Axicabtagene Ciloleucel (Yescarta)

Number: 0924

Policy

Note: REQUIRES PRECERTIFICATION*

Aetna considers axicabtagene ciloleucel (Yescarta) medically necessary as single agent therapy for the treatment of adults (18 years and older) with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Aetna considers repeat administration of axicabtagene ciloleucel experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers axicabtagene ciloleucel experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Acute lymphoblastic leukemia (ALL)
• Follicular lymphoma
• Indolent non-Hodgkin lymphoma (NHL)
• Mantle cell lymphoma
• Marginal zone lymphoma
• Primary central nervous system (CNS) lymphoma

Exclusion Criteria:

• History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., bladder, breast, cervix) or follicular lymphoma unless disease free for at least 3 years
• History of allogeneic stem cell transplantation
• Prior CAR T cell therapy or other genetically modified T cell therapy
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.  Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment
• Known history of infection with HIV or hepatitis B (HBsAG positive) or hepatitis C virus (anti-HCV positive).  A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing
• Subjects with detectable cerebrospinal fluid (CSF) malignant cells, or brain metastases, or with a history of CNS lymphoma, CSF malignant cells or brain metastases
• History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

Note: * Precertification of axicabtagene ciloleucel is required of all Aetna participating providers and members in applicable plan designs.  For precertification of axicabtagene ciloleucel, call 1-877-212-8811.

See also CPB 0799 - Tocilizumab (Actemra) and CPB CPB 0920 - Tisagenlecleucel (Kymriah)

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in adults.  About 72,000 new cases of NHL are diagnosed in the US yearly, and DLBCL represents about 1/3 newly diagnosed cases.  Axicabtagene ciloleucel (formerly KTE-C19), a chimeric antigen receptor (CAR) T cell therapy, has been studied for use in adult patients with large B-cell lymphoma including DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Roberts and colleagues (2017) stated that the development of clinically functional CAR T cell therapy is the culmination of multiple advances over the past 30 years.  Axicabtagene ciloleucel is an anti-CD19 CAR T cell therapy in development for patients with refractory DLBCL, including transformed follicular lymphoma (TFL) and PMBCL.  Axicabtagene ciloleucel is manufactured from patients' own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express a CAR that re-directs them to recognize CD19-expressing cells.  Studies have reported the feasibility of manufacturing axicabtagene ciloleucel in a centralized facility for use in multi-center clinical trials and have demonstrated potent anti-tumor activity in patients with refractory DLBCL.  Main acute toxicities are neurologic events as well as cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms.  The authors concluded that axicabtagene ciloleucel holds promise for the treatment of patients with CD19-positive malignancies, including refractory DLBCL.

On October 18, 2017, the Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta) for the treatment of adults with relapsed or refractory (r/r)large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL, PMBCL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.  The safety and effectiveness of Yescarta were established in a multi-center clinical trial of 101 adults with r/r large B-cell lymphoma.  Yescarta is the 2nd gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).  Moreover, Yescarta is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma.

The Prescribing Information of Yescarta described a single-arm, open-label, multi-center trial that examined the effectiveness of a single infusion of Yescarta in adults with relapsed or r/r aggressive B-cell NHL.  Eligible patients had refractory disease to the most recent therapy or relapse within 1 year after autologous hematopoietic stem cell transplantation (HSCT).  The study excluded patients with prior allogeneic HSCT, any history of CNS lymphoma, Eastern cooperative oncology group (ECOG) performance status of 2 or greater, absolute lymphocyte count of less than 100/μL, creatinine clearance less than 60 ml/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection fraction of less than 50 %, or active serious infection.  Following lympho-depleting chemotherapy, Yescarta was administered as a single intravenous infusion at a target dose of 2 × 10⁶ CAR-positive viable T cells/kg (maximum permitted dose: 2 × 10⁸ cells).  The lympho-depleting regimen consisted of intravenous (iv) cyclophosphamide 500 mg/m2 and iv fludarabine 30 mg/m2, both given on the 5th, 4th, and 3rd day prior to initiation of Yescarta.  Bridging chemotherapy between leukapheresis and lympho-depleting chemotherapy was not permitted.  All patients were hospitalized for Yescarta infusion and for a minimum of 7 days afterward.  Of 111 patients who underwent leukapheresis, 101 received Yescarta.  Of the patients treated, the median age was 58 years (range of 23 to 76), 67 % were men, and 89 % were white.  Most (76 %) had DLBCL, 16 % had TFL, and 8 % had PMBCL.  The median number of prior therapies was 3 (range of 1 to 10), 77 % of the patients had refractory disease to a 2nd or greater line of therapy, and 21 % had relapsed within 1 year of autologous HSCT; 1 out of 111 patients did not receive the product due to manufacturing failure; 9 other patients were not treated, primarily due to progressive disease or serious adverse reactions following leukapheresis.  The median time from leukapheresis to product delivery was 17 days (range of 14 to 51 days), and the median time from leukapheresis to infusion was 24 days (range of 16 to 73 days).  The median dose was 2.0 × 10⁶ CAR-positive viable T cells/kg (range of 1.1 to 2.2 × 106 cells/kg).  Effectiveness was established on the basis of complete remission (CR) rate and duration of response (DOR), as determined by an independent review committee.  The median time to response was 0.9 months (range of 0.8 to 6.2 months).  Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial remission (PR).  Of the 52 patients (51.5 %) who achieved CR, 14 initially had stable disease (7 patients) or PR (7 patients), with a median time to improvement of 2.1 months (range of 1.6 to 5.3 months).  Treatment with Yescarta can result in severe side effects, which usually appear within the first 1 to 2 weeks, but some side effects may occur later.  The most common non-laboratory adverse reactions (incidence greater than or equal to 20 %) are: CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.  The Prescribing Information of Yescarta carries a boxed warning for CRS and neurologic toxicities, which can be fatal or life-threatening. 

Axicabtagene ciloleucel is also being investigated for the treatment of acute lymphoblastic leukemia (ALL), follicular lymphoma, indolent NHL, mantle cell lymphoma, and marginal zone lymphoma.

Appendix

Dosing Information:

• Yescarta is available as a cell suspension for infusion
• Yescarta comprises a suspension of 2 × 10⁶ CAR-positive viable T cells/kg of body weight, with a maximum of 2 × 10⁸ CAR-positive viable T cells in approximately 68 ml
• Pre-medicate with acetaminophen and an H1-antihistamine
• Confirm availability of tocilizumab prior to infusion
• Dosing is based on the number of CAR-positive viable T cells
• The target Yescarta dose is 2 × 10⁶ CAR-positive viable T cells/kg body weight, with a maximum of 2 × 10⁸ CAR-positive viable T cells

Source: Highlights of Prescribing Information. Axicabtagene ciloleucel (Yescarta). Kite Pharma, Inc.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met::
Axicabtagene ciloleucel (Yescarta) - no specific code:
ICD-10 codes covered if selection criteria are met:
C82.0 - C82.99	Follicular lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma.
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma

The above policy is based on the following references: