Advancing LBCL Treatment Through MRD Monitoring and Allogeneic CAR T-Cell Therapy

In a clinical trial showcase at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, investigators discussed the phase 2 ALPHA3 trial (NCT06500273).¹ Commenced in June 2024, the study is currently enrolling participants at 28 treatment centers in the US and could advance first-line treatment of large B-cell lymphoma (LBCL) in several ways.

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First, an assay utilizing a novel methodology to detect minimal residual disease (MRD) could facilitate the prospective identification of approximately one-third of patients who will relapse following response to first-line chemoimmunotherapy (CIT). Second, responders who are found to have MRD following standard CIT could benefit from chimeric antigen receptor (CAR) T-cell therapy as consolidation treatment. This would represent an escalation from the current standard clinical follow-up with or without routine imaging. Finally, the study could mark a milestone in the development of allogeneic, or off-the-shelf, CAR T-cell agents and help to address the disadvantages of currently available therapies, namely the time needed for the manufacture of a patient-specific product.

Current Management of LBCL in Remission

It is well established, particularly in the literature describing medium- and long-term outcomes following rituximab (Rituxan; Biogen and Genentech, Inc), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP), that although approximately 60% of patients with LBCL can achieve disease cure with first-line CIT alone, a small fraction will have primary refractory disease and the remaining third will experience disease relapse within 2 years of the completion of induction therapy.^1,2 National Comprehensive Cancer Network guidelines recommend follow-up with history, physical examination, and laboratory evaluation every 3 to 6 months for up to 5 years.³

Imaging, however, is an aspect of surveillance for which there is little consensus. Although routine PET/CT may be useful to expedite the detection of disease relapse, particularly in high-risk patients,⁴ improvement in clinical outcomes has not been demonstrated.⁵ Furthermore, some studies have documented a high incidence of false-positive results, resulting in increased radiation exposure and possibly leading to repeat biopsies following these findings.⁶ This has led to the exploration of viable alternative methods of surveillance that are ideally more accurate and less invasive.

Emerging Role of MRD Monitoring in LBCL

Literature supporting the adoption of MRD monitoring to inform the management of LBCL has lagged behind that of other lymphoid malignancies, particularly B-cell acute lymphoblastic leukemia. However, data are beginning to emerge, specifically showing the use of assays that detect the presence of circulating tumor DNA (ctDNA). Baseline levels of ctDNA have been shown to correlate with clinically relevant parameters, including International Prognostic Index scores and lactate dehydrogenase levels.⁷

More recently, data were presented at the ASH meeting in 2023 that demonstrated the prognostic significance of detectable ctDNA on cycle 4, day 1 of induction therapy, as well as at the end of treatment (EOT). The presence of ctDNA at EOT was associated with worse clinical outcomes, including progression-free survival (PFS) with an HR of 7.8 and overall survival (OS) with an HR of 10.8.⁸ The assay described in this abstract, using phased variant enrichment and detection sequencing technology, was used to determine patient eligibility for ALPHA3.

Advantages and Concerns of Allogeneic CAR T-Cell Therapy

Autologous CAR T-cell therapy has dramatically altered the treatment landscape of LBCL since the initial approval of axicabtagene ciloleucel (Yescarta; Kite Pharma, Inc) in 2017. It has more recently become the new standard of care for second-line treatment in patients with LBCL with early relapse (< 12 months), based on the strength of the data presented in the ZUMA-7 trial (NCT03391466).⁹

However, the prospect of allogeneic CAR T-cell therapy does present several advantages. Lymphotoxic chemotherapy may cause lingering lymphocyte dysfunction, and T cells from healthy donors could theoretically yield improved efficacy. Other benefits include the potential to redose or combine CAR T cells with different antigenic targets. Most prominently, though, is the elimination of the vein to vein time from the collection of T cells via apheresis to the infusion of the CAR T product into the patient.^10,11

Concerns presented by the prospect of allogeneic CAR T-cell therapy include the development of graft-vs-host disease (GVHD) and rapid elimination of the T cells through alloimmunization. Gene editing tactics have been employed to address these concerns, including the use of nucleases to disrupt the αβ T-cell receptor and mitigate the risk of GVHD.¹¹ The addition of anti-CD52 monoclonal antibodies to lymphodepletion may also have a role in enhancing T-cell depletion prior to CAR T-cell infusion.

