A Review of Selected Presentations From the 60th American Society of
Hematology Annual Meeting • December 1-4, 2018 • San Diego, California
2-Year Follow-Up and High-Risk Subset Analysis of ZUMA-1, the Pivotal Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
Axicabtagene ciloleucel is an autologous chimeric antigen receptor (CAR) T-cell therapy directed at the CD19 antigen.1 The patient’s T cells are engineered to express the single-chain extracellular variable domain against CD19, as well as the CD3ζ and CD28 intracellular domains to enhance T-cell activation. Axicabtagene ciloleucel is approved in the United States for the treatment of relapsed or refractory large B-cell lymphoma in patients who have received at least 2 prior systemic therapies.2 The multicenter, single-arm phase 1/2 ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma) evaluated axicabtagene ciloleucel in patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma. Eligible patients had not responded to their most recent chemotherapy regimen or had relapsed within 12 months after undergoing an autologous stem cell transplant. Patients had received prior treatment with an anti-CD20 monoclonal antibody and an anthracycline. Enrolled patients initially received treatment with a conditioning regimen consisting of daily cyclophosphamide (500 mg/m2) plus fludarabine (30 mg/m2) for 3 days. Patients then received axicabtagene ciloleucel with a target dose of 2 × 106 CAR T cells/kg. The primary endpoint was the objective response rate (ORR).
The ZUMA-1 study enrolled 108 patients in the phase 1 and phase 2 portions of the trial.3 The patients’ median age was 58 years (range, 23-76 years), one-fourth were ages 65 years or older, and 68% were male. An Eastern Cooperative Oncology Group (ECOG) performance status of 1 was reported in 57% of patients, and 83% had stage III/IV disease. Forty-four percent of patients had an International Prognostic Index (IPI) score of 3 or 4, and 70% of patients had received 3 or more prior therapies. Seventy-four percent of patients were refractory to a second-line or later line of therapy, 65% had progressive disease as their best response to their most recent treatment, and 23% had relapsed after autologous stem cell transplant. After a median of 15.4 months of follow-up, the ORR was 82%, with a complete response (CR) rate of 54%. The ongoing response rate was 42%. In the initial analysis, adverse events (AEs) that occurred beyond 6 months were generally manageable infections. There were no reports of late-onset treatment-related cytokine release syndrome or neurologic events.
An analysis presented at the 60th American Society of Hematology annual meeting provided long-term data. After a median of 27.1 months of follow-up, 39% of patients had an ongoing response according to investigator assessment.4 CRs were seen in 37%. Among the patients who had an initial response at 12 months, 93% had an ongoing response at 24 months. A concordance of 81% was observed between investigator assessment and central review of response. In the phase 2 trial, 33 patients had double-expressor or high-grade B-cell lymphoma. These patients initially had a 91% ORR, including a CR rate of 70%. With the longer follow-up, 48% of these patients showed an ongoing response, all of which were CRs. Among the 39 patients overall who had an ongoing response, 2 (5%) underwent allogeneic stem cell transplant. (No patients underwent an autologous stem cell transplant.) Among patients in the overall study population, the investigator-assessed median duration of response was 11.1 months (95% CI, 4.2 months to not reached; Figure 1), the median progression-free survival (PFS) was 5.9 months (95% CI, 3.3-15.0 months; Figure 2), and the median overall survival was not reached (95% CI, 12.8 months to not reached). Among 32 patients with an ongoing response at 24 months, 21 (66%) had detectable, gene-marked CAR T cells in the peripheral blood.
There were no reports of late-onset cytokine release syndrome, neurologic events, or death. The most frequent AEs of grade 3 or higher were cytopenias. Cytopenias present at month 3 or afterward included neutropenia (11%), thrombocytopenia (7%), and anemia (3%). All late-onset serious AEs were unrelated to treatment with axicabtagene ciloleucel, and all of these AEs resolved, with the exception of 1 case of myelodysplastic syndrome. One patient developed 2 incidents of grade 2 infection that were considered related to treatment with axicabtagene ciloleucel.
References
1. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T cell immunotherapy for human cancer [published online January 25, 2019]. Am J Hematol. doi:10.1002/ajh.25418.
2. Yescarta [package insert]. Santa Monica, CA: Kite Pharma Inc; 2017.
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. Neelapu SS, Ghobadi A, Jacobson CA, et al. 2-year follow-up and high-risk subset analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients with refractory large B cell lymphoma [ASH abstract 2967]. Blood. 2018;132(suppl 1).
Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real-World Experience
A retrospective analysis evaluated real-world outcomes in patients who received axicabtagene ciloleucel as the standard of care at 17 academic centers in the United States.1 All patients had undergone leukapheresis as of August 31, 2018, and the study included all patients for whom axicabtagene ciloleucel manufacture was intended. There were 295 patients in the intention-to-treat population and 274 patients in the modified intention-to-treat population. Among 295 patients who underwent leukapheresis by the cutoff date, 274 received 3 days of conditioning with daily cyclophosphamide (500 mg/m2) plus fludarabine (30 mg/m2) followed by infusion of the CAR T-cell product. The product did not meet specifications for 7 patients, 12 patients died from causes secondary to lymphoma, 1 patient had nonmeasurable disease, and 1 patient was removed from the study after developing an infection. The median time from leukapheresis to the start of conditioning therapy was 21.5 days. Bridging therapy was administered to 158 patients, and consisted of chemotherapy (58%), corticosteroids (24%), irradiation (13%), and other regimens (7%). The median follow-up was 3.9 months.
Among the 274 patients in the modified intention-to-treat population, the median age was 60 years (range, 1-83 years), and 33% were ages 65 years or older. The B-cell lymphoma subtype was DLBCL in 68%, transformed follicular lymphoma in 26%, and PMBCL in 6%. Eighty-one percent of patients had an ECOG performance status of 0 or 1, and 81% of patients had stage III/IV disease. The IPI score was 3 or higher in 55% of patients. Three-fourths of patients had received 4 or more prior lines of therapy. One hundred patients had primary refractory disease, and 121 were refractory to their second or later line of treatment. Ninety-five patients (33%) had relapsed after autologous stem cell transplant.
