AXICABTAGENE CILOLEUCEL (also known as CAR19) is an anti-CD19 chimeric antigen receptor (CAR) T-cell product approved by U.S. Food and Drug Administration to treat selected hematologic malignancies.1 To appreciate the clinical trial findings summarized here, from selected abstracts presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, it is prudent to review the initial data that led to its approval.1 A summary of these data is shown in Table 1, and ongoing areas of inquiry for these immunotherapies are featured in Table 2.
TABLE 1: FDA APPROVAL FOR AXICABTAGENE CILOLEUCEL IMMUNOTHERAPY
On October 18, 2017, the FDA granted regular approval to axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.1
- Approval was based on a single-arm multicenter trial of 111 adult patients (ZUMA-1 trial).
- Of the 101 patients evaluated for efficacy, the ORR as assessed by independent central review was 72%, with a CR rate of 51% (95% CI = 41%–62%).
- Among patients achieving CR, the estimated median DOR was not reached (95% CI = 8.1 months to not estimable), after a median follow-up of 7.9 months.
- The estimated median DOR among patients in PR was 2.1 months (95% CI = 1.3–5.3 months).
- Serious adverse reactions, including CRS and neurologic toxicity, occurred in 52% of patients.
- Fatal cases of CRS (Lee criteria) and neurologic toxicity occurred.
- The recommended dose of axicabtagene ciloleucel is a single IV infusion with a target of 2 106 CAR T-cell–positive viable T cells/kg (maximum 2 108), preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.
- Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.
CAR = chimeric antigen receptor; CI = confidence interval; CR = complete remission; CRS = cytokine release syndrome; DLBCL = diffuse large B cell lymphoma; DOR = duration of response; FDA = U.S. Food and Drug Administration; IV = intravenous; ORR = overall response rate; PR = partial response.
ABSTRACT 2289: Patient-reported and neurocognitive outcomes with axicabtagene ciloleucel as part of a clinical trial or standard of care at Moffitt Cancer Center2
Key Findings: Of 29 participants, 11 completed neurocognitive testing at baseline and at 30 days. Patient-reported symptoms spiked at 14 days after CAR T-cell therapy before returning to levels similar to those at baseline. The most common symptoms at 14 days after therapy were decreased appetite, fatigue, and dry mouth. By 90 days, the most common symptoms were fatigue, insomnia, and joint pain; no patients reported moderate to severe symptoms at this time. Nonsignificant improvements were observed in physical health quality of life (mean increase = 1.43; P = .37) and mental health quality of life (mean increase = 2.66, P = .07) from baseline to 90 days.
Clinical Implications: These study results indicate that moderate-to-severe patient-reported symptoms were transient after axicabtagene ciloleucel, although a majority of patients reported ongoing, low-grade symptoms at 90 days after treatment. Quality of life and neurocognition did not significantly change over time. These preliminary findings warrant larger future studies with longer follow-up.
ABSTRACT 4656: Target antigen downregulation and other mechanisms of failure after axicabtagene ciloleucel therapy3
Study Rationale and Details: More than 50% of patients will have disease progression after therapy. A total of 69 patients with refractory large B-cell lymphoma were referred for axicabtagene ciloleucel therapy from October 2017 to June 2018. The investigators assessed peripheral blood CAR T-cell numbers at days 7, 14, 21, and 28 by flow cytometry and monitored disease response with positron-emission tomography/computed tomography at day 28, 3 months, and 6 months after axicabtagene ciloleucel therapy.
Key Findings: Of 22 of patients who underwent axicabtagene ciloleucel infusion, 8 (36%) did not respond or relapsed after day-28 response. Five patients (62%) who failed to respond to therapy had loss or downregulation of CD-19, which emphasizes that single-target antigen loss is a common mechanism of treatment failure. However, lack of CAR T-cell expansion was noted in multiple patients, suggesting there may be T-cell–intrinsic causes of treatment failure.
Clinical Implications: Further studies are necessary to help identify and predict which patients with refractory large B-cell lymphomas will benefit from axicabtagene ciloleucel.
ABSTRACT 95: Prediction of axicabtagene ciloleucel–related toxicities in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) using point-of-care cytokine measurements4
Key Findings: In this analysis of 20 patients, the investigators observed a correlation between severe cytokine-release syndrome and elevated serum cytokine levels of interleukin 6 (IL-6) and angiopoietin 2/angiopoietin 1 ratio at day 1, suggesting these biomarkers may be used to predict severe toxicity. Furthermore, patients with high grades of cytokine-release syndrome had elevated levels of IL-15 at day 7. There were no significant correlations between serum cytokine levels and CAR T-cell–related encephalopathy syndrome or between those who required tocilizumab/steroids vs those who did not, likely due to the small sample size. Although this study is limited by its small sample size, the current observations correlate with previously published biomarkers data in patients enrolled in clinical trials.
Clinical Implications: Monitoring of cytokines using a point-of-care device is feasible and will be useful clinically. High-risk patients may be identified early, and such monitoring may help guide intervention in real time. For example, elevated IL-6 levels on day 1 might inform earlier use of tocilizumab. Further investigation is ongoing.
