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CAR T Trial Results and Toxicity Management

Insights From: Nilanjan Ghosh, MD, PhD, Levin Cancer Institute; David Maloney, MD, PhD Fred Hutchinson Cancer Research Center
Published: Thursday, Dec 20, 2018

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Transcript: 

David Maloney, MD, PhD:
I do not believe that neurologic toxicity or cytokine release syndrome should be managed in the outpatient setting; this should be a mandatory admission to the hospital. At our center, significant fever in the outpatient setting succeeding CAR [chimeric antigen receptor] T-cell therapy is a compulsory admission for immediate monitoring and treatment. As more experience is gained, it may be possible—if a product is associated with low-level CRS—that intensive fluid or oxygen support and intensive care will not be required; however, I do not see this happening in the near future. All of the CAR T-cell products can be associated with severe symptoms of cytokine release syndrome or neurology toxicity.

Grade 2 CRS is certainly not managed in the outpatient setting: This requires immediate hospitalization. Even grade 1 CRS should be managed, in my opinion, as an inpatient.

Nilanjan Ghosh, MD, PhD: There have been 3 trials looking at the safety and efficacy of CD19 CAR T-therapy in the relapsed or refractory B-cell lymphoma setting: The ZUMA study, which looked at axicabtagene ciloleucel [Yescarta]; the TRANSCEND study, which looked at lisocabtagene maraleucel [JCAR017]; and the JULIET study, which looked at tisagenlecleucel [CTL019]. All 3 studies have shown an efficacy in patients with refractory or relapsed B-cell lymphoma—especially the ZUMA study, which was reported in the New England Journal of Medicine, and then updated at the 2018 American Society of Clinical Oncology [ASCO] Annual Meeting, which showed an overall response rate of 82% and complete response rate of 58%. It is important to note that patients who had an initial partial response converted into a complete response. In terms of adverse effects, 94% of the patients had CRS if you include all grades—13% had grade 3 or 4. The neurotoxicity occurred in 64% of these patients if you include all grades—28% had grade 3 or 4, from which 3 deaths occurred.

In the JULIET study, the overall response rate was 52% and the complete response rate was 40%. This was evaluated at 3 months, which is a very important endpoint when looking at the durability of response. The neurotoxicity in the study was not as prevalent: It was less than 10%, in terms of serious neurotoxicity effects. The CRS in this study was 52%, with 22% experiencing grade 3 or 4. About half of the patients who had a partial response converted into a complete response with longer follow-ups. About 40% of patients in both the ZUMA and JULIET studies seemed to have a complete response at 3 months.

Finally, looking at the TRANSCEND study, which was updated at the 2018 American Society of Clinical Oncology Annual Meeting, the overall response rate was 80%, with the complete response rate at 59%. The complete response rate of the core cohort—which is what I’m referring to when talking about this study—was 45%. Notably, the adverse-effect profile is rather favorable in this study. The overall rate of CRS, if you include all grades, was 37%; only 1% had grade 3 or 4. The overall neurotoxicity rate was 25%, of which 15% had grade 3 or 4. In all 3 of these studies, tocilizumab with or without dexamethasone was used to treat neurotoxicity or CRS.

The overall management of these adverse effects is complex. In general—depending on the grade of these toxicities—they may need just supportive care. In terms of CRS, a fever is typically the first sign of occurrence. You may administer antipyretics such as acetaminophen during incipient signs. If the blood pressure drops, the fluids are the first thing you manage; however, there may be complications such as capillary leak, for which you use vasopressors. Furthermore, they may need oxygen support, for which you use tocilizumab to mitigate and prevent the progression of CRS. This is extremely important because the early intervention has shown to be essential in preventing severe adverse effects.

 Early intervention with these agents does not seem to interfere with the efficacy of the CAR T-cell therapy. In terms of neurotoxicity, dexamethasone is the primary option, in addition to some form of steroid depending on the severity of the adverse effects. If there is more severe CRS, a higher dose of steroid may be used. There’s always a concern that the steroids will have an adverse effect upon the CAR T cells; but this is of course used as a last resort.

Antiseizure prophylaxis is also considered when managing neurotoxicity since seizures can occur. Additional adverse effects of neurotoxicity include confusion, encephalopathy, and aphasia, all of which are worrisome. The important message is, if intervened and treated properly, the majority of these adverse effects are reversible. As you can see from these 3 studies, there is little mortality from CAR T-cell therapy. In fact, the JULIET and TRANSCEND studies exhibited no deaths from CRS or neurotoxicity. In the ZUMA study, there was only a 3% mortality rate, which is significant considering the fact that many of the patients had these adverse effects.

Lastly, I want to mention that we do not have substantial long-term data; however, the 3-month period is very important for assessing responses that can help predict the long-term outcomes. Across the 3 trials, it appears that around 40% to 45% of patients may be in remission at 3 months. It appears that if they are in remission—especially complete remission at 3 months—there is going to be a durable response.

David Maloney, MD, PhD: As you’ve heard, there are different profiles associated with the 3 CAR T-cell products that are either commercially available or in late-stage clinical trials. There appears to be some differences in terms of the rate of CRS onset. The total overall grade of the cytokine release syndrome in terms of the severe grade 3 and 4 toxicity seems to be less with lisocabtagene maraleucel—at least in the clinical trial results that we have today, which could provide a number of advantages. I think healthcare economics could clearly be a major factor in determining which products will be the most successful in the marketplace eventually. This also will depend on efficacy maintenance long term.


