A Review of Selected Presentations From the 61st ASH Meeting • December 7-10, 2019 • Orlando, Florida
CD19-Loss With Preservation of Other B-Cell Lineage Features in Patients With Large B-Cell Lymphoma Who Relapsed Post–Axi-Cel
The multicenter, single-arm phase 1/2 ZUMA-1 study (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma) evaluated axicabtagene ciloleucel in patients with refractory large B-cell lymphoma.1,2 The phase 2 portion of the trial originally enrolled 111 patients into 2 cohorts. The 77 patients in cohort 1 had diffuse large B-cell lymphoma (DLBCL), and the 24 patients in cohort 2 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The primary endpoint was the objective response rate (ORR). After a median follow-up of 27.1 months, the ORR was 83%, with a complete response (CR) rate of 58%. The 2-year rate of progression-free survival (PFS) was 39%. The 2-year rate of overall survival (OS) was 51%. The median OS was not reached. After a median follow-up of 39.1 months, the 3-year OS rate was 47%.
Approximately 60% of patients relapse or progress after treatment with axicabtagene ciloleucel.1 Mechanisms that enable relapse may include loss or modification of CD19 and involvement of the immune tumor environment.3 To gain further insight regarding mechanisms of treatment failure after axicabtagene ciloleucel infusion, a post-hoc analysis analyzed tumor tissue obtained from patients in cohorts 1 and 2 in the ZUMA-1 trial who responded and subsequently relapsed.4 The protein expression of markers of B-cell lineage was centrally assessed with immunohistochemistry (IHC). For select cases, IHC was followed by immunofluorescence staining and confocal microscopy. Assessed markers included CD19 (cytoplasmic domain), CD20 (cytoplasmic domain), CD22 (surface domain), CD79a (surface domain), and PAX5 (nuclear stain). CD19 splice variants were evaluated by RNA sequencing. Tumor samples included 82 with pretreatment IHC, 18 IHC samples from patients who initially responded and then relapsed, 16 paired samples (pre- and postrelapse) with IHC, and 5 paired samples with RNA sequencing.
A consistent axicabtagene ciloleucel treatment effect was observed across all baseline levels of CD19. Median baseline CD19 H-scores were 200 for the 49 patients with a CR as the best response, 260 for the 22 patients with a partial response, and 250 for the 11 patients with stable or progressive disease (Figure 1). The median H-score was 190 in 32 patients with an ongoing response and 240 in 35 patients who had relapsed. Prior to treatment, 90% of tumor biopsies were positive for CD19, and 96% were positive for CD20. Expression of CD19 and/or CD20 was reported in 98% of samples. All 13 patients with CD19-positive samples had relapsed within 6 months of receiving axicabtagene ciloleucel therapy. The 5 patients with CD19-negative samples had a more varied course, with relapses observed between approximately 2 months and 15 months. Among 18 biopsies taken after progression, 5 (28%) did not express CD19; however, all of the samples showed at least minimal expression of the other B-cell antigens. Among the 18 postprogression biopsy samples, 72% expressed CD19, 94% expressed CD22, and 100% expressed CD20, CD79a, and PAX5. Among the 16 paired samples, 4 (25%) showed a loss of CD19 expression at the time of relapse (Figure 2). Downregulation of CD19 was demonstrated by RNA sequencing in 1 patient.
IHC showed expression of CD20 in all samples at relapse. A combination of immunofluorescence and confocal microscopy showed that CD20 expression was maintained on the cell membrane at progression. CD20 expression was of particular interest because patients had received previous treatment with rituximab.
A separate study of pediatric patients with acute lymphoblastic leukemia who received treatment with chimeric antigen receptor (CAR) T-cell therapy showed that alternative splicing of CD19 could result in expression of a truncated CD19 variant that provided some CD19 activity, but failed to trigger killing by CD19-directed CAR T-cell therapy.5 Samples from the ZUMA-1 study also revealed alternative splicing, with loss of exon 2 and/or exons 5 and 6. Alternative splicing events were significantly different in baseline samples vs those obtained after relapse (P<.05). Taken together, the results suggest that the efficacy of CD19-directed CAR T-cell therapy could potentially be improved by simultaneous or sequential targeting of CD19 plus other B-cell antigens.
References
1. 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(1):31-42.
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(26):2531-2544.
3. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel in patients with refractory aggressive non-Hodgkin lymphoma [ASH abstract 578]. Blood. 2017;130(suppl 1).
4. Neelapu SS, Rossi JM, Jacobson CA, et al. CD19-loss with preservation of other B cell lineage features in patients with large B cell lymphoma who relapsed post–axi-cel [ASH abstract 203]. Blood. 2019;134(suppl 1).
5. Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282-1295.
Pivotal Safety and Efficacy Results From TRANSCEND NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel in
Relapsed/Refractory Large B-Cell Lymphomas
Lisocabtagene maraleucel is a CD19-directed CAR T-cell product that contains a 4-1BB costimulatory domain to increase T-cell proliferation and persistence.1 The product is administered using a defined ratio of CD4-positive and CD8-positive CAR T cells. The multicenter phase 1 TRANSCEND NHL 001 trial (Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-Cell Non-Hodgkin Lymphoma) evaluated lisocabtagene maraleucel in adults with relapsed or refractory large B-cell lymphoma.2 Patients in the DLBCL cohort had relapsed or refractory DLBCL–not otherwise specified, including transformed indolent lymphoma; high-grade B-cell lymphoma with MYC and the BCL2 and/or BCL6 rearrangements; primary mediastinal B-cell lymphoma; or follicular lymphoma of grade 3B. Patients had received at least 2 prior lines of therapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The study permitted enrollment of patients who had undergone prior autologous or allogeneic stem cell transplant (SCT), as well as those with secondary central nervous system (CNS) lymphoma.
Bridging therapy was allowed after leukapheresis; however, patients were required to have a positive positron emission tomography result prior to lymphodepletion. Lymphodepletion was accomplished with a 3-day regimen of fludarabine (30 mg/m2) plus cyclophosphamide (300 mg/m2). Lisocabtagene maraleucel was administered within a week of lymphodepletion. In the dose-finding portion of the study, lisocabtagene maraleucel was administered to 60 patients at 3 dose levels: 50 × 106, 100 × 106, or 150 × 106. Among 344 patients who underwent leukapheresis, 294 received an infusion of CAR T cells. Lisocabtagene maraleucel with conforming product was administered to 269 patients with large B-cell lymphoma, and 256 were included in the large B-cell lymphoma efficacy set. Forty-six patients received dose level 1, 169 received dose level 2, and 41 received dose level 3.
