THE CASE

A 68-year-old man with relapsed stage IIIA diffuse large B-cell lymphoma (DLBCL) without comorbidities is referred for consideration of chimeric antigen receptor T-cell (CAR-T) therapy. Molecular profiling of a pathological specimen at diagnosis demonstrated germinal center double-hit lymphoma. He received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for initial therapy, followed by progression at six-month restaging. He then received two cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) as second-line therapy, with plans for consolidative autologous hematopoietic stem cell transplantation. Now, his positron emission tomography/computed tomography scan demonstrated bilateral involvement of the axillary, inguinal, retroperitoneal, and para-aortic nodes, the largest conglomerate, which measures 3 cm in its largest dimension. Autologous transplantation is deferred, and the patient is referred for consideration of salvage CAR-T therapy. Vital organ test results included a negative respiratory viral swab, normal pulmonary function, adequate left ventricular ejection fraction on echocardiogram, and a low-risk psychosocial profile showing strong caregiver support. Laboratory studies, including C-reactive protein (CRP), are normal except for elevated lactate dehydrogenase. He reports some fatigue and decreased exercise tolerance; however, he continues to walk three miles daily.

QUESTIONS

How are cytokine release syndrome (CRS) and neurotoxicity, common toxicities of CAR-T therapy, described to the patient?

No patient should expect to go through CAR-T therapy without some bumps in the road. The treatment timeline and steps must be described in detail, both verbally and via robust written material, by the treating physician and a care coordinator. This includes vital organ testing, the apheresis procedure, fludarabine and cyclophosphamide conditioning chemotherapy, infusion of the cells, and the monitoring and likelihood of toxicities. The two most common toxicities after CAR-T therapy are CRS and neurotoxicity, now called “immune effector cell–associated neurotoxicity syndrome” (ICANS).1  High fevers are the hallmark of CRS, which is associated with elevation of cytokines and chemokines after adoptive transfer of CAR-Ts. Hypotension, hypoxia, and resultant organ failure occur in more severe cases. ICANS is a constellation of signs and symptoms that can range from mild confusion to severe aphasia, obtundation, or seizures. The incidence of CRS and ICANS is approximately 58 and 21 percent, respectively, with tisagenlecleucel, and roughly 93 and 64 percent with axicabtagene ciloleucel, which are the two currently approved agents available for third-line DLBCL treatment.2,3  Regulatory approval for lisocabtagene maraleucel, with CRS and ICANS rates of approximately 42 and 30 percent, respectively, in DLBCL, is expected in 2021.4  Even “mild” cases of CRS can involve prolonged high fevers of 40°C and severe constitutional symptoms. Severe CRS occurs in one to 13 percent of patients, while severe ICANS occurs in 10 to 37 percent of patients, with incidence varying across the different agents.

Both CRS and ICANS are typically transient, with almost all cases resolving within two weeks of CAR-T treatment. The chance of a patient dying from the treatment itself as opposed to progressive DLBCL is approximately 3 percent, with infections or rare complications associated with CRS (e.g., multiorgan dysfunction) or ICANS (e.g., cerebral edema) as likely causes. While the toxicity rates may impact the decision as to which CAR-T therapy to select, differences in the pivotal trial designs preclude direct comparisons of not only toxicity rates but also efficacy of the therapies; therefore, physician and center preference play a large role.

What are the primary points that should be discussed in multidisciplinary tumor board? What findings may preclude a consensus to proceed, and influence a decision to delay or cancel the procedure?

The care team is composed of numerous clinicians including infectious disease specialists, nocturnists, psychologists, nurses, pharmacists, and social workers.5  A multidisciplinary tumor board allows for discussion of patients at consult and again immediately prior to proceeding with CAR-T therapy, with a goal of consensus recommendation for therapy. Essential points of discussion include confirmation of diagnostic testing, the prior lines of therapy, clarification of comorbidities, elucidation of social support, and consideration of performance status. Not only must the patient meet the label approved indication or clinical trial eligibility for CAR-T therapy, but the team must be sure that the patient can benefit without undue risk of death or comorbidity. Several of the same features associated with high rates of toxicity are also associated with decreased opportunity for prolonged disease-free survival (DFS).6  The common and easily identifiable clinical features are a poor performance status and high disease burden.7  Patients with poor performance status often have elevation of proinflammatory markers such as CRP, ferritin, and IL-6, which are also independently associated with higher CRS and ICANS rates and lower opportunity for durable response.8  High tumor burden, when measured by a multidimensional approach or by metabolic tumor volume, is also associated with worse clinical outcomes.9  However, the opportunity for prolonged DFS following CAR-T therapy remains even in patients with these poor prognostic baseline features. Older patients without comorbidities can expect efficacy and toxicity outcomes similar to those of younger patients, though older patients who develop severe CRS or ICANS may require a longer recovery period owing to deconditioning brought on by a prolonged bed-bound state.10 