Cemacabtagene ansegedleucel (cema-cel, ALLO-501A; Allogene Therapeutics, Inc) is an anti-CD19 allogeneic CAR T-cell therapy that is currently in clinical development for LBCL and other lymphoid malignancies. It is genetically modified and does not express genes for either a T-cell receptor or CD52. These steps have been taken for the purpose of avoiding GVHD and rendering the drug insensitive to T-cell depletion by anti-CD52 monoclonal antibody. Phase 1 data from the ALPHA (NCT03939026) and ALPHA2 (NCT04416984) trials have shown treatment response in two-thirds of patients with no major safety signals.^12,13 The agent now enters phase 2 of development for use in LBCL with MRD after induction therapy.

ALPHA3 Study Design

The ALPHA3 study seeks to evaluate the efficacy and safety of cema-cel as consolidation treatment in patients with LBCL and demonstrated response to a full course of standard first-line CIT, as well as evidence of MRD utilizing the assay previously described. The subtypes of LBCL included are listed in the TABLE. Standard first-line therapy regimens accepted are R-CHOP; dose-adjusted rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (R-EPOCH); and a modified regimen of R-CHOP (Pola-R-CHP), in which vincristine is replaced with polatuzumab vedotin (Polivy; Genentech, Inc).

DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus.

The trial will proceed in a randomized, open-label fashion in 2 parts. In part A, patients will be randomly assigned 1:1:1 to observation alone or cema-cel preceded by standard lymphodepletion with fludarabine and cyclophosphamide or the same lymphodepletion regimen with the addition of the anti-CD52 monoclonal antibody, ALLO-647 (Allogene Therapeutics, Inc). One of the 2 lymphodepletion regimens will be chosen based on the results of an interim analysis, and part B participants will be randomly assigned 1:1 to either this regimen followed by cema-cel or observation alone.

The primary outcome is event-free survival, as assessed by an independent review committee. Secondary outcomes will include PFS, OS, MRD clearance, and safety. Investigators hope to randomly assign 240 patients at 50 treatment centers and anticipate the enrollment of participants into 2026.

REFERENCES

1. Westin JR, Herrera AF, Lynch R, et al. ALPHA3, a pivotal phase 2 study of first-line consolidation with cemacabtagene ansegedleucel (cema-cel) in patients with large B-cell lymphoma and minimal residual disease after response to standard therapy. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA.

2. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. New Engl J Med. 2002;346(4):235-242. doi:10.1056/NEJMoa011795

3. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2024. Accessed December 23, 2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf

4. Petrausch U, Samaras P, Haile SR, et al. Risk-adapted FDG-PET/CT-based follow-up in patients with diffuse large B-cell lymphoma after first-line therapy. Ann Oncol. 2010;21(8):1694-1698. doi:10.1093/annonc/mdq015

5. Thompson CA, Ghesquieres H, Maurer MJ, et al. Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma. J Clin Oncol. 2014;32(31):3506-3512. doi:10.1200/JCO.2014.55.7561

6. Avivi I, Zilberlicht A, Dann EJ, et al. Strikingly high false positivity of surveillance FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era. Am J Hematol. 2013;88(5):400-405. doi:10.1002/ajh.23423

7. Roschewski M, Rossi D, Kurtz DM, Alizadeh AA, Wilson WH. Circulating tumor DNA in lymphoma: principles and future directions. Blood Cancer Discov. 2022;3(1):5-15. doi:10.1158/2643-3230.BCD-21-0029

8. Sworder BJ, Yoon SE, Kim SJ, et al. Prognostic utility of minimal residual disease (MRD) after curative intent induction therapy for DLBCL: a prospective real-world ctDNA study. Presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA.

9. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. New Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

10. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19(3):185-199. doi:10.1038/s41573-019-0051-2

11. Rodriguez Arocho CI, Davila ML, Sallman DA, eds. CAR-T overview and novel cellular therapeutic options, including TCR gene transfers. In: Sallman DA, Chaudhury A, Nguyen J, Zhang L, eds. Handbook of Hematologic Malignancies, 2nd edition. Demos Medical; 2020:407-414.

12. Locke FL, Lekakis LJ, Eradat HA, et al. Phase 1 results with anti-CD19 allogeneic CAR T ALLO-501/501A in relapsed/refractory large B-cell lymphoma (r/r LBCL). J Clin Oncol. 2023;41(suppl 16):2517. doi:10.1200/JCO.2023.41.16_suppl2517

13. Locke FL, Munoz JL, Tees MT, et al. ALLO-647 for lymphodepletion in the allogeneic CAR T setting: safety experience with ALLO-501/501A in patients (pts) with relapsed/refractory (r/r) large B-cell and follicular lymphomas. Presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA.