Westin and Sehn Carve Out the Role of CAR T-Cell Therapy and Transplant in Primary Refractory DLBCL

CAR T-cell therapy, autologous stem cell transplant (ASCT), and novel agents each have a role to play in the second-line management of patients with primary refractory diffuse large B-cell lymphoma (DLBCL), according to Jason Westin, MD, MS, FACP, and Laurie H. Sehn, MD, MPH, who provided perspective on the optimal use of each modality during a case-based presentation at the 2022 Pan Pacific Lymphoma Conference.^1,2

Westin, director, Lymphoma Clinical Research, section chief, Aggressive Lymphoma, and associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, started the session by presenting a case of a 70-year-old man with a failure to thrive with progressive bowel obstruction. The man had decreased urine output, a performance status of 1, rising lactate dehydrogenase (LDH) of 1.5 x the upper limit of normal, and an International Prognostic Index (IPI) of 4. A biopsy confirmed high-grade double-hit DLBCL with MYC and BCL2 translocations.

The patient was started with dose-adjusted R-EPOCH and although his gastrointestinal (GI) symptoms improved during the first cycle of chemotherapy, he developed worsening shoulder pain in weeks 2 and 3 of cycle 2 of treatment. An interim PET scan performed after 2 cycles of treatment confirmed a significant improvement in tumor burden but persistent hypermetabolic lesion in the right humerus and a standardized uptake value of 7.

“There is a lot of controversy in our field about how we interpret an interim positive PET [result],” Westin said. “We know the negative predictive value is strong, but the positive predictive value is rather poor.”

As such, a bone biopsy was performed on the lesion in the humerus, confirming CD10-positive B-cell lymphoma. Westin argued that the patient was unlikely to achieve a complete response (CR) at the end of treatment, and as such, alternative regimens should then be considered. However, patients with refractory disease have poor outcomes with salvage chemotherapy, which led Westin to consider a clinical trial.

“[ZUMA-12 (NCT03761056)] was the clinical trial we had open at the time, which I’ll argue is something we should consider for our patients who have high-risk disease in the frontline setting: an early switch to a CAR T-cell therapy,” Westin said.

The phase 2 trial enrolled patients with high-grade double-hit or triple-hit B-cell lymphoma and large B-cell lymphoma with an IPI score of at least 3.³ Patients had to have a positive interim PET scan following 2 cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.

Patients underwent leukapheresis and optional nonchemotherapy bridging therapy followed by conditioning chemotherapy consisting of 30 mg/m² of intravenous (IV) fludarabine and 500 mg/m² of IV cyclophosphamide on days –5, –4, and –3. They subsequently received a single IV infusion of axicabtagene ciloleucel (axi-cel; Yescarta) at 2 x 10⁶ CAR T cells/kg on day 0.

The CR rate achieved with the CAR T-cell therapy was “impressive,” according to Westin, at 78% (n = 29) and benefit was consistent across subgroups. The 1-year event-free survival rate with axi-cel was 72.5% (95% CI, 53.1%-84.9%).

In terms of safety, cytokine release syndrome (CRS) occurred in all patients, but the rate of grade 3 CRS was low, at 8%, Westin said.

Westin acknowledged that although axi-cel could be saved for relapse, findings presented at the 2021 ASH Annual Meeting and Exposition comparing the populations in ZUMA-12 and ZUMA-1 (NCT02348216) showed better CAR T-cell expansion in patients who had received less chemotherapy.⁴

With this in mind, the patient was enrolled to ZUMA-12. He developed late, low-grade CRS and immune effector cell–associated neurotoxicity syndrome (ICANS) but went on to achieve a CR with treatment.

“He’s more than 2 years out now without any relapse or any late toxicities,” Westin said. “Should you switch all patients with a positive interim PET? No. However, if you have circulating tumor DNA or a positive biopsy, it’s reasonable to consider switching to a different therapy. Having a non-chemotherapy option for chemorefractory disease makes treatment switch more attractive.”

Laurie H. Sehn, MD, MPH, a clinical associate professor in the division of medical oncology at the University of British Columbia and the British Columbia Cancer Agency, subsequently presented a case of a 66-year-old man with stage IVB DLBCL with lymphadenopathy above and below the diaphragm. He had a large bowel mass that was biopsied, confirming germinal center B-cell DLBCL and was negative for MYC, BCL2, and BCL6 on fluorescence in situ hybridization.

