CAR T Cell Agents Show Variance in Different Lymphoma Subtypes

Administration of chimeric antigen receptor (CAR) T-cell therapy to patients with non-follicular low-grade lymphoma (NHL) may experience different efficacy outcomes than patients with aggressive B-cell lymphomas, according to a single-institution retrospective data presented during the European Hematology Association Virtual Annual Congress.

The commonly used CAR T-cell products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are approved by the FDA as treatment of patients with large B-cell lymphoma (LBCL), a patient population that predominantly has diffuse large B cell lymphoma (DLBCL), or transformed follicular lymphoma (FL) but rarely are seen with low-grade lymphomas like transformed marginal zone lymphoma (MZL), transformed chronic lymphocytic leukemia (CLL), or small lymphocytic leukemia (SLL). This reality rationalized the need to further explore CAR T cell therapy in low-grade lymphomas to determine how outcomes compare to CAR T-cell therapy use in LBCL subtypes as carried out in the retrospective study.

A total of 128 patients received 1 of the standard of care (SoC) CAR T-cell products in the study. Of the patients who were treated, 74 had de novo DLBCL, 33 had transformed FL, and 4 had primary mediastinal B-cell lymphoma (PMBCL). For the transformed NHL subtypes, 11 with transformed MZL, and 6 with transformed CLL/SLL.

A population of 110 patients received axi-cel, of whom the diagnoses were de novo DLBCL in 67, transformed FL in 32, PMBCL in 4, transformed MZL in 5, and transformed CLL/SLL in 2. At a median follow-up of 7.7 months, the DLBCL and PMBCL groups ha a PFS of 7.16 months (95% CI, 0.8-135.%. PFS was not reached for the transformed FL group and was 5.15 for the non-transformed NHL group (95% CI, not available [NA]), with a P value of ,54).

Among patients with transformed NHL, the median progression-free survival (PFS) was 1.3 months (95% CI, 0.7-1.8) versus 10.1 months (95% CI, not assessed [NA]) for patients with all other histologies. The median overall survival (OS) in this group was 9.8 months (95% CI, 1.6-17.9 months), but was not reached (NR) for the other histologies (P =.01).

Across the various subtypes of lymphomas included in the study, the median PFS for patients with de novo DLBCL was 10.1 months (95% CI, 2.4-17.7 months) and was NR in the transformed FL, PMBCL, and TMZL subtypes. For patients with transformed NHL, however, the median PFS was 0.82 months (95% CI, NA), which led to P value of .001.

Eighteen patients whose treatment data were retrospectively analyzed received tisa-cel instead of axi-cel, and of those patients, 7 had de novo DLBCL, 1 had transformed FL, 6 had TMZL, and 4 had transformed CLL/SLL. The median PFS with tisa-cel was NR versus 1.3 months (95% CI, 0.0-4.0 months) for all other histologies (P =.0007). The median OS was also NR for the transformed NHL cohort and also for all other histologies (P =0.13).

The safety analysis showed a small percentage (17.6%) of grade 3/4 cytokine release syndrome (CRS) in the transformed NHL group and 7.2% in patients who fall under the other histologies (P =.15). There were also cases of grade 3/4 neurotoxicity, which occurred in 26.1% of the transformed NHL population and 23.5% of the patients with other histologies (P =1.0).

To determine possible synergy of the CAR T-cell agents and other drugs, tisa-cel was administered to 10 of the patients with transformed FL in combination with ibrutinib (Imbruvica) dosed at 420 to 560 mg per day. The median PFS for the combination was NR compared to 1.3 months in the axi-cel group (P =.011). The median OS with tisa-cel plus ibrutinib was also NR versus 9/8n months with axi-cel (P =.013). Notably, objective responses were observed in 3 of the transformed CLL/SLL patients who received the combination.

Treatment with tisa-cel plus ibrutinib lead to grade 3/4 CRS in 10% of patients versus 42.9% with axi-cel (P =.25).

Based on data from this retrospective analysis, investigators lead by Lucia Rubio Lopes-Garcia, conclude recommend further clinical investigation to understand the synergy between SoC CAR T-cell agents and drugs like ibrutinib.

_Reference:

_{Rubio L, Vinal D, Bachmeier, et al. Outcome of anti-CD19 CAR-T Cell Therapy For Transformed Non Follicular Lymphoma. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP1500.}