Among the 269 patients treated with lisocabtagene maraleucel, the median age was 63 years (range, 18-86 years). Fifty-one percent had DLBCL–not otherwise specified, and 3% of all patients had secondary CNS lymphoma. Thirty-eight percent had a high disease burden, and the median number of prior systemic therapies was 3 (range, 1-8). Two-thirds of patients had chemotherapy-refractory disease, 44% had never achieved a CR with prior treatment, and 59% received bridging therapy during the study. High-risk features associated with shortened OS were noted in 89% of patients.
After a median follow-up of 12.0 months (range, 11.2-16.7 months), the ORR was 73% (95% CI, 67%-78%), with a CR rate of 53% (95% CI, 47%-59%). The median time to first CR or partial response was 1.0 months (range, 0.7-8.9 months). Response durability is shown in Figure 3. Clinically meaningful response rates were observed across all subgroups. Among all patients, 12-month PFS was 44.1% (95% CI, 37.3%-50.7%) and 12-month OS was 57.9% (95% CI, 51.3%-63.8%).
Nearly all patients (99%) developed a treatment-emergent adverse event (AE) of any grade. The most common events were neutropenia (63%), anemia (48%), and fatigue (44%). The most common grade 3/4 AEs were neutropenia (60%), anemia (38%), and thrombocytopenia (27%). Grade 5 treatment-emergent AEs occurred in 7 patients; in 4 patients, these deaths were considered related to lisocabtagene maraleucel. They were caused by diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syn–
drome, and cardiomyopathy.
There were no reports of grade 5 cytokine-release syndrome or neurotoxicity. Any-grade cytokine-release syndrome occurred in 42% of patients, including 1% with grade 3 and 1% with grade 4. Thirty percent of patients developed a neurologic AE of any grade, including 9% with grade 3 and 1% with grade 4. Prolonged infections of at least grade 3 were reported in 37% of patients, and 12% had infections of grade 3 or higher.
References
1. Havard R, Stephens DM. Anti-CD19 chimeric antigen receptor T cell therapies: harnessing the power of the immune system to fight diffuse large B cell lymphoma. Curr Hematol Malig Rep. 2018;13(6):534-542.
2. Abramson JS, Palomba L, Gordon LI, et al. Pivotal safety and efficacy results from TRANSCEND NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas [ASH abstract 241]. Blood. 2019;134(suppl 1).
KTE-X19, an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, in Patients With Relapsed/Refractory Mantle Cell Lymphoma: Results of the Phase 2 ZUMA-2 Study
Patients with mantle cell lymphoma who progress after treatment with a Bruton tyrosine kinase (BTK) inhibitor have a median OS of less than 6 months.1 KTE-X19 is a CD19-directed CAR T-cell therapy that contains a CD3ζ T-cell activation domain and a CD28-signaling domain. The KTE-X19 CAR T cells are manufactured using a process that removes circulating tumor cells.2 The multicenter, international phase 2 ZUMA-2 trial (A Phase 2 Multicenter Study Evaluating Subjects With Relapsed/Refractory Mantle Cell Lymphoma) evaluated KTE-X19 in patients with relapsed or refractory mantle cell lymphoma.3 Enrolled patients had received up to 5 prior therapies, which had to include chemotherapy with an anthracycline or bendamustine, an anti-CD20 monoclonal antibody, and a BTK inhibitor. Patients had at least 1 measurable lesion and an ECOG performance status of 0 or 1. The trial excluded patients who had undergone prior allogeneic SCT or had previously received CD19-targeted therapy or CAR T-cell therapy. After enrollment and leukapheresis, patients could receive bridging therapy with dexamethasone, ibrutinib, or acalabrutinib. Conditioning chemotherapy consisted of fludarabine (30 mg/m2) plus cyclophosphamide (500 mg/m2) on days –5, –4, and –3. The CAR T cells were administered at a dose of 2 × 106 KTE-X19 cells per kilogram of body weight by means of a single intravenous infusion on day 0. The first tumor assessment occurred on day 28. The primary endpoint was the ORR as assessed by an independent review committee and included the first 60 patients who received treatment.4
Among the 74 patients enrolled in the trial, 69 received conditioning chemotherapy. The KTE-X19 product was successfully manufactured for 71 patients (96%), and 68 patients (92%) received the KTE-X19 infusion. The safety analysis included all 68 patients who received the KTE-X19 infusion. The median time from leukapheresis to delivery of the KTE-X19 cells to the study site was 16 days. The 68 patients were a median age of 65 years (range, 38-79 years), 85% had stage IV disease, and 56% had a Mantle Cell Lymphoma International Prognostic Index score indicating intermediate- or high-risk disease. The median number of prior therapies was 3 (range, 1-5), and 43% had relapsed after autologous SCT. Sixty-eight percent were refractory to treatment with a BTK inhibitor, and 32% had relapsed after treatment. To control disease progression prior to study treatment, 37% of patients received bridging therapy.
After a median follow-up of 12.3 months (range, 7.0-32.3 months), the ORR was 93% (95% CI, 84%-98%) and the CR rate was 67% (95% CI, 53%-78%). The median time to an initial response was 1.0 month (range, 0.8-3.1 months), and the median time to a CR was 3.0 months (range, 0.9-8.3 months). Thirty-five percent of patients converted from a partial response to a CR, and 5% converted from stable disease to a CR. The ORR was consistent across most subgroups. Median PFS and median OS were not reached. Twelve-month PFS was 61% (95% CI, 45%-74%), and 12-month OS was 83% (95% CI, 71%-91%). The median duration of response was not reached (Figure 4). Remission was maintained in 57% of all patients and 78% of patients with a CR. Among the first 28 patients treated, 43% remained in continued remission without additional therapy after a median follow-up of 27.0 months (range, 25.3-32.3 months).
The most common treatment-emergent AEs of any grade included pyrexia (94%), neutropenia (87%), and thrombocytopenia (74%). The most common grade 3/4 hematologic AEs consisted of neutropenia (85%), thrombocytopenia (51%), and anemia (50%). The most common treatment-emergent grade 3/4 AEs were hypophosphatemia (22%, all grade 3), hypotension (19% grade 3 and 3% grade 4), and hypoxia (12% grade 3 and 9% grade 4). Grade 5 AEs included 1 case of organizing pneumonia on day 37 and 1 case of staphylococcal bacteremia on day 134.