Transcript Edtied for Clarity

 
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Transcript: 

David Maloney, MD, PhD:
I do not believe that neurologic toxicity or cytokine release syndrome should be managed in the outpatient setting; this should be a mandatory admission to the hospital. At our center, significant fever in the outpatient setting succeeding CAR [chimeric antigen receptor] T-cell therapy is a compulsory admission for immediate monitoring and treatment. As more experience is gained, it may be possible—if a product is associated with low-level CRS—that intensive fluid or oxygen support and intensive care will not be required; however, I do not see this happening in the near future. All of the CAR T-cell products can be associated with severe symptoms of cytokine release syndrome or neurology toxicity.

Grade 2 CRS is certainly not managed in the outpatient setting: This requires immediate hospitalization. Even grade 1 CRS should be managed, in my opinion, as an inpatient.

Nilanjan Ghosh, MD, PhD: There have been 3 trials looking at the safety and efficacy of CD19 CAR T-therapy in the relapsed or refractory B-cell lymphoma setting: The ZUMA study, which looked at axicabtagene ciloleucel [Yescarta]; the TRANSCEND study, which looked at lisocabtagene maraleucel [JCAR017]; and the JULIET study, which looked at tisagenlecleucel [CTL019]. All 3 studies have shown an efficacy in patients with refractory or relapsed B-cell lymphoma—especially the ZUMA study, which was reported in the New England Journal of Medicine, and then updated at the 2018 American Society of Clinical Oncology [ASCO] Annual Meeting, which showed an overall response rate of 82% and complete response rate of 58%. It is important to note that patients who had an initial partial response converted into a complete response. In terms of adverse effects, 94% of the patients had CRS if you include all grades—13% had grade 3 or 4. The neurotoxicity occurred in 64% of these patients if you include all grades—28% had grade 3 or 4, from which 3 deaths occurred.

In the JULIET study, the overall response rate was 52% and the complete response rate was 40%. This was evaluated at 3 months, which is a very important endpoint when looking at the durability of response. The neurotoxicity in the study was not as prevalent: It was less than 10%, in terms of serious neurotoxicity effects. The CRS in this study was 52%, with 22% experiencing grade 3 or 4. About half of the patients who had a partial response converted into a complete response with longer follow-ups. About 40% of patients in both the ZUMA and JULIET studies seemed to have a complete response at 3 months.

Finally, looking at the TRANSCEND study, which was updated at the 2018 American Society of Clinical Oncology Annual Meeting, the overall response rate was 80%, with the complete response rate at 59%. The complete response rate of the core cohort—which is what I’m referring to when talking about this study—was 45%. Notably, the adverse-effect profile is rather favorable in this study. The overall rate of CRS, if you include all grades, was 37%; only 1% had grade 3 or 4. The overall neurotoxicity rate was 25%, of which 15% had grade 3 or 4. In all 3 of these studies, tocilizumab with or without dexamethasone was used to treat neurotoxicity or CRS.

The overall management of these adverse effects is complex. In general—depending on the grade of these toxicities—they may need just supportive care. In terms of CRS, a fever is typically the first sign of occurrence. You may administer antipyretics such as acetaminophen during incipient signs. If the blood pressure drops, the fluids are the first thing you manage; however, there may be complications such as capillary leak, for which you use vasopressors. Furthermore, they may need oxygen support, for which you use tocilizumab to mitigate and prevent the progression of CRS. This is extremely important because the early intervention has shown to be essential in preventing severe adverse effects.

 Early intervention with these agents does not seem to interfere with the efficacy of the CAR T-cell therapy. In terms of neurotoxicity, dexamethasone is the primary option, in addition to some form of steroid depending on the severity of the adverse effects. If there is more severe CRS, a higher dose of steroid may be used. There’s always a concern that the steroids will have an adverse effect upon the CAR T cells; but this is of course used as a last resort.

Antiseizure prophylaxis is also considered when managing neurotoxicity since seizures can occur. Additional adverse effects of neurotoxicity include confusion, encephalopathy, and aphasia, all of which are worrisome. The important message is, if intervened and treated properly, the majority of these adverse effects are reversible. As you can see from these 3 studies, there is little mortality from CAR T-cell therapy. In fact, the JULIET and TRANSCEND studies exhibited no deaths from CRS or neurotoxicity. In the ZUMA study, there was only a 3% mortality rate, which is significant considering the fact that many of the patients had these adverse effects.

Lastly, I want to mention that we do not have substantial long-term data; however, the 3-month period is very important for assessing responses that can help predict the long-term outcomes. Across the 3 trials, it appears that around 40% to 45% of patients may be in remission at 3 months. It appears that if they are in remission—especially complete remission at 3 months—there is going to be a durable response.

David Maloney, MD, PhD: As you’ve heard, there are different profiles associated with the 3 CAR T-cell products that are either commercially available or in late-stage clinical trials. There appears to be some differences in terms of the rate of CRS onset. The total overall grade of the cytokine release syndrome in terms of the severe grade 3 and 4 toxicity seems to be less with lisocabtagene maraleucel—at least in the clinical trial results that we have today, which could provide a number of advantages. I think healthcare economics could clearly be a major factor in determining which products will be the most successful in the marketplace eventually. This also will depend on efficacy maintenance long term.


Transcript Edtied for Clarity

 
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