In our clinical practice, the presence of several of the following features typically preclude selection of CAR-T therapy as a treatment option: dynamic rapidly progressing disease (daily measurable growth or significant growth between cycles of salvage), poor performance status (Eastern Cooperative Oncology Group performance status, 2-4) that cannot be expected to improve with bridging therapy, or extreme elevation of ferritin or CRP. Early referral to a CAR-T treatment center is key to avoid these situations, with referral consideration at first relapse after frontline therapy.

Is it possible to deliver CAR-T therapy in the outpatient setting? What factors must be considered before choosing inpatient versus outpatient therapy?

Conditioning chemotherapy before CAR-T infusion is typically administered in the outpatient setting. Most patients treated on the pivotal clinical trials were then admitted for CAR-T therapy infusion to allow for close monitoring and management of toxicities. In real-world practice, many centers are infusing tisagenlecleucel on an outpatient basis. Axicabtagene ciloleucel is rarely infused as an outpatient due to high rates of CRS-associated fevers, accompanied by neutropenia associated with the conditioning chemotherapy, within a few days of infusion. Beyond the safety profile of the CAR-T therapy, other factors must be considered before selecting a patient for outpatient infusion, including 24-hour caregiver availability and capability, performance status, comorbidities, and distance to the treating center. Patients with extremely high tumor burden or proinflammatory markers are generally poor candidates for outpatient infusion.

The ability to give CAR-Ts as an outpatient should not be confused with ease of setting up and managing a CAR-T program. The infrastructure necessary to safely administer CAR-Ts on an outpatient basis is greater than that needed to treat patients in the hospital. Requirements include additional caregiver training, 24-hour on-call staff trained on CAR-T therapy adverse effects, easy admission procedures and bed availability if CRS/ICANS develop, lodging within minutes of the treating center, and a robust outpatient treatment facility to allow for frequent visits and potential intravenous treatments.

CASE CONTINUATION

A decision is made to proceed with axicabtagene ciloleucel. The patient receives fludarabine and cyclophosphamide conditioning without incident and is admitted for CAR-T therapy infusion. On day +2, the patient is found to have a temperature of 39.8°C and low blood pressure, which responds to intravenous fluid infusion and does not require vasopressor support. The patient does not have signs or symptoms of ICANS.

How is CRS managed? When does the risk for CRS end?

CRS management has evolved over the past several years, with recognition that intervention with the IL-6R blocking antibody tocilizumab at lower grades of toxicity may prevent the development of severe CRS without impacting an opportunity for prolonged DFS.11  The Society for Immunotherapy of Cancer recently released guidelines on the management of immune effector cell toxicities,12  and the American Society for Transplantation and Cellular Therapy is also finalizing management guidelines. These guidelines are extremely helpful as a starting point; however, there is wide variability in toxicity management across treatment centers and for different patient populations, as well as the treatment algorithms suggested by CAR-T commercial manufacturers and trial sponsors.

This patient has a grade 2 CRS by the American Society for Transplantation and Cellular Therapy criteria, and our general practice is to consider administration of a dose of tocilizumab, which is most likely to cause the fever and blood pressure to improve and prevent escalation into a more severe CRS toxicity. There is a theoretical concern that single-agent tocilizumab without concomitant use of steroids during early-stage CRS may increase the risk for ICANS. To counteract this possibility for older patients or those with high tumor burden, we will often also administer a single dose of 10 mg intravenous dexamethasone along with the tocilizumab. The patient must be continuously monitored for resolution of the toxicity, and if CRS and particularly hypotension persists, additional doses of tocilizumab with corticosteroids may be warranted. CRS is most often a single continuous event that starts within the first week after infusion of CAR-Ts. ICANS is often temporally distinct with a later onset and resolution. New or recurrent CRS and ICANS events are extremely rare beyond day +28, and should new symptoms develop, a rigorous work-up for alternate causes should be considered.