Any-grade cytokine-release syndrome was reported in 91% of patients, including 15% with grade 3/4. No cases of grade 5 cytokine-release syndrome occurred. The median time to onset was 2 days (range, 1-13 days). Management consisted of tocilizumab in 59% of patients and corticosteroids in 22%. Cytokine-release syndrome resolved in all patients, at a median duration of 11 days.
Neurologic AEs of any grade occurred in 63% of patients; they were grade 3/4 in 31%. No grade 5 neurologic AEs occurred. The most common symptoms of neurotoxicity included any-grade tremor (35%), encephalopathy (31%), and confusion (21%). Treatments of neurologic AEs included tocilizumab (26%) and corticosteroids (38%). The median time to onset of neurologic AEs was 7 days (range, 1-32 days). The median duration of neurologic AEs was 12 days, with eventual resolution in 86% of patients (37/43). Patients with more robust expansion of KTE-X19 cells were more likely to experience high-grade cytokine-release syndrome and neurologic events.
References
1. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127(12):1559-1563.
2. Sabatino M, Hu J, Sommariva M, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood. 2016;128(4):519-528.
3. Wang M, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL): results of the phase 2 ZUMA-2 study [ASH abstract 754]. Blood. 2019;134(suppl 1).
4. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Earlier Steroid Use With Axicabtagene Ciloleucel (Axi-Cel) in Patients With Relapsed/Refractory Large B-Cell Lymphoma
Axicabtagene ciloleucel is an autologous CAR T-cell therapy in which T cells from the patient are genetically modified to bind to CD19, thus enhancing the killing of cancer cells.1 Common AEs from CAR T-cell therapy include cytokine-release syndrome and neurotoxicity, both of which require rigorous management. The phase 2 ZUMA-1 trial evaluated axicabtagene ciloleucel in patients with refractory large B-cell lymphoma.2,3 Cohort 1 included 77 patients with DLBCL, and cohort 2 included 24 patients with primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Eligible patients had not responded to their most recent chemotherapy or had relapsed within 12 months after autologous SCT. Patients had an ECOG performance status of 0 or 1. After receipt of a conditioning regimen consisting of low-dose cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) delivered on days –5, –4, and –3, patients received an infusion of 2 × 106 CD19-directed CAR T cells per kilogram of body weight. Among 101 evaluable patients, the median follow-up was 27.1 months. The ORR was 83%, including a CR rate of 58%. After a median follow-up of 39.1 months, the median OS was 25.8 months and the 3-year OS rate was 47%. Cytokine-release syndrome of grade 3 or higher was observed in 13% of patients, and neurologic events of grade 3 or higher occurred in 32%.
Two additional cohorts were added to evaluate management of cytokine-release syndrome and neurologic AEs.4,5 Patients in cohort 3 received prophylactic tocilizumab on day 2, which reduced the rate of severe cytokine-release syndrome to 3% (1/34), but did not reduce the incidence of severe neurologic AEs. An additional safety expansion cohort was therefore added to evaluate the effect of earlier corticosteroid use on the rates of these AEs.4 Patients enrolled in cohort 4 had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, transformed follicular lymphoma, or high-grade B-cell lymphoma. They had received at least 2 prior lines of therapy. After leukapheresis, patients were allowed to receive bridging therapy, including dexamethasone, high-dose methylprednisolone plus rituximab, or bendamustine plus rituximab. Following 3 days of conditioning with cyclophosphamide and fludarabine, patients received a target dose of 2 × 106 CAR T cells/kg. Patients with grade 1 cytokine-release syndrome received tocilizumab and/or corticosteroid therapy if no improvement was observed after 3 days. Patients with grade 1 neurotoxicity received corticosteroid therapy, and tocilizumab was added for grade 2 or higher neurologic AEs.
Among the 41 patients in cohort 4 who received the axicabtagene ciloleucel infusion, 46% had stage IV disease. Their median age was 66 years (range, 19-77 years). Thirty-four percent of patients had undergone a prior SCT, 37% had disease progression after their most recent chemotherapy, and 20% had relapsed after autologous SCT.
CAR T-cell expansion was similar in cohorts 1 and 2 vs cohort 4 (Figure 5). In cohorts 1 and 2, the rate of grade 3 or higher cytokine-release syndrome was 13%. The rate was reduced to 2% in cohort 4. The rate of grade 3 or higher neurologic AEs decreased from 28% in cohorts 1 and 2 to 17% in cohort 4. No cases of grade 4 or 5 cytokine-release syndrome or neurologic AEs were observed in cohort 4. Compared with cohorts 1 and 2, the rates of cytokine-release syndrome and neurologic AEs of grade 3 or higher were reduced in cohort 4 for patients with a low or high tumor burden.
The mean cumulative corticosteroid dose was 13 ± 156 mg in cohorts 1 and 2 vs 5235 ± 76 mg in cohort 4. Peak levels of biomarkers including interferon-γ, interleukin-2, and C-reactive protein were lower in cohort 4 vs cohorts 1 and 2. In cohort 4, the ORR was 73%, with a CR rate of 51%. The median duration of response was 8.87 months, and 54% of patients had an ongoing response at the time of the report (Figure 6).
References
1. Hopfinger G, Jäger U, Worel N. CAR-T cell therapy in diffuse large B cell lymphoma: hype and hope. Hemasphere. 2019;3(2):e185.
2. 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(1):31-42.
3. 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(26):2531-2544.
4. Topp MS, van Meerten T, Houot R, et al. Earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B cell lymphoma [ASH abstract 243]. Blood. 2019;134(suppl 1).
5. Locke FL, Neelapu SS, Bartlett NL, et al. Preliminary results of prophylactic tocilizumab after axicabtagene ciloleucel (axi‑cel; KTE‑C19) treatment for patients with refractory, aggressive non‑Hodgkin lymphoma [ASH abstract 1547]. Blood. 2017;130(suppl 1).
Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR-T Consortium
The US CAR-T Lymphoma Consortium evaluated real-world outcomes in patients with DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who received treatment with axicabtagene ciloleucel.1,2 The study identified 298 patients who underwent leukapheresis and 275 who received the axicabtagene ciloleucel infusion. Approximately half of patients (52%) were older than 60 years. ECOG performance status was 2 to 4 in 20%. The International Prognostic Index score was 3 to 5 in 54%. Twenty-three patients had triple-hit genetics, 75% had received 3 or more prior lines of therapy, and 43% did not meet the inclusion criteria for the ZUMA-1 trial.
