Axicabtagene Ciloleucel (Yescarta)

Number: 0924

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses axicabtagene ciloleucel (Yescarta) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

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

1. Exclusions

   Aetna will not provide coverage for members with any of the following exclusions:

   1. Primary central nervous system lymphoma; or
   2. Previous treatment course with the requested medication or another CD19-directed chimeric antigen receptor (CART) T-cell therapy; or
   3. ECOG performance status greater than or equal to 3 (see Appendix); or
   4. Inadequate and unstable kidney, liver, pulmonary or cardiac function; or
   5. Active hepatitis B, active hepatitis C or a clinically significant active systemic infection; or
   6. Active inflammatory disorder.

2. Criteria for Initial Approval

   1. Adult large B-cell lymphomas

      Aetna considers axicabtagene ciloleucel (Yescarta) medically necessary as treatment of B-cell lymphomas in members 18 years of age or older when either of the following criteria are met:

      1. The member has received prior treatment with two or more lines of systemic therapy and has any of the following B-cell lymphoma subtypes:

         1. Diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma; or
         2. Histologic transformation of indolent lymphomas to DLBCL; or
         3. Diffuse large B-cell lymphoma (DLBCL); or
         4. Primary mediastinal large B-cell lymphoma; or
         5. High-grade B-cell lymphomas (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified); or
         6. Human immunodeficiency virus (HIV)-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specific); or
         7. Monomorphic post-transplant lymphoproliferative disorder (B-cell type); or
         8. Follicular lymphoma; or
         9. Extranodal marginal zone lymphoma of the stomach (gastric MALT); or
         10. Extranodal marginal zone lymphoma of nongastric sites (nongastric MALT); or
         11. Nodal marginal zone lymphoma; or
         12. Splenic marginal zone lymphoma; or

      2. The member has received prior treatment with first-line chemoimmunotherapy and has any of the following B-cell lymphoma subtypes:

         1. Diffuse large B-cell lymphoma (DLBCL); or
         2. Primary mediastinal large B-cell lymphoma; or
         3. High-grade B-cell lymphomas (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified); or
         4. Human immunodeficiency virus (HIV)-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specific); or
         5. Monomorphic post-transplant lymphoproliferative disorder (B-cell type).

   2. Pediatric primary mediastinal large B-cell lymphoma

      Aetna considers axicabtagene ciloleucel (Yescarta) medically necessary for treatment of pediatric primary mediastinal large B-cell lymphoma in members less than 18 years of age when the member has received prior therapy with at least two prior chemoimmunotherapy regimens and achieved partial response.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   See Dosage and Administration information.

4. Related Policies

   1. CPB 0799 - Tocilizumab (Actemra)
   2. CPB 0920 - Tisagenlecleucel (Kymriah)

Dosage and Administration

Axicabtagene ciloleucel (Yescarta) is available as a cell suspension for infusion for autologous and intravenous use only administered in a certified healthcare facility.

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.

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: Kite Pharma, 2022

Experimental and Investigational

Aetna considers axicabtagene ciloleucel (Yescarta) 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)
• Burkitt lymphoma
• Indolent non-Hodgkin lymphomas (NHL) (other than diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma, histologic transformation of indolent lymphomas to DLBCL)
• Mantle cell lymphoma
• Primary central nervous system (CNS) lymphoma
• Solid tumors.

