ABSTRACT:

Chimeric antigen receptor T-cells (CAR-T) therapy is an advanced therapy product which involves the modification and reprogramming of T cells to generate new fusion protein for combating cancer cells. CAR-T therapy is a recognised immunotherapy for treating relapsed/ refractory large B-cell lymphoma, in combination with conditioning chemotherapy and leukapheresis. Two of the early established CAR-T products, tisagenlecleucel (Kymriah^®) and axicabtagene ciloleucel (Yescarta^®), were approved by the U.S. Food and Drug Administration for such lymphoma. The pivotal JULIET trial of tisagenlecleucel, had demonstrated a high response rate in patients and high tendency of reaching relapse-free. Common adverse reactions identified including cytokine release syndrome (CRS), neurotoxicity, and abnormal blood count. Two landmark trials, ZUMA-1 and ZUMA-7, had shown that axicabtagene ciloleucel might prolong the survival of patients with presenting adverse reactions of CRS and neurologic toxicity. More studies have been conducted to examine the efficacy and expanding roles of axicabtagene ciloleucel. Currently, only tisagenlecleucel is registered in Hong Kong since March 2020. In view of these findings and the increasing recognition and utilization of the two CAR-T therapy products, this review highlights the mechanism of action as well as efficacy and safety profile of tisagenlecleucel and axicabtagene ciloleucel. The newer data on efficacy contributing to their expanded indications, different monitoring parameters and management of adverse reactions are discussed. The comparative analysis of both CAR-T products and potential role of axicabtagene ciloleucel in Hong Kong are addressed in the context of this review.

 

Keywords

Relapsed/ Refractory Large B-Cell Lymphoma, CAR-T Therapy, Tisagenlecleucel, Axicabtagene ciloleucel, Kymriah^®, Yescarta^®

INTRODUCTION

Disease Background - Refractory/Relapsed Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a cancer type that affects the lymphatic system, specifically the B lymphocytes. The uncontrolled growth of abnormal B cells in patients causes formation of solid tumors in various parts of the body. DLBCL, of note, is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 25% to 30% of NHL worldwide [1].

The etiology of DLBCL remains largely unknown [2]. However, certain risk factors have been identified, including increased age and weakened immune system [3]. Genetic factors and certain chromosomal abnormalities, including translocation and mutations, have also been associated with an increased risk of developing DLBCL [4]. Conventional chemotherapy, the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), can be given as the initial treatment [2]. However, approximately 40% of DLBCL patients experience disease relapse or are refractory to first-line chemoimmunotherapy, which indicates the failure of first-line chemotherapy causing refractory or relapsed DLBCL (R/R DLBCL) [5].

 

Introduction of CAR-T Therapy

Chimeric antigen receptor T-cells (CAR-T) therapy is an immunotherapy used to treat different NHL disorders. In R/R DLBCL, the process starts by collecting T-cells from peripheral blood cells from individual patients [6]. Since the cancer cells may disguise themselves as healthy cells, autologous T cells may not be capable of eradicating the cancer cells, hence require modification. After harvesting the patient's own T cells, the genetic information is modified to express a chimeric antigen receptor on their cell surface. The modified T cells will be readministered back to the patient, which allows for the more effective recognition of cancer cells (B cells) and targeting specific antigens present on them resulting in cancer cell death [6].

The first CAR-T therapy launched was tisagenlecleucel (tisa-cel), which was approved by the U.S. Food and Drug Administration (FDA) in 2017 for the treatment of refractory/relapsed B cell precursor acute lymphoblastic leukemia (R/R BCP-ALL) in pediatric and young adult [7]. Since then, CAR-T therapies have been developed and approved for other cancers, including DLBCL and follicular lymphoma [7] [8]. Eligibility for CAR-T therapy depends on various factors, including type and stage of cancer, previous treatments, and individual health status [9]. However, CAR-T therapy is considered for patients who have not responded to standard treatments or have relapsed after previous therapies [9]. CAR-T therapy is still new and complex. Ongoing research and clinical trials are carrying on to improve and assess its effectiveness and safety, with the aim to expand its use to other types of cancer.