Patients in the real-world population were slightly younger than those in the ZUMA-1 trial.2 The median age was 58 years vs 60 years. The proportion of patients ages 65 years or older was 25% vs 33%. In the ZUMA-1 trial, all patients had an ECOG performance status of 0 or 1. In the real-world analysis, the ECOG performance status was 0 or 1 in 81%, 2 in 15%, and 3 or 4 in 4%. In ZUMA-1, 83% of patients had stage III/IV disease. ZUMA-1 included lower proportions of patients with an IPI score of 3 or higher (44% vs 55%), patients who had received 4 or more prior therapies (70% vs 75%), and patients who had relapsed following autologous stem cell transplant (23% vs 33%). The ZUMA-1 trial included patients with DLBCL (76%), transformed follicular lymphoma (15%), and PMBCL (7%). In the real-world study, 253 evaluable patients had DLBCL, including 151 (60%) with germinal center B-cell–like DLBCL and 102 (40%) with activated B-cell–like DLBCL. Among 272 patients with available genetic data, fluorescence in situ hybridization identified double-hit or triple-hit genetics in 23% and double-expressor genetics in 38%.
The real-world study included 124 patients (43%) who would not have met the eligibility requirements of the ZUMA-1 trial at the time of leukapheresis. Criteria that would have led to exclusion from ZUMA-1 included low platelet levels (13%), active deep vein thrombosis or pulmonary embolism (9%), prior anti-CD19 or CAR T-cell therapy (8%), inadequate glomerular filtration (8%), history of lymphoma in the central nervous system (8%), symptomatic pleural effusion (4%), inadequate ejection fraction (4%), and prior allogeneic stem cell transplant (2%).
In the real-world analysis, the median follow-up was 3.9 months. The best ORR at day 90 was 81%, including a CR rate of 57%. Covariates associated with an increased likelihood of an ongoing CR at 90 days included female sex (P=.009), an ECOG performance status of 0 or 1 (P=.024), relapsed disease (P=.011), nonbulky disease (P=.040), and meeting the eligibility requirements for ZUMA-1 (P=.037). The median PFS was 6.18 months (95% CI, 4.57 months to not reached; Figure 3), and the estimated 6-month overall survival was 72% (95% CI, 65%-80%).
Rates of any-grade cytokine release syndrome were similar in the real-world study and the clinical trial (92% vs 93%; Table 1). Grade 3 or higher cytokine release syndrome occurred in 7% vs 13%. The median time to onset of cytokine release syndrome was 3 days vs 2 days. Neurotoxicity of any grade was observed in similar proportions of patients (69% vs 65%), as was neurotoxicity of grade 3 or higher (33% vs 31%). The median time to onset of neurotoxicity was also similar (6 vs 5 days). Patients in the real-world study were more likely to have received tocilizumab (63% vs 45%) or corticosteroids (55% vs 29%). However, the studies had similar rates of grade 5 AEs (3%-4%) and treatment-related deaths (1%-2%).
References
1. Nastoupil LJ, 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 91]. Blood. 2018;132(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.
Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance, and Toxicity
Another multicenter, retrospective study assessed the real-world efficacy and toxicity outcomes following axicabtagene ciloleucel treatment.1 The study also evaluated patient characteristics, use of bridging therapy, and biomarkers to predict response or toxicity. The study enrolled patients who were treated with commercially available axicabtagene ciloleucel from December 2017 through October 2018 at 6 academic medical centers in the United States. Patient selection, supportive care, assessment of toxicity and response, and toxicity management were performed according to institutional practice. Bridging therapy was used at the discretion of the treating physician. Serial peripheral blood samples were taken between days 0 and 28 from 4 patients with a response and 4 without a response. Frozen peripheral blood mononuclear cells were then evaluated by single-cell mass cytometry using a panel of 38 metal-tagged monoclonal antibodies. Serial biopsies from 2 patients with primary disease resistance were evaluated by multiplex immunofluorescence and standard immunohistochemistry.
The analysis included 104 patients, and 60% would not have qualified for enrollment in the ZUMA-1 trial.2 The patients’ median age was 63.8 years (range, 21-80 years). Disease subtypes included DLBCL (43%), high-grade B-cell lymphoma (15%), and PMBCL (6%). The ECOG performance status was 0 or 1 in 90%, and the IPI score was 3 to 5 in 46%. Genetic analysis showed that 20% of patients were double hit and 4% were triple hit. A prior autologous stem cell transplant was reported in 27% of patients, and 3% had undergone allogeneic stem cell transplant. Ninety-one percent of patients were refractory to their most recent therapy. Forty percent of patients received bridging therapy.
Thirteen patients (11%) under-went leukapheresis but never received the axicabtagene ciloleucel infusion. Among these patients, 6 had pro-gressive disease, 2 had an infection, 1 had a CR after bridging therapy, and 1 had another malignancy. In 3 patients, the axicabtagene ciloleucel product could not be manufactured to specification.
After a median follow-up of 5.6 months, the best ORR in 95 patients was 71%. Among the intention-to-treat population, the ORR was 62%. The ORR at 6 months in 51 evaluable patients was 43%. The median duration of response was 4.9 months (95% CI, 4.9 months to not reached; Figure 4). The median PFS was 5.6 months (95% CI, 2.9 months to not reached; Figure 5). The median overall survival was not reached.
Cytokine release syndrome of any grade occurred in 94% of patients, and was grade 3 or higher in 16%. The median time to onset of cytokine release syndrome was 1 day (range, 0-14 days), and the median duration was 6 days (range, 1-27 days). Neurotoxicity of any grade was observed in 76% of patients, including 39% with neurotoxicity of grade 3 or higher. The median time to onset of neurotoxicity was 5 days (range, 0-34 days), and the median duration was 8 days (range, 1-52 days). Tocilizumab was administered to 67% of patients and corticosteroids to 64%.
Half of patients with an initial PR developed a CR with longer follow-up. Nonrelapse mortality was 7%, and consisted of cytokine release syndrome, infection, and cardiac events, all occurring in 2 patients each, and neurotoxicity in 1 patient. Thirty percent of patients were transferred to the intensive care unit, and 19% were readmitted.