After a median follow-up of 13.8 months, the median PFS was 7.16 months. The median OS was not reached. Multivariate analysis showed a worse OS among patients who received bridging therapy vs those who did not (hazard ratio [HR], 1.8; 95% CI, 1.0-2.7; P=.03). Bridging therapy was used by 53% (n=158 patients). In contrast, bridging chemotherapy was used by no patients in the ZUMA-1 trial, 92% of those in the JULIET trial (Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients), and 59% of those in the TRANSCEND NHL 001 trial.3-5
Bridging therapy consisted of chemotherapy in 54%, only corticosteroids in 23%, radiation therapy in 12%, and targeted therapy in 10%. Patients who received bridging therapy were more likely to experience cytokine-release syndrome of at least grade 3 (9% vs 5% in those who did not), neurotoxicity of at least grade 3 (34% vs 28%), nonrelapse mortality (7.1% vs 1.5%), and death after lymphoma relapse (37% vs 17%). Among patients who underwent leukapheresis, use of bridging therapy was also associated with a reduced median PFS (HR, 1.6; P=.002) and a reduced median OS (HR, 2.45; P<.001; Figure 7).
The efficacy of axicabtagene ciloleucel was similar among the 4 cohorts of different bridging strategies (P>.05). After propensity score matching, the P values ranged from 0.30 to 1.0. Outcomes were compared between the 104 patients without bridging therapy who were matched by propensity score to 104 patients who did receive bridging treatment. Among patients who underwent leukapheresis, the median PFS was similar (HR, 1.2; P=.3). However, the median OS was superior in the cohort of patients who had not received bridging therapy (HR, 1.7; P=.02).
References
1. Jain MD, Jacobs MT, Nastoupil L, et al. Characteristics and outcomes of patients receiving bridging therapy while awaiting manufacture of standard of care axicabtagene ciloleucel CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium [ASH abstract 245]. Blood. 2019;134(suppl 1).
2. Nastoupil L, Jain MD, Spiegel JY, et al. Axicabtagene ciloleucel (axi-cel) CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: real world experience [ASH abstract 627]. Blood. 2018;132(suppl 1).
3. 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(26):2531-2544.
4. Abramson JS, Palomba L, Gordon LI, et al. Pivotal safety and efficacy results from TRANSCEND NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood. 2019;134(suppl 1).
5. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
Real-World Data of High-Grade Lymphoma Patients Treated With CD19 CAR-T in England
In England, axicabtagene ciloleucel and tisagenlecleucel are currently available through the Cancer Drugs Fund, which provides interim funding for novel treatments until their clinical and cost-effectiveness can be determined.1 Patients are approved to receive CAR T-cell therapy based on findings from a weekly meeting of the National CAR-T Clinical Panel, which includes independent clinical experts, patient representatives, and delegates from 7 CAR T-cell treatment centers. The latter are located in geographically dispersed areas across England. The panel aims to use a transparent and objective approval process to provide equitable treatment access across regions, as well as to monitor national capacity, assess outcomes and use of resources, and build expert competency. Eligibility criteria are similar to those for the ZUMA-1 and JULIET trials.2,3 Eligible patients have progressive disease based on Response Evaluation Criteria in Solid Tumors.4 A fresh biopsy is generally required for consideration of treatment.
The National Health Service England conducted a study to obtain real-world data on CAR T-cell therapy for the treatment of B-cell lymphoma.1 The study enrolled 125 patients, of whom 116 underwent leukapheresis and 91 received a CAR T-cell infusion. Sixty-two patients received axicabtagene ciloleucel and 29 received tisagenlecleucel. The median time from approval to infusion was 63 days (range, 41-114 days). Lymphoma subtypes included de novo DLBCL (71%), transformed follicular lymphoma (18%), primary mediastinal B-cell lymphoma (6%), and transformed marginal zone lymphoma (5%). Seventy-six percent of patients had stage III/IV disease, and one-third had bulky disease (≥7.5 cm). Extranodal disease was present in 43% of patients, and 43% had received at least 3 prior lines of therapy. Bridging therapies included chemotherapy with or without corticosteroids (57%), corticosteroids only (16%), and radiotherapy with or without corticosteroids (10%).
Among 56 patients who received treatment with axicabtagene ciloleucel, 21% had a CR and 16% had a partial response. Early progression occurred in 59% of patients, and 4% died. Among 24 patients who received a tisagenlecleucel infusion, 17% had a CR and 12% had a partial response. Early progression was noted in 71%. After a median follow-up of 7.0 months, the median OS was 9.1 months for the overall population of 124 evaluable patients (Figure 8). Among patients who were approved for CAR T-cell therapy, the median OS was not reached for those who did receive a CAR T-cell infusion (n=91) vs 2.3 months for patients who did not receive an infusion (n=33). The preliminary analysis suggests a lower rate of ongoing remissions compared with outcomes from pivotal clinical trials.2,3
Cytokine-release syndrome of grade 3 or higher was observed in 11% of patients. Management consisted of tocilizumab in 65% and corticosteroids in 29%. Admission to an intensive care unit was needed by 34% of patients. Hematologic AEs of grade 3 or higher included neutropenia (19%) and thrombocytopenia (19%). Treatment-related mortality was 2%.
References
1. Kuhnl A, Roddie C, Martinez-Cibrian N, et al. Real-world data of high-grade lymphoma patients treated with CD19 CAR-T in England [ASH abstract 767]. Blood. 2019;134(suppl 1).
2. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel in patients with refractory aggressive non-Hodgkin lymphoma [ASH abstract 578]. Blood. 2017;130(suppl 1).
3. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Post-Marketing Use Outcomes of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Axicabtagene Ciloleucel, for the Treatment of Large B-Cell Lymphoma in the United States
An ongoing study in the United States is using the infrastructure created by the Center for International Blood and Marrow Transplant Research (CIBMTR) to evaluate the real-world safety and efficacy of axicabtagene ciloleucel.1 The study includes patients who received axicabtagene ciloleucel and agreed to share their data with the CIBMTR. Follow-up will last for 15 years as part of a postmarketing regulatory requirement. The study has a planned accrual of 1500 large B-cell lymphoma patients. The objectives are to describe early safety and efficacy outcomes and to analyze treatment patterns based on age. The study included patients with large B-cell lymphoma who received commercial axicabtagene ciloleucel after approval by the US Food and Drug Administration.
Among 750 enrolled patients, 533 attended a first follow-up appointment. Most of these patients (63%) were younger than 65 years. There were 326 patients with at least 6 months of follow-up, and 218 were younger than 65 years.