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

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
0537T	Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
0538T	preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
0539T	receipt and preparation of CAR-T cells for administration
0540T	CAR-T cell administration, autologous
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Q2041	Axicabtagene Ciloleucel, up to 200 Million Autologous Anti-CD19 CAR T Cells, Including Leukapheresis And Dose Preparation Procedures, Per Infusion
ICD-10 codes covered if selection criteria are met:
B20	Human immunodeficiency virus [HIV] disease
C82.00 - C82.99	Follicular lymphoma
C83.00 - C83.09	Small cell B-cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma.
C85.10 – C85.19	Unspecified B-cell lymphoma
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma
C85.80 - C85.89	Other specified types of non-Hodgkin lymphoma
C88.4	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [Gastric/non gastric MALT-lymphoma]
D47.Z1	Post-transplant lymphoproliferative disorder (PTLD)
ICD-10 codes not covered if selection criteria are met:
A00 – B99.9	Certain infectious and parasitic diseases [active, uncontrolled]
C11.0 - C11.9	Malignant neoplasm of nasopharynx
C12	Malignant neoplasm of pyriform sinus
C13.0 - C13.9	Malignant neoplasm of hypopharynx
C14.0-C14.8	Malignant neoplasm of other and ill-defined sites in the lip, oral cavity and pharynx
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
C17.0 - C17.9	Malignant neoplasm of small intestine
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal
C22.0	Liver cell carcinoma
C22.1	Intrahepatic bile duct carcinoma
C23 - C24.9	Malignant neoplasm of gall bladder and other and unspecified parts of biliary tract
C25.0 - C25.9	Malignant neoplasm of pancreas
C26.0 - C26.9	Malignant neoplasm of other and ill-defined digestive organs
C30.0 - C30.1	Malignant neoplasm of nasal cavity and middle ear
C31.0 - C31.9	Malignant neoplasm of accessory sinuses (paranasal)
C33 - C34.92	Malignant neoplasm trachea, bronchus, and lung
C37	Malignant neoplasm of thymus
C38.0 - C38.8	Malignant neoplasm of heart, mediastinum and pleura
C39.0 - C39.9	Malignant neoplasm of other and ill-defined sites in the respiratory system and intrathoracic organs
C40.00 - C40.92	Malignant neoplasm of bone and articular cartilage of limbs
C41.0 - C41.9	Malignant neoplasm of bone and articular cartilage of other and unspecified sites
C43.0 - C43.9	Malignant melanoma of skin
C44.00 - C44.201	Other and unspecified malignant neoplasm of skin
C46.1	Kaposi’s sarcoma of soft tissue
C47.0 - C47.9	Malignant neoplasm of peripheral nerves, autonomic nervous system, connective and soft tissue
C48.0 - C48.8	Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of female and male breast
C51.0 - C51.9	Malignant neoplasm of vulva
C52	Malignant neoplasm of vagina
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C55	Malignant neoplasm of uterus, part unspecified
C56.1 - C56.9	Malignant neoplasm of ovary
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C58	Malignant neoplasm of placenta
C60.0 - C60.9	Malignant neoplasm of penis
C61	Malignant neoplasm of prostate
C62.00 - C62.92	Malignant neoplasm of testis
C63.00 - C63.9	Malignant neoplasm of other and unspecified male genital organs
C64.1 - C68.9	Malignant neoplasm of kidney and other and unspecified urinary organs
C69.00 - C69.92	Malignant neoplasm of eye and adnexa
C70.0 - C70.9	Malignant neoplasm of meninges
C71.0 - C71.9	Malignant neoplasm of brain
C72.0 - C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
C73	Malignant neoplasm of thyroid gland
C7A.1 - C7A.8	Malignant poorly differentiated neuroendocrine tumors
C80.0 - C80.1	Malignant neoplasm without specification of site
C83.70 - C83.79	Burkitt lymphoma
C85.10 - C85.99	Other specified and unspecified types of non-Hodgkin lymphoma
D00.00 - D09.9	Carcinoma in situ
E08.00 - E11.9	Diabetes mellitus
I00 – I99.9	Diseases of circulatory system [inadequate and unstable cardiac function]
J00 – J99	Diseases of respiratory system [inadequate and unstable pulmonary function]
K70 – K77	Disorders of liver system [inadequate and unstable liver function]
L40.0 - L40.9	Psoriasis
M00.00 – M99.9	Diseases of musculoskeletal system and connective tissue [active inflammatory disorder]
N00.0 – N29	Disorders of kidney and ureter system [inadequate and unstable kidney function]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
• 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 (NOS), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
• Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy

Limitations of Use:

Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

Compendial Uses

• Histologic transformation of indolent lymphomas to DLBCL
• Human immunodeficiency virus (HIV)-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specific)
• Monomorphic post-transplant lymphoproliferative disorder (B-cell type)
• Marginal zone lymphomas (MZL):
  
  
  • Extranodal MZL of the stomach (gastric mucosa associated lymphoid tissue (MALT) lymphoma)
  • Extranodal MZL of nongastric sites (nongastric MALT lymphoma)
  • Nodal MZL
  • Splenic MZL
    
