Second-Line Axi-Cel Elicits Complete Metabolic Responses in Transplant-Ineligible LBCL


Second-line treatment with axicabtagene ciloleucel led to an investigator-assessed, 3-month complete metabolic response rate of 71.0% in patients with large B-cell lymphoma who were ineligible for autologous stem cell transplant.

Francois Lemonnier, MD, PhD

Francois Lemonnier, MD, PhD

Second-line treatment with axicabtagene ciloleucel (axi-cel; Yescarta) led to an investigator-assessed, 3-month complete metabolic response (CMR) rate of 71.0% (95% CI, 58.05%-81.80%) in patients with large B-cell lymphoma who were ineligible for autologous stem cell transplant (ASCT), according to data from the final analysis of the phase 2 ALYCANTE trial (NCT04531046).

Findings presented at the 2023 EHA Congress showed that evaluable patients (n = 62) experienced a 3-month objective response rate (ORR) of 75.8%, including a partial response (PR) rate of 4.8%, per investigator assessment. No patients had stable disease (SD), 11.3% of patients had progressive disease, and 12.9% of patients were not evaluated. Notably, 59.7% of patients remained in CMR at 6 months.

Per investigator assessment of best response, the ORR was 90.3%, including a CMR rate of 79.0%, a PR rate of 11.3%, and SD and progressive disease rates of 4.8% each.

“The study met its primary end point with a CMR [rate] of 71% at 3 months vs a 12% expected [CMR rate] with historical controls,” presenting study author Francois Lemonnier, MD, PhD, of the Lymphoid Malignancies Unit at Henri-Mondor University Hospital in Créteil, France, said.

The single-arm, open-label, multicenter trial conducted at 20 centers in France enrolled patients with aggressive B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), and grade 3B follicular lymphoma, who were relapsed or refractory within 12 months of first-line chemoimmunotherapy.

Patients needed to be ineligible for ASCT per physician assessment and at least 1 of the following:

  • At least 65 years of age
  • At least 18 years of age with a Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of at least 3
  • At least 18 years of age and underwent prior ASCT as first-line consolidation

Other key inclusion criteria included an ECOG performance status of 0 to 2, adequate vascular access for leukapheresis, an absolute neutrophil count of at least 1 G/L, a platelet count of at least 75 G/L, an absolute lymphocyte count of at least 0.1 G/L, creatinine clearance of at least 40 mL/min, serum alanine transaminase/aspartate transaminase of no more than 2.5 times the upper limit of normal (ULN), a total bilirubin of no more than 26 µmol/L (unless a patient had Gilbert’s syndrome), a left ventricular ejection fraction of at least 45%, and a baseline oxygen saturation of at least 92% on room air.

Following leukapheresis, bridging therapy with 1 or 2 cycles of R-GEMOX or corticosteroids was optional. After patients underwent lymphodepleting chemotherapy with 30 mg/m2 of fludarabine per day plus 500 mg/m2 of cyclophosphamide per day for 3 days, they received a single infusion of axi-cel.

Patients underwent a PET scan and circulating tumor DNA (ctDNA) analysis on day 14 and at months 1, 3, 6, 9, and 12. Patients were enrolled between April 26, 2021, and June 15, 2022, and the data cutoff for the final analysis was January 19, 2023. The median follow-up was 12 months (range, 2.1-17.9).

Investigator-assessed 3-month CMR rate was the primary end point. Secondary end points included 3-month CMR rate per independent review committee (IRC) assessment, event-free survival (EFS), duration of response, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life.

The median age for patients treated with axi-cel was 70 years (range, 49-81), and 53.2% of patients were at least 70 years of age. Additionally, 75.8% of patients were male, 3.2% of patients underwent prior ASCT, and 32.3% of patients had a HCT-CI score of at least 3. The majority of patients had an ECOG performance status of 0 or 1 (98.4%), an International Prognostic Index score of 2 or higher (88.8%), Ann Arbor stage III or IV disease (74.2%), and were refractory to their first line of therapy (54.8%). Furthermore, 11.3% of patients had lactate dehydrogenase of at least the ULN at baseline, and 19.4% had a C-reactive protein serum level of more than 30 mg/L at infusion.

Regarding histology, 83.9% of patients had DLBCL, 9.7% had HGBCL with MYC and BCL2 rearrangements with or without BCL6 rearrangements, 1.6% had follicular lymphoma with possible transformation to DLBCL not otherwise specified, 1.6% had grade 3B follicular lymphoma, and 3.2% had grade 1, 2, or 3A follicular lymphoma.

Additionally, 83.9% of patients underwent bridging therapy. Among these patients, 98.1% received R-GEMOX, and 17.3% were given corticosteroids. The best response to bridging therapy included CMR (7.7%), partial metabolic response (26.9%), no response/stable disease (26.9%), progressive metabolic disease (36.5%), and not evaluated (1.9%). The median time between inclusion and axi-cel infusion was 41.5 days (min, 21; max, 71).

A total of 69 patients underwent leukapheresis, and 7 patients were not infused with axi-cel due to death (n = 1), cutaneous nocardiosis (n = 1), complete remission prior to the infusion of CAR T-cell therapy (n = 1), absence of documented relapsed on biopsy prior to axi-cel infusion (n = 1), withdrawal of consent (n = 1), progressive disease (n = 1), and receipt of an investigational medical product and second-line chemotherapy for progression (n = 1).

Five patients infused with axi-cel died prior to month 3 due to adverse effects (AEs; n = 3) and lymphoma (n = 2). At data cutoff, 50 patients were still alive, and 7 more deaths were reported due to AEs (n = 3), lymphoma (n = 3), and unknown (n = 1).

Additional data showed that per IRC assessment, the 3-month ORR was 69.4%, including CMR, PR, SD, and progressive disease rates of 66.1%, 3.2%, 1.6%, and 14.5%, respectively. Notably, 14.5% of patients were not evaluated for 3-month response. Regarding best response, the IRC ORR was 91.9%, including CMR, PR, SD, and progressive disease rates of 82.3%, 9.7%, 1.6%, and 6.5%.

Lemonnier noted that 3-month CMR rates were similar across evaluated subgroups.

At day 14 following axi-cel infusion, 61.1% of evaluable patients (n = 33/54) had a negative PET-CT, and 48.1% (n = 25/52) had undetectable ctDNA.

The median EFS was 12.3 months, and the 12-month EFS rate was 51.2% (95% CI, 38.3%-62.8%). The median PFS was 11.8 months with a 12-month PFS rate of 48.8% (95% CI, 34.0%-62.0%). The median OS was not reached, and the 12-month OS rate was 78.3% (95% CI, 64.7%-87.1%).

Regarding safety, any-grade cytokine release syndrome (CRS) occurred in 93.5% of patients, including grade 1/2 CRS in 85.5% of patients and grade 3/4 CRS in 8.1% of patients. The median time to onset of CRS was 1.5 days (range, 1-3) and the median duration was 5 days (range, 4-9). Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 51.6% of patients, including grade 1/2 ICANS in 37.1% of patients and grade 3/4 ICANS in 14.5% of patients. The median time and duration of ICANS was 6 days (range, 5-8) and 5 days (range, 3-8), respectively. Notably, 77.4% of patients received tocilizumab (Actemra), and 64.5% of patients received corticosteroids.

Additionally, 25.8% of patients were transferred to the intensive care unit. The rate of prolonged grade 3 or higher cytopenia was 37.1%. Grade 3/4 infections were reported in 29.0% of patients, and 9.7% of patients experienced grade 5 infections. The non-relapse mortality rate was 9.7%.

AEs leading to death included pulmonary mucormycosis (n = 1), sepsis with multi-organ failure secondary to mesenteric infarction (n = 1), perineal infection (n = 1), bronchopulmonary aspergillosis (n = 1), and COVID-19 (n = 2).


Houot R, Bachy E, Cartron G, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma in transplant-ineligible patients: final analysis of ALYCANTE, a phase 2 LYSA study. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S233.

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