 

CAR-T Therapy Options for R/R DLBCL

Tisa-cel and axicabtagene ciloleucel (axi-cel) are CAR-T therapies that obtained approvals for the indication of R/R DLBCL [8]. Clinical trials have demonstrated remarkable response rates and remissions in adult patients with R/R DLBCL. Despite demonstrating impressive efficacy, the use of CAR-T therapy also exhibits drawbacks. Cytokine release syndrome (CRS) and neurologic toxicities are its significant adverse events, so patients require management and monitoring closely [10]. Additionally, the high cost and complexity of CAR-T therapy lead to barriers to widespread use [11].

 

TISAGENLECLEUCEL (KYMRIAH®)

Mechanism of Action in R/R DLBCL

Pharmacologically, tisa-cel involves a lentiviral vector to encode an anti-CD19 chimeric antigen receptor (CAR) and hence reprogram patient's T cells [12]. A CAR is made from a single-chain antibody fragment (scFv) which targets the CD19 of the B cells. The scFv is connected by a linker with a CD8α hinge, which is to stabilize CAR expression, and a transmembrane domain, which is for transduction of ligand recognition signals [12,13,14]. After readministering the modified T cells into the patient's bloodstream, modified T cells recognize CD19-expressing target cells, and the intracellular domains then activate the downstream signaling cascades that result in T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines that kill cancer cells [15].

 

EFFICACY OF TISAGENLECLEUCEL

Pivotal Study for Tisagenlecleucel

In July 2015, the pivotal study JULIET (ClinicalTrials.gov Identifier: NCT02445248) was initiated to evaluate the efficacy and safety of tisa-cel in patients with R/R DLBCL [16]. It is a phase two, single-arm, multicenter, international study that enrolled 165 patients. Patients recruited in the study were at least 18 years of age and had priorly received at least two lines of therapy containing rituximab and anthracycline; and were ineligible for, or relapse after, receiving autologous transplantation. The exclusion criteria included having received CD-19-directed therapy or allogeneic transplant before, or active central nervous system (CNS) involvement in DLBCL and primary mediastinal DLBCL. Among the enrolled patients, 93 of them received the infusion and were evaluated for efficacy. The primary endpoint for the study was the overall response rate (ORR) using Lugano classification. The various efficacy-associated secondary endpoints included response duration, time to response, safety, cellular kinetics data, and overall survival (OS).

A propitious result was identified in the study [16]: a best ORR of 52% was seen (95% CI, 41 – 62) in which 40% of the patients achieved complete response (CR) and 12% of them achieved partial response. Although the median duration of response was not established in the study, the estimated relapse-free probability at different time frames was developed. It was estimated that at 12 months, 63.4% of patients were likely to be relapse-free. The OS was measured in the study as well [17]: the percentages of survival at 12, 36, and 60 months were 48.2%, 36.6%, and 31.7% respectively; and the median month of survival was reported to be 11.1 (95% CI, 6.6 - 23.9). In view of the efficacy profile derived from the JULIET study, the FDA approved the use of tisa-cel in adult patients with large B-cell lymphoma, with requirements similar to those stated in the study (e.g. adult patients who received at least two lines of therapy previously) [18].

 

Newer Efficacy Data in Treating R/R DLBCL

A newer BELINDA (ClinicalTrials.gov Identifier: NCT03570892) trial started in 2019 also aimed at studying the efficacy of tisa-cel among patients with DLBCL, as well as those with other diseases subtypes such as high grade B-cell lymphoma and primary mediastinal B-cell lymphoma [19]. The patient demographics showed over 60% of enrolled patients were diagnosed with DLBCL, reflecting it was the most common type of aggressive B-cell lymphoma in the study, and the trial results can provide valuable insights on the efficacy evaluation of tisa-cel in this review.

