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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


May 1, 2018–Tisagenlecleucel (KYMRIAH™, Novartis Pharmaceuticals Corp.) a CD19-directed genetically modified autologous T-cell immunotherapy, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.(With Pharmacist's Application to Practice)

August 30, 2017–Tisagenlecleucel (KYMRIAH®, Novartis Pharmaceuticals Corp.) for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.(With Pharmacist's Application to Practice)


May 1, 2018 with PAP

KYMRIAH Package Insert

On May 1, 2018, the Food and Drug Administration approved tisagenlecleucel (KYMRIAH™, Novartis Pharmaceuticals Corp.) a CD19-directed genetically modified autologous T-cell immunotherapy, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

Approval was based on a single-arm, open-label, multi-center, phase 2 trial (JULIET, NCT02445248) in adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma. Eligible patients must have been treated with at least two prior lines of therapy, including an anthracycline and rituximab, or relapsed following autologous hematopoietic stem cell transplant. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy.

The overall response rate (ORR) as assessed by an independent review committee for the 68 evaluable patients was 50% (95% CI: 37.6, 62.4) with a complete response (CR) rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response (DOR) was longer in patients with a best overall response of CR, as compared to a best overall response of partial response (PR). Among patients achieving CR, the estimated median DOR was not reached (95% CI: 10.0 months, not estimable [NE]). The estimated median response duration among patients in PR was 3.4 months (95% CI: 1.0, NE).

The most common adverse reactions (incidence >20%) in patients on the trial were cytokine release syndrome (CRS), infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. Because of the serious risks of CRS and neurologic toxicities, FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy.

The recommended dose of tisagenlecleucel for relapsed or refractory adult DLBCL is 0.6 to 6.0 x 108 CAR-positive viable T cells. Tisagenlecleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.

Full prescribing information is available at: KYMRIAH Package Insert

FDA granted this application priority review, breakthrough therapy designation, and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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 or by calling (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Tisagenlecleucel for Adult Patients with Relapsed or Refractory Large B-Cell Lymphoma

Author: Christina Bachmeier, PharmD BCOP
Clinical Pharmacist, Cellular Immunotherapy
Moffitt Cancer Center
Tampa, FL

What is the potential role for tisagenlecleucel in the treatment of relapsed or refractory large B-cell lymphoma?1-9

