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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


October 18, 2017 

https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm

Axicabtagene ciloleucel (Yescarta) was the second chimeric antigen receptor (CAR) T-cell therapy approved by the U.S. Food and Drug Administration (FDA); approval was given on October 18, 2017.1 The CD19-directed genetically modified autologous T-cells were approved to treat adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMLCL), high grade B-cell lymphoma, and transformed follicular lymphoma (TFL), after two or more lines of systemic therapy.2 This therapy is not indicated for the treatment of patients with primary central nervous system lymphoma. Tisagenlecleucel (Kymriah), the first FDA-approved CAR T-cell therapy (approved in August 2017), has a similar CD19-directed CAR T-cell construct; however, it is indicated for patients 25 years or younger or treatment of acute lymphoblastic leukemia (ALL).3

To formulate axicabtagene ciloleucel, a patient’s own T-cells are harvested and genetically modified ex vivo by retroviral transduction to express a CAR comprising a murine anti-CD19 single-chain variable fragment (scFv) linked to CD28 and CD3-zeta costimulatory domains.2 The anti-CD19 CAR T-cells are expanded and infused back into the patient, where they can recognize and eliminate CD19-expressing malignant target cells. Patients eligible for axicabtagene ciloleucel have limited treatment options and even lower cure rates.4 This innovative therapy has the potential to fill a much needed gap in one of the most commonly diagnosed hematologic malignancies.5

Following the FDA’s approval, Kite Pharma has been actively working with 30 centers to provide access to axicabtagene ciloleucel and has plans to expand to 70–90 centers nationally.6 A list of authorized centers is available at www.yescarta.com. List price in the United States for axicabtagene ciloleucel is $373,000. Kite is not offering an outcome-based reimbursement contract for Medicare patients not achieving responses 1 month after therapy as Novartis did with tisagenlecleucel.7

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing to 800.FDA.0178 or mailing the postage-paid address form provided online, or by telephoning 800.FDA.1088.

Full prescribing information for axicabtagene ciloleucel is available at https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm.


Pharmacist's Applications to Practice

Axicabtagene Ciloleucel (Yescarta) for Treatment of Adult Patients with Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy

Author: Katie Culos, PharmD BCOP
Adult Stem Cell Transplant Clinical Pharmacist
Vanderbilt University Medical Center
Nashville, TN

What is the potential role for axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma?

  • Approval of this immunotherapy creates a new paradigm in treatment of large B-cell lymphoma, with unprecedented response rates and a true potential for cure. As the authors commented in the ZUMA-1 study, these response rates significantly improve on historical data, like that of patients treated with current salvage regimens (platinum/anthracycline-containing regimens) in the SCHOLAR trial, which reported objective response rate (ORR) of 26% and median overall survival of 6.3 months.2,4
    • To qualify for axicabtagene ciloleucel, patients must have evidence of CD19-positive active disease with adequate organ and bone marrow function, as well as the absence of central nervous system (CNS) involvement, active infection, or inflammatory disorders.2
    • Of note, the clinical trials excluded patients with Eastern Cooperative Oncology Group scores of 2 or greater, CNS involvement, serious infection, or history of allogeneic transplant.2
  • The viability of axicabtagene ciloleucel was first demonstrated in a single-arm open-label phase-1 trial (ZUMA-1) of 7 diffuse large B-cell lymphoma (DLBCL) patients; 5 patients displayed a response to therapy, 3 of these maintained disease control 1 year out.5 The phase-2 portion of ZUMA-1 (n = 101) was conducted in the United States (21 centers) and Israel (1 center) and recruited adult non-Hodgkin lymphoma (NHL) patients with refractory disease or relapse within 1 year of an autologous stem cell transplant (auto-SCT).
    • Prior to cell infusion, all patients received lympho-depleting chemotherapy with 3 days of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 followed by 2 days of rest.
    • Median time from leukapheresis to delivery of the product was 17 days.2
    • The target dose of axicabtagene ciloleucel is 2 × 106 CAR-positive viable T-cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T-cells.
    • Median patient age was 58 years old, 69% received three prior lines of therapy, 21% relapsed after auto-SCT, and 26% had primary refractory disease.
    • The most recent analysis published 1 year out included 108 (phase 1 and 2) patients.
    • Primary end point of ORR = 82% (95% confidence interval [CI], 72–89, p < .001) compared to a historical 20% response rate; complete remission [CR] = 52%.
    • Between subtypes, 70% of primary mediastinal large B-cell lymphoma (PMLCL) + transformed follicular lymphoma (TFL) (n = 24) patients achieved a CR versus 47% of DLBCL (n = 77) patients.
    • Responses were quick (range .8–6 months), and in patients without a CR at 1 month following administration, 23 patients managed to attain a CR without additional therapies. Median duration of response was 11.1 months, and median overall survival has not been reached. Median follow-up was 15.4 months and 42% of patients were reported to be in remission.
    • Toxicity profile is similar to that seen with tisagenlecleucel but did display more frequent cytokine release syndrome (CRS) (93% vs. 79%) and equivalent neurotoxicity (63% vs. 65%).2,8
  • National Comprehensive Cancer Network (NCCN) treatment guidelines for B-cell lymphoma have been recently updated to include axicabtagene ciloleucel as an appropriate third-line treatment option (category 2A) in the approved patient populations.9 Other treatment options in this setting include chemotherapy, auto-hematopoietic cell transplant, radioimmunotherapy, and clinical trial.
  • Clinical evaluation is currently under way to compare this agent in the second-line setting with auto-SCT.10
  • Internationally, axicabtagene ciloleucel has received regulatory support for treatment of DLBCL in the European Union and is currently under review by the European Medicines Agency.6
  • Retreatment with lympho-depleting chemotherapy and axicabtagene ciloleucel was allowed in ZUMA-1 under the following conditions, although a subgroup analysis of patients retreated was not available:
    • Partial response (PR) or CR at the 3-month disease assessment
    • Subsequent disease progression more than 3 months after axicabtagene ciloleucel infusion
    • Sustained CD19 positivity
    • Original study eligibility
    • No subsequent treatment
    • No dose-limiting toxicity from the prior infusion
    • Minimal toxicity with lymphodepleting chemotherapy
    • No known neutralizing antibodies.
  • Novartis is currently conducting an international phase-2 trial of tisagenlecleucel (CTL019) in adult relapsed or refractory DLBCL patients.11 Interim results show 81 patients reporting an ORR of 53.1% (95% CI, 42–64), p < .0001) with 39.5% CR and 13.6% PR.12 Grade 3 or 4 adverse events were reported in 86% of patients, and CRS was reported in 58%; no deaths were attributed to CRS or neurotoxicity.
  • Juno Therapeutics, Inc., also has a CD19-directed construct JCAR017 in development at two dose levels.13 In the DLBCL cohort of 68 patients, the authors reported a best ORR of 75% (CR 56%) and a CRS rate of 30%.