The BELINDA trial was a phase three, double arm, randomized, open label, multicenter trial which compared the efficacy of tisa-cel with standard care. The standard care group received platinum-based chemotherapy followed by conditioning chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) depending on the response.

The study result did not indicate that tisa-cel has superiority in reference to the standard care group. The hazard ratio for any event or death for tisa-cel group compared to standard care was found to be 1.07 (95% CI, 0.82 – 1.40, P = 0.61). The median event-free survival (EFS) was 3 months in both treatment arms. The response at week 6 among the tisa-cel patients was 38.3% compared to 53.8% in standard care patients. Finally, progressive disease was seen in 25.9% of patients from the tisa-cel group compared to 13.8% in the standard care group. Based on these results, the BELINDA trial did not demonstrate superiority of utilizing tisa-cel as a replacement for the standard chemotherapy and autologous HSCT.

 

Evaluation

The abovementioned studies showed mixed results about the therapeutic efficacy of tisa-cel in R/R DLBCL. It is noted that the number of studies evaluating the efficacy of tisa-cel compared with standard care is scarce, and the superiority of tisa-cel over standard care cannot yet be determined. Therefore, additional studies are warranted to address this issue seen in the existing trials.

The differences in setting or protocol between trials can also inadvertently affect the outcome measure in the studies. In the JULIET trial, 92% of the patients received a combination of chemotherapy like rituximab, gemcitabine, and etoposide before infusion, while 82.7% of patients in the BELINDA trial received platinum-based systemic bridging therapy. More patients received bridging therapy in JULIET, and the medication regimens used in the two trials were also not consistent. The use of bridging therapy before tisa-cel infusion may impose an effect on the study outcome, and this is a particular problem when there is no clear description about the amount of bridging therapy used in the trials. Additionally, the JULIET trial excluded the patients with primary mediastinal large B-cell lymphoma (a subtype of DLBCL) while they are included in the BELINDA trial. Thus, there is a possibility that the JULIET trial overestimated the efficacy of tisa-cel.

Ongoing studies include a prospective cohort study assessing the effectiveness of tisa-cel in Brazilian patients with B-cell malignancy (ClinicalTrials.gov Identifier: NCT05541341) and a Novartis-sponsored single arm interventional trial (ClinicalTrials.gov Identifier: NCT04094311). A more comprehensive clinical benefit profile of tisa-cel can be obtained after these studies are completed.

 

SAFETY OF TISAGENLECLEUCEL

Adverse Events

The adverse events of tisa-cel are summarized with data from the JULIET study, PR(AG)404/2020 study (a retrospective study with data collected from 10 Spanish institutions), and a match comparison study (an analysis of a retrospective French registry study comparing tisa-cel and axi-cel in matched populations) (Table 1) [16, 20, 21]. Other common adverse events associated with tisa-cel in the JULIET study are also shown (Table 2). Cautions should be exercised when interpreting the adverse event rates as varied clinical criteria were used for reporting adverse event across the three studies, and the summarized rates in this review is only intended to provide a general picture of the incidence of these adverse events.

 

Table 1: Rates of adverse events in patients receiving tisa-cel therapy

Table 2: Other common adverse events of tisa-cel in JULIET

In all three studies, CRS had the highest occurrence. CRS is a common adverse event reported in CAR-T therapy, as activated CAR-T cells release cytokines, followed by subsequent activation of endogenous immune cells, namely monocytes and macrophages, resulting in further release of cytokines [22]. Due to the high occurrence of CRS, a specific treatment algorithm is required. Moreover, it is noted that the incidence of CRS of any grade in a real-life setting is even higher than that recorded in the pivotal trial, so it is deemed important to counsel patients on the possible CRS signs and symptoms such as fever, hypoxia, and hypotension, and to briefly address the management approach [22].