    

• Pediatric primary mediastinal large B-cell lymphoma

Axicabtagene ciloleucel is available as Yescarta (Kite Pharma, Inc.) and  is a CD19-directed genetically modified autologous T cell immunotherapy which binds to CD19-expressing cancer cells and normal B cells. Yescarta is prepared from a patient's own T cells which are harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) consisting of a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 and CD3-zeta co-stimulatory domains. Upon anti-CD19 CAR T cell engagement with CD19-expressing target cells, the previously mentioned domains activate downstream signaling reactions that lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines, and ensuing death of CD19-expressing cells (Kite Pharma, 2021b).

Per the prescribing information, axicabtagene ciloleucel (Yescarta) carries the following boxed warnings:

• Cytokine release syndrome (CRS) : CRS, including fatal or life-threatening reactions, occurred in 224/254 (88%) of all patients with non-Hodgkin lymphoma (NHL) receiving Yescarta, including ≥ Grade 3 CRS in 10%. CRS occurred in 101/108 (94%) of patients with large B-cell lymphoma (LBCL) in ZUMA-1, including ≥ Grade 3 in 13%. CRS occurred in 123/146 (84%) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 CRS in 11/146 (8%) of patients with iNHL.
• Neurologic toxicities: Neurological toxicities occurred in 206/254 (81%) of all patients with NHL receiving Yescarta, including ≥ Grade 3 in 26%. Neurologic toxicities occurred in 94/108 (94%) of patients with LBCL, including ≥ Grade 3 in 31%. Neurologic toxicities occurred in 112/146 (77%) of patients with iNHL, including ≥ Grade 3 in 21%.

Axicabtagene ciloleucel (Yescarta) carries the additional warnings and precautions (Kite Pharma, 2021b):

• Hypersensitivity reactions
• Serious infections; Infections (all grades) occurred in 119/254 (47%) of all patients with NHL. Grade 3 or higher infections occurred in 19% of patients, Grade 3 or higher infections with an unspecified pathogen in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%.
• Prolonged cytopenias
• Hypogammaglobulinemia: Hypogammaglobulinemia occurred in 17% of all patients with NHL.
• Secondary malignancies
• Effects on ability to drive and use machines.

Per the prescribing information, the most common non-laboratory adverse reactions (occurrence ≥ 20%) in patients with NHL are CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, febrile neutropenia, nausea, infections with pathogen unspecified, decreased appetite, chills, diarrhea, tremor, musculoskeletal pain, cough, hypoxia, constipation, vomiting, arrhythmias, and dizziness.

Central Nervous System Lymphoma

Yi et al (2022) noted that CAR T-cell therapy has significantly improved the outcomes of patients with r/r B-NHL; however, most clinical trials excluded patients with CNS involvement due to uncertain safety and effectiveness.  On January 1, 2022, these investigators searched PubMed to identify all published literature associated with current commercial CAR T-cell therapies for B-NHL, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), and lisocabtagene maraleucel (liso-cel).  Studies that involved patients with either primary or secondary CNS lymphoma, and evaluated response rate, AEs, or survival were included and summarized.  These researchers summarized the findings of 11 studies qualified for their inclusion criteria, reporting 58 lymphoma patients with CNS Involvement with 44 evaluable for clinical response (CR), 25 for immune effector cell-associated neurotoxicity syndrome (ICANS) and 48 for CRS.  Objective response was achieved in 62 % (16/26) of patients, and CR was achieved in 52 % (23/44) of patients; 44 % (11/25) developed ICANS, and 35 % (17/48) developed severe ICANS (grade-III or higher).  CRS was reported in 63 % (15/24) of patients, while severe CRS (grade-III or higher) was reported in 7 % (3/42) of patients.  The authors concluded that CAR T-cell therapy may benefit patients with CNS lymphoma with promising response rates and acceptable AE.  Moreover, these researchers stated that definite conclusions cannot be made until data with a larger sample size are available.