ABSTRACT 96: Safety of axicabtagene ciloleucel CAR T-cell therapy in older adults with relapsed or refractory DLBCL treated at MD Anderson Cancer Center5
Key Findings: Of 61 patients, 44 patients (72%) were younger than age 65 and 17 patients (28%) were 65 years of age or older. The overall response rates and complete response rates at day 30 were comparable between the two groups.
The cytokine-release syndrome was observed in 91% and 83% of the patients in the younger and older adults, respectively. However, most cytokine-release syndrome events were grade 1 to 2. Grade 3 or higher cytokine-release syndrome was observed in 18% vs 11% in the younger vs older age groups (P = .67). CAR T-cell–related encephalopathy syndrome was observed in 71% and 58% of the patients in the younger and older age groups, respectively. Grade ≥ 3 CAR T-cell–related encephalopathy syndrome was observed in 39% vs 29% in the younger vs older age groups (P = .58). The median hospitalization period was comparable between the two groups.
Clinical Implications: Toxicities due to cytokine-release syndrome and/or CAR T-cell–related encephalopathy syndrome seem to be comparable in the older and younger patients with relapsed or refractory DLBCL.
ABSTRACT 2967: The 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 lymphoma6
Key Findings: As of August 2017, all 108 patients had at least 1 year of follow-up, with a median follow-up of 15.4 months. The objective response rate was 82%, with a complete remission rate of 58%. The complete remission rate was 53% in patients with disease refractory to at least 2 consecutive prior lines of therapy and 72% in patients who had relapsed within 12 months after autologous hematopoietic cell transplantation.
High-risk genetics were assessed in the 47 evaluable pretreatment tumor samples. A total of 37 patients (79%) had double- or triple-hit, or were double-expressors and had an overall response rate of 89% including a complete remission rate of 68%. Overall, 42% of patients had ongoing responses, with a median follow-up of 15.4 months, including 49% of patients with high-risk genetics.
At 12 months, B-cell recovery was observed in more than half of the patients with ongoing remission.
About one-third of patients had grade 0 to 1 cytokine-release syndrome and neurologic events, yet they showed comparable efficacy (overall response rate, 86%; complete remission, 65%) with the overall patient population; however, they did experience lower peak/AUC CAR T-cell levels than did the overall population. High-grade cytokine-release syndrome and neurologic events were largely managed with tocilizumab and steroids, with little need for an intensive or invasive intervention. Grade ≥ 3 cytokine-release syndrome and neurologic events were generally reversible.
Clinical Implications: High rates of durable response were observed in patients with high-grade B-cell lymphoma and double-expressor B-cell lymphoma, with approximately half maintaining complete remission at ≥ 1 year. The efficacy in the protocol-defined high-risk group was comparable to that in the overall patient population. The median overall survival was not reached at 2 years, with an estimated 24-month survival proportion of 50.5% (95% confidence interval = 40.2%–59.7%). This finding represents a major improvement in clinical outcomes for these patients, for whom the expected median overall survival with conventional therapies is approximately 6 months, with a 2-year overall survival of about 20%.7,8
ABSTRACT 91: Axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma after commercialization: Data from 17 U.S. academic centers9
Key Findings: As of June 2018, 211 patients underwent leukapheresis with intention to manufacture commercial axicabtagene ciloleucel. Of them, 165 patients (78%) had completed axicabtagene ciloleucel infusion.
Safety was evaluable in 163 patients. Grade 3 cytokine-release syndrome and neurologic events occurred in 7% and 31% of patients, respectively. Tocilizumab was administered in 62% of patients, and 57% received corticosteroids. There were no grade 5 neurologic events.
Of 112 patients evaluable at day 30, the overall response rate was 79%, with 50% complete remission, 29% partial response, 6% stable disease, and 14% progressive disease. Of 39 patients evaluable at day 100, 59% of patients had an ongoing response (complete remission 49%, partial response 10%). At the time of abstract submission, more detailed patient characteristics and treatment course data were available for 134 of the 165 patients infused. Bridging therapy between apheresis and infusion was given in 56% of these patients. Of 134 patients, 66 (49%) would not have met the eligibility criteria for ZUMA-1 at the time of leukapheresis. The median time from leukapheresis to the start of conditioning chemotherapy was 21 days, and the median time from leukapheresis to axicabtagene ciloleucel infusion was 26 days.
Clinical Implications: Although this multicenter retrospective study is limited by relatively short follow-up, 30-day responses are comparable to the best responses observed on the pivotal, single-arm multicenter phase I to II ZUMA-1 clinical trial. It is important to note that safety appears comparable to the ZUMA-1 trial, despite nearly half the patients failing to meet the ZUMA-1 eligibility criteria.7-9
ABSTRACT 576: Elevated axicabtagene ciloleucel expansion detected by immunophenotyping is associated with toxicity in DLBCL.10
Key Findings: Of 25 patients who underwent apheresis, 3 died of progressive lymphoma prior to infusion. Overall, the median day-7 peak in vivo axicabtagene ciloleucel expansion using anti-CAR19 flow cytometry was 38 CAR T cells/mL, matching reverse transcription–polymerase chain reaction measured levels reported in the ZUMA-1 trial. The majority of CAR T cells were CD8-positive.
