MRD and Other Predictors From FELIX for Obe-Cel Success in R/R B-ALL

A month before the 66th American Society of Hematology Annual Meeting and Exposition (ASH 2024) opened in San Diego, California, the FDA approved obecabtagene autoleucel (obe-cel; Aucatzyl, Autolus Therapeutics) for adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL).¹

Approval was based on the phase 1b/2 FELIX study (NCT04404660), which appeared in the New England Journal of Medicine (NEJM) on November 27, 2024.² Study authors presented additional data during ASH 2024 regarding the depth of molecular responses as well as risk stratification that could predict which patients will have the best outcomes.^3,4

Elias Jabbour, MD | Image credit: MD Anderson

Authors, including lead US investigator Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center, outlined in NEJM how obe-cel differs from earlier chimeric antigen receptor (CAR) T-cell therapies. “Unlike tisa-cel [tisagenlecleucel] and brexu-cel [brexucabtagene autoleucel], which both use the same high-affinity single-chain variable fragment (scFv) to recognize CD19, obe-cel uses a different scFv with intermediate affinity due to a fast binding off-rate,” they wrote.²

This difference is believed to reduce toxicity while improving the therapy’s persistence, they wrote; Jabbour referred to patients’ ongoing response as a “plateau,” as seen in the graphic presentation of survival data, which he called “transformative” in CAR T-cell therapy. A study of obe-cel in pediatric patients is recruiting (NCT06173518).

Findings in NEJM show that remission occurred in 77% of the 127 evaluable patients, with 55% having complete remission (CR) and 21% having complete remission with incomplete hematologic recovery (CRi). The median event-free survival (EFS) was 11.9 months, with a 6-month rate of 65.4% and a 12-month rate of 49.5%. Median overall survival (OS) was 15.6 months.²

On the safety front, grade 3 or higher cytokine release syndrome (CRS) developed in only 2.4% of the patients, and grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS) developed in 7.1% of the patients.² According to experts who discussed obe-cel during a Peer Exchange with The American Journal of Managed Care (AJMC) sister publication OncLive® in November 2024, obe-cel appears to offer a much-improved safety profile without any drop-off in efficacy relative to other CAR T-cell options.⁵

At ASH, Jabbour presented an abstract highlighting “the correlation between the depth of measurable residual disease (MRD)–negative remission and clinical outcomes” on patients who were treated with obe-cel.³ In short, the results showed that patients who did not achieve an MRD of less than 10-6 had poorer outcomes.

According to the data, 76% of the 127 patients infused with obe-cel had samples available for next-generation sequencing (NGS) analysis; of these 96, 73 patients (76%) achieved CR or CRi, and 68 of the 73 (93%) had at least 1 postinfusion bone marrow sample for NGS evaluation.

Based on best response achieved, 6% of patients had MRD equal to or more than 10^-4 leukemic cells, meaning MRD positive, while 94% reached MRD of under 10^-4 leukemic cells; in addition, 10% (7/68) had MRD between 10^-4 and 10^-6 and 84% (57/68) had MRD less than 10^-6.

At a median follow-up of 21.5 months, among responders, results were as follows:

• for patients with MRD equal to or more than 10^-4: median duration of response (DOR), 1.5 months; median EFS, 0 months; median OS, 2.2 months
• for patients with MRD between 10^-4 and 10^-6: median DOR, 3.8 months; median EFS, 4.5 months; median OS, 8.9 months for patients with MRD less than 10^-6: median DOR, 17.1 months; median EFS, 15.1 months; median OS, not evaluable 12-month EFS rates were 10%, 0%, and 61%, while 12-month OS rates were 20%, 27%, and 85%, respectively.
  

AJMC spoke with Jabbour about the relationship between the MRD results and patient outcomes, as well as next steps.

AJMC: What did the results show about the relationship between MRD negativity and patient outcomes?

Jabbour: Obe-cel induces a higher rate of MRD negativity by NGS. The patients who respond and achieve MRD negativity by NGS at 1 month post infusion have an improvement in the [EFS and OS]. In fact, 70% of the patients who achieve an MRD-negative remission are alive at a median [follow-up] of up to 21.8 months.

However, the benefit was seen at a higher level in patients with a low tumor burden at lymphodepletion; patients with blast [cells in the bone marrow] above 75% did benefit, but not to the extent of those patients with a lower tumor burden.

AJMC: Are there any particular findings FELIX has shown investigators about sequencing this therapy relative to other therapies that are available for B-ALL?

Jabbour: Compared with the other treatments available for ALL and many other CAR T-cell [therapies], obe-cel is safer, and it seems to induce a plateau where patients do not relapse after a certain time. If they respond, they have the deepest measure—they seem to have a plateau that we have not shown with the other CAR T cells. However, I think what we need to do as a sequence; when you have somebody relapsing, collect them for obe-cel, but then try to start to actually reduce them to the maximum and give CAR T as a consolidation. Because what we’ve seen so far is that patients who respond have a low tumor burden at lymphodepletion, and then obe-cel has the best benefit—survival is at 80% and higher, which is great, and that eventually will offset the need for transplantation.

AJMC: Are there particular characteristics of patients for whom obe-cel is particularly appropriate?

Jabbour: This therapy is safe with the dose [with low rates of] CRS and ICANS, and it has more durable responses with the plateau. Obviously, this should be offered for every patient today with R/R B-ALL.

AJMC: What are the next areas for study?

Jabbour: With the promising evidence we have today, we need to move [it], obviously, to the front line—that will happen in 2025.

References
1. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. News release. FDA. November 8, 2024. Accessed December 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
2. Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia. N Engl J Med. 2024;391(23):2219-2230. doi:10.1056/NEJMoa2406526
3. Jabbour E, Park JH, Shaughnessy P, et al. Obecabtagene autoleucel (obe-cel) for adult relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): deep molecular remission may predict better outcomes. Presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA. Abstract 963.
4. Roddie C, Park JH, Shaughnessy P, et al. Risk factors associated with sub-optimal outcomes following obecabtagene autoleucel (obe-cel) for relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): what we have learned from the FELIX trial. Presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA. Abstract 4845.
5. Doherty K. Obe-cel approval expands CAR T-cell therapy options in relapsed/refractory ALL. OncLive. 2024;25(15):22-25. https://www.onclive.com/view/obe-cel-approval-expands-car-t-cell-therapy-options-in-relapsed-refractory-all