According to univariate analysis, inferior outcomes were associated with an ECOG performance status of 2, 3, or 4 and increased tumor bulk. Biomarkers associated with a higher likelihood of response included a low C-reactive protein (CRP) level at baseline (P=.004) and a high absolute lymphocyte count at the time of leukapheresis (P=.003). A CRP level of less than 30 mg/L at baseline was significantly associated with response duration, PFS, and overall survival (P<.05), and a peak ferritin level of less than 5000 ng/mL was significantly associated with PFS and overall survival (P<.05). A significant correlation was observed between a high peak CRP level and high-grade neurotoxicity (P=.009) and between a high peak ferritin level and high-grade neurotoxicity or cytokine release syndrome (P<.001).
In the overall study population, the populations of CD4-positive and CD8-positive CAR T cells peaked at day 7. In patients with a response to axicabtagene ciloleucel, markers of T-cell activation, such as Ki67, were upregulated in both CAR-positive and CAR-negative T cells.
The 2 patients with primary refractory disease had different mechanisms of resistance. Biopsies from patient 1 at day 37 after treatment showed no CD19 expression and high expression levels of programmed cell death ligand 1 (PD-L1), both of which would protect tumor cells from axicabtagene ciloleucel. Biopsies from patient 2 taken at day 58 after treatment were CD19-positive and PD-L1–negative; however, no CAR T cells were visible.
References
1. Jacobson CA, Hunter B, Armand P, et al. Axicabtagene ciloleucel in the real world: outcomes and predictors of response, resistance and toxicity [ASH abstract 92]. Blood. 2018;132(suppl 1).
2. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [ASH abstract 578]. Blood. 2017;130(suppl 1).
Phase I/II Trial of Multi-Target Chimeric Antigen Receptor Modified T Cells (4SCAR2.0) Against Relapsed or Refractory Lymphomas
CAR T-cell therapy has induced high CR rates in many studies of patients with hematolo-gic malignancies.1 However, the technology is still relatively new, and modifications to CAR T-cell products could improve patient outcomes. A fourth-generation CAR T-cell product, 4SCAR, was designed to improve safety compared with earlier generations.2 In addition to a tumor-targeting single-chain variable fragment region, the 4SCAR product includes regions for antigen cosignaling, T-cell activation and survival, and a safety switch mediated by inducible caspase-9.
The 4SCAR19 product (CD19-scFv/CD28/CD137/CD27/CD3ζ-iCasp9) is directed at the CD19 antigen. In a study of children and adults with acute B-cell lymphoblastic leukemia who received conditioning chemotherapy followed by an infusion of 4SCAR19, 87% of patients (96/110) had a CR, including 51 children and 45 adults.2 Among 69 patients with a bone marrow blast cell count of less than 50%, 91.3% achieved a CR, while the 33 patients with a blast count of at least 50% had a CR rate of 75.8%. After a median of 115.5 days (range, 0-455 days), 55% of patients relapsed. The median survival was 222 days (range, 23-1041 days). Grade 1/2 cytokine release syndrome was observed in 88% of patients, and grade 3/4 cytokine release syndrome occurred in 12%. Among the patients with cytokine release syndrome, 35% had at least 50% blast cells in the bone marrow. The data show high response rates, regardless of the tumor burden. No significant correlation was observed between the CAR T-cell dose and patient response. Patients with a high tumor burden at baseline tended to relapse more quickly, owing to the tumor’s loss of the CD19 antigen and CAR T-cell exhaustion.
The 4SCAR2.0 product was developed to address tumor antigen escape and T-cell exhaustion.3 The product has been successfully used to develop a CAR T-cell therapy that recognizes CD19 plus another antigen, such as CD20, CD22, CD30, CD38, CD70, or the prostate-specific membrane antigen (PSMA). PSMA is not expressed in normal vasculature, but is highly expressed in numerous tumor types. PSMA is present in a small subset of glial cells, suggesting that agents that target this antigen would be associated with a low level of off-target effects. Among 40 B-cell lymphoma specimens, 98% were positive for PSMA according to immunohistochemistry. Patients can receive several infusions of the 4SCAR2.0 product. A CAR T-cell product with the mouse single-chain variable fragment directed at CD19 can be repetitively infused into the same patient without inducing anti-CAR antibodies. CAR T-cell products directed against different antigens can be infused into the same patient, with simultaneous expansion of both products.
A phase 1/2 study enrolled lymphoma patients with stable or progressive disease who had no further treatment options and a life expectancy exceeding 2 months.3 Biopsies were stained for target antigens, including CD19, CD20, CD22, CD30, CD38, CD70, and PSMA. Among the 18 patients enrolled, 11 had DLBCL, 3 had PMBCL, 3 had follicular lymphoma, and 1 had another B-cell lymphoma subtype. The 4SCAR2.0 product was manufactured to recognize CD19 plus 1 other antigen: CD22 (n=10), CD20 (n=3), CD30 (n=2), CD38 (n=1), CD70 (n=1), or PSMA (n=1). A CR was seen in 10 patients, and a PR in 7. Disease progression occurred in 1 DLBCL patient whose CAR T-cell product was directed at CD19 and CD22. Sequential infusions improved the response rate (Figure 6).
References
1. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T cell immunotherapy for human cancer [published online January 25, 2019]. Am J Hematol. doi:10.1002/ajh.25418.
2. Chang LJ, Dong L, Liu YC, et al. Safety and efficacy evaluation of 4SCAR19 chimeric antigen receptor-modified T cells targeting B cell acute lymphoblastic leukemia—three-year follow-up of a multicenter phase I/II study [ASH abstract 587]. Blood. 2016;128(15).
3. Chang LJ, Li Y, Tu S, et al. Phase I/II trial of multi-target chimeric antigen receptor modified T cells (4SCAR2.0) against relapsed or refractory lymphomas [ASH abstract 225]. Blood. 2018;132(suppl 1).