What role can the pharmacist play in the management of patients on axicabtagene ciloleucel?

  • Administration of axicabtagene ciloleucel is a complex process; a true interdisciplinary approach is necessary, with pharmacy serving as a vital component. Because this is a high-cost therapy, extensive financial evaluation must be completed, and the proper infrastructure must be in place before patients are approved for treatment. Logistics for storage, dispensing, and administration may vary per institution; however, they will likely follow previously implemented auto-SCT cell-infusion procedures. Unique to this product (as compared with autologous stem cells) is a National Drug Code number and the potential for a medication label to be applied by pharmacy staff either in the cell-processing lab or at the bedside.
  • To safely monitor and treat patients with CRS and neurologic toxicity, a Yescarta risk evaluation and mitigation strategy (REMS) program has been created, requiring all hospitals and associated clinics to be enrolled in order to dispense the product.14 All relevant staff members must be trained and must successfully complete a Yescarta REMS program knowledge assessment. Patients must also receive a medication guide and patient wallet card and must remain within 2 hours of the certified treatment center for at least 4 weeks following treatment.
  • Ninety-five percent of patients in the phase-2 trial experienced grade-3 toxicity, most commonly fever (85%), neutropenia (84%), and anemia (66%).5 CRS occurred in 93% of patients; however, only 13% reported reactions of grade 3 or greater. Fever, hypoxia, and hypotension were the most common CRS symptoms. Onset of CRS occurred at a median of 2 days (range: 1–12 days) after infusion and lasted 7 days on average (range: 2–58 days). Two patients experienced grade-5 events concurrent with CRS, specifically, hemophagocytic lymphohistiocytosis and cardiac arrest. Neurologic toxicity occurred in 64% of patients with 28% grade 3 or higher. The most common symptoms were encephalopathy, confusional state, and aphasia. Median onset was day 5 (range: 1–17 days), with median resolution 17 days after infusion. Tocilizumab and dexamethasone were administered in 43% and 27% of patients, respectively, without any reported effect on efficacy.
  • Pharmacists have an active role in lympho-depleting chemotherapy (fludaradine and cyclophosphamide) and supportive care medications to manage the common and serious toxicities, such as CRS and neurotoxicity. For the lympho-depleting chemotherapy, mesna is not typically used because of the low cyclophosphamide dose. Axicabtagene ciloleucel prescribing information and NCCN guidelines outline management strategies for CRS and neurotoxicity, including tocilizumab and corticosteroids dosing recommendations.2,12 Outside of treatment of CRS or neurotoxicity, corticosteroids are not recommended because they may have a potential impact on CAR T-cell efficacy.
  • Prior to infusion of axicabtagene ciloleucel, patients receive acetaminophen 650 mg by mouth and diphenhydramine 12.5 mg intravenously or orally.2 On-site inventory and an active order for tocilizumab (minimum of 2 doses) must also be confirmed before cell administration.
  • Axicabtagene ciloleucel is infused without a leuko-depleting filter over 30 minutes by gravity or use of peristaltic pump.2 Central line is preferred for administration. The product is stable at room temperature for 3 hours.
  • Patients are required to be monitored daily for 7 days following infusion for signs and symptoms of CRS and neurotoxicity.2

