For:
Pediatric and Young Adult B-cell ALL
Important Safety Information


WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

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Indication
KYMRIAH is a CD19‑directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B‑cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Efficacy

KYMRIAH attained and sustained remission in the majority of patients

A potentially definitive treatment

Pivotal Trial Design

ELIANA was a global phase 2 pivotal trial to evaluate the efficacy and safety of KYMRIAH® (tisagenlecleucel) in patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL).1 The Prescribing Information reports the interim analysis, which formed the basis for FDA approval of KYMRIAH and was based on 68 infused patients, of whom 63 were evaluable for response at 3 months.2 Since the approval of KYMRIAH in 2017, an updated analysis with longer-term data has been published.

  • The updated analysis is based on 75 infused patients, all of whom were evaluable for response at 3 months3
    • Enrolled patients were between 3 and 23 years of age (median age, 11 years)
    • 8% of participants had primary refractory disease4
    • Patients received a median of 3 prior therapies, with 53% having received 1 stem cell transplant (SCT) and 8% having received 2 SCTs3
    • Median time from most recent relapse to KYMRIAH infusion was 3.5 months3

Primary end point: Overall remission rate (ORR)* within 3 months postinfusion.

*The trial required remission status to be maintained for at least 28 days without clinical evidence of relapse.1

Overall Remission Rate

~8 of 10 patients achieved minimal residual disease negative (MRD–) remission at 3 months after treatment with KYMRIAH.1,2 MRD– status is a strong marker for positive prognosis.5


ORR AT 3 MONTHS

100‭% ‭MRD–‬‬‬‬

  • All patients in remission were MRD– ‭in both the interim analysis (n=52) and the ‭updated analysis (n=61)1,2‬‬‬‬‬‬‬

Day 28 Assessment1,2,6‬‬‬‬‬‬

  • ≥95% ‭of responders achieved MRD– remission by Day 28 ‭assessmentǁ‭ in both the interim analysis (n=52) and the ‭updated analysis (n=61)‬‬‬‬‬‬‬‬‬‬‬‬‬

MRD– was defined as MRD by flow cytometry <0.01%.2

ORR consisted of complete remission (CR) and complete remission with incomplete blood count recovery (CRi, defined as less than 5% of blasts in the bone marrow, no evidence of extramedullary disease, and without full recovery of peripheral blood counts with or without blood transfusion). Remission status was required to be maintained for at least 28 days without clinical evidence of relapse.2

§Five patients who were infused with KYMRIAH were excluded from the efficacy set in the interim analysis. The efficacy analysis set (n=63) is a subset of the full analysis set (N=68), which consisted of all patients treated with KYMRIAH at least 3 months prior to data cutoff.2,6

ǁDay 28 assessment initially defined as ±7 days; definition changed to ±4 days after 1 site was enrolled, 3 patients were enrolled, and 1 patient was treated.3

Remission Was Achievable With KYMRIAH Regardless of Patients’ Clinical Characteristics3,6

 NR, not reported.

§Five patients who were infused with KYMRIAH were excluded from the efficacy set in the interim analysis. The efficacy analysis set (n=63) is a subset of the full analysis set (N=68), which consisted of all patients treated with KYMRIAH at least 3 months prior to data cutoff.2,6

The area of each box is proportional to the number of patients in the particular grouping. The 95% CIs are exact Clopper-Pearson CIs calculated for each subgroup.6

#Includes 8 patients categorized with chemorefractory disease at study entry.6

DOR and OS

Durable Remission1,2

The median duration of CR/CRi among the responders was not reached in both the updated analysis (n=61) and the interim analysis (n=52).

  • Updated analysis median follow-up: 7.5 months from response (maximum 19.3 months)
  • Interim analysis median follow-up: 4.8 months from response (range: 1.2 to 14.1+ months)

DURATION OF REMISSION** (UPDATED ANALYSIS [n=61/75])1,3

**DOR was defined as time since onset of CR or CRi to relapse or death due to underlying cancer, whichever is earlier, censoring for new cancer therapy including SCT.2

Interim Analysis (n=52/63)6

  • 75% of responders estimated to still be in remission at 6 months
  • 64% of responders estimated to still be in remission at 9 and 12 months


KYMRIAH Persistence Based on Pharmacokinetics2

KYMRIAH was present in the blood and bone marrow, and was measurable beyond 2 years.


