DW, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638.