Zhang et al (2022) stated that encouraging response has been achieved in r/r B-cell lymphoma treated by CAR-T therapy.  The safety and effectiveness of CAR-T therapy in CNS lymphoma (CNSL) are still elusive.  In a retrospective study, these researchers analyzed 15 patients with r/r secondary CNSL receiving CD19-specific CAR-T cell-based therapy.  Subjects were infused with CD19, CD19/CD20 or CD19/CD22 CAR-T cells following a conditioning regimen of cyclophosphamide and fludarabine.  The ORR was 73.3 % (11/15), including 9 (60 %) with CR and 2 (13.3 %) with PR.  During a median follow-up of 12 months, the median PFS was 4 months, and the median OS was 9 months.  Of 12 patients with systemic tumor infiltration, 7 (58.3 %) achieved CR in CNS, and 5 (41.7 %) achieved CR both systemically and in CNS.  Median DOR for CNS and systemic disease were 8 and 4 months, respectively.  At the end point of observation, of the 7 patients achieved CNS disease CR, 1 was still alive with sustained CR of CNS disease and systemic disease.  The other 6 died of systemic progression.  Of the 15 patients, 11 (73.3 %) experienced grades I to II CRS, and no patient had grades III to IV CRS.  ICANS occurred in 3 (20 %) patients, including 1 (6.6 %) with grade-IV ICANS.  All the CRS or ICANS were manageable.  The authors concluded that the CD19-specific CAR-T cell-based therapy appeared to be a promising therapeutic approach in secondary CNSL, based on its anti-tumor effects and an acceptable side effect profile, meanwhile more strategies are needed to maintain the response.  Moreover, these researchers stated that their findings were limited by the retrospective nature of the analyses, small number of cases (n = 15) and non-uniform CAR-T cell types.  These investigators plan to carry out a prospective, clinical study to further clarify the safety and effectiveness of CAR T-cell therapy for secondary CNSL, as well as the selection and application timing of subsequent maintenance therapy.

Diffuse Large B-cell Lymphoma

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 (2018) 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 U.S. Food and Drug Administration (FDA) approved Yescarta (axicabtagene ciloleucel) 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.

Neelapu and co-workers (2017) stated that in a phase-I clinical trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.  In this multi-center, phase-II clinical trial, these researchers enrolled 111 patients with DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy.  Patients received a target dose of 2×10⁶ anti-CD19 CAR T cells/kg body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine.  The primary end-point was the rate of objective response (calculated as the combined rates of complete remission [CR] and partial remission [PR]); secondary end-points included overall survival, safety, and biomarker assessments.  Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99 %) and administered to 101 (91 %).  The objective response rate (ORR) was 82 %, and the CR rate was 54 %.  With a median follow-up of 15.4 months, 42 % of the patients continued to have a response, with 40 % continuing to have a CR.  The overall rate of survival at 18 months was 52 %.  The most common adverse events (AEs) of grade-3 or higher during treatment were neutropenia (in 78 % of the patients), anemia (in 43 %), and thrombocytopenia (in 38 %).  Grade-3 or higher CRS and neurologic events occurred in 13 % and 28 % of the patients, respectively; 3 of the patients died during treatment.  Higher CAR T-cell levels in blood were associated with response.  The authors concluded that in this multi-center study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the CRS, and neurologic events.

Sharma and colleagues (2018) noted that B-cell NHL are the most common hematological malignancies, which despite improvements in chemo-immunotherapy, carry a uniformly poor prognosis in the relapsed/refractory setting.  CD19 is an antigen expressed on the surface of most malignancies arising from the B cells, and adoptive transfer of anti-CD19 chimeric antigen receptor (CAR)-expressing T cells has been shown to be effective in treating these B-cell malignancies.  Axicabtagene ciloleucel (KTE-C19) is an autologous anti-CD19 CAR T-cell therapy that has shown high ORRs and a manageable safety profile in patients with relapsed or refractory B-cell malignancies who lack effective and curative therapeutic options.  Axi-cel is currently approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma, and is also being evaluated in other B-cell malignancies in ongoing clinical trials. 

Jain and associates (2018) stated that adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment.  Axicabtagene ciloleucel was initially developed at the National Cancer Institute (NCI) and has recently been commercially approved by the FDA for relapsed or refractory aggressive NHL including DLBCL and its variants.  The ZUMA-1 phase-I and phase-II clinical trials formed the basis of the FDA approval of this product, and these investigators discussed the particulars of the clinical trials and the pharmacology of axi-cel.