Among the 533 patients who attended a first follow-up appointment, the median age was 61 years (range, 19-86 years), and 66% were male. The ECOG performance status was 0 or 1 in 80% of patients and 2 or higher in 4%. (The score was unknown in 15%.) The disease was transformed lymphoma in 30%, double- or triple-hit lymphoma in 36%, and chemotherapy-resistant in 62%. Thirty-two percent of patients had received a prior autologous SCT. The median time from diagnosis to axicabtagene ciloleucel infusion was 16 months. Compared with patients in the ZUMA-1 trial,2 those in the current study were older (median age, 61 vs 58 years), were more likely to have high-risk genetics (36% vs 11%), and were more likely to have undergone autologous SCT (32% vs 25%).
The ORR was 74% among the 533 patients who attended a first follow-up appointment. ORR was 79% in patients ages 65 years or older vs 71% in younger patients (P=.07). The 326 patients with at least 6 months of follow-up had an ORR of 84% (Figure 9). ORR was 92% in older patients vs 80% in younger patients (P=.02). The median duration of response was similar for both older and younger patients (P=.170), as were the median PFS (P=.059) and median OS (P=.618).
Cytokine-release syndrome of any-grade occurred in 80% of younger patients vs 84% of older patients. Rates of high-grade cytokine-release syndrome were 8% vs 10%, respectively. In both age groups, the median time to cytokine-release syndrome was 3 days, and the median duration was 7 days. Cytokine-release syndrome resolved in 94% of patients younger than 65 years and in 93% of patients ages 65 years and older. The rate of grade 3 or higher neurologic toxicity was 19% in younger patients vs 22% in older patients. Neurotoxicity resolved in 89% vs 87%, respectively. The median time to onset was 6 days for both cohorts. The median duration of neurotoxicity was 7 vs 10 days. Rates of subsequent neoplasms were similar for both age groups.
References
1. Pasquini MC, Locke FL, Herrera AF, et al. Post-marketing use outcomes of an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, axicabtagene ciloleucel (Axi-Cel), for the treatment of large B cell lymphoma (LBCL) in the United States (US) [ASH abstract 764]. Blood. 2019;134(suppl 1).
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(26):2531-2544.
Tisagenlecleucel Chimeric Antigen Receptor T-Cell Therapy for Adults With Diffuse Large B-Cell Lymphoma: Real World Experience From the Center for International Blood & Marrow Transplant Research Cellular Therapy Registry
A registry to track long-term outcomes among patients treated with CAR T-cell therapy was initiated in September 2018.1 The registry will follow 2500 patients with lymphoma, including 1000 with acute lymphoblastic leukemia, for 15 years. Cohorts will be analyzed based on forms of infusion, safety, efficacy, and CAR T-cell manufacturing. An initial cohort of 116 patients with non-Hodgkin lymphoma received the tisagen-lecleucel infusion. Patients were a median age of 65 years (range, 15-89 years). Double- or triple-hit genetics was reported in 41%, and 27% had transformed lymphoma. Thirty-two percent had refractory disease, and 28% had received prior SCT.
The median time from diagnosis to administration of CAR T-cell therapy was 15 months, and the median time from the start of manufacturing to CAR T-cell infusion was 32 days. The median number of viable CAR T cells was 1.7 × 108 (range, 0.4 × 108 to 6.8 × 108). Most patients (89%) received cyclophosphamide plus fludarabine for lymphodepletion.
After a median follow-up of 4.5 months, the ORR was 58%, with a 40% CR rate. The 3-month duration of response was 75.2%. Three-month PFS was 61.6%, and 3-month OS was 79.6%.
Forty-nine percent of patients developed any-grade cytokine-release syndrome. Grade 4 cytokine-release syndrome occurred in 1%, and grade 5 cases occurred in 2%. The median time to onset of cytokine-release syndrome was 4 days (range, 2-14 days), and the median duration was 5 days (range, 4-8 days).
Any-grade neurotoxicity occurred in 16% of patients. Grade 3, 4, and 5 neurologic AEs were observed in 1%, 4%, and 1% of patients, respectively. The median time to onset of neurologic AEs was 8 days (range, 2-27 days), and the median duration was 14 days (range, 5-25 days).
Efficacy and safety outcomes were similar for CAR T-cell preparations that had between 60% and 79% viable CAR T cells and those with a viability of at least 80% of cells (Figure 10). The ORR was 54% in patients who received the lower viability preparation vs 59% for those who received the higher viability preparation. The 3-month duration of response was 70% vs 79%, respectively, and 3-month OS was 75% vs 84%. Any-grade cytokine-release syndrome rates were 38% vs 49%, and rates of any-grade neurotoxicity were 13% vs 17%. The ORR was numerically lower among patients infused with preparations in the lowest quartile of viable CAR T cells, but the difference was not significant. All of the grade 3 to 5 cytokine-release syndrome events occurred in patients who received CAR T-cell preparations in viability quartile 3 (1.69-2.26 × 108 cells).
The CIBMTR registry and the JULIET trial provided similar outcome data, including for ORR (58% vs 52%) and CR rate (40% vs 38%).2 Rates of high-grade cytokine-release syndrome were lower in the CIBMTR registry (4% vs 23%), as were rates of high-grade neurotoxicity (5% vs 11%). However, the 2 trials used different grading guidelines for cytokine-release syndrome.
References
1. Jaglowski S, Huan Z, Zhang Y, et al. Tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy for adults with diffuse large B-cell lymphoma (DLBCL): real world experience from the Center for International Blood & Marrow Transplant Research (CIBMTR) cellular therapy (CT) registry [ASH abstract 766]. Blood. 2019;134(suppl 1).
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
Highlights in CAR T-Cell Therapy From the 61st American Society of Hematology Annual Meeting: Commentary
Caron A. Jacobson, MD
Several studies in chimeric antigen receptor (CAR) T-cell therapy presented at the 61st American Society of Hematology (ASH) meeting provided important insights into the use of this treatment. Results from clinical trials were presented for lisocabtagene maraleucel and KTE-X19. Follow-up analyses and real-world reports examined data for axicabtagene ciloleucel and tisagenlecleucel.
Clinical Trial Data
Dr Jeremy S. Abramson and colleagues presented results of the TRANSCEND NHL 001 trial,1 the third pivotal study of a CD19-directed CAR T-cell product. The study evaluated lisocabtagene maraleucel in patients with relapsed/refractory large B-cell lymphoma. Lisocabtagene maraleucel is a 4-1BB CAR product, like tisagenlecleucel. A unique aspect to lisocabtagene maraleucel is that it is formulated in a 1:1 ratio of CD4 to CD8 T cells. TRANSCEND started as a nonpivotal registrational study. It originally had different eligibility criteria compared with previous registrational studies, but was later modified to include a core cohort that would be used for registration purposes. Data were presented at the ASH meeting.1 The study evaluated different doses and numbers of infusions in a dose-finding portion. However, the study treated a majority of patients (n=126) at the confirmed recommended phase 2 dose in a single infusion. A key point of the study concerns the broad population. It not only included the largest cohort of patients treated with aggressive B-cell non-Hodgkin lymphoma among the pivotal studies,2,3 it also included patients who would have been excluded from the other studies, including those with an Eastern Cooperative Oncology Group performance status of 2, those with secondary central nervous system lymphoma, those who had undergone a prior allogeneic transplant, those with a creatinine clearance between 30 and 60 mL/min, and those with a cardiac ejection fraction between 40% and 50%.
The number of patients who had their cells collected was 344, but the number of patients included in the efficacy analysis was only 256. There are several reasons for this drop-off. Thirty-three patients died after undergoing leukapheresis and before receiving the infusion. An additional 17 patients underwent leukapheresis but did not receive the infusion, 6 owing to disease-related complications. The CAR T-cell product could not be manufactured for 2 patients. Twenty-five patients were excluded from the efficacy analysis because the CAR T-cell product did not meet the protocol specifications for infusion. These patients still received the infusion, but under a protocol such as the single-patient Investigational New Drug program. Lastly, 13 patients were treated but not evaluable because they had a complete response to bridging therapy or they had not undergone positron-emission tomography (PET). The PET scan was required to measure their response to bridging therapy and to establish a new baseline scan against which to judge their response to lisocabtagene maraleucel.
The overall response rate (ORR) was based on a modified intention-to-treat analysis that included only the patients who received lisocabtagene maraleucel. The rate will decrease if the analysis included all patients who underwent leukapheresis. With CAR T-cell therapy, the efficacy and safety of an individual product are certainly important concerns, but so is the proportion of patients who will be able to receive the product after leukapheresis.
Dr Abramson presented the safety data first.1 Lisocabtagene maraleucel is potentially safer than the 2 CAR T-cell products approved in this space, axicabtagene ciloleucel and tisagenlecleucel, based on the data from clinical trials.2,3 The rate of grade 3 or higher cytokine-release syndrome (CRS) was 2%, and the median time to onset of CRS was 5 days. Therefore, fewer patients required admission to the intensive care unit after developing CRS. CRS typically arises 5 days after infusion, raising the potential for administration in the outpatient setting, where patients can be monitored and then hospitalized only if needed. Any-grade cytokine release syndrome occurred in 42% of patients, indicating that many patients can avoid hospitalization. Neurologic toxicity of grade 3 or higher occurred in 10% of patients, which is a fairly low number. Any-grade neurologic toxicity was reported in 30% of patients.
Hospitalization in the intensive care unit was required by 7% of patients, despite the lower incidence of grade 3 or higher CRS. This observation underscores the data showing that these therapies have considerable high-grade toxicity and risk, and that patients treated with them require access to a medical center that can deliver high-quality, specialized management in an intensive care unit.
With respect to efficacy, the rates of overall response and complete response were similar to those seen with the other T-cell products.2,3 The complete response rate was 53%, and the ORR was 73%. The responses were durable, persisting at 6 and 12 months; in a Kaplan-Meier graph, the curve for the duration of response appeared to plateau around that time. The presence of high-risk disease characteristics did not impact response. However, other clinical trials and analyses suggest that patients with a higher disease burden are less likely to have a complete response after CAR T-cell therapy.2,4,5
The TRANSCEND trial provided efficacy data according to disease histology. This study is the first in CAR T-cell therapy to show a separate response rate for patients with primary mediastinal large B-cell lymphoma. These patients, along with patients with transformed follicular lymphoma, did better than patients with high-grade B-cell lymphoma, diffuse large B-cell lymphoma, and other transformed indolent lymphomas.
There has been a question regarding the long-term benefits of bridging therapy given between T-cell collection and T-cell infusion on efficacy as well as toxicity. The pivotal trials had different allowances for bridging therapy. In the TRANSCEND trial, the use of bridging therapy did not impact outcome.1 As mentioned, the TRANSCEND trial had a broader eligibility criteria than previous studies, enrolling patients with high-risk characteristics, such as comorbidities involving cardiac or renal function, patients who had undergone allogeneic transplant, and patients with central nervous system disease. An analysis suggested that patients without comorbidities had a better outcome than patients with comorbidities, which is an important new observation. Patients with comorbidities still did better after CAR T-cell therapy than they would have with other available therapies; this finding highlights that these patients still benefit from this treatment, although they represent an unmet medical need and require more effective and safer cellular therapy options.
This study demonstrates that lisocabtagene maraleucel is a highly active CAR T-cell therapy with a potentially safer toxicity profile that could allow administration in the outpatient setting. In the clinic, it will be important to see how many patients can receive treatment after leukapheresis. If manufacturing is efficient and patients are able to receive treatment, then lisocabtagene maraleucel will be an important addition to this field once it is approved by the US Food and Drug Administration (FDA).
Dr Michael Wang and colleagues presented a study of KTE-X19 in patients with mantle cell lymphoma.6 This study is the first in CAR T-cell therapy to enroll a large series of patients with mantle cell lymphoma. KTE-X19 is similar to axicabtagene ciloleucel in all attributes except for one. The manufacturing process of KTE-X19 selects out T cells from potential leukemia or lymphoma cells, thereby removing the circulating tumor cells before expansion and activation. The study enrolled patients with fairly high-risk disease. Patients had received previous treatment with chemoimmunotherapy and a Bruton tyrosine kinase (BTK) inhibitor. Their expected survival was short. Between leukapheresis and infusion, patients could receive bridging therapy with either corticosteroids or a BTK inhibitor. The median time from leukapheresis to delivery of KTE-X19 was 16 days.
The product was successfully manufactured for 96% of patients and administered to 92% of patients. These data are similar to those in the ZUMA-1 trial.2 Approximately 17% of patients had a TP53 mutation, 70% had a high Ki-67, and more than 30% had blastoid or pleomorphic morphology. All of these characteristics predict for inferior outcomes with conventional therapies.
