CAR T-Cell Therapy Presents a Paradigm Changing Option in DLBCL

CASE SUMMARY

• A 67-year-old man presented with fatigue, back pain, and lymphadenopathy.
• Medical history: Hypertension is well controlled with medication​.
• Physical exam: Left posterior cervical, 1.5-cm node; right anterior cervical node, 2.5 cm; left supraclavicular node, 2.0 cm​
• PET-CT scan: multiple enlarged mesenteric and retroperitoneal nodes, with the largest being 5.3 × 3.1 cm​.
• Bone marrow biopsy: negative​
• Lymph node biopsy: confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal cent B-cell, double expressor lymphoma.
  • Immunohistochemistry (IHC) positive for: CD20, BCL-6, BCL-2 (50% of cells), MYC (> 40% of cells), Ki67 85%, MUM1​
  • IHC negative for: CD10​
• Fluorescence in situ hybridization: negative for translocations involving MYC, BCL2, BCL6​
• Labs: Lactate dehydrogenase elevated, CBC normal​
• Stage III; non-germinal center
• International prognostic indicator: high-intermediate risk
• ECOG performance score: 1 ​
• Rituximab (Rituxan), cyclophosphamide, hydroxydaunomycin, vincristine sulfate (Oncovin), and prednisone was initiated for 6 cycles.
• Back pain resolved​
• Post-treatment PET scan demonstrated a complete response with a Deauville score of 2; patient was observed​ after.

Eight months after completion of therapy​

• The patient complained of fever, night sweats, and back pain. ​
• A palpable lymph node in left groin was discovered on physical examination​.
• PET and CT scan: new left inguinal lymph node, increase in size of residual nodes, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​.
• Biopsy confirmed DLBCL, but next generation sequencing was not performed.
• The patient was referred to nearest transplant and cellular therapy center for evaluation.

Targeted Oncology: What are the current options for a patient like this?

SAIRAH AHMED, MD: The current treatment landscape for [patients with] DLBCL has changed dramatically over the last 5 or 6 years. For the frontline setting, we often still use chemoimmunotherapy, but in the second-line setting, depending on the time of relapse, chimeric antigen receptor [CAR] T-cell therapy has been approved for both transplant eligible and ineligible patients.¹ After 12 months [of treatment], if someone has disease that relapses and they are transplant eligible, we still agree that transplant is certainly a viable option, and can potentially have a long-lasting curative effect. In terms of the third-line setting, there are a number of new agents, including CD19 targeting agents, CD79 targeting agents, checkpoint inhibitors, but more recently CD20 targeting bispecific [have emerged].¹

How do you approach sequencing these therapies for these patients?

Sairah Ahmed, MD​

Associate Professor

Department of Lymphoma/Myeloma, Division of Cancer Medicine

Director of CART Program

The University of Texas MD Anderson Cancer Center​

Houston, TX

The way that we sequence these drugs is very much dependent on the patient in front of us and their comorbidity status, and somewhat on how comfortable we are in utilizing some of these newer drugs. My colleagues…came up with an algorithm for second-line treatment [for patients with] large B-cell lymphoma, looking at where are we going to have the most efficacy with the treatment options that we have.² We know that the vast majority of patients who have DLBCL are going to have early relapses, and that the majority of them will be eligible for CAR T-cell therapy and, potentially, 40% of those patients who receive second-line CAR T-cell therapy are going to have a durable remission, which would functionally be a cure.

What about for patients not eligible for CAR T-cell therapy?

For patients who are not eligible for CAR T-cell therapy, there are other options, but none of them, at this point in time, have been shown to be curative. Now, for patients who are eligible for transplant and have relapsed after 1 year, about 50% of them, based on historic data, are going to have a response to second-line treatment and therefore be able to proceed to autologous stem cell transplant, and about 50% of those patients will be cured of their disease.²

Where does CAR T-cell therapy stand in the third-line setting?

Patients will potentially have the option for CAR T-cell therapy in the third-line setting, and again, that same 40% durable remission is still what we quote in [this later setting].³ In terms of being able to offer patients curative intent treatment, the advent of CAR T-cell therapy has given us one more time point at which we can potentially have the opportunity for [a curative therapy for these patients]…. There are also data to show that the patient can have a transplant before as well as after CAR T-cell therapy, and there are some patients who can still go on to allogeneic transplant after CAR T-cell therapy or other CAR T-cell therapies beyond just CD19 targeting [therapies].⁴

^References

^{1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 2.2024. Accessed May 23, 2024. https://tinyurl.com/nvndmfnc}

^{2. Westin J, Sehn LH. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift? Blood. 2022;139(18):2737-2746. doi:10.1182/blood.2022015789}

^{3. Testa U, Leone G, Pelosi E, et al. CAR-T cell therapy in large b cell lymphoma. Mediterr J Hematol Infect Dis. 2023;15(1):e2023066. doi:10.4084/MJHID.2023.066}

^{4. Zurko J, Ramdial J, Shadman M, et al. Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma. Haematologica. 2023;108(1):98-109. doi:10.3324/haematol.2022.281242}