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 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 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.

On April 1, 2022, the U.S. Food and Drug Administration (FDA) approved Yescarta (axicabtagene ciloleucel) for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy. FDA approval was based on supporting data from the ZUMA-7 study (FDA, 2022).

In the ZUMA-7 study, an international, open-label, multicenter, randomized (1:1), phase 3 trial, Locke and colleagues (2022) evaluated the safety and efficacy of axicabtagene ciloleucel (Yescarta) in patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months following first-line chemoimmunotherapy. Patients were randomized to receive Yescarta (n=180) administered as a single intravenous infusion target dose of 2 x 106 CAR-positive viable T cells/kg (maximum allowable dose as 2 x 108 cells) or second-line standard therapy (n=179), consisting of 2 or 3 cycles of investigator chosen, protocol-established chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy. The primary endpoint was event-free survival and the secondary endpoints were response and overall survival. Median follow-up was at 24.9 months with a median event-free survival of 8.3 months in the Yescarta arm and 2.0 months in the second-line standard therapy arm. The 24-month event-free survival was 41% and 16%, in the respective arms (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; p<0.001). A response was noted in 83% (with a complete response in 65%) of patients in the Yescarta arm and 50% (with a complete response in 32%) of patients in the second-line standard therapy arm. The estimated overall survival at 2 years was 61% in the Yescarta arm and 52% in the second-line standard therapy arm. Grade 3 or greater adverse events were noted in 91% of patients receiving Yescarta versus 83% of those receiving second-line standard therapy. Among those patients receiving Yescarta, ≥ grade 3 cytokine release syndrome was noted in 6% and ≥ grade 3 neurologic events were noted in 21%. No deaths were attributed to cytokine release syndrome or neurologic events. The investigators concluded that Yescarta therapy showed significant improvements for event-free survival and response with the anticipated level of high-grade toxic effects as compared to second-line standard therapy for the patient population that was studied.

Indolent Follicular Lymphoma

Follicular lymphoma (FL) is a form of indolent non-Hodgkin lymphoma (NHL) characterized by slow malignant tumor growth and can become increasing aggressive over time. FL is the most frequently occurring form of indolent lymphoma and the second most frequent type of lymphoma worldwide. It is responsible for an estimated 22% of all lymphomas diagnosed globally. At present, the treatment options for relapsed or refractory indolent FL after two or more lines of therapy are rather sparse (Kite, 2021a).

On March 5, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Yescarta (axicabtagene ciloleucel) the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This FDA Breakthrough Therapy Designation and a priority review approval was based on results from the ZUMA-5 trial. The trial design consisted of an ongoing single-arm, open-label, multi-center study evaluating 146 patients (≥18 years old) with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL), who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Efficacy was based on objective response rate (ORR) and duration of response (DOR). Ninety-one percent of all FL patients (n=81) responded to a single infusion of Yescarta, including 60% of patients who achieved a complete remission. Additionally, 13 of the 25 patients who reached a partial remission met imaging guidelines for a complete remission without confirmation by negative bone marrow biopsy following treatment. Median DOR was yet to be achieved. Of the 146 patients evaluated for safety, Grade 3 or higher cytokine releasing syndrome (CRS) and neurologic toxicities were seen in 8% and 21% of patients, respectively. The median time to start of CRS and neurologic toxicities were 4 days (range: 1 to 20 days) and 6 days (range 1 to 79 days), respectively. The most frequent (≥10%) greater than or equal to Grade 3 adverse reactions included febrile neutropenia, encephalopathy, and infections with pathogen unspecified (Kite, 2021a).