Cytokine-release syndrome was graded by Lee criteria,11 which consist of a treatment algorithm for managing cytokine-release syndrome based on a revised grading system. The assessment categorizes the grades as follows: grade 1 = fever and constitutional symptoms; grade 2 = hypotension (responding to fluids or one low-dose pressor), hypoxia (responding to less than 40% O2), and organ toxicity (grade 2); grade 3 = hypotension (requiring multiple or high-dose pressors), hypoxia (requiring at least 40% O2), and organ toxicity (grade 3 or 4); grade 4 = mechanical ventilation and organ toxicity (grade 4).11 Neurotoxicity was assessed according to CARTOX (a CAR T-cell therapy–associated 10-point neurologic assessment).12 Patients with grade 2 cytokine-release syndrome had significantly higher peak expansion of CAR T cells (both CD4-positive and CD8-positive) as compared with those with either grade 0 or 1 cytokine-release syndrome. Grades 2 to 4 neurotoxicity were significantly associated with peak total and CD8-positive CAR T cells but not CD4-positive cells. Two patients with the most robust CAR T-cell expansion experienced grade 4 neurotoxicity, including status epilepticus (which required multiple antiepileptics and intubation). Peak CAR T-cell expansion in the blood did not correlate with complete response or overall response rate at day 28 and did not differ between patients who did or did not require steroids.
Clinical Implications: Analysis of 22 patients showed an overall response rate of 86% and a complete remission rate of 45%, despite 36% of them being ineligible for the ZUMA-1 trial and steroid use in 82%. Blood CAR T-cell expansion was associated with both cytokine-release syndrome and neurotoxicity but not clinical response. Detection of a high concentration of CAR T cells in affected lymph nodes 2 days after infusion suggests that quantification of CAR T cells at disease sites may be predictive of clinical response. ■
Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; as well as Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Levine is Barbara and Edward Netter Professor in Cancer Gene Therapy; Founding Director, Clinical Cell and Vaccine Production Facility Center for Cellular Immunotherapies; Deputy Director, Technology Innovation and Assessment, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Abramson Cancer Center University of Pennsylvania, Philadelphia.
DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca Pharmaceuticals. Dr. Levine has stock and other ownership interest in Tmunity Therapeutics and Brammer Bio; has received honoraria from Novartis, Terumo, CRC Oncology, and Cure Genetics; is a consultant/advisor for Brammer Bio, Incysus, Ori Biotech, and Avectas; a patent or intelluctual property interest with the University of Pennsylvania licensed to Novartis and licensed to Tmunity Therapeutics.
REFERENCES
1. U.S. Food and Drug Administration: FDA approves axicabtagene ciloleucel for large B-cell lymphoma. Available at www.fda.gov/drugs/informationondrugs/approveddrugs/ucm581296.htm. Accessed January 18, 2019.
2. Jim HSL, Hoogland AI, Collier A, et al: Patient-reported and neurocognitive outcomes in patients treated with axicabtagene ciloleucel. 2018 ASH Annual Meeting & Exposition. Abstract 2289. Presented December 1, 2018.
3. Oak J, Spiegel JY, Sahaf B, et al: Target antigen downregulation and other mechanisms of failure after axicabtagene ciloleucel (CAR19) therapy. 2018 ASH Annual Meeting & Exposition. Abstract 4656. Presented December 3, 2018.
4. Faramand R, Kotani H, Morrissey D, et al: Prediction of CAR T-related toxicities in R/R DLBCL patients treated with axicabtagene ciloleucel using point of care cytokine measurements. 2018 ASH Annual Meeting & Exposition. Abstract 95. Presented December 1, 2018.
5. Sano D, Nastoupil LJ, Fowler NH, et al: Safety of axicabtagene ciloleucel CD19 CAR T-cell therapy in elderly patients with relapsed or refractory large B-cell lymphoma. 2018 ASH Annual Meeting & Exposition. Abstract 96. Presented December 1, 2018.
6. 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 in patients with refractory large B cell lymphoma. 2018 ASH Annual Meeting & Exposition. Abstract 2967. Presented December 2, 2018.
7. 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 20:31-42, 2019.
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9. Nastoupil LJ, Jain MD, Spiegel JY, et al: Axicabtagene ciloleucel CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory large B-cell lymphoma: Real world experience. 2018 ASH Annual Meeting & Exposition. Abstract 91. Presented December 1, 2018.
10. Spiegel JY, Sahaf B, Hossain N, et al: Elevated axicabtagene ciloleucel (CAR- 19) expansion by immunophenotyping is associated with toxicity in diffuse large B-cell lymphoma. 2018 ASH Annual Meeting & Exposition. Abstract 576. Presented December 3, 2018.
11. Lee DW, Gardner R, Porter DL, et al: Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188-195, 2014.
12. Neelapu SS, Tummala S, Kebriaei P, et al: Chimeric antigen receptor T-cell therapy: Assessment and management of toxicities. Nat Rev Clin Oncol 15:47- 62, 2018.