The trial showed an impressive ORR of 93%, including a complete response rate of 67%. The median follow-up was approximately 12 months. Approximately 47% of patients had at least 2 years of follow-up, and responses were durable. It is necessary to have a longer follow-up in mantle cell lymphoma compared with large cell lymphoma to hypothesize whether a therapy might offer a potential cure. The results of this study, though, are promising. At 12 months, 57% of patients were still in response. Among patients with a complete response, this response was maintained in 78%.
The side effect profile was similar to that of axicabtagene ciloleucel in large cell lymphoma. Grade 3 or higher CRS occurred in 15% of patients. The median time to onset was 2 days. The rate of grade 3 or higher neurologic toxicity was 31%. It appeared that patients with better CAR T-cell expansion were more likely to respond and to achieve minimal residual disease (MRD) negativity. However, increased production of CARs corresponds with high-grade toxicity.
This study is the first to show that a CAR T-cell therapy can achieve an impressive response rate and good durability of response in a high-risk, refractory population of patients with mantle cell lymphoma. This treatment has the potential to change the natural history of the disease for many patients. These data will likely lead to approval from the FDA.
Follow-Up Analysis
Dr Sattva S. Neelapu and colleagues evaluated rates of CD19 loss in a small cohort of patients who received axicabtagene ciloleucel.7 The study documented a reasonably high rate of CD19 loss. Before treatment, 90% of patients were CD19-positive. This rate dropped to 72% after treatment among the samples evaluated by immunohistochemistry. There seemed to be a selection for tumor cells that had lower CD19 antigen expression. The study also identified patients who had alternative splicing of CD19 that led to a loss of the epitope that the CAR binds to. Importantly, the study showed that nearly all of the patients who lost CD19 still retained other B-cell antigens. This study not only documented the rates of CD19 loss in large cell lymphoma after axicabtagene ciloleucel, but also provided rationale for studying dual-antigen CARs that target more than one B-cell antigen simultaneously. Ongoing phase 2 multicenter clinical trials are evaluating this presently, with results expected in the next few years.8,9
Real-World Reports
There were several real-world reports, some drawn from the Center for International Blood & Marrow Transplant Research (CIBMTR) database. A study by Dr Samantha Jaglowski evaluated real-world use of tisagenlecleucel in 80 patients.10 Rates of overall response and complete response were similar to those in clinical trials. The follow-up is short at this time. However, between 60% and 70% of patients appear to maintain their response at the 3-month mark, which is predictive of durable remissions in clinical trials.2,3
The JULIET study of tisagenlecleucel used a different grading scale for CRS than the other trials, and the rate of grade 3 or higher events was 22%.3 In the real-world analysis, 80 patients were evaluated for CRS based on the standardized scale set forth by the American Society for Transplantation and Cellular Therapy.11 The rate of grade 3 or higher cytokine release syndrome was only 3%, which is similar to the rate in the TRANSCEND study, which evaluated lisocabtagene maraleucel, the other 4-1BB CAR.1 The improved rates of CRS may reflect both the use of a modern toxicity grading scale as well as improvements in treating and managing CRS. Rates of grade 3 or higher neurologic toxicity, as assessed using an updated consensus scale, were also lower in the real-world study vs the JULIET trial. These rates were 6% in the real-world series vs 12% in the JULIET study.3 Again, this may reflect improvements in toxicity management and treatment. In this real-world study, efficacy was similar to that in the JULIET clinical trial, but safety was improved.
Dr Marcelo Pasquini presented data from the CIBMTR for 533 patients treated with axicabtagene ciloleucel.12 Efficacy is similar to that in clinical trials, with an ORR of 70% to 80%, and a complete response rate of approximately 50%. After at least 6 months of follow-up, a complete response persisted in most patients. This analysis evaluated data according to age to allay concerns that this is a therapy that should be limited to younger patients. Interestingly, in older patients, the response rates were higher, and responses were more durable.
In the real-world analysis, grade 3 or higher CRS occurred in less than 10% of patients, which is lower than in the ZUMA-1 trial.2 This decrease likely reflects improvements in management. However, only approximately 15% of patients did not have CRS. The rate of grade 3 or higher neurologic toxicity was approximately 20%, which is also better than that seen in the ZUMA-1 trial,2 but higher than that seen with lisocabtagene maraleucel or tisagenlecleucel.1,3 Neurologic toxicity was not increased in patients who were older than 65 years. This real-world analysis supports the use of axicabtagene ciloleucel in the older population.
Dr Michael D. Jain and colleagues from the US CAR T-cell consortium evaluated bridging therapy in a real-world cohort of patients treated with axicabtagene ciloleucel. Bridging therapy was used by 53% of patients.13 Bridging therapy consisted of chemotherapy in 54%, corticosteroids in 23%, radiation in 12%, and targeted agents in 10%. Patients who received bridging therapy had several poor-risk characteristics. They were more likely to have a poor performance status, advanced-stage disease, a high International Prognostic Index, and bulky disease. These patients probably had worse disease, were sicker at baseline, and were less likely to respond in general.
There was no difference in the rates of CRS and neurotoxicity in the groups that did or did not receive bridging therapy. However, the rate of nonrelapse mortality and death (presumably related to treatment) was 7.1% in patients who received bridging therapy and 1.5% in patients who did not. There was also a higher rate of death related to lymphoma relapse, at 37% vs 17%, respectively. Patients who received bridging therapy had decreased progression-free survival and overall survival. When using a propensity score matching analysis to control for factors associated with worse outcomes, bridging therapy remained an independent predictive factor for inferior overall survival. Patients treated with CAR T cells after bridging therapy still have better outcomes than patients treated with the current standard of care, but like the patients with comorbidities in the TRANSCEND study, they represent an unmet need.
This study also used a propensity score matching analysis to control for factors that predict for higher-risk disease. The worse rates of progression-free survival and overall survival seen in patients who received bridging therapy persisted in this analysis. All types of bridging therapies were associated with the worse outcome.
Like the TRANSCEND trial, this analysis showed that outcome is inferior among patients with comorbidities and who undergo bridging therapy.1 Patients treated with CAR T cells after bridging therapy still have better outcomes than patients treated with the current standard of care, but they represent an unmet need.
An analysis of real-world data from England of patients treated with CAR T-cell therapy found that toxicity was better but efficacy was worse as compared with data from clinical trials.2,3,14 In England, the mechanism for identifying and approving therapy for an individual patient involves a comprehensive central review process. Patients are selected for treatment with CAR T-cell therapy only if they are in good physical condition. Selected patients must wait much longer to receive treatment compared with patients in the United States. It may be that the decreased efficacy in this analysis reflects this delay, by allowing the disease to progress.