  • Tisagenlecleucel was approved by the U.S. Food and Drug Administration (FDA) on May 1, 2018, for adult patients with relapsed or refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after the patients had received two or more lines of systemic therapy.
  • Use in treating large B-cell lymphomas is the second indication for the chimeric antigen receptor (CAR) T-cell product tisagenlecleucel. This CD19-directed autologous T-cell therapy was originally approved in August 2017 for the treatment of pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). It was the first CAR T-cell product to receive approval by the FDA and is now the first CAR T-cell product with two different disease indications.
  • Axicabtagene ciloleucel was the first CAR T-cell product approved for relapsed or refractory large B-cell lymphoma on October 18, 2017. In addition to approval for treating DLBCL, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, axicabtagene ciloleucel is approved for treating primary mediastinal large B-cell lymphoma.
  • The preliminary results (as of December 2017) of the phase-2 single-arm open-label international JULIET trial (N = 81) demonstrated an overall response rate (ORR) of 53% with tisagenlecleucel in adult patients with relapsed or refractory DLBCL. This included 39.5% who achieved a complete response (CR) and 13.6% who had a partial response (PR). These rates were 30% and 7% for patients evaluable at 6 months, respectively. At 6 months the probability of being relapse free was 74%, and the overall survival rate was 65%. Median overall survival has not been reached. No patients proceeded to hematopoietic stem cell transplant (HSCT) while in a complete response.
    • Eligible patients received two or more lines of prior chemotherapy with disease progression or failure to respond to chemotherapy, had progressive disease after autologous HSCT, or were ineligible for autologous HSCT. Key exclusion criteria include prior anti-CD19 therapy or active central nervous system (CNS) involvement.
    • In contrast to the clinical trial leading to FDA approval of axicabtagene ciloleucel, bridging chemotherapy between apheresis and the start of lymphodepletion was permitted in the JULIET trial; 90% of patients received bridging.
    • Lympho-depleting chemotherapy prior to tisagenlecleucel included fludarabine 25 mg/m2 given intravenously (IV) and cyclophosphamide 250 mg/m2 IV daily for 3 days, followed by 2 rest days prior to CAR T infusion. Fludarabine and cyclophosphamide doses used for lymphodepletion were lower than doses used prior to axicabtagene ciloleucel. An alternate lymphodepletion option includes bendamustine 90 mg/m2 IV daily for 2 days in patients who experienced prior grade-4 hemorrhagic cystitis or resistance to a previous cyclophosphamide-containing regimen. Lymphodepletion may be omitted if the patient’s white blood cell count is less than 1 x 109/L within 1 week of tisagenlecleucel infusion. In the trial, 93% of patients received lymphodepletion.
    • Twenty-six patients received the cell infusion as outpatients; of these 20 remained outpatients for 3 or more days after the infusion.
    • The package insert for tisagenlecleucel reports the results of only 68 patients evaluable for efficacy. Twenty-four patients were removed from the analysis for one of three reasons: no re-baseline scans following bridging chemotherapy and tisagenlecleucel infusion (n = 15), no evidence of disease at re-baseline (n = 8), or misclassification of a neuroendocrine tumor as DLBCL (n = 1). ORR for the nonexcluded patients was 50%, including 32% in CR and 18% in PR. Median duration or response has not yet been reached.
  • The National Comprehensive Cancer Network (NCCN) treatment guidelines for B-cell lymphoma were updated to include tisagenlecleucel as a third-line treatment option for the FDA-approved indications.
  • Tisagenlecleucel and axicabtagene ciloleucel have not been compared in a clinical trial for efficacy or safety. Both products are CD19-directed CAR T-cell products; however, they are composed of different costimulatory domains. Tisagenlecleucel contains 4-1BB, and axicabtagene ciloleucel, CD28. In general, the CD28-based CAR T-cell construct exhibits a greater peak expansion, whereas CAR T cells using 4-1BB costimulation show greater longevity (persistence); however, further data are needed to confirm these findings and to determine whether the costimulatory domain used has an impact on clinical outcomes.
  • The tisagenlecleucel turnaround time for CAR T production is 22 days, in contrast to a 17-day median turnaround time with axicabtagene ciloleucel. In addition, on the JULIET trial, 11 of 160 patients did not receive tisagenlecleucel because of a manufacturing failure. Axicabtagene ciloleucel was successfully manufactured for 99% of patients on ZUMA-1.
  Overall Response Rate Last Follow-Up Overall Survival Cytokine Release Syndrome Neurotoxicity
Tisagenlecleucel 50%
CR 32%
PR 18%
6 months,
CR 30%
6 months,
64.5%
Any grade, 74%;
Grade>3, 23%
Any grade, 58%;
Grade>3, 18%
Axicabtagene ciloleucel 82%
CR 58%
PR 24%
15.4
months,
CR 40%
6 months, 78%;
12 months, 59%;
18 months, 52%
Any grade, 94%;
Grade>3, 13%
Any grade, 64%;
Grade>3,
28%

 

  • Rates of efficacy and safety are similar for tisagenlecleucel and axicabtagene ciloleucel in large B-cell lymphoma. Comparisons across the clinical trials, especially the differences in toxicity grading and management, should be interpreted with caution because of trial variability.