A type of neurological toxicity known as immune effector cell-associated neurotoxicity syndrome (ICANS) is another significant adverse event observed in CAR-T therapy patients. ICANS is closely related to and results from CRS: increased cytokine level in the systemic system indirectly causes blood-brain-barrier disruption, allowing myeloid cell infiltration into the brain parenchyma and triggering CNS immune response together with resident microglia [23]. Therefore, the key to managing ICANS is resolving CRS.

Abnormal blood cell count and infectious complications were also frequently observed in the three studies. The mechanism of blood cell abnormality is still poorly understood based on current state of knowledge. Infections in patients are caused by their immunosuppression and cytopenia status [24], and fatal infection had occurred with the use of tisa-cel in R/R DLBCL patient.

For adverse events of higher severity, CRS, ICANS, hematotoxicities, and infections were the ones with higher occurrence (Table 3). It is noteworthy that adverse events of grade ≥ 3 were generally lower in real-world studies compared to the pivotal trial, especially for CRS and ICANS. The possible reasons include earlier and more extensive use of tocilizumab (an interleukin-6 receptor antagonist) and corticosteroids, the standard medications for CRS management, along with more clinical experience in CAR-T therapy patient management [21].

Management and monitoring for adverse reactions

Certain approaches have been adopted to treat the adverse reactions upon the administration of tisa-cel, and the ones for CRS, ICANS, cytopenia, and infections are reviewed here.

CRS

CRS, if suspected, should be managed based on the recommendations [25] (Table 4).

ICANS

Treatment approaches of ICANS depends on assessment of its severity, and whether the patient has any concurrent CRS [25]. For patients without CRS, treatment options include supportive care with IV hydration and corticosteroid. For patients with CRS, tocilizumab and corticosteroid should be considered. Mechanical ventilation is reserved for severe patients who require airway protection, and non-sedating anticonvulsant (e.g. levetiracetam) should be considered for selected patients who are at risk of seizure disorder (e.g. those with seizure history and CNS disease).

Cytopenia

There is no standard protocol for cytopenia management, and individuals are managed based on their clinical

manifestations [26]. Current clinical practice includes blood transfusion and administration of hematopoietic growth factors including granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO) [27]. TPO receptor agonists and sirolimus are also used for mitigation [27]. Monitoring patients’ blood count is essential, and G-CSF should be provided when ANC is < 0.5 x 109/L [28]. Transfusion is given to maintain a hemoglobin level of ≥ 8 g/dL when symptomatic anemia is observed or hemoglobin level is < 6 g/dL [28]. Erythropoietin (EPO) can be given for anemia control and to minimize the need for blood transfusion [28]. As for platelet count, when platelet level is < 10 x 109/L or bleeding is observed, either TPO or platelet transfusion is provided [28]. When fibrinogen is < 100 mg/dL, administer cryoprecipitate [28].

 

Infections

Tisa-cel should not be initiated in patients with active uncontrolled infection until the infection is resolved. Clinicians should also be aware of febrile neutropenia and evaluate for infection, and inform the patients to report any signs and symptoms of an infection such as fever and chills [25]. Infections are managed based on individual species of bacterium, fungus or virus according to the local guidelines [21]. As infection risk increases with prolonged cytopenia, cytopenia should be managed as mentioned [28].

 

 

AXICABTAGENE CILOLEUCEL (YESCARTA®)

 

Mechanism of Action in R/R DLBCL

Axi-cel fuses chimeric antigen receptors onto the T-cells after genetic modification and exhibits the same elimination effect of the abnormal B-cells as tisa-cel. It is composed of a scFv which targets the CD-19 of B-cells. The differences between the two CAR-T products are the subtype of hinge and transmembrane domain, which are both CD-28 subtypes [29]. These signals can increase the expansion, longer-term persistence and potency of CAR-T cells. When the scFv binds to CD19-expressing B-cells, the CAR transmits a signal to promote T-cell expansion, activation and hence elimination of the excess B-cells [13].