Clinical Responses to CAR.CD30-T Cells in Patients With CD30+ Lymphomas Relapsed After Multiple Treatments Including Brentuximab Vedotin
CAR T-cell therapy is limited by the tumor’s ability to stop expressing the target antigen and by inherent tumor antigen heterogeneity.1 To address the need for more versatile targeting, a CAR T-cell therapy targeting CD30 was developed.2 CD30 is universally expressed on the cells of Hodgkin lymphoma and anaplastic large-cell lymphoma, and in some patients with other T-cell and B-cell lymphomas.3 CD30 represents an attractive target for Hodgkin lymphoma therapies because it is overexpressed on Hodgkin lymphoma cells and minimally expressed on normal cells. Brentuximab vedotin is an antibody-drug conjugate that targets CD30 and is used to treat patients with CD30-expressing lymphomas.4 In a phase 1 dose-escalation study, CD30-directed CAR T-cell therapy without prior lymphodepletion treatment was safe and showed efficacy, with a CR in 1 out of 7 patients with relapsed Hodgkin lymphoma.
A phase 1b/2 study evaluated CD30-direct CAR T-cell therapy (CD30-CAR) after lymphodepletion in patients with CD30-positive Hodgkin or non-Hodgkin lymphoma who required treatment after at least 2 previous lines of therapy.5 The phase 1b portion followed a standard 3 + 3 design to test 2 dose levels: 1 × 108 CAR T cells/m2 and 2 × 108 CAR T cells/m2. Lymphodepletion treatment consisted of bendamustine monotherapy (90 mg/m2) for 2 days or bendamustine (70 mg/m2) plus fludarabine (30 mg/m2) for 3 days. Patients could receive bridging therapy after leukapheresis. Lymphodepletion therapy began on day 1, followed by infusion of CD30-CAR T cells on days 3 to 6. The trial enrolled 22 patients with classical Hodgkin lymphoma, 1 patient with enteropathy-associated T-cell lymphoma, and 1 patient with Sézary syndrome. The patients’ median age was 34.5 years (range, 23-69 years), and they had received a median of 7.5 prior lines of therapy (range, 3-17). Prior therapies included brentuximab vedotin (96%), checkpoint inhibitors (67%), autologous stem cell transplant (71%), and allogeneic stem cell transplant (29%).
Manufacture of CAR-CD30 cells was completed in 25 patients. Eight patients underwent lymphodepletion with bendamustine monotherapy, which improved expansion of CAR-CD30 T cells after infusion compared with no lymphodepletion. All 3 patients treated at the lower dose level of CAR-CD30 T cells had progressive disease at the 6-week assessment. Among 5 patients treated at the higher dose level, 1 patient had stable disease, 1 had progressive disease, and 3 had a CR. However, the latter 3 patients all had a CR after treatment with bridging chemotherapy, prior to the CAR T-cell infusion. The combination of bendamustine plus fludarabine was superior to bendamustine alone in increasing levels of interleukin (IL) 15 (P=.02) and IL-7 (P=.02), which led to sustained increases in these 2 cytokines for 2 weeks after the CAR T-cell infusion. Sixteen patients received bendamustine plus fludarabine as lymphodepletion therapy. These patients had a CR rate of 75%. Two patients achieved a CR prior to lymphodepletion. Two patients had a PR, 1 had stable disease, and 1 had progressive disease. Patients treated with bendamustine plus fludarabine prior to the infusion of CAR-CD30 T cells had a significantly improved PFS compared with those who received bendamustine monotherapy (396 vs 55 days; P=.001; Figure 7).
Three patients developed grade 1/2 cytokine release syndrome. No neurotoxicity was observed in any of the patients who received the CAR-CD30 infusion. A mild rash was observed in 8 patients.
References
1. Ramos CA, Heslop HE, Brenner MK. CAR-T cell therapy for lymphoma. Annu Rev Med. 2016;67:165-183.
2. Hong LK, Chen Y, Smith CC, et al. CD30-re-directed chimeric antigen receptor T cells target CD30(+) and CD30(-) embryonal carcinoma via antigen-dependent and Fas/FasL interactions. Cancer Immunol Res. 2018;6(10):1274-1287.
3. Pierce JM, Mehta A. Diagnostic, prognostic and therapeutic role of CD30 in lymphoma. Expert Rev Hematol. 2017;10(1):29-37.
4. Adcetris [package insert]. Bothell, WA: Seattle Genetics, Inc; 2018.
5. Grover NS, Park SI, Ivanova A, et al. Clinical responses to CAR-T cells in patients with CD30+ lymphomas relapsed after multiple treatments including brentuximab vedotin [ASH abstract 681]. Blood. 2018;132(suppl 1).
Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients With Relapsed or Refractory Large B-Cell Lymphoma
In the ZUMA-1 study of axicabtagene ciloleucel, the ORR and rate of ongoing response at 12 months did not significantly differ between patients younger than 65 years vs those 65 years or older.1 Safety outcomes in these 2 patient populations were not reported. A retrospective analysis evaluated safety and efficacy outcomes in younger vs older patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at a single institution.2 Patients received conditioning chemotherapy consisting of cyclophosphamide plus fludarabine on days –5 to –3 prior to infusion with axicabtagene ciloleucel. The axicabtagene ciloleucel infusion was administered on day 0, with a target dose of 2 × 106 CAR T cells/kg. Enrolled patients had received axicabtagene ciloleucel between June 18, 2015 and September 17, 2018 as the standard of care or through participation in the ZUMA-1 or ZUMA-9 (Axicabtagene Ciloleucel Expanded Access Study) clinical trials. Patients remained in the hospital and were monitored for toxicities for at least 7 days after administration of the CAR T-cell infusion. Patients with at least 30 days of follow-up after the axicabtagene ciloleucel infusion were considered evaluable for safety. Cytokine release syndrome and CAR T-cell–related encephalopathy syndrome were graded according to the CAR T-Cell Therapy–Associated Toxicity (CARTOX) system.3 Res-ponses were evaluated based on Lugano 2014 criteria.4
All 72 patients included in the study were evaluable for safety, and 67 were evaluable for efficacy. Most patients (n=52) were younger than 65 years. In the cohort of younger patients, the median age was 42 years (range, 23-64 years), 26.9% were female, and 94.2% had an ECOG performance status of 0 to 2. Stage III/IV disease was noted in 80.8% of patients. Disease histologies included DLBCL (59.6%), PMBCL (21.2%), and transformed follicular lymphoma (19.2%). In the cohort of older patients, the median age was 68 years (range, 65-83 years), 25% were female, and 95% had an ECOG performance status of 0 to 2. Stage III/IV disease was present in 90% of patients. Histologic subtypes included DLBCL (80%) and transformed follicular lymphoma (20%). A similar proportion of patients in each arm received axicabtagene ciloleucel treatment as the standard of care (55%-58%). More patients in the older cohort had an IPI score of 3 to 5 (67% vs 85%), and more patients in the younger cohort had received 3 or more prior lines of therapy (79% vs 60%).
