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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Chimeric Antigen Receptor (CAR) T-cell therapy using Kymriah ^TM (tisagenlecleucel) may be considered medically necessary when:

• Used 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, and
• The prescriber is enrolled in the Kymriah Risk Evaluation and Mitigation Strategy (REMS) program.

Chimeric Antigen Receptor (CAR) T-cell therapy, for all other indications is considered experimental, investigational and/or unproven.

The spontaneous regression of certain cancers (e.g. renal cell carcinoma and melanoma) supports the idea that a patient’s immune system can delay tumor progression and, on infrequent occasions, can eliminate tumors altogether. These observations have led to research into various immunologic therapies designed to stimulate a patient’s own immune system.

Immunotherapy uses the body’s own immune system to battle diseases such as cancer. It may increase the body’s ability to detect and kill cancer cells. T-cells collected from a patient’s blood are genetically engineered to create special receptors on the T-cells surface, these receptors are called chimeric antigen receptor (CAR). CARs allow the T-cells to identify a specific protein on targeted cells.

T-cells are harvested from the patient through an apheresis process, and then sent to a laboratory or manufacturing facility where they are genetically re-engineered, and multiplied. The patient may be given a brief course of one or more chemotherapy agents before the patient is infused with the CAR T-cells. Cytokine-release syndrome (CRS) is a significant side effect in patients who have been treated with CAR T-cell therapy. Following infusion of the T-cells, cytokines are released into the blood stream. Cytokine release syndrome includes but is not limited to, fatal or life-threatening reactions, altered mental status, fever, and hypotension, and may require intensive care.

CAR T-cell Therapy for Acute lymphoblastic leukemia

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a diverse hematologic disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. In 2016, there were approximately 6590 new cases of ALL and an estimated 1430 deaths. (3)

The National Cancer Institute (NCI) notes that ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years. (4)

CTL019, also known as Kymriah (tisagenlecleucel) (Novartis) is an anti-CD19 CAR T-cell therapy. Kymriah has been developed to treat patients up to 25 years of age, with relapsed and refractory acute lymphoblastic leukemia. A treatment course consists of lymphodepleting chemotherapy followed by an infusion of Kymriah 2 to 14 days after its completion. Dosing for Kymriah is based on the patient’s weight. (14)

CAR T-cell Therapy for B-cell Lymphomas

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a form of non-Hodgkin lymphoma (NHL).

DLBCL is an aggressive form of lymphoma, that occurs generally in adults. In 2016, an estimated 72,580 new cases of non-Hodgkin lymphoma will be identified in the U. S. This accounts for 4.3% of new cancers in the U.S. (1)

An emerging new therapy KTE-C19, also known as a axicabtagene ciloleucel, or “axi-cel” (Kite Pharma) is a CAR T-cell therapy that uses a patient’s own T-cells which are engineered with chimeric antigen receptor (CAR) gene to target the antigen CD19, which is located on the cell surface of B-cell lymphomas and leukemias. These engineered cells are used to kill cancer cells. (2)

Cells are collected from patients who have refractory aggressive NHL, and then sent to a manufacturing facility where the chimeric antigen receptor gene is inserted into the T-cells. The genetically engineered T-cells are grown and then at a later date re-infused back into the patient.

Axicabtagene ciloleucel, Kite Pharma, Inc., plans on submitting a Biologics License Application (BLA) to the U. S. Food and Drug Administration (FDA) to treat patients with refractory diffuse large B-cell lymphoma. Currently no clearance has been received from the FDA for this product.

Regulatory Status

The U. S. Food and Drug Administration approved the Biologics License Application (BLA) for Kymriah (tisagenlecleucel) on August 30, 2017. (16) 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. The FDA labeling for Kymriah includes a boxed warning for Cytokine Release Syndrome (CRS) and Neurological Toxicities. (14) The boxed warning clarifies that Kymriah is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of the risk of CRS and neurological Toxicities. Required components of the Kymriah REMS program include:

• Healthcare facilities that dispense and administer Kymriah must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for administration within 2 hours after Kymriah infusion, if needed for treatment of CRS.
• Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer KYMRIAH are trained about the management of CRS and neurological toxicities. (14)

A recent literature review was performed through August 31, 2017. The following is a summary of key references to date.