 

EFFICACY OF AXICABTAGENE CILOLEUCEL

 

Pivotal study for axicabtagene ciloleucel

In April 2015, the ZUMA-1 trial (ClinicalTrials.gov Identifier: NCT02348216) was started to evaluate the safety and efficacy of axi-cel with refractory aggressive non-Hodgkin lymphoma [30]. This single-arm, multi-center, phase 1 and 2 clinical trial recruited 108 patients with R/R DLBCL, other non-Hodgkin lymphomas, or chemotherapy-refractory disease. Subsequently, the FDA approved axi-cel to be a treatment for adult patients with R/R DLBCL after two or more lines of systemic therapy based on the study results [31]. Among the 101 patients evaluated, the ORR was 72% and the complete remission rate was 51% (95% CI: 41%, 62%). The patients with the best overall response with complete remission had a longer duration of response than those with partial response. A new alternative option was provided for patients as a third-line treatment. The study continued to collect patient data in follow-ups and more efficacy data was published until 2021. The progression-free survival (PFS) and OS in Phase 2 (Pivotal Study) cohort 1 were 5.1 months and 11.5 months respectively. Due to the potential of axi-cel being utilized as a more front-line treatment, more refinement of the design of ZUMA-1 trial had been made and new clinical trials arose in the next decade.

 

Newer efficacy data in treating R/R DLBCL

A new pivotal ZUMA-7 trial (ClinicalTrials.gov Identifier: NCT02601313) was launched in 2018 after the first approval of axi-cel. The efficacy of axi-cel versus standard care as second-line therapy in patients with R/R DLBCL was compared [32]. This international, randomized, open-labeled, multi-centered, phase 3 clinical trial recruited 359 patients above 18 years old with histologically proven DLBCL and had relapsed or refractory disease after conditioning chemotherapy without a history of autologous or allogeneic stem cell transplantation, and were randomized on 1:1 basis to receive either axis-cel or standard care treatment. This is unique since previous clinical trials only included one intervention and did not have side-by-side comparisons with conventional treatment options. Among the 359 randomized patients, the median ORR in the axi-cel group was 83%, which is significantly higher than 50% identified in the standard care group. In terms of duration of response, the median month in the axi-cel group was 26.9, which is longer than median 8.9 months found in the standard care group [32]. Another study analyzing the same trial highlighted the survival indices between the two treatment arms [33]. In terms of EFS, it was significantly longer in the axi-cel group (8.3 months) than in the standard care group (2.0 months) with a hazard ratio of 0.40. Moreover, the estimated 18-month EFS rate of the axi-cel arm and the standard therapy arm was 41.5% and 17% respectively.

 

With the clear improvement and superiority of axi-cel in terms of EFS and the percentage of patients with a response, the FDA further approved axi-cel for adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy in April 2022, which widened its utilization and more patients with R/R DLBCL having the eligibility to access axi-cel [34].

 

At the end of the ZUMA-7 trial, the PFS and death rate between the two intervention groups have been analyzed. In the axi-cel treatment group, the PFS at a median of 47.2 months of follow-up was 14.7 months [32], while that in the standard care group was 3.7 months. The final OS rate could not be evaluated since the median and upper limit of CI of OS were not reached due to an insufficient number of events for both treatment arms. In summary, this trial revealed that the axi-cel treatment arm had a higher response rate and survival rate than the standard care group for R/R DLBCL patients as treatment after failing chemotherapy. This underlines a clinical advantage of axi-cel as administering CAR T-cells earlier in the treatment course may be beneficial to patients, which suggests that it can potentially be a promising treatment option.