At day 30 after infusion with axicabtagene ciloleucel, the ORR was 78% in the younger cohort vs 94% in the older cohort, but this difference was not significant (P=.1675). The CR rates were 50% in the younger cohort vs 71% in the older cohort (P=.2699). The median overall survival was 15.4 months overall, and was similar for both groups of patients (P=.27).
Rates of cytokine release syndrome across all grades were comparable between the younger and older patients (P=.18; Figure 8). Rates of CAR T-cell–related encephalopathy syndrome were also similar across all grades for younger vs older patients (P=.29). Tocilizumab was used in 63.5% of the younger patients and in 75.0% of the older patients (P=.41). The use of corticosteroids was more frequent in younger patients, at 52%, vs 30% in older patients (P=.002; Figure 9). Patients in both cohorts were hospitalized for a median of 16 days (P=.62). Rates of admission to the intensive care unit were 42% in younger patients vs 35% in older patients (P=.38).
References
1. 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.
2. Sano D, Nastoupil LJ, Fowler N, et al. Safety of axicabtagene ciloleucel CD19 CAR T-cell therapy in elderly patients with relapsed or refractory large B-cell lymphoma [ASH abstract 96]. Blood. 2018;132(suppl 1).
3. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
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.
Cytokine Monitoring in R/R DLBCL Patients Treated With Axicabtagene Ciloleucel: Associations With Toxicities and Outcomes
Two commonly observed AEs associated with CAR T-cell therapy are cytokine release syndrome and neurotoxicity—notably, CAR T-cell–related encephalopathy syndrome. Both cytokine release syndrome and CAR T-cell–related encephalopathy syndrome can lead to hospitalization and death. As a result, patients who receive CAR T-cell infusions require vigilant monitoring and prompt treatment of toxicities. Because CAR T-cell therapy induces the expression of numerous cytokines associated with an immune response, identification and monitoring of serum biomarkers could enable earlier intervention in patients who are likely to develop severe toxicity.
A phase 1 trial investigated the safety and long-term outcomes of CAR T-cell therapy in 53 patients with relapsed or refractory B-cell acute lymphoblastic leukemia.1 After a median follow-up of 29 months, the CR rate was 83%. After infusion, however, 14 patients (26%) developed severe cytokine release syndrome. One patient died from severe cytokine release syndrome and multiorgan failure. Another 31 patients (58%) developed grade 1/2 cytokine release syndrome. Symptoms of cytokine release syndrome included fever, tachycardia, hypotension, respiratory distress, and hypoxemia. To manage cytokine release syndrome, treatments included supportive care only (42%), tocilizumab plus a glucocorticoid (25%), tocilizumab alone (11%), and glucocorticoids only (8%). Neurologic AEs consisted of confusion, disorientation, aphasia, encephalopathy, and seizure. Neurologic AEs of grade 2, 3, or 4 were observed in 2%, 36%, and 6% of patients, respectively. There were no reports of grade 5 neurotoxicity or cerebral edema.
The relationship between the cyto–kine levels and CAR T-cell–associated toxicities was evaluated in patients with relapsed or refractory DLBCL.2 To determine which cytokines to monitor, a panel of 38 was retrospectively analyzed in serum samples from 53 patients with acute B-cell lymphoblastic leukemia enrolled in the phase 1 trial discussed above.1 Cytokine levels were compared in patients who did or did not develop cytokine release syndrome or neurotoxicity requiring treatment. The analysis revealed that, on days 0 to 2, patients with cytokine release syndrome or neurotoxicity requiring intervention had increased levels of several cytokines, including interferon γ and IL-2, IL-6, and IL-15. For the study of patients with DLBCL, levels of these 4 cytokines were examined, as well as those of angiopoietins 1 and 2, IL-1β, and tumor necrosis factor α.2 Levels of CRP and ferritin were also evaluated. Serum samples were collected at baseline and on day 0. Samples were also collected daily during hospitalization. Cytokine release syndrome and CAR T-cell–related encephalopathy syndrome were graded daily during hospitalization. The study enrolled 30 patients with relapsed or refractory DLBCL who received treatment with axicabtagene ciloleucel at a single center. After collection, samples were analyzed with a point-of-care device that revealed serum cytokine levels within 90 minutes. Results were validated using a standard multiplex assay. Cytokine release syndrome and CAR T-cell–related encephalopathy syndrome were prospectively graded based on revised criteria.3,4
The median age of the 30 patients was 64 years (range, 47-75 years), and 70% were male. Half had de novo DLBCL, and half had transformed indolent lymphoma. Twenty percent had bulky disease, 90% had Ann Arbor stage III/IV disease, and 80% had an IPI score of 3 or higher at the time of leukapheresis. Sixty percent of patients had received 3 or more lines of therapy prior to study entry. Bridging chemotherapy was used in 67%, and 27% had received prior autologous stem cell transplant.
At day 30, the ORR was 70%, including a CR rate of 50%. At day 90, the ORR was 57% (12/21) and the CR rate was 46% (10/21).
