OA-34: Feasibility of a novel academic anti-BCMA chimeric antigen receptor T-cell (CART) (HBI0101) for the treatment of relapsed and refractory AL amyloidosis

Introduction: While anti-BCMA chimeric antigen receptor T-cell therapy (CART) have proven safe and efficient in multiple myeloma (MM), its application to AL amyloidosis (AL), has been restricted, due to the frailty of this population and rarity of disease. HBI0101 therapy is a novel anti-BCMA CAR T-based therapy developed at Hadassah Medical Center for MM treatment. In a phase Ia/b study (NCT04720313), HBI0101 has demonstrated manageable safety with therapeutic efficacy in over 50 MM patients. Although BCMA targeting in AL has been questioned because of relatively low expression of this antigen on AL plasma cells (PC), we have previously reported that this level of expression is sufficient to enable PC eradication by HBI0101 CART ex vivo. Based on this observation, we have included 8 AL patients in our study, which represent the largest cohort of AL treated with BCMA-CART reported so far.

Methods: Eight AL patients with relapsed/refractory disease were included, with a median of 6 prior lines of therapy (range: 3-10), all resistant to their last line. Six patients were penta-refractory, and five were resistant to belantamab. Seven of eight had cardiac involvement, including 4 with MAYO-stage IIIa/IIIb. The patients were treated within the following cohorts: 1 received 150x10^6 CART cells, 2 received 450x10^6 and 5 received 800x10^6. Two of the patients were treated on a compassionate basis due to concomitant myelodysplastic syndrome (MDS) / ECOG 4 performance status.

Results: Adverse events (AEs) were manageable, with cytokine-released syndrome (CRS) observed in 6/8 (grade 1-2- 4 patients; grade 3 - 2 patients). Hematologic AEs included: grade 3-4 neutropenia in 5/8, Grade 2-3 anemia in 2 patients, and in one case worsening to grade 4 of pre-existing thrombocytopenia. Two patients developed initial AL related organ deterioration, subsequently resolved. None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANs). There were no treatment-related deaths. HBI0101 therapy induced remarkable responses in these 8 heavily pretreated AL patients, achieving overall response rate of 100%, including a fast and efficient complete response in 5 patients, a very good partial response in 2, and a partial response in 1 patient. Minimal residual disease (MRD) negativity based on flow cytometry 10^-5 was achieved in 5/8. The hematologic responses translated to clinical improvement in all patients, while 6/8 thus far met the official criteria for organ responses. With a median follow-up that is still short (7.3 months (m), range: 2.5-16.5), the median duration of response thus far is 5m (range: 2.5-16.5).

Conclusions: In the largest cohort of AL patients reported to date, we demonstrated acceptable toxicity in this frail population, and remarkable efficacy translating into organ responses. Our data suggests that BCMA-CART modality may become a powerful clinical tool to improve organ function and survival even in advanced AL patients.