The patient was treated with 6 cycles of R-CHOP and achieved a CR; however, 6 months later, the patient developed GI bleeding and was found to have recurrent DLBCL of the GI tract. He was started on 2 cycles of R-GDP and achieved a CR, with the intention of heading to ASCT.

“Our longstanding management for relapsed/refractory DLBCL has been to take patients down the ASCT route,” Sehn stated. However, only approximately half of patients will respond to salvage chemotherapy and proceed to transplant, making the decision on what to pursue a difficult one, Sehn explained.

The 3 randomized trials that have evaluated second-line CAR T-cell therapy—ZUMA-7 (NCT03391466), TRANSFORM (NCT03575351), and BELINDA (NCT03570892)—have yet to show an overall survival (OS) benefit, supporting the rationale to opt for a stepwise approach.

Sehn noted that although all 3 trials demonstrated that CAR T-cell therapy would be the preferred approach in the second-line setting in the intent-to-treat population, they do not provide insight into the preferred approach for patients who respond to salvage chemotherapy.

“This is a scenario we all face because most people do receive bridging therapy prior to going on to CAR T-cell therapy, even if your intention is to give it in the second-line setting,” Sehn said. “As such, we all face this question.”

Although not randomized data, Sehn highlighted findings from a Center for International Blood and Marrow Transplant Research retrospective registry analysis which showed that patients in partial remission after salvage chemotherapy had a lower rate of relapse and disease progression (P = .010), as well as improved OS (P = .007).⁵

Moreover, supplementary findings from the ZUMA-7 trial demonstrated a comparable duration of response among responders, regardless of whether they were randomized to axi-cel or standard of care (HR, 0.763; 95% CI, 0.488-1.108).⁶

Additionally, Sehn stated that the one-size-fits-all design of the CAR T-cell therapy trials is not likely to hold up in the real world because not everyone will benefit from cellular therapy. Sehn cited data published in Blood Advances showing that predictive factors, including at least 2 extranodal sites, total metabolic tumor volume greater than 80 mL, and elevated LDH, is associated with poor outcomes following CAR T-cell therapy.⁷

“In the CAR T trials, everybody went to CAR T based on an intent-to-treat approach, and even though those arms did better, most patients did relapse or progress subsequently,” Sehn said. “Just blindly taking everyone on to CAR T is probably not going to be feasible in most clinical settings.”

In addition, the short- and long-term toxicities associated with CAR T-cell therapy are worth considering, said Sehn, who highlighted CRS, ICANS, prolonged cytopenias, hypogammaglobulinemia, CD19 loss, and B-cell aplasia in particular, which was present in 34% of patients on the ZUMA-7 trial up to 18 months after infusion.⁵

For patients who are not candidates to receive CAR T-cell therapy or ASCT, Sehn highlighted the potential of novel agents such as polatuzumab vedotin-piiq (Polivy) plus bendamustine and rituximab (Rituxan) and the combination of tafasitamab-cxix (Monjuvi) and lenalidomide (Revlimid), which have shown responses of 40.2% and 60%, and a median progression-free survival of 5.1 months and 11.6 months, respectively.^7,8

“For patients with primary refractory or early relapsing DLBCL, the data do argue for CAR T-cell therapy as the preferred potential second-line therapy. However, there’s still a role for ASCT; [this approach] still might be suitable for patients who respond to salvage or bridging therapy,” Sehn concluded. “One of the main things we need to figure out is who shouldn’t go to CAR T-cell therapy, as it’s unlikely to work for patients with fully uncontrollable disease. As far as the novel agents go, there are encouraging data to suggest that these [drugs] will improve outcomes in the refractory setting, although we do need predictive markers to figure out which option to select for which patient.”

References

1. Westin J. Why did you do that? Primary refractory DLBCL. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI.
2. Sehn LH. Primary refractory DLBCL – why did you do that? Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI.
3. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742. doi:10.1038/s41591-022-01731-4
4. Neelapu SS, Dickinson M, Munoz J, et al. Primary analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large B-cell lymphoma (LBCL). Blood. 2021(suppl 1):739. doi:10.1182/blood-2021-148009
5. Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission. Blood. 2022. 139(9):1330-1339. doi:10.1182/blood-2021013289
6. 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
7. Vercellino L, Di Blasi R, Kanoun S, et al. Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020;4(22):5607-5615. doi:10. 1182/bloodadvances.2020003001
8. Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6(2):533-543. doi:10.1182/bloodadvances.2021005794
9. Salles G, Duell J, Gonzalez Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4