Clinical Pearls

  • Axicabtagene ciloleucel cell levels peaked 2 weeks after infusion and remained present in most patients 180 days after infusion.2 Response and neurologic toxicity was associated with CAR T-cell expansion and peak area under the curve; however, CRS was not.
  • Several biomarkers were also associated with CRS or neurotoxicity.15 Grade 3 or higher neurologic events were significantly associated with interleukin-2, ferritin, and myeloid growth factor.
  • Additional information presented at the Annual American Society of Hematology Meeting and Exposition in December 2017 shed light on response and durability characteristics.16 In patients who did not respond or who relapsed, 30% presented with CD19-negative disease, and more than 60% of those for whom treatment was unsuccessful showed tumor presence of PD-L1. Studies are under way to further investigate these treatment barriers.
  • Prolonged cytopenias can develop in patients during and after CAR T-cell therapy.2 Patients may be supported with myeloid growth factor until neutrophils stabilize. By contrast, prescribing information for tisagenlecleucel does not recommend use of myeloid growth factor during the first 3 weeks after infusion or until CRS is resolved. Prophylactic anti-infectives are also administered at many centers during neutropenic periods, with escalation to empiric intravenous antibiotics if febrile neutropenia presents.
  • Hypogammaglobinemia occurred in 15% of patients.2 Routine monitoring of immunoglobulin levels is recommended with supplementation of less than 400 mg/dl.
  • Seizures are a rare but serious neurotoxicity reported with CAR T-cell therapy and have occurred with axicabtagene ciloleucel.2 Prophylaxis with an agent such as levetiracetam is a common practice; however, dose and duration may be institution specific.
  • Depending on disease burden prior to therapy, patients could be at risk for tumor lysis syndrome (TLS). Evaluation of TLS parameters and initiation of prophylactic allopurinol may be considered as a conservative measure.

 

References

  1. U.S. Food and Drug Administration. Approved Cellular and Gene Therapy Products: Yescarta (axicabtagene ciloleucel). October 18, 2017. Available at https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm. Accessed December 14, 2017.
  2. Yescarta (axicabtagene ciloleucel) [package insert]. Santa Monica, CA: Kita Pharma; October 2017.
  3. U.S. Food and Drug Administration. Approved Cellular and Gene Therapy Products: Kymriah (tisagenlecleucel). September 27, 2017. Available at https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm. Accessed December 14, 2017.
  4. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800-1808.
  5. 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;377:2531-2544.
  6. Yahoo Finance. Kite’s Yescarta™ (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy. Available at https://finance.yahoo.com/news/kite-yescarta-axicabtagene-ciloleucel-becomes-214300935.html. Accessed December 19, 2017.
  7. Pharma Intelligence. Novartis Begins CAR-T Payment Experiments With Outcomes-Based Contract With CMS. Available at https://pharmaintelligence.informa.com/resources/product-content/car-t-payment-experiments-with-outcomes-based-contract Accessed December 19, 2017.
  8. Kymriah [package insert]. East Hanover, NJ: Novartis Pharmaceutical, Inc.; 2017.
  9. National Comprehensive Cancer Network. B-cell Lymphomas. Version 7.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf . Accessed December 19, 2017.
  10. Kite Pharma. Kite Pharma Details KTE-C19 Launch Preparedness and Near-Term, Next Generation CAR/TCR Product Candidates at Investor Day. Available at http://ir.kitepharma.com/releasedetail.cfm?ReleaseID=994338. Accessed December 19, 2017.
  11. ClinicalTrials.gov. Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET). Available at https://clinicaltrials.gov/ct2/show/NCT02445248. Accessed December 19, 2017.
  12. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-Cell lymphoma [abstract]. Annual American Society of Hematology Meeting and Exposition, Atlanta, GA, December 9–12, 2017. Abstract 577.
  13. Abramson JS, Palomba ML, Gordon LI, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort [abstract]. Annual American Society of Hematology Meeting and Exposition. Atlanta, GA, December 9–12, 2017. Abstract 581.
  14. Yescarta (axicabtagene ciloleucel) Risk Evaluation and Mitigation Strategy. Available at https://www.yescartarems.com/. Accessed December 19, 2017.
  15. 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;375:2321-2334. https://www.nejm.org/doi/full/10.1056/NEJMoa1707447. doi:10.1056/NEJMoa1707447. Suppl. [Epub ahead of print].
  16. American Society of Hematology. CAR T-Cell Therapies Drive Outcomes in Lymphoma, Myeloma: Treatments Hold Promise for People with Hard-to-Treat Blood Cancers. Available at www.hematology.org/Newsroom/Press-Releases/2017/8062.aspx. Accessed December 19, 2017.

 

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