Acute lymphoblastic leukemia

The efficacy and safety of Kymriah were noted in one multicenter single-arm trial included in the Kymriah package insert information from the FDA website. Eighty-eight patients were enrolled, 9% of the enrolled subjects did not received the product due to manufacturing failure. Sixty-eight patients with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) were treated with Kymriah and evaluated. (14) Sixty-three were evaluable for efficacy. The median age of the 63 evaluable patients was 12 years (range, 3-23 years). Six patients (10%) had primary refractory disease, 30 patients (48%) had one prior stem cell transplantation, 5 patients (8%) had two stem cell transplantations. Fifty-two patients (83%) of the 63 infused patients, achieved complete remission or complete remission with incomplete blood count recovery (CR/CRi), all were minimal residual disease (MRD) negative. Median time to onset of CR/CRi was 29 days with onset of CR/Cri between 26 and 31 days for 50/52 (96%) responders. Some of the most common adverse reactions noted included the following: Cytokine release syndrome (79%), Hypogammaglobinemia (43%), infections-pathogen unspecified (41%), pyrexia (40%), decreased appetite (37%), headache (37%), encephalopathy (34%), hypotension (31%), bleeding episodes (31%), tachycardia (26%), acute kidney injury (22%) and delirium (21%).

Maude, et al. (2014) infused autologous T-cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory acute lymphoblastic leukemia (ALL). (7) Thirty children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Results reported that sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). All the patients experienced the cytokine-release syndrome. Twenty-seven percent of the patients developed severe cytokine-release syndrome. Severe cytokine-release syndrome was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. The authors concluded chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed.

B-cell Lymphomas

The ZUMA-1 phase 1 multicenter study, evaluated KTE-C19, an autologous chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory diffuse large B-cell lymphoma (DLBCL). (5) Seven patients were treated with KTE-C19. Patients received low-dose conditioning chemotherapy for 3 days followed by KTE-C19 at a target dose of 2 × 10⁶ CAR T cells/kg. The primary endpoint was the incidence of dose-limiting toxicity (DLT). Seven patients received KTE-C19. One patient had a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. CRS and neurotoxicity grade ≥ 3 were noted in 14% (n=1/7) and 57% (n=4/7) of the patients respectively. The overall response rate reported was 71% (n=5/7) and complete response (CR) rate was 57% (n=4/7). Ongoing complete response rate (all at 12 plus months) were reported in 3 patients. The authors note CAR T-cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.

Ongoing and Unpublished Clinical Trials

An online search of ClinicalTrials.gov on August 31, 2017 located 172 studies using the search term CAR T Cell therapy.

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CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

1. National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program Cancer Stat Facts: Non-Hodgkin Lymphoma. Available at: < https://seer.cancer.gov> (accessed on February 1, 2017)
2. Kite Pharma’s CMO talks exclusively to Phacilitate Cell & Gene Therapy World (December 16, 2016) Latest Interviews. Available at: <http//www.bioleaders.com> (accessed on January 31, 2017)
3. NCCN – Acute Lymphoblastic Leukemia Version 2.2016. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Available at: <http://www.nccn.org> (accessed on February 15, 2017).
4. National Cancer Institute. Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version. Available at: <https://www.cancer.gov> (accessed on February 15, 2017).
5. Locke, F., Neelapu, S., Bartlett, N. et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol Ther. 2017 Jan 4;25(1):285-295. PMID 28129122
6. A Phase 1-2 Multi-Center Study Evaluating KTE-C19 in subjects With Refractory Aggressive Non-Hodgkin Lymphoma (ZUMA-1) (NCT02348216) Available at: <https://clinicaltrials.gov> (accessed on January 31, 2017)
7. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16; 371(16):1507-17. PMID 25317870
8. KTE-C19 Product information. Available at:< http://kitepharma.com> (accessed on January 31, 2017)
9. Diffuse Large B-Cell Lymphoma (last updated 6-28-2016). Available at: <https://rarediseases.info.nih.gov> (accessed on February 1, 2017).
10. NCCN - B-Cell Lymphoma Version 1.2017. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Available at: <http://www.nccn.org> (accessed on February 1, 2017).
11. Chustecka Z., CAR T Cells Motoring to Market – by Next Year? (December 05, 2016) Available at: <http://www.medscape.com> (accessed on February 2, 2017).
12. Chimeric Antigent Receptor (CAR) T-Cell Therapy. Leukemia and Lymphoma Society® (2017). Available at: <https://www.lls.org> (accessed on February 2, 2017).
13. Adoptive Immunotherapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2015 December) Therapy 8.01.01.
14. U. S. Food and Drug Administration. Highlights of Prescribing information Kymriah ^TM (tisagenlecleucel). Available at: <http://www.fda.gov> (accessed August 31, 2017).
15. U. S. Food and Drug Administration. FDA News Release FDA approval brings first gene therapy to the United States CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia. (August 30, 2017). Available at: <http://www.fda.gov> (accessed August 31, 2017).
16. U. S. Food and Drug Administration. BLA approval letter for tisagenlecleucel. (August 30, 2017). Available at: <http://www.fda.gov> (accessed August 31, 2017).