Ahmed Discusses Why the Wait for Liso-Cel Is Worth It

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​
• Laboratory results: Lactate dehydrogenase elevated, complete blood count 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: How does the time of return with axicabtagene ciloleucel (axi-cel; Yescarta) compare to lisocabtagene maraleucel (liso-cel; Breyanzi) when treating patients with DLBCL?

SAIRAH AHMED, MD: The criticism of the ZUMA-7 trial [NCT03391466] is that they were potentially choosing better patients, because they did not allow bridging therapy on the study.¹ I think some of that criticism is valid, but the other thing is that axi-cel comes back much quicker than the other chimeric antigen receptor T-cell therapies, in terms of manufacture time. On the trial, the average time of return was between 15 to 17 days, and now in reality, they've cut that down to 12 days. So, you get the product fast, [and during those] 12 days you probably...can hold [a patient who doesn't have severe disease] with radiation and steroids. For liso-cel…you're waiting 3 to 4 weeks for that product, but there's no way that you can hold somebody's disease that long on steroids.

Please describe the TRANSFORM trial (NCT0357531) set-up and results.

[The study] was a 1:1 randomization [comparing standard of care and liso-cel], where patients could get up to 3 cycles of salvage chemotherapy.² The trial did allow crossover, so if you had less than a partial response on the transplant arm, you could go over to the CAR T-cell therapy arm. The primary end point was event-free survival [EFS]. [On this study], EFS and progression-free survival were improved with liso-cel over the standard of care.²

What were the other notable outcomes from the trial?

The overall survival [OS] has not been shown to be statistically significant, and part of that's probably due to patient crossover, and even when they adjust for crossover, they are just at an HR [of approximately] 0.4.³ So, maybe with longer follow up, we'll see an OS benefit with liso-cel. If you look at the data, my guess is that [that OS benefit is] there, it's just that we aren't able to see it based on the way that this trial was designed.

In terms of outcomes, [there was a] complete response rate in the liso-cel arm of 68% [95% CI,63.7%-82.5%] vs 40% [95% CI, 33.2%-54.2%] in the standard of care arm [P < .0001]. Again, OS was not shown to have benefit yet, but the overall response rate was quite high [with liso-cel compared with the standard-of-care arm] at 80% [95% CI, 78.3%-93.1%] vs 45% [95% CI, 38.3%-59.6%]. Patients who respond do have a very good overall duration of response as well.³

What were the toxicities with this regimen?

The main non-CAR T-cell associated toxicity, in terms of cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS], was hematologic adverse events.³ In terms of CRS and ICANS, this is certainly a product that has less of an unique toxicity...and that's probably because of the 4-1BB costimulatory molecule, so you have a slower expansion, slower proliferation rate, and instead of that big spike, the CRS and ICAN events decreased [their grades] overall. So, any grade of CRS was seen in 49% [of patients], while [the rate of] events higher than grade 3 was very low. Any-grade events of ICANS [occurred at a rate of] 11%, while grade 3 or higher was about 4%.

^References

^{1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large b-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133}

^{2. Abramson JS, Johnston PB, Kamdar M, et al. Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL. Blood Adv. 2022;6(23):5969-5979. doi:10.1182/bloodadvances.2022008106}

^{3. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730}