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Study Overview
Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.
Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.
Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.
Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x106 CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.
Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.
Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.
Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.
Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.
Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.
Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.
Commentary
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.
Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.
One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.
The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.
Applications for Clinical Practice
CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.
1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 2017;130:1800–8.
2. Brentjens RJ, RIviere I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011;118:4817–28.
3. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545–54.
4. Kochenderfer JN, Somerville RP, Lu T, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther 2017;25:2245–53.
Study Overview
Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.
Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.
Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.
Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x106 CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.
Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.
Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.
Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.
Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.
Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.
Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.
Commentary
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.
Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.
One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.
The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.
Applications for Clinical Practice
CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.
Study Overview
Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.
Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.
Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.
Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x106 CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.
Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.
Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.
Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.
Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.
Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.
Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.
Commentary
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.
Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.
One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.
The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.
Applications for Clinical Practice
CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.
1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 2017;130:1800–8.
2. Brentjens RJ, RIviere I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011;118:4817–28.
3. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545–54.
4. Kochenderfer JN, Somerville RP, Lu T, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther 2017;25:2245–53.
1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 2017;130:1800–8.
2. Brentjens RJ, RIviere I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011;118:4817–28.
3. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545–54.
4. Kochenderfer JN, Somerville RP, Lu T, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther 2017;25:2245–53.