Large B-Cell Lymphoma

Neelapu et al (2023) noted that in phase 2 of a single-arm, multi-center, registrational study (the ZUMA-1 Trial), axicabtagene ciloleucel (axi-cel) autologous anti-CD19 CAR T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL).  These researchers examined outcomes in ZUMA-1 after 5 years of follow-up.  Eligible patients received lympho-depleting chemotherapy followed by axi-cel (2 × 10[6] cells/kg).  Investigator-assessed response, survival, safety, and pharmacokinetics were evaluated in patients who had received treatment.  The ORR in these 101 patients was 83 % (58 % CR rate); with a median follow-up of 63.1 months, responses were ongoing in 31 % of patients at data cut-off.  Median OS was 25.8 months, and the estimated 5-year OS rate was 42.6 %.  Disease-specific survival (DSS; excluding deaths unrelated to disease progression) estimated at 5 years was 51.0 %.  No new serious AEs or deaths related to axi-cel were observed after additional follow-up.  Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91 % of patients.  Ongoing responses at 60 months were associated with early CAR T-cell expansion.  The authors concluded that this 5-year follow-up analysis of the ZUMA-1 Trial showed sustained OS and DSS, with no new safety signals in patients with refractory LBCL.  Protracted B-cell aplasia was not required for durable responses.  These researchers stated that these results supported the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas.

Solid Tumors

Baybutt and colleagues (2019) noted that in 2017, the FDA approved the first 2 novel cellular immunotherapies using synthetic, engineered receptors known as CARs, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients.  This approval marked a major milestone in the use of antigen-directed "living drugs" for the treatment of relapsed or refractory blood cancers, and with these 2 approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted.  These researchers discussed the challenges, advances, and novel approaches being used to implement CAR T-cell immunotherapy for the treatment of solid tumors.  The authors concluded that given the difficulty in treating solid tumors with CAR T cells, the success witnessed in CD19‐directed CAR T‐cell therapy may appear serendipitous.  There is potentially some truth to this because CAR T‐cell therapy to treat T‐cell acute lymphoblastic leukemia (T‐ALL) has not been developed concurrently with B‐cell ALL CAR T‐cell therapy, given the risk for fratricide when targeting T‐cell antigens expressed in not only T‐ALL cells but also in the CAR T cells themselves.  Experience with CD19‐directed CAR T‐cell therapy has encouraged the CAR T‐cell community to confront the problems associated with expanding this therapy to other tumor types.  In fact, in the case of T‐ALL, Cooper et al (2018) have created a CAR that targets the T‐cell antigen CD7 and, to avoid CAR T‐cell fratricide, have used CRISPR/Cas9 to delete CD7 in the CAR T cells.  The necessary strategies to create more effective CAR T‐cell therapies are being developed, and this review has outlined some of the approaches investigators are taking to enhance the efficacy of these cells both within CD19‐targeted therapy and beyond.  These researchers stated that although a one‐size‐fits‐all approach is ideal, and investigators are seeking a cytokine signaling pathway that is a panacea for the limitations of treating solid tumors and unleashing the full potential of CAR T cells, the reality is that each cancer is unique and will ultimately require unique approaches to effectively eradicate disease using CAR T cells.

Radiation Therapy as a Bridging Strategy for CAR T Cell Therapy with Axicabtagene Ciloleucel in Diffuse Large B-Cell Lymphoma

Sim and colleagues (2019) stated that axicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory r/r-DLBCL.  Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration.  The optimal bridging therapy is not known and patients are often chemo-refractory.  These researchers presented a case series of patients receiving radiation as a bridge to axi-cel.  Between December 2017 and October 2018, a total of 12 patients were intended to receive bridging radiation before axi-cel.  The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease greater than or equal to 10 cm in diameter.  All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range of 6 to 36.5 Gy).  Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions; 7 patients received concurrent chemotherapy; 11 patients underwent axi-cel infusion and 1 did not.  Median follow-up was 3.3 months (range of 1.1 to 12.0 months).  No significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion.  One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period.  After axi-cel infusion, 3 of 11 patients (27 %) experienced severe CRS or neurotoxicity.  At 30 days, the ORR was 81.8 % (11 of 12 evaluable; 1 stable disease [SD], 1 out-of-field progression), with CR in 27 % (3 of 11).  At last follow-up, the best ORR was 81.8 %, with a CR attained in 45 % (5 of 11).  Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median of 0.25 k/uL).  The authors concluded that radiation (with or without concurrent chemotherapy) could be safely administered as a bridge to axi-cel in high-risk lymphoma.  Moreover, these researchers stated that caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout.  They stated that future investigation is needed to optimize the use of bridging radiation before CAR T therapy.

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Appendix

Table: ECOG Perfomance Status

Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work)
2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3	Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4	Completely diabled. Cannot carry on any self-care. Totally confined to bed or chair.
5	Dead

Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.

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References