What role can the pharmacist play in the management of patients on tisagenlecleucel?1-3,10-14

  • Because of the black-box warning for cytokine release syndrome (CRS) and neurological toxicities, tisagenlecleucel is available only through a risk evaluation and mitigation strategy (REMS) program. This practice is consistent with the use of tisagenlecleucel for the previous indication, ALL, and the use of axicabtagene ciloleucel.
  • Pharmacists can play an active role in recognizing and managing CRS and neurotoxicity. In addition, pharmacists can contribute to the accurate assessment and grading of these toxicities and help ensure that the management is correct based on toxicity grade. CRS is graded differently depending on the CAR T-cell product (tisagenlecleucel vs. axicabtagene ciloleucel). Pharmacists can help in the dosing and appropriate use of tocilizumab and corticosteroid treatment.
  • Consistent with the use of the medication in ALL, the most common adverse effect is CRS, with 74% of patients experiencing the syndrome and 23% encountering grade 3 or higher CRS (according to the Penn Grading Scale) during the JULIET study. For the treatment of CRS, 21% of patients received tocilizumab or corticosteroids, 6% received a single dose of tocilizumab, 13% received two doses of tocilizumab, and 13% received corticosteroids in addition to tocilizumab. The median time to onset of CRS was 3 days (range, 1–51 days), with a median time to resolution of 8 days (range, 1–36 days).
  • Fifty-eight percent of patients had neurological toxicities, with 18% grade 3 or higher; this rate is similar to those seen with tisagenlecleucel use in ALL (72%, all grades; 21%, grade 3 or higher). The most common neurological toxicities were headache (21%) and encephalopathy (16%; 11%, grade 3 or higher). No patients experienced cerebral edema. The median duration of neurotoxicity was 14 days.
  • In contrast to recommendations for axicabtagene ciloleucel, no treatment (including corticosteroids) is recommended for neurotoxicity related to tisagenlecleucel. Supportive care alone is recommended. Examples of supportive care include, but are not limited to, aspiration precautions, intravenous hydration, converting oral medications to IV, and avoidance of sedating medications.
  • Tisagenlecleucel is provided as a single infusion containing 0.6–6 x 108 CAR-positive viable T cells. The infusion bag volume ranges from 10 to 50 ml, and the dose may be contained in up to three cryopreserved bags. As part of the REMS program, a minimum of two doses of tocilizumab are required to be on site for each patient within 2 hours of the infusion if needed for the treatment of CRS. Premedication with acetaminophen and diphenhydramine (or an alternate H1-antihistamine) should be administered 30-60 min prior to infusion. Corticosteroids should be avoided starting the first day of lymphodepletion chemotherapy except in the treatment of life-threatening adverse events.

Clinical Pearls1,3,11,12

  • Patients with an Eastern Cooperative Oncology Group performance status greater than 2, CNS involvement, or serious infections were excluded from the clinical trial. Clinical judgment should be used in selecting patients for tisagenlecleucel treatment.
  • Tisagenlecleucel should be infused 2–11 days after completion of lymphodepletion chemotherapy.
  • In the clinical trial leading to the approval of axicabtagene ciloleucel, ZUMA-1, the Lee criteria were used for grading CRS. In the JULIET study of tisagenlecleucel in a similar patient population, the UPenn criteria were utilized. Rates of CRS cannot be directly compared because of differences in the grading systems.
  • Prolonged cytopenias have been observed for several weeks following lymphodepletion and tisagenlecleucel infusion. In the JULIET study, 40% of patients experienced thrombocytopenia, and 25% had neutropenia that had not resolved by day 28. Administration of myeloid growth factors, especially granulocyte macrophage colony–stimulating factor, is not recommended for 3 weeks following tisagenlecleucel infusion or before CRS has resolved. This statement is included in the labeling for tisagenlecleucel; however, it is not in the labeling for axicabtagene ciloleucel.
  • Hypogammaglobulinemia, an on-target off-tumor effect, occurred in 14% of patients. There is no current standard for intravenous immune globulin replacement. Immunoglobulin levels should be monitored and replaced according to institution guidelines.

References

  1. Kymriah (tisagenlecleucel) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; May 2018.
  2. Yescarta (axicabtagene ciloleucel) [package insert]. Santa Monica, CA: Kita Pharma; October 2017.
  3. 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. Blood. 2017;130(suppl 1):577.
  4. ClinicalTrials.gov. Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET). Available at https://clinicaltrials.gov/ct2/show/NCT02445248. Accessed May 24, 2018.
  5. U.S. Food and Drug Administration. Approved products: Kymriah (tisagenlecleucel). May 7, 2018. Available at https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm. Accessed May 25, 2018.
  6. National Comprehensive Cancer Network. B-Cell Lymphomas. Version 4.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed May 25, 2018.
  7. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822–1826.
  8. van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14:499–509.
  9. 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.
  10. Kymriah (tisagenlecleucel): Risk Evaluation and Mitigation Strategy. Available at http://www.kymriah-rems.com. Accessed May 25, 2018.
  11. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–195.
  12. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139.
  13. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-448.
  14. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47-62.