OVERALL SURVIVAL (OS, UPDATED ANALYSIS [N=75])1,3,4

  • 76% estimated OS of infused patients at 12 months3
  • OS was a secondary efficacy end point of the global phase 2 pivotal trial3
  • OS data are not in the Prescribing Information and should be interpreted with caution in a single-arm trial. The statistical significance of OS is not known
  • Transplant does not appear to improve the estimated OS4
  • 87% of responders did not proceed to SCT at a median follow-up of 13.1 months after KYMRIAH infusion to data cutoff1
  • Median follow-up for OS: 10.5 months3

 NE, not evaluable.

Patient-Reported QOL

KYMRIAH led to a decrease in severity of problems related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression at Months 3 and 6 compared with Baseline as assessed via the EQ-5D questionnaire.3


Quality of Life (QOL) Improvements Were Observed as Early as 3 Months After KYMRIAH Infusion3,a

aPatient-reported outcome results are mean values from patients ≥8 years of age who achieved CR or CRi during 3 months (n=48). Population at each time point is the number of patients with nonmissing score at that time point.3

  • The QOL study is not part of the Prescribing Information. The PedsQL, EQ VAS, and EQ-5D models were evaluated and validated in a patient population other than pediatric ALL, N values decreased over time, and the study’s statistical significance was not evaluated, and therefore should be interpreted cautiously

Pedi-CART19 (CHP 959) Supportive Trial

A supportive, proof-of-concept study of CTL019

Supporting Trial: CHP 959

CHP 959 was a single-site, phase 1/2, supportive, proof-of-concept study of CTL019 (N=62) initiated in 2012.9 These data were not included in the KYMRIAH Prescribing Information.

  • CHP 959 comprised 3 cohorts:
    • 56 patients with non–CNS3 ALL
    • 4 patients with CNS3 ALL
    • 2 patients with lymphoma
  • All the patients infused in this trial received product manufactured by the University of Pennsylvania
  • Enrolled patients between 1 and 24 years of age (median, 11 years) (n=56 non–CNS3 ALL)
  • 95% of participants had relapsed disease; 5% were refractory to initial therapy
  • 89% of patients received ≥3 prior regimens; 64% received prior SCT
  • 57% of patients had high baseline disease burden (≥5% blasts) (n=56 non–CNS3 ALL)

Primary end point: Safety, feasibility, and duration of CAR-T cells in vivo.††
Secondary end point: Anti-tumor activity, including10:

  • Day 28 overall response rate (CR + CRi)
  • DOR (from the date of CR/CRi to relapse or death due to underlying cancer)

  CNS, central nervous system.

††Determined via reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of whole blood.9

  • There were some differences noted between this study and the pivotal ELIANA study and results should be interpreted with caution

DURATION OF REMISSION (N=56 non–CNS3 ALL)9

Patients Responded to Treatment With CTL019, Across Disease Characteristics11

  • Data presented here are based on a different analysis of CHP 959 with a population of 60 patients


REMISSION RATES BY BASELINE DISEASE BURDEN (N=60)11

  CR, complete response.

‡‡<0.01% MRD by flow cytometry.11

 

CNS INVOLVEMENT (N=60)11

CNS status at infusionPatients, n (%)
CNS1 54 (90)
CNS2§§ 4 (7)
CNS3ǁǁ 2 (3)
CNS3ǁǁ within 12 months of infusion 16 (27)

Remission Rates11

  • 83% of patients with CNS2 or CNS3 status at infusion (n=5/6) achieved CNS remission
  • 73% of evaluable patients with prior CNS disease (n=11/15) achieved continuous remission as long as 2.5 years
  • No CNS relapses in entire cohort (N=60), with 4 bone marrow relapses in CNS cohort (n=15) at time of analysis
  • Experience with KYMRIAH in patients with active CNS leukemia is limited and these data should be interpreted with caution