 

Expanding role of axicabtagene ciloleucel for patients who are ineligible for autologous stem cell transplantation (ASCT)

ZUMA-7 trials excluded patients who were ineligible for ASCT due to frailty, age, co-existing medical conditions, history of hepatitis B or other infections, and more, causing about half of patients with R/R DLBCL to be considered unfit to receive axi-cel in clinical practice. A one-of-a-kind clinical trial, ALYCANTE (ClinicalTrials.gov Identifier: NCT04531046) was initiated in March 2021 [35]. It was the first-ever study to evaluate the effectiveness of axi-cel in patients with R/R DLBCL who were ineligible for ASCT. This was a single-arm, open-label, multi-centered, phase 2 clinical trial that recruited 62 patients to receive a single axi-cel infusion. The primary outcome was measured after 3 months of the infusion and the results, which were encouraging, were published in late 2022. The complete metabolic response and ORR were 71.0% (95% CI, 58.1–81.8%) and 75.8% (95% CI, 63.3–85.8%) respectively. Follow-ups have been conducted to evaluate the survival rate of the participants. The median EFS rates at 6 and 12 months were 66.7% and 51.2% respectively, whereas the PFS rates at 6 and 12 months were 67.7% and 48.8% respectively. The estimated OS rate and median duration of response were not reached and would be statistically determined in the 3-year follow-up in 2025 [35].

Comparing the results from ALYCANTE with that from ZUMA-7, the results were consistent in terms of response rate and survival rate, providing a new insight into expanding the role of axi-cel to more suitable patients. However, ALYCANTE was different from ZUMA-7 trials in terms of study design, eligibility criteria, sample size, and demographics of participants, etc. For instance, the median age of patients in the ALYCANTE study was 70 years, which was older than that in the ZUMA-7 (59 years). The advanced age might influence the duration of survival or safety profile. Most notably, the study was a single-arm design with no active control group, which made the study prone to selection bias. Although the ALYCANTE study investigators supported axi-cel as second-line treatment for R/R DLBCL patients ineligible for ASCT based on the optimistic study results, the study itself was constrained by its own study limitations.

On a related note, lisocabtagene maraleucel (liso-cel) is a CAR-T agent that can be used for R/R DLBCL patients who are medically unfit for ASCT. Detailed discussion about liso-cel is beyond the scope of this review, but the trials evaluating the efficacy of axi-cel and liso-cel in R/R DLBCL patients ineligible for ASCT are summarized for comparison purpose (Table 5).

SAFETY OF AXICABTAGENE CILOLEUCEL

 

Safety concerns of axi-cel

The pharmaceutical company that developed axi-cel highlighted CRS and neurotoxicity as its two principal life-threatening toxicities, and the two toxicities are now included as boxed warnings in the prescribing information [38, 39].

CRS

Being the dose-limiting toxicity, similar to tisa-cel, occurrence of CRS was prevalent in axi-cel in both ZUMA-7 and ALYCANTE studies [32, 35], which is due to overactivated immunological cells and cytokines. The median onset time of CRS was 1.5 days and could last for 5 days. The majority of patients had mild (grade 1 or 2) cases of CRS, and only 6% patients were categorized in grade 3 or above.

 

Neurotoxicity

Occurrence of ICANS, a type of neurotoxicity in ALYCANTE study, was slightly less than CRS, whilst the severity was higher in both ZUMA-7 and ALYCANTE trials [32, 35]. Neurotoxicity is caused by the systemic capillary leak in the blood-brain barrier, facilitating infiltration of immune cells into the CNS, hence a cascade of inflammatory responses will occur inside the brain. The median onset time was 4 days after infusion with a resolution time of 5 days [40]. Neurological issues were mostly resolved, and none of the cases from the ZUMA-7 trial reported death due to neurological issues.

 

Comparison of various trials

Fludarabine and cyclophosphamide were included as conditioning chemotherapeutics agents in the ZUMA-7 trial [32]. As an anti-metabolite, fludarabine can cause peripheral neuropathy while cyclophosphamide is not typically associated with either CRS or neurotoxicity [41]. Use of fludarabine in the ZUMA-7 trial might explain the increased risk of neurotoxicity.