August 30, 2017 with PAP

https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf

On August 30, 2017, the U.S. Food and Drug Administration granted regular approval to tisagenlecleucel (KYMRIAH®, Novartis Pharmaceuticals Corp.) for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Tisagenlecleucel is the first chimeric antigen receptor (CAR) T-cell immunotherapy approved by the FDA. Tisagenlecleucel consists of autologous T cells collected in a leukapheresis procedure that are genetically modified with a new gene containing a CAR protein allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.

Approval of tisagenlecleucel was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had a prior hematopoietic stem-cell transplantation. Patients received a single dose of tisagenlecleucel intravenously within 2 to 14 days following the completion of lymphodepleting chemotherapy. Of the 63 patients who were evaluable for efficacy, the confirmed overall remission rate as assessed by independent central review was 82.5% (95% CI 70.9, 91.0), consisting of 63% of patients with complete remission (CR) and 19% with complete remission with incomplete hematological recovery (CRi). All patients with a confirmed CR or CRi were minimal residual disease negative by flow cytometry. Median remission duration was not reached (range: 1.2 to 14.1+ months).

The most common adverse reactions (incidence greater than 20%) are cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. Grade 3 or 4 adverse events were noted in 84% of patients.

Serious adverse reactions such as CRS, including fatal CRS and CRS-associated disseminated intravascular coagulation with intracranial hemorrhage, prolonged cytopenia, infection, cardiac failure, and cardiac arrest occurred in patients receiving tisagenlecleucel. FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy.

The recommended tisagenlecleucel dose is one infusion of 0.2 to 5.0 x 106 (CAR)-positive viable T cells per kg body weight intravenously for patients who are ≤ 50 kg, and 0.1 to 2.5 x 108 total CAR-positive viable T cells intravenously for patients who are > 50 kg, administered 2 to 14 days after lymphodepleting chemotherapy.

Full prescribing information for tisagenlecleucel is available at:
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf

The FDA also approved today tocilizumab (ACTEMRA®, Genentech Inc.) for the treatment of patients 2 years of age or older with cytokine release syndrome (CRS) that occurs with CAR T-cell therapy. In an analysis of data from clinical trials of CAR-T cells, 69% of patients with severe or life-threatening CRS had resolution of CRS within 2 weeks following one or two doses of tocilizumab.

Full prescribing information for tocilizumab is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125276s114lbl.pdf

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 http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Tisagenlecleucel for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Author: Alison M. Gulbis, PharmD BCOP
Manager, Clinical Pharmacy Services
Clinical Pharmacy Specialist, Stem Cell Transplant
University of Texas MD Anderson Cancer Center
Houston, TX

What is the potential role for tisagenlecleucel in the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL)?1-7