Persistence Based on Pharmacokinetics11

  • 98% of all patients treated had detectable levels of CTL019 in cerebrospinal fluid (CSF), with lumbar puncture showing detectable CTL019 at 1 year

§§CNS2 status defined as blast cells detected in a sample with <5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.12

ǁǁCNS3 status defined as blast cells detected in a sample with ≥5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.12

 

See Adverse Reactions for safety information from the CHP 959 trial.

 

References: 1. 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(5):439-448 2. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 3. Data on file. Study CTL019B2202. Novartis Pharmaceuticals Corp; Sept 2017. 4. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia [online supplemental appendix]. N Engl J Med. 2018;378(5):439-448. 5. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126(8):964-971. 6. Data on file. Study CTL019B. Novartis Pharmaceuticals Corp; Feb 2017. 7. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL™* 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3(6):329-341. 8. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5:70. 9. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Sept 2017. 10. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Dec 2016. 11. Maude SL, Teachey DT, Rheingold SR, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. Presented at: ASCO Annual Meeting; May 2016; Chicago, IL. 12. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.

Indication

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B‑cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Important Safety Information for KYMRIAH® (tisagenlecleucel)

WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids
  • Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed
  • KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS


Warnings and Precautions

Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 54 (79%) of the 68 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 33 (49%) of patients. The median time to onset of CRS in KYMRIAH trials was 3 days (range: 1-51), and in only 2 patients was onset after Day 10. The median time to resolution was 8 days (range: 1-36).

Of the 54 patients with r/r ALL who had CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (eg, methylprednisolone).

Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (96%), hypotension (67%), hypoxia (20%), and tachycardia (30%). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.

Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.

Ensure that 2 doses of tocilizumab are available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS 2 to 3 times during the first week, then for at least 4 weeks after treatment. Counsel patients to remain within proximity of the health care facility for at least 4 weeks following infusion and seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated.

Risk factors for severe CRS are high pre-infusion tumor burden (≥50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 21% of patients. Among patients who had a neurological toxicity, 88% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days (range: 1-359) from infusion, and the median duration was 6 days for patients with r/r ALL. The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

The most common neurological toxicities observed in r/r ALL studies included headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), sleep disorders (10%), dizziness (6%), tremor (9%), and peripheral neuropathy (4%). Other manifestations included seizures, mutism and aphasia.

Monitor patients for neurological events, specifically 2 to 3 times during the first week following KYMRIAH infusion, and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at www.kymriah-rems.com or 1‑844‑4KYMRIAH (1-844-459-6742).

Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH.

Serious Infections: Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 patients after infusion with KYMRIAH in clinical trials. Fifty-eight (33%) patients experienced grade ≥3 infections, including fatal infections in 2 (3%) patients with r/r ALL after KYMRIAH infusion. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately.

Febrile neutropenia (≥ grade 3) was also observed in 37% of patients with r/r ALL after KYMRIAH infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before cell collection for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. In patients with r/r ALL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had ≥ grade 3 neutropenia or thrombocytopenia, respectively. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia (IgG) can occur in patients with a complete remission after KYMRIAH infusion. Hypogammaglobulinemia was reported in 43% of patients with r/r ALL. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines.

The safety of immunization with live viral vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.

Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.

Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. Monitor lifelong for secondary malignancies. If a second malignancy occurs, call 1‑844‑4KYMRIAH (1-844-459-6742) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, including altered mental status or seizures, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Drug Interactions
HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false positive results in patients who have received KYMRIAH.

Pregnancy, Lactation, Females and Males of Reproductive Potential
No data are available of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at 1‑888‑669‑6682.

Adverse Reactions
The most common adverse reactions (>20%) in patients with r/r ALL were 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, edema, cough, and delirium.

Please see full Prescribing Information for KYMRIAH, including Boxed WARNING, and Medication Guide.