 

Apart from CRS and neurotoxicity, the ZUMA-7 trial also evaluated different adverse events. Different from the dose-limiting toxicities of axi-cel, the prevalence and severity of hematological adverse events was significantly higher. Neutropenia, anemia, and thrombocytopenia were among the most commonly reported adverse events in the axi-cel group, and there was large proportion of patients who experienced these adverse events of grade 3 or above. Hematological monitoring should be considered for patients receiving axi-cel treatment. The frequency of the hematological and other common adverse events in patients using axi-cel in the ZUMA-7 trial are shown (Table 6).

 

Management of adverse events

Since axi-cel and tisa-cel share similar mechanisms of action and adverse events profiles which primarily consist of CRS, neurotoxicity, and hematotoxicity, the toxicity management strategies are also similar. For specific adverse events such as pyrexia and emesis, supportive care (e.g. antipyretic and antiemetic) can be provided accordingly for symptomatic relief.

 

OVERALL COMPARISON OF TISAGENLECLEUCEL AND AXICABTAGENE CILOLEUCEL AND IMPLICATION FOR HONG KONG

Both tisa-cel and axi-cel show impressive clinical activities in R/R DLBCL. Although they belong to the same treatment category, there are differences between them in terms of evidence on therapeutic efficacy, adverse events, and patient eligibility criteria for use.

 

First, axi-cel has a higher risk of causing fatal toxic effects than tisa-cel. Apart from the JULIET, ZUMA, and ALYCANTE trials, a comprehensive analysis of the toxicity profiles between tisa-cel and axi-cel has been conducted using Vigilyze-VigiBase, the World Health Organization (WHO) database for global incidents of adverse drug reactions [42]. The analysis showed that 10%, 14%, and 29% more patients treated with axi-cel experienced immune system disorders, CRS, and nervous system disorders respectively than those treated with tisa-cel. This suggests that tisa-cel has a relatively less fatal safety profile than axi-cel. However, with close monitoring, the mortality rate of these fatal adverse events can be significantly lowered in both therapies [42].

 

Second, medical literature shows a better performance for tisa-cel than axi-cel. The real-life matched comparison study also evaluated the efficacy of tisa-cel in patients with R/R DLBCL in France [21]. The study analyzed the outcomes of 809 patients who were assigned to either tisa-cel or axi-cel groups. The ORR was 66% and the complete response rate was 42% in the tisa-cel group (P<0.001). The 1-year PFS was found to be 33.2% after a median follow-up time of 11.7 months. This highlights the clinical benefit of tisa-cel in terms of durable response in R/R DLBCL patients.

 

However, for patient eligibility criteria, axi-cel has a higher potential for expanded usage in Hong Kong. axi-cel is eligible as a second-line therapy for patients with R/R DLBCL failing the first-line therapy [34], and can serve as an alternative treatment option at an earlier stage for R/R DLBCL compared with tisa-cel. According to the ZUMA-7 trial, the 24-month EFS of the axi-cel group and standard-care group was 41% and 16% respectively. This shows that by using axi-cel in the earlier treatment, more R/R DLBCL patients can benefit from axi-cel, improving the overall chance of remission.

 

Tisa-cel received the FDA approval in May 2018 for treating R/R DLBCL after two or more lines of systemic therapy; while axi-cel received the FDA approval in October 2017 for treating R/R DLBCL after two or more lines of systemic therapy [18, 31]. Axi-cel, under the trade name Yikaida, also received China’s approval and became the first CAR-T therapy product for use in June 2021, and now with an indication for treating R/R DLBCL after receiving second-line or above systemic therapy in the country [43, 44]. At present, tisa-cel is the only CAR-T therapy product registered in Hong Kong. There is potential that axi-cel will become the second registered CAR-T therapy product with expanded use in Hong Kong, providing a valuable treatment option for R/R DLBCL with data supported by pharmacoeconomic analysis in Hong Kong in the future.