Cytokine release syndrome of any grade was reported in 97% of patients. Grade 3 or higher cytokine release syndrome occurred in 13%. The median time to onset of cytokine release syndrome was 4 days. Tocilizumab and corticosteroids were each used in 53% of patients. CAR T-cell–related encephalopathy syndrome of any grade was reported in 80% of patients. This syndrome was grade 3 or higher in 37%. The CARTOX score was less than 7 in 53% of patients.4 The median time to onset of CAR T-cell–related encephalopathy syndrome was 6 days.
Baseline levels of CRP and ferritin were elevated in patients who developed cytokine release syndrome or CAR T-cell–related encephalopathy syndrome of grade 3 or higher, compared with the rest of the study population (P<.05). Baseline levels of IL-6 were higher among patients who experienced cytokine release syn-drome (P=.03) or CAR T-cell–related encephalopathy syndrome (P=.0038) of grade 3 or higher. Baseline levels of angiopoietin were higher in patients who developed severe CAR T-cell–related encephalopathy syndrome (P=.0078). Patients who achieved a CR or PR were more likely to have lower baseline levels of CRP (P=.0012; Figure 10), ferritin (P=.0077), tumor necrosis factor (P=.0023), and IL-6 (P=.0017). Levels of catecholamines were elevated in patients with severe cytokine release syndrome (P=.0011).
References
1. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449-459.
2. Faramand R, Kotani H, Morrissey D, et al. Cytokine monitoring in R/R DLBCL patients treated with axicabtagene ciloleucel: associations with toxicities and outcomes [ASH abstract 95]. Blood. 2018;132
(suppl 1).
3. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.
4. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
Outcomes of Patients With Large B-Cell Lymphomas and Progressive Disease Following CD19-Specific CAR T-Cell Therapy
In patients with relapsed or refractory large B-cell lymphoma, CD19-directed CAR T-cell therapy has demonstrated efficacy, with durable CRs in approximately 40%.1-3 Among patients without a CR after CAR T-cell therapy, disease progression generally occurs within a few months. A study was conducted to describe outcomes in patients who developed progressive disease after CD19-specific CAR T-cell therapy.4 Bridging therapy was allowed in patients with active disease after leukapheresis and before the CAR T-cell infusion. Initial progressive disease was defined as progression at the first response assessment after the CAR T-cell infusion. After infusion with CAR T cells, patients did not receive any protocol-specified treatment for their lymphoma. The primary analysis was overall survival after progressive disease. The study did not include information on CAR T-cell products, construction, or dosing.
Among 58 patients in the study, progressive disease was considered initial in 30 patients and delayed in 28 patients. The median time to progressive disease after CAR T-cell infusion was 29 days in patients with initial progressive disease vs 73 days in patients with delayed progressive disease. The patients’ median age was 60 years (range, 26-75 years). The most common histology was DLBCL (58.6%), followed by high-grade B-cell lymphoma (20.7%), transformed follicular lymphoma (15.5%), and PMBCL (5.2%). Most patients had an IPI of 2 or 3 (63.8%), and 15.5% had an IPI of 4 or 5. The median level of lactate dehydrogenase was 210 U/L (range, 111-2339 U/L). Characteristics were generally similar among patients with initial progressive disease vs those with delayed progressive disease. One difference was that patients with initial progression had a higher median level of lactate dehydrogenase at baseline (P=.026).
Among the 58 patients, the median overall survival after progressive disease was 5.3 months. Median overall survival was 3.75 months among patients with initial progression vs 13.42 months in those with delayed progression (P=.038). Twenty patients overall (34.5%) were treated with bridging therapy, including chemotherapy with or without corticosteroids (45.0%), corticosteroids only (25.0%), a novel or targeted agent with or without corticosteroids (25.0%), and intrathecal chemotherapy. The median overall survival was 3.16 months in patients who received bridging therapy vs 7.14 months in those who did not (P=.37). Among patients who received bridging therapy and developed initial progressive disease, the median overall survival was 2.34 months vs 13.55 months in patients without bridging therapy who developed delayed progressive disease (P=.19). The median overall survival was 13.55 months in the 20 patients with no bridging therapy who developed delayed progressive disease vs 3.55 months in the other 38 patients (P=.059).
Forty-four patients (76%) went on to receive at least 1 subsequent therapy after progressive disease. The most common initial subsequent therapies included CAR T-cell therapy (14/44), a novel therapy (13/44), and chemotherapy with or without rituximab (7/44). Radiotherapy or inhibitors of programmed cell death protein 1 (PD-1) were administered to 4 patients each, and intrathecal chemotherapy or allogeneic stem cell transplant were administered to 1 patient each. The risk of death was reduced in patients treated with at least 1 therapy after progressive disease (hazard ratio, 0.48; 95% CI, 0.234-0.99; P=.0476). Six patients enrolled in a clinical trial as their next line of therapy. Five patients eventually underwent an allogeneic stem cell transplant, and 2 were alive at the time of the study report.
References
1. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T cell immunotherapy for human cancer [published online January 25, 2019]. Am J Hematol. doi:10.1002/ajh.25418.
2. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [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. Chow VA, Gopal AK, Maloney DG, et al. Outcomes of patients with large B-cell lymphomas and progressive disease following CD19-specific CAR T-cell therapy [ASH abstract 94]. Blood. 2018;132(suppl 1).
Highlights in CAR T-Cell Therapy in Lymphoma From the 60th American Society of Hematology Annual Meeting: Commentary
Frederick L. Locke, MD
Vice Chair and Associate Member
Department of Blood and Marrow Transplant and Cellular Immunotherapy
Co-Leader, Immunology Program
Moffitt Cancer Center
Tampa, Florida
The 60th American Society of Hematology (ASH) annual meeting had a number of remarkable abstracts that presented data in lymphoma patients treated with chimeric antigen receptor (CAR) T-cell therapy. Of particular interest were abstracts that highlighted data from patients treated outside of clinical trials with now standard-of-care CAR T-cell therapy, which demonstrated convincingly that the treatment is available and working in the real world. Importantly, community oncologists should consider their patients for early referral for CAR T-cell therapy. They should expect that up to 40% of patients with refractory diffuse large B-cell lymphoma (DLBCL) will have durable and long-lasting remissions of 2 years and longer, with minimal long-term safety risks.
The CAR T-cell therapy axi-scabtagene ciloleucel is approved by the US Food and Drug Administration (FDA) for adult patients with relapsed/refractory DLBCL, based on results from the ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma).1 I was a senior investigator in a real-world analysis of axicabtagene ciloleucel that was presented at the ASH meeting by Dr Loretta Nastoupil.2 The co–first author was Dr Michael Jain. The study provided data on patients with aggressive B-cell lymphomas who underwent apheresis for the manufacture of axicabtagene ciloleucel at 1 of 17 centers that formed an independent consortium. The study identified 295 patients who underwent apheresis prior to August 31, 2018. Among these patients, 274 received an infusion of axicabtagene ciloleucel by the data cutoff of October 31, 2018. The median follow-up duration was 3.9 months.
Remarkably, the percentage of patients who received CAR T-cell therapy was high, at 93%, and similar to the 91% who received axicabtagene ciloleucel infusion in the ZUMA-1 trial. The median time from leukapheresis to the start of conditioning chemotherapy was also similar to that in ZUMA-1, at 21.5 days. However, in stark contrast to ZUMA-1—in which no patient was allowed bridging therapy in the interval from apheresis to the start of conditioning chemotherapy and CAR T-cell infusion—in the real-world analysis, 55% of patients received some form of bridging therapy.
Baseline characteristics of the patients in the real-world analysis were somewhat similar to those of patients in ZUMA-1. Of note, 33% of the patients were 65 years or older, 75% had received 3 or more prior lines of therapy, and 35% had primary refractory disease. In a subset of 272 evaluable patients, 23% were double-hit or triple-hit according to fluorescence in situ hybridization (FISH), and 38% were double expressers by immunohistochemistry. There were several notable differences between the real-world population and patients in ZUMA-1. For example, 43% would not have met eligibility requirements for ZUMA-1 at the time of leukapheresis, for reasons such as low platelet count, active deep vein thrombosis or pulmonary embolism, prior anti-CD19 or CAR T-cell therapy, decreased renal function, history of central nervous system lymphoma or symptomatic effusion, decreased ejection fraction, and poor performance status. Despite the high percentage of patients who would not have been eligible for ZUMA-1, the safety of the therapy appeared similar in both studies. In the real-world analysis, cytokine release syndrome of any grade occurred in 92% of patients, but it was grade 3 or higher in only 7%, comparing favorably with the 13% seen in the ZUMA-1 trial. The rate of grade 3 or higher neurotoxicity was also similar, at 33% in this series vs 31% in ZUMA-1.
Perhaps most importantly, the efficacy of axicabtagene ciloleucel when given as a standard-of-care therapy appeared similar to that described in the ZUMA-1 trial. At a landmark of day 90, 81% of patients had achieved an objective response and 57% had a complete response at some time prior. These rates were comparable to the overall objective response rate of 82% and the complete response rate of 54% in ZUMA-1.1 There were several covariates associated with a lack of ongoing complete response at 3 months, including an ECOG performance status of 2 or higher, bulky disease (>10 cm), and failure to meet the eligibility criteria for ZUMA-1. However, the rates of complete response at 3 months continued to be favorable for these subgroups as compared with historical controls, indicating that all DLBCL patients who relapse after second-line therapy should at least be considered for axicabtagene ciloleucel therapy. I recommend that all community oncologists consider early referral, even at the time of first relapse, for consideration of CAR T-cell therapy or autologous stem cell transplant, depending upon the response to second-line therapy. Early referral is important considering the aggressive nature of refractory DLBCL and the lag time between vital organ testing and apheresis up until infusion of CAR T cells.
In conclusion, it appears that the safety and efficacy of standard-of-care axicabtagene ciloleucel in this real-world analysis were comparable to those in ZUMA-1, even though more than 40% of patients would not have met the eligibility criteria for the clinical trial. An ongoing analysis is identifying predictors of ongoing response with axicabtagene ciloleucel.
Dr Caron Jacobson presented the results of a similar real-world analysis of axicabtagene ciloleucel from other centers not represented in the prior study.3 This analysis included 104 patients, with a median follow-up of 5.6 months. Eleven percent of the patients did not undergo infusion with axicabtagene ciloleucel. Among those who were infused, 71% had a response, including a complete response in 44%. Adverse events included grade 3 or higher cytokine release syndrome in 16%, and grade 3 or higher neurotoxicity in 39%. Again, these findings were comparable to those in the ZUMA-1 trial. Univariate analysis showed inferior outcomes in patients with poor performance status (an ECOG score of 2 to 4) or increased tumor bulk. Duration of response, progression-free survival, and overall survival were improved among patients with lower levels of C-reactive protein—a marker of inflammation—on day zero at the time of the infusion. Like the analysis by Dr Nastoupil,2 this study demonstrated that axicabtagene ciloleucel can be successfully administered across multiple centers. It also showed that the use of bridging therapy among patients otherwise eligible for ZUMA-1 did not appear to improve outcomes or impact the rates of high-grade toxicities.
I was also fortunate to be a senior investigator in a retrospective real-world analysis by Dr Michael Jain, which provided some of the first data on the use of radiation therapy as a bridging agent while CAR T cells are being manufactured for standard-of-care administration.4 The 9 patients in this analysis had refractory disease as defined in the label for axicabtagene ciloleucel. The response to radiation therapy was assessed by local response at the site of the individual areas where the radiation was administered, and most patients had stable disease as an initial response to the radiation. One patient had a complete response in the irradiated areas, while another developed progressive disease in these areas. Following CAR T-cell therapy, which was performed after the radiation, 6 of 8 patients (75%) had a partial response or a complete response at the localized area of radiation.
Importantly, radiation as a bridge to CAR T-cell therapy appeared safe. Any-grade cytokine release syndrome was reported in 94% of patients; the syndrome was grade 3 or higher in 16%, similar to the rates of severe toxicity related to CAR T-cell therapy reported in ZUMA-1.1 This study showed that radiation may be used as a bridge for chemorefractory lymphoma patients who are awaiting manufacture of CAR T cells, even those with bulky masses or higher-risk disease. Further studies must be done to determine if there is an immunologic effect of radiation on CAR T-cell therapy.
Dr Dahlia Sano presented the results from a single-institution study that evaluated the outcomes of older patients with relapsed or refractory large-cell lymphoma treated with axicabtagene ciloleucel.5 The study demonstrated that response rates and survival were comparable between younger patients and those ages 65 years and older. Importantly, the safety was also comparable. The periods of hospitalization and days spent in the intensive care unit were similar between younger and older patients. Rates of tocilizumab use were also similar, but the use of corticosteroids was lower in elderly patients, at 30%, vs 52% in younger patients. This important study demonstrated that axicabtagene ciloleucel can be used safely in elderly patients with aggressive B-cell lymphomas.
Dr Natalie Grover presented results from an evaluation of patients in a phase 1b/2 trial of CD30-directed, CD28-costimulatory CAR T-cell therapy among adults with CD30-positive lymphoma who required treatment after 2 prior lines of therapy.6 This CAR T-cell therapy had been previously tested in a feasibility trial, which showed that it could be administered safely without the use of conditioning chemotherapy, and it did induce some complete responses.7 This follow-up trial added conditioning chemotherapy to lymphodeplete patients prior to administration of CAR T-cell therapy and a phase 1 dose-escalation/dose-finding arm to identify a safe dose of CAR T cells in combination with lymphodepletion. There were no dose-limiting toxicities, and the phase 2 trial was opened with a dose of 2 × 108 CAR T cells/m2. Twenty-four patients were evaluable by the data cut-off date: 22 had Hodgkin lymphoma and 2 had T-cell lymphoma. These patients were very heavily pretreated, with a median of 7.5 prior lines of therapy. Most had already received the CD30-targeted agent rituximab or checkpoint inhibitors. Patients underwent lymphodepletion with bendamustine at 90 mg/m2 for 2 days. The addition of lymphodepletion demonstrated an increased expansion of CAR T cells compared with data from a trial that did not use lymphodepletion, and there were no dose-limiting toxicities.7 Lymphodepletion with bendamustine alone did not clearly increase the response rates, and in the second part of the trial, there was a switch to using bendamustine plus fludarabine as the regimen for conditioning chemotherapy. After this change, 12 of 14 evaluable patients treated with bendamustine plus fludarabine had a complete response, including 2 patients with a complete response that lasted longer than a year. A statistically significant difference in progression-free survival was seen between patients who received the combination of bendamustine and fludarabine (396 days) vs patients who received bendamustine alone (55 days). This finding is concordant with a report from the Seattle group showing that cyclophosphamide plus fludarabine was superior to cyclophosphamide alone when utilizing a CD19-directed CAR T-cell therapy,8 suggesting that conditioning chemotherapy is important to the efficacy of CAR T-cell therapy. The authors concluded that this approach had an acceptable safety profile. It is encouraging to know that CD30-directed CAR T cells may be useful for the treatment of Hodgkin lymphoma and T-cell lymphoma. Large trials will be needed to confirm efficacy.
Dr Sattva Neelapu presented results from long-term follow-up of the ZUMA-1 trial, of which I was the senior author and co–lead investigator.9 These results were simultaneously published in The Lancet Oncology.10 This long-term analysis confirmed the originally reported outcomes, showing an overall response rate of 83% and a complete response rate of 58%. Now at a median follow-up of 27.1 months and with all patients eligible for 2-year follow-up, the median overall survival was not reached, and 39% of patients maintained an ongoing response. This finding is remarkable because in patients with DLBCL, a durable response lasting 2 years after upfront chemotherapy or consolidative autologous transplant predicts for remission at 5 years and later.11 This analysis therefore suggested that the lymphoma might not recur in many of these patients. Another key finding is that among patients in whom a single infusion of axicabtagene ciloleucel led to a partial response or complete response at 90 days after treatment, the chance for ongoing remission at 24 months was approximately 75%, suggesting that consolidative transplant is not necessary after CAR T-cell therapy to sustain remission. This long-term follow-up analysis identified only 4 additional serious adverse events, which were primarily infection-related and reversible. This study again highlights the finding that CAR T-cell therapy appears to induce durable remissions in patients with aggressive B-cell lymphoma.
Disclosure
Dr Locke is a scientific advisor to Kite Pharma and Novartis. He is a consultant to Cellular Biomedicine Group, Inc.
References
1. 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.
2. Nastoupil LJ, 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 91]. Blood. 2018;132(suppl 1).
3. Jacobson CA, Hunter B, Armand P, et al. Axicabtagene ciloleucel in the real world: outcomes and predictors of response, resistance and toxicity [ASH abstract 92]. Blood. 2018;132(suppl 1).
4. Jain MD, Chavez JC, Shah BD, et al. Radiation therapy as a bridging strategy for refractory diffuse large B-cell lymphoma patients awaiting CAR T manufacturing of axicabtagene ciloleucel [ASH abstract 4220]. Blood. 2018;132(suppl 1).
5. Sano D, Nastoupil LJ, Fowler N, et al. Safety of axicabtagene ciloleucel CD19 CAR T-cell therapy in elderly patients with relapsed or refractory large B-cell lymphoma [ASH abstract 96]. Blood. 2018;132(suppl 1).
6. Grover NS, Park SI, Ivanova A, et al. Clinical responses to CAR-T cells in patients with CD30+ lymphomas relapsed after multiple treatments including brentuximab vedotin [ASH abstract 681]. Blood. 2018;132(suppl 1).
7. Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest. 2017;127(9):3462-3471.
8. Turtle CJ, Berger C, Sommermeyer D, et al. Anti-CD19 chimeric antigen receptor-modified T cell therapy for B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes [ASH abstract 184]. Blood. 2015;126(suppl 23).
9. Neelapu SS, Ghobadi A, Jacobson CA, et al. 2-year follow-up and high-risk subset analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients with refractory large B cell lymphoma [ASH abstract 2967]. Blood. 2018;132(suppl 1).
10. 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.
11. Maurer MJ, Ghesquières H, Jais JP, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32(10):1066-1073.