CAR-T Cell Therapy in First Line for High Risk Diffuse Large B-Cell Lymphoma: Review of Efficacy and Cost-Effectiveness Against Standard of Care Chemo-Immunotherapy

Background:

Diffuse B-cell large cell Lymphoma (DLBCL) is refractory to initial therapy in 10 percent and relapses in up to one-third of patients. High-risk patients such as those with an International Prognostic Index (IPI) score of 3-5, with double or triple hit mutation and PET scan positive after two cycles of chemotherapy (PET-2 positive) have lower progression-free survival (PFS) and overall survival (OS) with standard rituximab-containing chemoimmunotherapy regimens. Chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 are promising, as they have demonstrated high efficacy in treating relapsed and refractory lymphomas with manageable side effects profiles. However, Axicabtagene ciloleucel (axi-cel) as first-line therapy has not been appropriately studied until a prospective phase 2 multicenter trial (ZUMA-12), which targets high-risk Large B-cell lymphoma as described by PET-2 positivity, double or triple-hit lymphomas and high-risk IPI scores (3-5). We report the efficacy and cost-effectiveness of axi-cel compared to standard chemoimmunotherapy regimens in high-risk LBCL.

Materials & Methods:

We searched articles from PubMed, Embase, WebofScience, and Cochrane from the date of inception till 7/10/2022. A total of 604 articles for DLBCL lymphoma belonging to three categories, "high IPI score," "double/triple hit lymphomas (DHL/THL)," and "PET2+," were filtered and narrowed to twenty-five trials. Thirteen trials focused on DHL/THL were included; six with high IPI scores and six with PET2+ were included for data extraction. The data for efficacy variables such as PFS, OS, and complete response (CR) was extracted. ZUMA-12 trial was used to extract data regarding CR.

Results:

Four thousand one hundred sixty-two patients with DHL/THL, high IPI score, and PET2+ were evaluated for OS, PFS, and CR. In patients with DHL/THL, 40% of patients who achieved chemoimmunotherapy achieved CR, as compared to 78% CR in patients with Zuma-12 who received CAR-T cell therapy. Of the 960 patients having DHL included in the analysis, 242 received the standard dosing regimen, R-CHOP; 91 received the intermediate dosing regimen, 65 received R-EPOCH; and 123 received DI regimens (either R-Hyper-CVAD/R-M/C or R-CODOX-M/RIVAC).

In patients with high IPI scores, 74% of patients who received standard of care chemoimmunotherapy achieved CR compared to 81% in patients in ZUMA-12 who received CAR-T cell therapy. Similarly, 64% of the patients who received conventional chemotherapy achieved CR and were PET-2 positive. All the patients in ZUMA 12 trial met PET2+ criteria with a Deauville score of 4 or 5. CR rates in PET2positive patients in ZUMA 12 were 78% CR (95% confidence interval (CI), 62-90) who received CAR-T cell therapy. Regarding cost-effectiveness according to Lexicomp, wholesale acquisition cost (WAC) for axi- cel as of 7/15/2022 is $424,000. This number is prior to any reimbursement the institution might receive after billing for the product. On the other hand, chemotherapy average wholesale price (AWP) as listed on Lexicomp; calculated based on the average 1.7m² patient are :

RCHOP- total cost: $8,957.41 per cycle; 6 cycles = $53,744.46

DA-R-EPOCH - prices based on starting dose level 1 (cycle 2 and beyond dosing/pricing are subject to change based on ANC and platelets throughout cycles): $8,645.23

Conclusion:

Axi-cel is a safe first-line treatment for adult patients with high-risk LBCL, including those with positive interim PET2 and either DHL/THL lymphomas or an IPI score of 3-5. The efficacy and outcomes can be improved by incorporating CAR-T cell therapy into managing double-hit and triple-hit diffuse large B-cell lymphoma who are PET-2 positive. Axi-cel is more costly than standard chemoimmunotherapy but it might potentially be more cost-effective if it results in improved PFS/Event-free survival (EFS). Patients who receive standard treatment regimens might have more costs related to the treatment of potential future relapsed/refractory disease, especially in DHL/THL. Unfortunately, frontline therapy clinical studies in high-risk LBCL are uncommon and difficult to execute due to the danger of disease progression during screening. Further research in these patient populations is needed to assess the benefit of Axi-cel as first-line therapy against standard chemoimmunotherapy and to calculate cost-effectiveness over time.

No relevant conflicts of interest to declare.