 

CONCLUSION

Tisagenlecleucel and axicabtagene ciloleucel are approved CAR-T therapy products for patients with R/R DLBCL, demonstrating significant efficacy in response rate and survival rate shown in recent studies. Adequate monitoring and supportive care have been outlined as the management approach to resolve the adverse reactions issue encountered by the patients. The FDA has approved high priority of axi-cel utilization in R/R DLBCL patients, while newer trials are investigating whether axi-cel will have a greater role in ASCT ineligible patients. The adoption of this second CAR-T therapy product in Hong Kong can be considered.

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[17] European Medicines Agency. Kymriah EPAR product information. European Medicines Agency Internet. Available from:  https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf Accessed 2025 Jun 30

[18] U.S. Food and Drug Administration. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. U.S. Food and Drug Administration Internet. Available from:

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-adults-relapsed-or-refractory-large-b-cell-lymphoma Accessed 2025 Jun 30

[19] Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, at al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022;386(7):629-39.

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[21] Bachy E, Le Gouill S, Di Blasi R, Sesques P, Manson G, Cartron G, et al. A real-world comparison of Tisagenlecleucel and Axicabtagene Ciloleucel Car T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med. 2022;28(10):2145-2154.

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Questions for Pharmacy Continuing Education Program

2 CE Units

Review of Current CAR-T Therapy for adults Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Tisagenlecleucel (Kymriah®) and Axicabtagene Ciloleucel (Yescarta®)

 

1.	Which of the following about CAR-T therapy is correct?   a) It is considered as a chemotherapy b) It cannot be used in elderly patients. c) It is a genetically modified allogeneic T cell therapy d) It is prepared from the patient's peripheral blood cells
2.	What type of cancer cells do tisagenlecleucel and axicabtagene ciloleucel target?   a) HLA-DR-expressing cancer cells b) CD-19-expressing cancer cells c) CD-20-expressing cancer cells d) PAX5-expressing cancer cells
3.	Based on the US FDA approved indication of tisagenlecleucel, which of the following patients can receive tisagenlecleucel for treating B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse?   a) 21-year-old patient b) 42-year-old patient c) 63-year-old patient d) 84-year-old patient
4.	Which study supported the US FDA approval of tisagenlecleucel for treating adults with relapsed or refractory large B-cell lymphoma?   a) ZUMA-1 b) ZUMA-7 c) JULIET d) ALYCANTE
5.	Which of the following is correct about BELINDA study?   a) It was a phase 2, double-blinded trial that was only conducted in the US. b) It compared the efficacy of tisagenlecleucel and lisocabtagene maraleucel for B-cell lymphomas. c) Its primary endpoint was the occurrence of neurotoxicity associated with CAR-T therapy. d) Diffuse large B-cell lymphoma was the most common disease subtype in the study population.
6.	Which of the following is NOT a sign or symptom of cytokine release syndrome?   a) Fever b) Hypertension c) Tachycardia d) Hypoxia
7.	Which of the following is the most appropriate treatment for Grade 2 cytokine release syndrome?   a) Mechanical ventilation, IV fluid, low-dose vasopressor, tocilizumab, methylprednisolone b) Antipyretic, oxygen, IV fluid, low-dose vasopressor, tocilizumab, methylprednisolone c) Antipyretic, antiemetic d) IV fluid, high-dose vasopressor, tocilizumab, methylprednisolone
8.	Which of the following is correct about immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CAR-T therapy?   a) Treatment options for ICANS are the same across different severities. b) Corticosteroid should be avoided in ICANS patients with concurrent cytokine release syndrome. c) Levetiracetam should be considered for seizure prophylaxis in ICANS patients with seizure history. d) It is only associated with tisagenlecleucel but not axicabtagene ciloleucel.
9.	Which of the following patients on CAR-T therapy should receive evaluation for infection risk?   a) Those with peripheral neuropathy b) Those with edema c) Those with aphasia d) Those with febrile neutropenia
10.	Which of the following is the only registered CAR-T therapy product in Hong Kong as of June 2025?   a) Tisagenlecleucel b) Axicabtagene ciloleucel c) Lisocabtagene maraleucel d) Obecabtagene autoleucel

 

Answers will be released in the next issue of HKPJ