  • On August 30, 2017, the U.S. Food and Drug Administration (FDA) approved the first gene therapy in the United States.
  • Tisagenlecleucel (CTL019) is an autologous T-cell therapy that is genetically modified to treat patients up to 25 years of age with B-cell ALL who have refractory disease or who failed 2 lines or more of therapy.
    • In the pivotal open-label multicenter single-arm phase-2 study (ELIANA) with tisagenlecleucel, efficacy was established on the basis of a complete response (CR) within 3 months of infusion.
      • Key inclusion criteria for patients in the study were these: age 3–21 years at the time of initial diagnosis, bone marrow lymphoblasts 5% or greater, adequate organ function, ineligibility for stem cell transplant (SCT), a second or greater bone marrow relapse at least 6 months after SCT (if applicable), CD19 tumor expression demonstrated within 3 months of the study, or failure to achieve a CR after two cycles of standard chemotherapy or, if the patient was Philadelphia chromosome positive, failure of two lines of tyrosine kinase inhibitors (TKIs) or contraindication to TKIs.
      • Excluded were patients with active central nervous system disease (CNS-3), isolated extramedullary relapse, active grade 2 to 4 graft-versus-host disease, concomitant genetic syndrome(s), active hepatitis B, or active hepatitis C; those who were human immunodeficiency virus (HIV) positive; pregnant or nursing women; and those who had received prior gene therapy.
      • The median patient age in the ELIANA study was 12 years, and 59% of patients had received a prior allogeneic SCT.
      • Of the 63 patients included in the efficacy evaluation, 83% achieved CR or a CR with incomplete count recovery (CRi), and all these patients had minimal residual disease (MRD)-negative bone marrow. At 4.8 months (median), 52 patients were evaluable for duration of remission (CR/Cri), and the median duration was not reached.
      • At 6 months after remission onset, the relapse-free probability was 75%. Survival probability at 6 months and 12 months was 89% and 79% respectively.
      • Of the responders, 13% went onto an allogeneic SCT within 6 months of remission.
    • In the ENSIGN study, which had similar inclusion and exclusion criteria, of the 29 patients who were infused with tisagenlecleucel, 69% had a CR or CRi at 6 months, and 62% were MRD negative.
  • CR rates for blinatumomab or inotuzumab ozogamicin were 43% within the first two cycles for blinatumomab in the TOWER trial and 81% (CR or CRi) for inotuzumab ozogamicin in the INOVATE-ALL trial, compared to the 83% reported for tisagenlecleucel at 3 months in the ELIANA study and 69% at 6 months in the ENSIGN study.

What role can the pharmacist play in the management of patients on tisagenlecleucel?2,8-10

  • Prior to receiving tisagenlecleucel, patients receive chemotherapy aimed at depleting T-lymphocytes, which should consist of fludarabine and cyclophosphamide.
  • Given the range of serious or life-threatening adverse effects that tisagenlecleucel can produce, pharmacists should be aware of how to identify and manage cytokine release syndrome (CRS) and neurotoxicity. A risk evaluation and mitigation strategy (REMS) is in place, requiring that those who order, dispense, and administer tisagenlecleucel be trained to recognize indications and manage toxicity.
    • In clinical trials, any grade of CRS (Penn grading scale) occurred in 79% of patients, and grade 3 or 4 CRS occurred in 49% of patients.
    • Patients at higher risk for severe CRS include those with high tumor burden, active infection, early onset of fever, and an inflammatory process.
    • Symptoms of CRS can be mild, moderate, or severe and life-threatening but are self-limiting with tisagenlecleucel.
    • CRS can manifest anytime from day 1 of the infusion of tisagenlecleucel until day 22 (median 3 days) and presents as high fever, hypotension, or organ toxicity (renal, pulmonary, hepatic, cardiac, or coagulopathy).
    • The interleukin-6 (IL-6) antagonist tocilizumab was granted expanded FDA approval for the management of severe or life-threatening CRS with tisagenlecleucel. It must be available on site for immediate use (2 doses per patient) in the event that a patient experiences CRS.
      • In the pivotal study, 50% of the patients who developed CRS received tocilizumab.
      • Tocilizumab does not require premedication.
    • Neurotoxicity was observed in 44% of patients (headache excluded), with grade 3 or 4 neurologic toxicities occurring in 18% of patients.           
      • Neurotoxicity occurred up to 8 weeks after administration of tisagenlecleucel and was observed early (with CRS), was delayed (when CRS was resolving), or occurred in the absence of CRS. Most of the neurologic events were transient.
      • Tocilizumab is not effective for isolated neurotoxicity.
      • In patients presenting with signs or symptoms of neurologic toxicity, a neurological workup should be performed, and supportive care should be given for tisagenlecleucel neurologic toxicity.
  • According to the REMS requirement, patients must be provided education regarding the signs and symptoms of CRS and neurotoxicity.
    • Patients should be educated to stay within 2 hours of the center that administered the tisagenlecleucel for up to 4 weeks and to return promptly if fever or other toxicities arise.
    • Patients should be educated not to drive or operate heavy machinery for up to 8 weeks after receiving tisagenlecleucel because of its neurologic effects.
    • Any patient who receives tisagenlecleucel should be provided a wallet card indicating this; the card should be shown to any healthcare provider who sees the patient or to hospital staff if the patient goes to the hospital.
  • Corticosteroids can be given in life-threatening emergencies but should not be used for premedication of tisagenlecleucel or after the infusion of tisagenlecleucel (duration not defined). Corticosteroids in doses used for physiologic dosing, as in adrenal insufficiency, are appropriate.
    • Corticosteroids can be given for resistant CRS that does not respond within 12–18 hours of administration of supportive modalities or tocilizumab.