DNA Levels and Response
CAR T-cell therapy is associated with high response rates, but also significant relapse rates. It appears that approximately 40% of patients will achieve long-term remissions.2,3 There is interest in trying to identify patients who may potentially relapse in order to administer interventions that could manipulate CAR T cells or other functional T cells to continue to fight against the residual lymphoma. Two abstracts presented at the ASH meeting evaluated MRD after use of axicabtagene ciloleucel in a commercial setting. A study presented by Dr Matthew J. Frank included a cohort of 64 patients.4 These patients had the same outcomes as were seen in the ZUMA-1 trial. The study followed MRD levels serially through month 12. The investigators assessed circulating tumor DNA sequences of the mutated immunoglobulin heavy chain (IgH) gene for patient-specific lymphoma. For this assessment, it is necessary to sequence IgH from an original tumor biopsy and then measure it in the blood at serial time points. Patients who had a high level of this gene before treatment were less likely to respond. The analysis by Dr Frank showed that patients who are MRD-negative at day 28—the typical time of the first PET assessment—were much more likely to maintain a response and had better progression-free survival and overall survival compared with patients who were MRD-positive.4 MRD negativity at this time was slightly superior to positron emission tomography in predicting improved long-term outcome.
A study presented by Dr Brian Sworder used a slightly different technology known as cancer personalized profiling by deep sequencing (CAPP-Seq), which measures circulating tumor DNA by identifying DNA sequences for a prespecified set of highly mutated genes in large cell lymphoma.5 As with the previous study, this analysis showed that higher pretreatment circulating tumor DNA levels correlated with increased tumor burden and a lower likelihood of a durable response. Outcome was worse in patients with detectable circulating tumor DNA at day 28. An interesting aspect about this technology is that the sequence for the actual CAR can be incorporated into the panel, and the CAR T cells can be tracked over time to measure expansion and persistence. The study showed that CAR T-cell expansion did not correlate with outcome. The investigators evaluated the mutational burden in patients before treatment. Patients who developed progressive disease had a different disease mutation profile from those who did not. These data are preliminary, but they suggest how this technology might be used to predict response.
A study presented by Dr Veronika Bachanova and colleagues evaluated 115 tisagenlecleucel products to explore two questions.15 The first concerned viability. The FDA has set a viability for tisagenlecleucel to be in specification of 80%,16,17 although patients in the clinical trial had a T-cell viability of 70% or higher.3 The analysis by Dr Bachanova showed that there was no difference in outcomes for patients who had cells that were 70% viable vs 80% viable. In the real world, patients who have a T-cell viability of less than 80% receive treatment under an expanded access protocol and not under commercial settings. However, this analysis supports expansion of the FDA label to encompass T-cell viability of 70% or greater. The analysis also examined the CD4 to CD8 T-cell composition of the product that was infused into the patients. There was no ratio that predicted for improved or decreased efficacy. However, patients who received a product with a higher proportion of CD4 CAR T cells had increased rates of grade 3 or higher CRS.
Disclosure
Dr Jacobson is a consultant for Kite, Novartis, Celgene, BMS, Precision Biosciences, Humanigen, and Nkarta. She has received research funding from Pfizer.
References
1. Abramson JS, Palomba L, Gordon LI, et al. Pivotal safety and efficacy results from TRANSCEND NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas [ASH abstract 241]. Blood. 2019;134(suppl 1).
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(26):2531-2544.
3. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.
4. Frank MJ, Hossain N, Bukhari A, et al. Detectable circulating tumor DNA 28 days after the CD19 CAR T-cell therapy, axicabtagene ciloleucel, is associated with poor outcomes in patients with diffuse large B-cell lymphoma [ASH abstract 884]. Blood. 2019;134(suppl 1).
5. Sworder B, Kurtz DM, Macaulay C, et al. Circulating DNA for molecular response prediction, characterization of resistance mechanisms and quantification of CAR T cells during axicabtagene ciloleucel therapy [ASH abstract 550]. Blood. 2019;134(suppl 1)
6. Wang M, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL): results of the phase 2 ZUMA-2 study [ASH abstract 754]. Blood. 2019;134(suppl 1).
7. Neelapu SS, Rossi JM, Jacobson CA, et al. CD19-loss with preservation of other B cell lineage features in patients with large B cell lymphoma who relapsed post–axi-cel [ASH abstract 203]. Blood. 2019;134(suppl 1).
8. ClinicalTrials.gov. A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). https://clinicaltrials.gov/ct2/show/NCT03105336. Identifier: NCT03105336. Accessed February 13, 2020.
9. ClinicalTrials.gov. Efficacy and safety of axicabtagene ciloleucel as first-line therapy in participants with high-risk large B-cell lymphoma (ZUMA-12). https://clinicaltrials.gov/ct2/show/NCT03761056. Identifier: NCT03761056. Accessed February 13, 2020.
10. Jaglowski S, Huan Z, Zhang Y, et al. Tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy for adults with diffuse large B-cell lymphoma (DLBCL): real world experience from the Center for International Blood & Marrow Transplant Research (CIBMTR) cellular therapy (CT) registry [ASH abstract 766]. Blood. 2019;134(suppl 1).
11. 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(4):625-638.
12. Pasquini MC, Locke FL, Herrera AF, et al. Post-marketing use outcomes of an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, axicabtagene ciloleucel (axi-cel), for the treatment of large B cell lymphoma (LBCL) in the United States (US) [ASH abstract 764]. Blood. 2019;134(suppl 1).
13. Jain MD, Jacobs MT, Nastoupil L, et al. Characteristics and outcomes of patients receiving bridging therapy while awaiting manufacture of standard of care axicabtagene ciloleucel CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium [ASH abstract 245]. Blood. 2019;134(suppl 1).
14. Kuhnl A, Roddie C, Martinez-Cibrian N, et al. Real-world data of high-grade lymphoma patients treated with CD19 CAR-T in England [ASH abstract 767]. Blood. 2019;134(suppl 1).
15. Bachanova V, Tam CS, Borchmann P, et al. Impact of tisagenlecleucel chimeric antigen receptor T-cell therapy product attributes on clinical outcomes in adults with relapsed or refractory diffuse large B-cell lymphoma [ASH abstract 242]. Blood. 2019;134(suppl 1).
16. Yescarta [package insert]. Santa Monica, CA: Kite; 2019.
17. Kymriah [package insert]. East Hanover, NJ: Novartis; 2018.