The patient is placed on broad spectrum antibiotics in the face of neutropenia and fever. His temperature and blood pressure normalize after a single treatment of tocilizumab and dexamethasone. In the absence of other new symptoms, he is discharged on day +10 following neutrophil count recovery. On day +30 and again on day +90, his restaging scans show complete remission.

What are the infection risks for patients?

Patients undergoing CAR-T therapy are at risk for infections. Conditioning chemotherapy often leads to neutropenia, and broad-spectrum prophylactic antibiotic coverage is warranted. In a subset of patients, cytopenias do not resolve within a few weeks and may persist for months following CAR-T therapy.13  This is typically accompanied by hypocellular bone marrow, and in the absence of dysplasia, patients typically recover counts over time. For such cases, the use of growth factors should be considered. CD4 T cell counts recover slower than CD8 T cells counts, and Pneumocystis jirovecii pneumonia prophylaxis should be given. Normal B cells generally recover in six to 24 months after therapy, and IgG levels often remain low during this period. In the absence of recurrent infections, we do not reflexively treat low IgG levels with intravenous immunoglobulin. Late infections after CAR-T therapy can occur, and social distancing and general hygiene should continue until immune cell counts have normalized. Importantly, a patient with DLBCL in complete remission at day +90 after tisagenlecleucel or axicabtagene ciloleucel has a high (nearly 75%) likelihood of remaining in ongoing remission at two years and beyond, and long-term survivorship issues should be considered.14 

References

References
1.
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
.
2019
;
25
:
625
-
638
.
2.
Neelapu
SS
,
Locke
FL
,
Bartlett
NL
, et al.
Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma
.
N Engl J Med
.
2017
;
377
:
2531
-
2544
.
3.
Schuster
SJ
,
Bishop
MR
,
Tam
CS
, et al.
Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma
.
N Engl J Med
.
2019
;
380
:
45
-
56
.
4.
Abramson
JS
,
Palomba
ML
,
Gordon
LI
, et al.
Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study
.
Lancet
.
2020
;
396
:
839
-
852
.
5.
Locke
FL
,
Anasetti
C
.
Transplanters drive CARs to the clinic by brewing ICE-T: the Moffitt roadmap
.
J Immunother Cancer
.
2017
;
5
:
59
.
6.
Locke
FL
,
Rossi
JM
,
Neelapu
SS
, et al.
Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma
.
Blood Adv
.
2020
;
4
:
4898
-
4911
.
7.
Nastoupil
LJ
,
Jain
MD
,
Feng
L
, et al.
Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: Results from the US Lymphoma CAR T Consortium
.
J Clin Oncol
.
2020
;
38
:
3119
-
3128
.
8.
Faramand
R
,
Jain
M
,
Staedtke
V
, et al.
Tumor microenvironment composition and severe cytokine release syndrome (CRS) influence toxicity in patients with large B-cell lymphoma treated with axicabtagene ciloleucel
.
Clin Cancer Res
.
2020
;
26
:
4823
-
4831
.
9.
Dean
EA
,
Mhaskar
RS
,
Lu
H
, et al.
High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma
.
Blood Adv
.
2020
;
4
:
3268
-
3276
.
10.
Neelapu
SS
,
Jacobson
CA
,
Oluwole
OO
, et al.
Outcomes of older patients in ZUMA-1, a pivotal study of axicabtagene ciloleucel in refractory large B-cell lymphoma
.
Blood
.
2020
;
135
:
2106
-
2109
.
11.
Dholaria
BR
,
Bachmeier
CA
,
Locke
F
.
Mechanisms and management of chimeric antigen receptor T-cell therapy-related toxicities
.
BioDrugs
.
2019
;
33
:
45
-
60
.
12.
Maus
MV
,
Alexander
S
,
Bishop
MR
, et al.
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events
.
J Immunother Cancer
.
2020
;
8
:
e001511
.
13.
Logue
JM
,
Zucchetti
E
,
Bachmeier
CA
, et al.
Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma
.
Haematologica
.
2020
; doi:
10.3324/haematol.2019.238634. [Epub ahead of print]
.
14.
Locke
FL
,
Ghobadi
A
,
Jacobson
CA
, et al.
Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial
.
Lancet Oncol
.
2019
;
20
:
31
-
42
.

Competing Interests

Dr. Locke has been a scientific advisor to BMS; Kite, a Gilead Company; and Novartis.