Clinical Pearls11-13

  • Tisagenlecleucel is available only at certain treatment centers in the United States. Currently 31 centers are identified as select treatment centers, but only 13 are currently certified to treat patients. This number will likely increase.
  • Tisagenlecleucel is provided by the manufacturer as a patient-specific single-dose unit that contains up to 2.5 x 108 CAR-positive viable T-cells. Two possible dosage ranges will be prepared, depending on the patient’s weight at the time leukapheresis is performed to collect the cells.
    • For patients weighing 50 kg or more: administer .2 to 5 x 106 CAR-positive T-cells per kg.
    • For patients weighing more than 50 kg: administer .1 to 2.5 x 108 CAR-positive T-cells
    • A certificate of analysis for the actual “dose” of CAR-positive viable T-cells will accompany the product for each patient.
  • The tisagenlecleucel dose should be premedicated with acetaminophen and diphenhydramine (or another antihistamine) 30–60 minutes prior to the infusion.
  • Tisagenlecleucel should be infused within 30 minutes after it has thawed and is at room temperature. A leukocyte-depleting filter should not be used.
  • Avoid myeloid growth factors, especially granulocyte macrophage colony–stimulating factor, during the first 3 weeks after tisagenlecleucel infusion or until resolution of CRS.
  • C-reactive protein, a surrogate for IL-6 activity, and ferritin are associated with CRS but cannot predict the development of severe CRS.
  • B-cell aplasia can persist for up to 1 year after the patient has received tisagenlecleucel; patients may therefore be at increased risk for infection and may require intravenous immunoglobulin.
  • Tisagenlecleucel can cause a false-positive human immunodeficiency virus test because it is genetically modified using a lentiviral vector.
  • Data are lacking regarding the length of time that contraception should be used by males or females of reproductive potential after tisagenlecleucel infusion. Because there is a risk of transduced cells crossing the placenta, which may result in B-cell lymphopenia, pregnancies occurring after tisagenlecleucel infusion should be reported to Novartis Pharmaceuticals Corporation at 1.888.669.6682.

References

  1. 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 October 14, 2017.
  2. Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): update to the interim analysis [abstract]. European Hematology Association Annual Meeting Abstracts 2017; Abstract S476.
  3. ClinicalTrials.gov. Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL (ELIANA). Available at https://clinicaltrials.gov/ct2/show/NCT02435849. Accessed October 24, 2017.
  4. Maude SL, Pulphisher MA, Boyer MW, et al. Efficacy and safety of CTL019 in the first US phase II multicenter trial in pediatric relapsed/refractory acute lymphoblastic leukemia: results of an interim analysis. [Abstract]. American Society of Hematology meeting abstract. Blood. 2016;128:2801.
  5. ClinicalTrials.gov. Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients. Available at https://clinicaltrials.gov/ct2/show/NCT02228096. Accessed October 24, 2017.
  6. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836-847.
  7. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-753.
  8. National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia. Version 5.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed November 7, 2017.
  9. Kymriah (tisagenlecleucel) [package insert]. Novartis Pharmaceuticals Corp. East Hanover, NJ. August 2017.
  10. Kymriah (tisagenlecleucel): Risk Evaluation and Mitigation Strategy. Available at http://www.kymriah-rems.com/. Accessed October 14, 2017.
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